Clinical Management of Dystonia in Childhood

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1 Pediatr Drugs DOI /s REVIEW ARTICLE Clinical Management of Dystonia in Childhood Quyen N. Luc 1 Jyes Querubin 2 Ó Springer International Publishing Switzerland 2017 Abstract Dystonia is one of the most frequent movement disorders in childhood. It can impede normal motor development and cause significant motor disability. The diagnostic evaluation of childhood dystonia is challenging due to the phenotypic variability and heterogeneous etiologies. Evidence to guide the diagnostic evaluation and treatment is limited. Assessment is primarily directed by clinical history and distinctive examination findings. Neuroimaging is typically necessary to evaluate for acquired or complex inherited dystonias. A trial of levodopa can be both diagnostic and therapeutic in children with dopa-responsive dystonia. However, for the majority of children with early-onset dystonia, treatment is symptomatic with varying efficacy. There is a paucity of therapeutic trials for childhood dystonia and most treatment recommendations are consensus or expert opinion driven. This review summarizes the available evidence and guidelines on the diagnostic evaluation and pharmacological treatment of childhood-onset dystonia and provides practical frameworks to approach both issues based on best evidence. & Quyen N. Luc QLuc@chla.usc.edu 1 2 Pediatric Movement Disorders Program, Children s Hospital Los Angeles, University of Southern California, 4650 Sunset Blvd., Mailstop 82, Los Angeles, CA, USA Children s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA Key Points Dystonia is a clinical diagnosis based on history and distinctive examination findings. Medications should be started at a low dose and gradually increased for symptomatic improvement. Levodopa should be considered in all children with dystonia without a known cause. 1 Introduction Dystonia is a movement disorder characterized by involuntary sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both [1 3]. Dystonic movements are typically patterned, twisting, and may be tremulous. They can be very brief or quite sustained due to impaired muscle relaxation. They are often initiated or worsened by attempts at voluntary movement and are associated with overflow muscle activation. The severity and quality of the symptoms can vary with body position, emotional state, or level of consciousness. Like other movement disorders, dystonia can increase with stress or excitement and ceases during sleep [4, 5]. The term dystonia is use to describe both the physical sign or symptom of abnormal movements or postures (phenomenology), as well as the clinical and genetic syndromes characterized by dystonic movement [6, 7]. The etiologies of dystonia in childhood are numerous. In certain disorders, dystonia is the main or only manifestation, but in

2 Q. N. Luc, J. Querubin many disorders, dystonia exists as just one neurological sign or symptom among others. This makes the diagnostic evaluation and treatment of a child with dystonia challenging. In this article, we attempt to provide a comprehensive literature review of the diagnostic approaches, etiologies, and common pharmacological therapies for childhood dystonia and offer a practical diagnostic strategy and treatment guideline. A literature search up to September 2016 was performed in PubMed and Ovid using combinations of search terms: pediatric, children, childhood, dystonia, treatment, medications, drugs, trihexyphenidyl, levodopa, baclofen, botulinum toxin, and benzodiazepine. The references of articles were reviewed to identify relevant publications. The National Guidelines Clearinghouse and the Cochrane library were also searched. There are several Cochrane reviews on the use of botulinum toxin A and B for treatment of cervical dystonia. Searches of the clinical policies and guidelines of the American Academy of Neurology (AAN), Child Neurology Society and Movement Disorder Society were also conducted. The AAN published evidence-based recommendations regarding the use of botulinum toxin for adult focal dystonias in 2008 and 2016 [8, 9]. The European Federation of Neurological Societies (EFNS) has also released updated guidelines on diagnosis and treatment of primary dystonias [2]. Available guidelines and recommendations for diagnostic evaluation and treatment of childhood dystonia are largely consensus and expert opinion driven. There is a paucity of randomized controlled studies in children with dystonia. Research in this area is hampered by several factors [10]. Childhood dystonia is clinically heterogeneous with different causes and anatomical distributions. Although there are clinical rating scales to assess isolated dystonia, there is no universal or valid methodology to assess dystonia when it is combined with other movement disorders, making it difficult to quantify dystonia and its effects on function, particularly in children with acquired or complex inherited dystonia [11]. 2 Phenomenological Diagnosis Dystonia is primarily a clinical diagnosis based on history, examination, and visual pattern recognition. There are no specific diagnostic tests to identify abnormal movements or postures as dystonic but surface electromyography can complement the clinical examination and be helpful in identifying the pattern of muscle activation and co-contraction [12 14]. There are several cardinal physical signs used to recognize and diagnose dystonia: dystonic postures and movements, task specificity, sensory tricks, activation with volitional movements, and muscle overflow activation [6]. The first and most important step in diagnosing dystonia is the correct identification of dystonic movements and postures. These are repeated patterns or fragments of movements that are superimposed upon or substituted for volitional movements. Dystonic postures and movements are typically stereotyped, predictable contractions of the same muscles. There are common dystonic postures that are observed repeatedly in different children; however, each child with dystonia has an individualized set of recurrent postures or movements. Dystonia can be movement or task specific. In this situation, abnormal involuntary muscle contractions only occur with selected movements and not with others that may use the same muscles, such as seen with writer s cramp or musician s dystonia. Additionally, individuals with focal dystonia commonly report utilizing a sensory trick of geste antagoniste. This phenomenon is characterized by the relief of dystonic movements by lightly touching the affected or an adjacent body part. Sensory tricks are not seen in all types of dystonia but their presence is strongly suggestive of the diagnosis. Dystonia frequently is initiated or exacerbated by volitional movements and may not be present at rest. Attempted volitional movements can cause unintentional muscle activity in adjacent body parts so that there is spread of the abnormal movement to surrounding muscles resulting in muscle overflow activation [15, 16]. Dystonia is typically not a primary disorder of tone. It may cause hypertonia when there are sustained dystonic postures with protracted involuntary muscle contraction. However, dystonic postures do not necessarily imply the presence of hypertonia [17]. Tone may be normal or even decreased when dystonic postures are not present. Involuntary sustained dystonic postures can be difficult to distinguish from spasticity, particularly in the lower extremities. Dystonia and spasticity may occur in the same limb. This is seen commonly in dyskinetic cerebral palsy. Dystonia may also be confused with chorea, myoclonus, or tremor when the dystonic postures are frequent and rapid [18]. 3 Classification An international consensus committee of movement disorders experts proposed a revised classification scheme for dystonia in 2013 [1]. The new classification system uses two axes to facilitate clinical recognition, diagnostic evaluation, and treatment. Axis I organizes the clinical characteristics of each patient into four subcategories: age at onset, body distribution, temporal pattern and associated features including the presence of other movement disorders, neurological or systemic manifestations (Table 1). The second axis addresses etiology (Table 2). There are

3 Clinical Management of Dystonia in Childhood Table 1 Classification of dystonia: clinical characteristics [1] 1. Age of onset Infancy Birth to 2 years Childhood 3 12 years Adolescence years Early adulthood years Late adulthood Over 40 years 2. Body distribution Focal One muscle group/extremity Segmental C2 contiguous muscle groups Multifocal C2 non-contiguous muscle groups Generalized (with or without leg involvement) C3 muscle groups Hemi-dystonia Ipsilateral arm and leg 3. Temporal pattern Disease course Static Progressive Variability Persistent Action specific Diurnal fluctuation Paroxysmal 4. Associated features Isolated dystonia Combined dystonia With another movement disorder Complex dystonia With other neurological or systemic manifestations (i.e., seizures, intellectual disability, eye findings, etc.) Table 2 Classification of dystonia: etiology [1] Nervous system pathology Evidence of degeneration Evidence of structural (often static) lesions No evidence of degeneration or structural lesion Inheritance pattern Inherited Autosomal dominant Autosomal recessive X-linked recessive Mitochondrial Acquired Non genetic cause Idiopathic Sporadic Familial two descriptors: nervous system pathology and pattern of inheritance. The consensus committee proposed replacing the terms primary and secondary dystonia with inherited, acquired or idiopathic dystonia to reduce ambiguity and resolve inconsistencies in the previous terminology [1]. Inherited dystonias refer to syndromes with proven genetic origin; acquired dystonias have an identified specific nongenetic cause; and idiopathic dystonias have an unknown or yet-to-be-identified cause. 4 Diagnostic Evaluation for Etiology Childhood onset dystonia is a clinically and etiologically heterogeneous condition. There are numerous causes for childhood dystonia and the diagnostic workup is often challenging; however, recently several new approaches have been suggested for assessment of dystonia based on the revised 2013 classification system [19 21]. There are several special considerations when evaluating a child with dystonia. The age of symptom onset has a significant influence on the differential diagnosis and investigational studies [19]. Children need to be evaluated in relation to their developmental age. Developmentally appropriate toddlers may have normal overflow movements that diminish as their motor skills advance [11]. Infants and young children also may experience transient or developmental conditions with dystonic movements and postures such as benign paroxysmal torticollis and benign idiopathic dystonia of infancy. Although these movements suggest a transient neuronal dysfunction, these conditions typically self-resolve with no long-term dystonic sequelae [22, 23]. If the clinical presentation does not fit with one of these transient disorders of infancy and childhood then the clinical

4 Q. N. Luc, J. Querubin Fig. 1 Diagnostic algorithm for evaluation of childhood dystonia [19, 20] Childhood Dystonia History and Physical Examina on Yes Disease specific tes ng Obvious clues to e ology? No Yes Is it isolated dystonia? No Perform brain MRI Abnormal, obvious clues to e ology? Yes No Consider levodopa trial No Consider biochemical and gene c Responsive? studies based on clinical syndrome Yes Consider trial of levodopa Biochemical or gene c confirmatory tes ng characteristics listed in Table 1 should be used to develop a differential diagnosis and focus diagnostic testing. In some clinical situations, these descriptors may be sufficient to determine if the child has an inherited, acquired, or idiopathic dystonia. However, if the history and physical examination are not elucidating then further assessment is warranted. In Fig. 1 we propose a general framework to initiate diagnostic evaluation. Given the wide phenotypic spectrum in childhood dystonias, neuroimaging, preferably a MRI of the brain, should be obtained in almost all scenarios [2]. In children with isolated dystonia, a trial of levodopa ought to be considered for diagnosis and therapy. In any child with dystonia without obvious clues for an acquired cause, further metabolic, mitochondrial, and/or genetic testing is warranted. Which tests to prioritize will depend on the clinical situation, but a recent study reported higher diagnostic yield and shorter duration of work up using nextgeneration sequencing techniques [24]. The diagnostic approach to childhood dystonia is evolving as genetic tools become more accessible, rapid, and powerful. 4.1 Acquired Dystonias There is a long list of possible causes for acquired dystonia as outlined in Table 3 [1, 4, 24]. Discussion of every cause is beyond the scope of this article but we will review several of the more common or treatable ones Cerebral Palsy Dyskinetic cerebral palsy is the most common cause of acquired childhood dystonia. It represents approximately 6 15% of cerebral palsy cases and has a total incidence of per thousand in Western countries [25 27]. While dystonia is the primary feature in dyskinetic cerebral palsy, it is also frequently identified in other types of cerebral palsy. Dystonia most often affects the arms. The legs may have a combination of spasticity and dystonia or spasticity alone. Other movement disorders such as bradykinesia or choreoathetosis are also frequently observed [4] Medications and Drugs Childhood dystonia can be caused by several medications and drugs. These typically present as acute dystonic reactions, akathisia, or tardive dyskinesia [28, 29]. They are most commonly associated with dopamine receptor blocking neuroleptics and antiemetic medications [29 31]. Acute dystonic reactions classically consist of uncontrolled tongue movements, opisthotonus, or cervical dystonia. They commonly respond well to treatment with intravenous diphenhydramine (1 mg/kg) or other anticholinergics and withdrawal of the causative agent [32] Autoimmune Disorders Autoimmune disorders such as anti-n-methyl-d-aspartate receptor (NMDAR) encephalitis, antiphospholipid syndrome, and acute demyelinating encephalomyelitis are increasingly recognized causes of extrapyramidal movement disorders including dystonia [33]. Anti-NMDAR encephalitis is characterized by a stepwise progression of psychiatric symptoms, encephalopathy, seizures, and movement disorders. The characteristic movement disorder is comprised of repetitive, semirhythmic ocular, jaw, facial,

5 Clinical Management of Dystonia in Childhood Table 3 Acquired dystonias Category Autoimmune Brain injury Cerebral palsy Drug Infection Neoplastic Psychogenic Toxin Vascular Possible causes NMDAR encephalitis, demyelinating disorders Trauma, neurosurgery Pre-, peri-, or postnatal brain injury (hypoxic ischemic encephalopathy, kernicterus, congenital malformations) Neuroleptics, antiemetics (dopamine receptor blocking drugs), dopamine receptor stimulants, anticonvulsants (phenytoin and carbamazepine), antihistaminics, antimalarials, calcium channel blockers, stimulants Encephalitis, human immunodeficiency virus Brain tumor, paraneoplastic syndrome Conversion disorder Carbon monoxide, cyanide, ethylene glycol, manganese, methanol, disulfiram and 3-nitropropionic acid Stroke, hemorrhage, arteriovenous malformation NMDAR N-methyl-D-aspartic acid receptor lingual, limb and trunk movements, with oculogyric deviation, opisthotonus, and dystonic limb posturing [34]. Although initially considered to be a paraneoplastic syndrome, an underlying neoplasm is infrequently identified in girls younger than 12 and rarely in boys; the younger the patient, the less likely that a tumor will be detected [35, 36]. Immunotherapy and oncological treatment leads to full or substantial recovery in the majority of children. Early recognition of anti-nmdar encephalitis along with other autoimmune-mediated movement disorders is important as symptoms are frequently amendable with immunotherapy. 4.2 Inherited Dystonia Over 30 inherited forms of dystonia have been identified. They can be subcategorized into three groups: isolated, combined, and complex inherited dystonias. The clinical heterogeneity of many inherited dystonias makes clinical pattern recognition difficult. MRI of the brain is recommended to evaluate for acquired causes of dystonia and complex inherited dystonias. A levodopa trial should be considered as part of the diagnostic evaluation of non-acquired early onset dystonias as it may be faster than biochemical or genetic testing. Targeted gene analysis is also recommended as first or second tier testing with classical presentations of dystonia syndromes. For more complex clinical pictures, laboratory studies should be guided by clinical and family history, neurological signs, neuroimaging findings, and associated neurological and systemic manifestations. In these situations, given the complexity of the evaluation, use of gene panels or nextgeneration sequencing may have a higher diagnostic yield at lower cost [24, 37] Isolated Inherited Dystonias Isolated inherited dystonia syndromes consist of disorders in which dystonia is the primary or sole finding, such as in DYT1 or DYT6. These syndromes essentially have normal conventional MRI studies; however, other neuroimaging modalities including diffusion tensor imaging and functional MRI have found white and gray matter signal abnormalities [38, 39]. If the clinical suspicion is high, appropriate gene testing is recommended [2, 40]. Early onset DYT1 due to TOR1A gene mutations is the most common cause of inherited childhood dystonia. The classical presentation starts with twisting of an extremity, typically the leg, and progresses to other extremities and the trunk but often spares the neck and face [40, 41]. However, many phenotypic variations have been reported. Gene expressivity varies even within families and the penetrance of DYT1 dystonia is only 30% [42, 43]. DYT6 due to THAP1 gene mutations should be considered in children with generalized isolated dystonia with prominent craniocervical involvement. Spasmodic dysphonia is also a significant feature [44, 45]. DYT6 also infrequently presents similarly to DYT1 with focal limb onset Combined Inherited Dystonias Combined inherited dystonias have dystonia as a prominent feature with the addition of another movement disorder, most commonly myoclonus as in DYT11 (myoclonus dystonia syndrome) or parkinsonism in DYT5 (dopa-responsive dystonia). Genetic mutations leading to dysfunction of the tetrahydrobiopterin and/or dopamine synthesis pathways

6 Q. N. Luc, J. Querubin cause dopa-responsive dystonia. The classical phenotype is of a progressive dystonia presenting before 20 years of age with diurnal symptom fluctuations and a striking response to levodopa treatment [46, 47]. Parkinsonian features may develop later in the disease course but this is rare in children. The most common form of dopa-responsive dystonia is caused by heterozygous mutations in the GTP cyclohydrolase 1 (GCH1) gene. Myoclonus-dystonia syndrome is caused primarily by mutations in the SGCE gene. Typically, patients have early childhood onset upper-body myoclonus and dystonia. There is a subgroup that presents with lower limb dystonia progressing to more pronounced myoclonus and upper body involvement. Children with later onset disease have more prominent cervical involvement [48]. Behavioral and psychiatric symptoms have also been reported. The myoclonus is often responsive to alcohol [49] Complex Inherited Dystonias Complex inherited dystonias encompass a wide spectrum of hereditary neurodegenerative and metabolic disorders. Dystonia may be present but is not always a prominent feature in the disease process. Laboratory studies should be tailored for each child based on the clinical course, neuroimaging findings, and associated neurological and systemic manifestations. Table 4 compiles a wide ranging but incomplete list of laboratory tests with a special emphasis on identifying treatable forms of inherited dystonia [4, 20]. If the differential diagnosis cannot be narrowed then nextgeneration sequencing may be considered before or after biochemical testing depending on the processing time. 5 Pharmacological Therapies Current treatment options for childhood dystonia consist of physical and supportive therapy, oral medications, chemodenervation with botulinum toxin, and neurosurgical procedures. This review focuses on the pharmacological treatments with best evidence of efficacy and consistent endorsement by movement disorders experts for management of dystonia in childhood. The evidence for pharmacological management of dystonia is limited. Most therapeutic trials for childhood dystonia are not randomized controlled studies and treatment guidelines are based largely upon expert opinion. Despite increasing knowledge of the pathophysiology of dystonia, treatment remains largely symptomatic. The goal of treatment includes relieving involuntary movements, correcting abnormal postures, preventing contractures, reducing pain, and improving motor function and quality of life [50]. Therapeutic options must be tailored to each child. Most children with dystonia need a combination of several drugs and treatments [10]. Table 5 lists common medications used to treat childhood dystonia in suggested therapeutic order. Dosing recommendations are primarily based on small studies or empirical observation. Generally, medications should be started at a low dose and titrated gradually for effect. 5.1 Levodopa Levodopa (L-3,4-dihydroxyphenylalanine) is a precursor to catecholamine neurotransmitters: dopamine, norepinephrine, and epinephrine. It penetrates the blood brain Table 4 Laboratory tests to identify inherited dystonia syndrome [5, 20] Diagnostic tests Serum amino acids Blood smear Plasma biotinidase Serum/urine copper, serum ceruloplasmin Serum/urine/CSF creatine and guanidinoacetate Serum/CSF glucose Iron studies Serum/CSF Lactate/pyruvate Lysosomal enzymes Serum manganese CSF tetrahydrobiopterin and dopamine metabolites Serum uric acid Vitamin E Urine organic acids Disorders Homocystinuria, maple syrup urine disease, phenylketonuria, Hartnup disorder Neuroacanthocytosis, chorea-acanthocytosis Biotinidase deficiency Wilson s disease Creatine deficiency syndrome Paroxysmal exertion-induced dyskinesia Aceruloplasminemia, neuroferritinopathy Mitochondrial disorders, pyruvate dehydrogenase complex deficiency Arylsulfatase A deficiency, GM1, GM2 gangliosidosis, Krabbe disease Brain manganese accumulation Dopa responsive dystonia Lesch-Nyhan syndrome Ataxia with vitamin E deficiency Glutaric aciduria type I, methylmalonic acidemia,3-methylglutaconic aciduria, propionic acidemia CSF cerebral spinal fluid

7 Clinical Management of Dystonia in Childhood Table 5 Common medications used to treat childhood dystonia Medication Mechanism of action Dosing Common adverse effects Levodopa (combined with carbidopa) Trihexyphenidyl Baclofen Clonazepam Diazepam Tetrabenazine Penetrates blood brain barrier, converted to dopamine Inhibits central muscarinic acetylcholine receptors Binds GABA-B receptors Binds GABA-A receptors Binds GABA-A receptors Vesicular monoamine transporter type 2 inhibitor Start 1 mg/kg/day divided TID Titrate weekly by 1 mg/kg divided TID Goal: 5 10 mg/kg/day Start 1 2 mg per day divided TID Increase by 1 2 mg/week divided TID Goal: 1 2 mg/kg/day divided TID Start 0.3 mg/kg/day divided BID or TID Titrate weekly by mg/kg divided TID Goal: 1 2 mg/kg/day Start mg/kg BID Increase by 0.01 mg/kg/day Goal: mg/kg/day divided BID/ TID Nausea, orthostatic hypotension, insomnia, dyskinesias Constipation, urinary retention, irritability, behavioral changes, dry mouth, blurry vision, chorea, drowsiness, cognitive changes Nausea, vomiting, confusion, lethargy, worsening hypotonia, avoid abrupt withdrawal Sedation, confusion, drooling, respiratory depression 0.1 mg/kg/day divided BID to QID Sedation, confusion, drooling, respiratory depression Titrate to effect Start mg/day divided TID Titrate weekly by mg divided TID Goal: mg/day (adult guidelines). Lower starting doses and slower titration may be needed in smaller children Somnolence, fatigue, nausea, parkinsonism, anxiety, depression, NMS, suicidality BID twice daily, GABA gamma aminobutyric acid, NMS neuroleptic malignant syndrome, QID four times a day, TID three times a day barrier and is converted into dopamine. Levodopa is typically administered with a peripheral dopa-decarboxylase inhibitor such as carbidopa. Carbidopa inhibits peripheral conversion of levodopa to dopamine, thereby limiting adverse effects caused by peripheral dopamine. While the mechanism of levodopa is known, the role of levodopa in treatment of dystonia still needs to be fully elucidated. Levodopa is the first-line treatment in dopa-responsive dystonia. In 1976, Segawa described two young children with progressive dystonia with diurnal features who demonstrated marked clinical response to levodopa [51]. Levodopa has been demonstrated to improve abnormal movements, postures, and gait in patients with dopa-responsive dystonia; however, responses may be variable or delayed [52]. Given the dramatic improvement with therapy, a trial of levodopa is recommended as first-line treatment in any child suspected of having dopa-responsive dystonia or with unexplained dystonia [53]. In a small number of case reports, levodopa was noted to be beneficial in acquired or complex inherited dystonias [54]. However, a randomized, double-blind, placebo-controlled trial of nine patients (age 9 27 years) with dyskinetic cerebral palsy found no improvement in upper limb function [55]. Further investigation into the efficacy of levodopa in secondary dystonia is needed. Overall, levodopa is well tolerated in children. Common adverse effects include nausea, dizziness, mood changes, orthostatic hypotension, and insomnia. Psychosis has also been reported. One retrospective study (n = 20, age 1 58 years) evaluating long-term response to levodopa in dopa-responsive dystonia described mild dyskinesias in 20% of their patients [56]. Levodopa should be given in combination with a dopadecarboxylase inhibitor (carbidopa), typically in a 4:1 ratio. The recommended starting dose in children is 1 mg/kg/day with gradual titration to a goal of 10 mg/kg/day [51]. Some children will not need to be fully titrated and respond well at lower doses of 4 5 mg/kg/day. Doses of mg/ kg/day have been reported in the literature and were well tolerated. A trial of at least 3 months is recommended [57]. 5.2 Trihexyphenidyl Anticholinergic medications such as trihexyphenidyl have traditionally been some of the most effective pharmacological agents for controlling generalized dystonia in childhood. While its exact mechanism is poorly understood, trihexyphenidyl is largely thought to block the action of acetylcholine on central muscarinic receptors in the striatum. This blockade of cholinergic transmission is

8 Q. N. Luc, J. Querubin expected to affect stimulation of dopaminergic transmission [58]. Besides botulinum toxin, trihexyphenidyl has the most robust evidence for management of dystonia and is generally considered first- or second-line treatment of dystonia in children. In a prospective, double-blind, crossover study comparing trihexyphenidyl versus placebo, 22 of 31 children and young adults (age 9 32 years) with segmental or generalized dystonia had a clinically significant response. More benefit was exhibited in patients who received treatment within 5 years of symptom onset [59]. Two open-label prospective trials also demonstrated significant improvement with trihexyphenidyl. The first trial described moderate to drastic improvement in 61 71% of children (n = 23, aged 3 17 years) with dystonia versus 19 38% of adults. The children also better tolerated trihexyphenidyl with less adverse effects [60]. In the second trial, Sanger et al. reported significant improvement in dominant arm function in 23 children (age 4 17 years) with dyskinetic cerebral palsy [61]. Additional retrospective studies in children with cerebral palsy have also indicated medication effectiveness with better responses in younger children (\3 years of age) and those with less underlying spasticity and higher cognitive levels [62 66]. Conversely, Rice and Waugh reported no significant improvement in dystonia severity in their double-blind, crossover study of 14 children (aged 2 17 years) with dyskinetic cerebral palsy [67]. It has been proposed that these conflicting results may reflect different responses to trihexyphenidyl within the various subtypes of cerebral palsy [63]. Although Sanger et al. reported significant goal attainment in the dominant arm at 15 weeks (washout); a subset of children with hyperkinetic features had significant worsening at the peak dose with return to baseline after trihexyphenidyl taper. The authors hypothesized that children with hyperkinetic features may not benefit or may actually worsen during treatment with trihexyphenidyl and advised consideration of subtypes for future studies [61]. Trihexyphenidyl is better tolerated in children than adults; however, adverse effects are common [60]. In a retrospective study of 101 children with cerebral palsy (aged 1 18 years), 91% tolerated the medication well but 69% reported some adverse effect. The most common adverse effects were constipation (42.6%), decreased urinary frequency (18.8%), irritability/behavioral change (12.9%), and dry mouth [64]. Blurry vision, chorea, rash, and increased somnolence have also been described and in one prospective, open-label trial, trihexyphenidyl was discontinued in three children due to uncontrolled chorea, rash, and irritability, respectively [61, 63]. Although children tolerate much higher doses of trihexyphenidyl than adults, cognitive adverse effects remain a concern and should be monitored closely. The recommended dosage of trihexyphenidyl is based on prospective therapeutic trials in children with dystonia [61, 67]. The consensus is to start at a low dose and gradually titrate every week to a goal of approximately 1 2 mg/kg/day divided into three doses. Higher doses have been studied and reported to be safe and efficacious although more adverse effects tend to arise [60, 67]. Trihexyphenidyl may require prolonged treatment of weeks to months before a response is seen [61]. 5.3 Baclofen Baclofen is a derivative of the inhibitory neurotransmitter gamma aminobutyric acid (GABA). It binds presynaptic L- isomer GABA-B receptors and functions as a GABA agonist. It causes inhibition of calcium influx and reduces motor neuron excitability in the brain, but more potently in the spinal cord; thereby inducing muscle relaxation [68]. Oral baclofen has poor lipid solubility and limited blood brain barrier penetration; therefore, higher doses of oral baclofen are required to achieve therapeutic effect. Intrathecal baclofen has a half-life of approximately 4 h and is cleared at 30 ml/h, similar to cerebrospinal fluid [69]. Oral baclofen is widely used for treatment of childhood dystonia, although therapeutic evidence is limited. It is largely considered a second- or third-line agent [70]. In a retrospective analysis by Greene et al., response to baclofen (n = 10) was significantly less compared with anticholinergics (n = 67), 10% versus 51% in patients with childhood dystonia (onset prior to 20 years) [65]. A subsequent retrospective study by Greene and Fahn described moderate to substantial improvement with baclofen in 7 out of 16 children (mean age 13.9 ± 4.1 years) with idiopathic dystonia [71]. Intrathecal baclofen as a treatment for dystonia has been described in the literature. Though the evidence of its efficacy is encouraging, studies consist mainly of observation case series [72]. Motta et al. described 19 children (aged 29 months to 6 years at implantation) with dystonia and cerebral palsy implanted with intrathecal baclofen pumps. At 12 months post-implant, significant improvements in dystonia scales were reported in all patients [73]. Albright et al. had equally successful results in their case series of 77 implanted patients (aged 3 42 years, median age 13 years) with severe generalized dystonia. Ninety-two percent of patients retained their response to intrathecal baclofen with significant improvement in dystonia score during a median follow-up of 29 months [74]. Several additional small case series and reports also describe high response rates in treatment of dystonia in children, with increased quality of life and ease of care but not necessarily motor function [69, 75]. These studies, however, are

9 Clinical Management of Dystonia in Childhood limited as they are small and inconsistent in their assessments and measurement scales. Although therapeutic evidence is inadequate, intrathecal baclofen can be considered when oral medications are ineffective for patients with severe dystonia, particularly when there is a component of spasticity. Intraventricular baclofen has also been presented as an alternative to intrathecal baclofen in patients with refractory dystonia; however, the case series are small and more data is needed about its safety and efficacy [76 78]. Oral baclofen is generally well tolerated in the pediatric population but mild adverse effects are common. In a large retrospective review, 43 of 171 children with dystonia (age at presentation years, 25th 75th percentile) exhibited adverse drug responses resulting in the discontinuation of baclofen [70]. Common adverse effects include drowsiness, dizziness, fatigue, constipation, and nausea. Baclofen also has been reported to exacerbate axial hypotonia, especially at high doses [71]. Adverse effects occur in 20 40% of patients with intrathecal baclofen pumps. Major surgical complications include infections, cerebrospinal fluid (CSF) leakage, and device problems related to the catheter or pump. Adverse effects from intrathecal baclofen can also arise and cause urinary retention, chemical meningitis, hypotonia, and sedation. In one large cohort of 430 children (aged 12 months to 14 years) with intrathecal baclofen pumps for treatment of spasticity and/or dystonia, a major complication occurred in 25% of patients, with catheter problems occurring in 15.1%, infection in 9.3% and CSF leakage in 4.9% of patients, but pump malfunction was rare (1%) [79]. Baclofen should not be stopped abruptly as this can result in baclofen withdrawal symptoms. Withdrawal symptoms have been precipitated by both oral and intrathecal baclofen. Symptoms of withdrawal include worsening spasticity, confusion, hallucinations, and seizures, but can escalate to hyperthermia, disseminated intravascular collapse, rhabdomyolysis, and multisystem organ failure [80, 81]. Withdrawal from intrathecal baclofen should be considered a medical emergency and treated promptly [79, 81 83]. Oral baclofen is typically titrated to effect. The dose should be started low, around 0.3 mg/kg/day divided into three doses and increased slowly [71]. A maximum dose of 40 mg/day has been recommended in children \2 years of age and 60 mg/day in older children; however, daily doses of mg have been safely reported [71, 84]. A trial of several weeks should be sufficient to determine response. Doses of intrathecal baclofen are 100- to 1000-fold lower than needed for oral dosing. An initial dose of 100 lg/day has been recommended with incremental increases for symptomatic improvement [69, 85]. Higher doses of intrathecal baclofen are typically needed for treatment of dystonia compared with spasticity with doses ranging from 200 to 2000 lg/day reported [74]. If there is insufficient or no response at levels of lg/day then use of intrathecal baclofen needs to be reassessed [74]. 5.4 Benzodiazepines Benzodiazepines are a commonly used treatment for childhood dystonia. They are believed to facilitate muscle relaxation by acting on the GABA-A receptor on GABA neurons. When bound to GABA-A receptors, benzodiazepines enhance the affinity of GABA binding which increases the frequency of chloride channel opening and heightens neuronal membrane permeable to chloride ions. This results in hyperpolarization of GABA neurons thereby potentiating neural inhibition. Benzodiazepines are typically considered second- or third-line agents for management of dystonia [86]. There are no comparison studies between the various benzodiazepines. However, longer acting benzodiazepines, such as diazepam and clonazepam, are more frequently reported in the literature. A retrospective study of both adults and children with dystonia (n = 116) found 16% of patients responded to clonazepam. Those with dystonia onset before 20 years of age had a better response (19%) than patients with later onset dystonia [65]. Another retrospective study of 33 children and adults with symptomatic hemidystonia (mean age of dystonia onset 20 years, range 1 69 years) identified some improvement with clonazepam and diazepam in 50% of medication trials [87]. Clonazepam has also been reported to have some benefit in children with myoclonus-dystonia [88, 89]. Generally, benzodiazepines are well tolerated in the pediatric population. Lumsden et al. retrospectively reviewed medication use in 278 children with dystonia (age of presentation years, 25th 75th percentile) and reported lower adverse drug responses to diazepam and clonazepam compared with trihexyphenidyl, baclofen, and levodopa [70]. Adverse effects include sedation, drooling, behavioral disinhibition, confusion, and respiratory depression. Increased oral secretions and sedation are the most common adverse effects limiting use in children. In addition, caution should be taken to avoid abrupt discontinuation of benzodiazepines as this can result in seizures, worsening dystonia, or withdrawal symptoms [86]. Tachyphylaxis, while not specifically reported in children with dystonia, can theoretically occur, thus necessitating escalating doses [90]. There is no evidence for standard dosing of benzodiazepines in regards to treatment of childhood dystonia. Dosing recommendations appear to be adapted from treatment of pediatric epilepsy and spastic cerebral palsy.

10 Q. N. Luc, J. Querubin The recommended initiating dose for clonazepam is mg/kg/day divided twice daily with gradual titration to mg/kg/day divided three times daily as tolerated [91]. Diazepam can be started at 0.1 mg/kg/day divided into two to four doses with gradual titration for effect. A week should be sufficient to evaluate response at a specific dose. Both medications have a fairly rapid mechanism of action but full effect may take several weeks due to the slow titration. 5.5 Tetrabenazine Tetrabenazine is a reversible vesicular monoamine transporter type 2 inhibitor. In presynaptic neurons it decreases monoamine uptake from the cellular cytoplasm into synaptic vesicles, therefore depleting dopamine, serotonin, and norepinephrine levels at the nerve terminals [92]. The therapeutic evidence for tetrabenazine is most robust for treatment of chorea in Huntington s disease (HD). Its effectiveness has also been studied in pediatric and adult dystonia, though evidence in children thus far is limited to small studies. One prospective randomized double-blind crossover study showed decreased movements in 9/12 adults with Meige syndrome and other dystonias [93]. In two smaller prospective studies, 3/8 adult patients with dystonia and 2/5 children and adults (aged 8 30 years) with dystonia musculorum deformans reported improvement with tetrabenazine [94, 95]. The efficacy of tetrabenazine has also been reported in multiple retrospective studies in children and adults with hyperkinetic movement disorders [96 98]. In a large-scale study of 108 adults with idiopathic dystonia, 62.9% had marked improvement in their movements with tetrabenazine [99]. A smaller retrospective study of 31 children with hyperkinetic movement disorders described improvement in 6/8 children (aged 2 17 years) with dystonia or chorea and dystonia [100]. Patients with tardive dystonia may respond better than idiopathic dystonia and tetrabenazine may be more effective for generalized compared with focal dystonias [92]. Larger double-blind placebo-controlled trials are still needed to better elucidate the efficacy of tetrabenazine in childhood dystonia, but it may be considered as third- or fourth-line treatment in children with hyperkinetic dystonia. Adverse effects from tetrabenazine are common but they tend to be dose-related and can be mitigated by reduction in medication [101]. In the same retrospective study of 31 children, 61% reported at least one adverse effect. The most frequent adverse effects were sedation (35%), behavioral changes (19%), depression (10%), worsening movements (6%), nausea (3%), and parkinsonism (3%) [100]. Children tend to experience less parkinsonism than adults. Severe adverse reactions to tetrabenazine have also been described including neuroleptic malignant syndrome, depression, and suicidality (for which tetrabenazine has a black box warning in the US). No standardized pediatric dosing guideline exists for tetrabenazine. Daily doses of mg, with an average daily dose 107 mg/day (3.7 mg/kg/day) were described in the retrospective study of 31 children by Jain et al. [102]. In the adult literature, daily dosing ranges from 6.25 to 300 mg, though the manufacturer-recommended maximum dosing is 100 mg/day [92]. In adults, the starting dose is 12.5 mg daily for 1 week then increasing by 12.5 mg weekly until adequate movement control is reached, typically mg divided three times daily [101]. In smaller children, a lower starting dose may be needed, mg/day, with gradual weekly increases as tolerated. The range of effective and tolerated doses is variable in children and ultimately some may require high dosing for efficacy. 5.6 Botulinum toxin Botulinum toxin acts by binding to specific sites on the presynaptic cholinergic nerve terminal. It blocks calcium influx into the pre-synaptic junction inhibiting release of acetylcholine and causing neuromuscular blockade. As a result, botulinum toxin produces chemodenervation of motor neurons. Botulinum toxin is considered first-line treatment for most types of focal dystonia in adults [2]. An AAN 2008 systemic review and 2016 update concluded that abobotulinumtoxina (abobont-a) and rimabotulinumtoxinb (rimabont-b) are effective and onabotulinumtoxina (onabont-a) and incobotulinumtoxina (incobont-a) are probably effective for treatment of cervical dystonia [9]. Botulinum toxin may be offered for blepharospasm, focal upper extremity dystonia, and adductor laryngeal dystonia (probably effective) and may be considered for focal lower limb dystonia (possibly effective) [8]. There are also several Cochrane reviews on botulinum toxin therapy for cervical dystonia. A single treatment of both botulinum toxin type A (onabont-a, abobont-a) and type B (rimabont-b) were found to be effective and safe for treating cervical dystonia [ ]. In addition, one prospective, randomized, double-blind controlled trial reported more objective and subjective benefit from abo- BoNT-A injections than trihexyphenidyl in adult patients with cervical dystonia [106, 107]. There are multiple studies examining the use of botulinum toxin for treatment of spasticity in children; however, there are only a few case reports evaluating their efficacy in childhood dystonia [108, 109]. Extrapolating from the adult literature, botulinum toxin can be considered for treatment of focal dystonia in children.

11 Clinical Management of Dystonia in Childhood Botulinum toxin is safe and well tolerated for treatment of focal adult dystonias. There have been several long-term longitudinal studies demonstrating its safety and continued effectiveness with prolonged treatment [110]. While systemic adverse effects such as generalized weakness, bulbar weakness, and respiratory compromise are possible, their occurrence is rare [111]. In a large meta-analysis, about 25% of onabont-a-treated patients of all ages reported mild to moderate adverse events compared to 15% in the control group. Focal weakness was the only adverse event that occurred significantly more often with onabont-a treatment than control [112]. Adverse reactions correlate to the location of the injections, dose, and frequency. Botulinum toxin dosing is based on body weight and the muscle group being injected. There is currently no standard botulinum toxin dosing guideline for dystonia in children. Injection dose is often extrapolated from data in adults with focal dystonia and children with spasticity. In studies of children with spasticity, the dosing varies but commonly ranges from 4 to 16 units/kg for onabont-a, units/kg for abobont-a, and 5 units/kg for incobont-a [ ]. Higher doses of onabont-a, units/kg, have been used in children\45 kg with spasticity with no increase in serious adverse reactions [118, 119]. The average interval between injections is 3 6 months. Two to four rounds of treatment may be needed to fully optimize response. 5.7 Other Medications Several other classes of medications including neuroleptics, anticonvulsants, and muscle relaxants have been used in treatment of childhood dystonia; however, evidence is limited. Further randomized controlled trials are required to elucidate efficacy. Gabapentin is an analog of GABA but its mechanisms of action are largely unknown. One retrospective study of 69 patients (aged 1 18 years) with dystonia described significantly improved dystonia severity as well as quality of life Fig. 2 General approach to pharmacological treatment of dystonia in children [124] Childhood Dystonia Is the e ology known and a Yes Disease specific therapy specific treatment available? No Consider a levodopa trial No Is dystonia focal? Responsive? Yes Con nue dopaminergic treatment No Yes Trihexyphenidyl Botulinum toxin Consider baclofen if concurrent spas city Benzodiazepines if epilepsy or other movements disorders Tetrabenazine if hyperkine c movements Gabapen n if epilepsy Clonidine if sleep problems Severe refractory dystonia: Consider intrathecal baclofen or other surgical therapies

12 Q. N. Luc, J. Querubin measures (sleep, mood, transferring, pain, and seating tolerance) in all patients [120]. Much higher doses of gabapentin seem to be required for effectiveness compared with treatment doses for neuropathic pain. Clonidine is a centrally acting alpha-2 agonist. One cohort of 24 patients (aged 2 19 years) with secondary dystonia described 83% improvement in at least one measure: seating tolerance, sleep, pain, tone, and involuntary movements. However, evidence is limited to subjective reports of improvement in activities of daily living and select qualityof-life measures. Adverse effects were reported in 50% of children, with daytime somnolence in 35%, increased movements in 12%, and decreased sleep in 4%. Only one patient stopped taking clonidine due to adverse effects [121]. Dopamine D2 antagonists have been used in treatment of dystonia, although their role is unclear as paradoxically these medications are known to cause acute dystonic reactions and tardive dystonias. Open-label trials of clozapine in adults with spasmodic torticollis did not show efficacy [53]. Risperidone is a neuroleptic with both anti-serotonergic and anti-dopaminergic activity. In a prospective, open-label study (n = 7), significant improvements in involuntary movement and abnormal postures were reported in adults with idiopathic and symptomatic dystonia [122]. Zolpidem is an imidazopyridine agonist with high affinity to benzodiazepine subtype receptor BZ1. In an open-label study (n = 34), Miyazaki et al. demonstrated a decrease in the dystonia rating scale in 27.8% of adults with generalized dystonia, 17.8% with blepharospasms, and 31% with hand dystonia [123]. No improvement was found in patients with cervical dystonia and sedation was the main dose-limiting adverse effect. 5.8 Treatment Summary Management of dystonia in childhood can be problematic. Children with dystonia may need to be tried on multiple medications, and therapeutic agents may have varying degrees of efficacy and tolerability. Pharmacological treatments are mainly symptomatic but a disease-specific therapy should be instituted if applicable. Fig. 2 outlines a general therapeutic approach to treatment of dystonia in childhood [124]. This should be tailored to each child based on their clinical history, coexisting neurological and systemic manifestations, drug tolerability, and treatment goals. 6 Conclusions Childhood-onset dystonia is a clinically and etiologically heterogeneous condition. There are numerous causes for childhood dystonia and the diagnostic workup is often challenging. A thorough history and physical examination are necessary to correctly identify the phenomenology, stratify the differential diagnosis, and guide diagnostic testing. Diagnostic testing, particularly a brain MRI, is typically necessary for evaluation of childhood dystonia. A trial of levodopa should also be strongly considered in any child with an unknown cause of dystonia. The etiology of many forms of dystonia is still not fully elucidated or identified and treatment for most children with dystonia is primarily symptomatic. There is a need for more therapeutic trials in children with dystonia as treatment guidelines are currently based largely upon small trials and expert opinion. In the absence of clear evidence-based guidelines, treatment must be tailored to the individual child and based on motor and functional goals. Acknowledgments The authors thank Genevieve Santillanes at the University of Southern California for her assistance in editing the manuscript. Compliance with Ethical Standards Funding The authors did not receive specific finding for the preparation of this manuscript. Conflict of interest Drs Luc and Querubin have no conflicts of interest. References 1. Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VSC, et al. Phenomenology and classification of dystonia: a consensus update. Mov. Disord. 2013;28: Albanese A, Asmus F, Bhatia KP, Elia AE, Elibol B, Filippini G, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur. J. Neurol. 2011;18: Fahn S, Bressman SB, Marsden CD. Classification of dystonia. Adv Neurol. 1998;78: Sanger T, Mink JW (2006) Movement Disorders. In: Swaiman KF, Ashwal S, Ferriero DM, Schor NF, editors. Swaiman s Pediatric Neurology Principle and Practice. 5th ed, p Singer HS, Mink JW, Gilbert DL, Jankovic J (editors). Dystonia. In: Movement disorders in childhood. 2nd ed. London: Academic Press; p Albanese A, Lalli S. Is this dystonia? Mov. 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