Parkinsonism and Related Disorders 20S1 (2014) S13–S16
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Movement disorders in childhood Francisco Cardoso * Professor of Neurology, Movement Disorders Unit, Neurology Service, Internal Medicine Department, UFMG, Belo Horizonte, MG, Brazil
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Keywords: Children Movement Disorders Tic Dystonia Tremor Chorea Stereotypy Parkinsonism
The aim of this article is to review movement disorders in children. They are common but have etiology and phenomenology different than in adults. Tics are the most common phenomena although in most instances they are mild and have a favorable long-term prognosis. Dystonia is the second most common phenomena but when present it is usually genetic or idiopathic and causes meaningful disability. Sydenham’s chorea is the most common cause of chorea in children worldwide. Systemic lupus erythematosus is a much rarer cause of chorea but it is always to be ruled out given the lack of a specific diagnostic marker for Sydenham’s chorea. Tremor, usually caused by drugs or essential tremor, is regarded as rather uncommon in children. Arguably, most pediatric patients with tremor do not seek medical attention because of the lack of disability. Stereotypies are relatively uncommon but their recognition is clinically relevant since they are usually associated with severe conditions such as autism and Rett syndrome. Parkinsonism is quite rare in children and either results from encephalitis or is a side effect of medications. Wilson’s disease must be ruled out in all children with movement disorders. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction The aim of this article is to provide an overview of the phenomenology of the main causes of movement disorders in children, tackling them by order of frequency. The focus of the review is on conditions where movement disorders are isolated or the predominant phenomena. For this reason, Wilson’s disease (WD), an autosomal recessive illness characterized by copper accumulation in the liver, cornea, brain and other organs, will not be described in further detail. Nevertheless, one must always bear in mind that WD needs to be ruled out in every single child with a movement disorder since if left untreated it inexorably leads to death [1]. In general, definitions will use a published consensus resulting from a meeting of specialists [2]. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. It should be added that in addition to motor tics there are also phonic ones that have the same features although of course they are sounds rather than movements [2]. Dystonia is defined according to the International Parkinson and Movement Disorders Society criteria, i.e., a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both [3]. Although there are authors who characterize * Correspondence: Francisco Cardoso MD PhD, Professor of Neurology, Av Pasteur 89/1107, 30150–290 Belo Horizonte MG, Brazil. Tel.: +55 31 3213 1055. E-mail address: [email protected] (F. Cardoso). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
athetosis as a separate phenomenon, the present author’s opinion is that it is merely a form of distal dystonia, often associated with cerebral palsy. The consensus meeting defined tremor as a rhythmic back-and-forth or oscillating involuntary movement about a joint axis [2]. The same group considers chorea as an ongoing randomappearing sequence of one or more discrete involuntary movements or movement fragments. Stereotypy, a controversial topic, has recently been defined as a non-goal-directed movement pattern that is repeated continuously for a period of time in the same form and on multiple occasions, and which is typically distractible [4]. Parkinsonism is defined as a combination of bradykinesia and at least one more of the additional cardinal signs: rigidity, tremor and postural instability [5]. Children often present with myoclonus but this phenomenon is beyond the scope of this article since in the majority of childhood cases it has an epileptic origin. 2. Tics Tics are the most common movement disorder in children. Several studies in different parts of the world report that near one fifth of students in elementary school have tics [6]. There is a clear association of tics with placement in special education: for instance, a study in Rochester, NY, found that 18.5% of students in regular education have tics whereas this figure increased to 23.4% among students of special education [7]. Tourette’s syndrome (TS) and its variants, such as chronic motor or vocal tics as well as transient tic of childhood, account for almost all cases of tics in children. This group of conditions usually have onset around age 8 years and are more common in boys. TS is defined
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by the presence of multiple motor tics, at least one phonic tic, duration of at least one year and onset before age 21 years. The etiology remains to be determined although these conditions are thought to result from a combination of genetic predisposition and environmental factors. A feature rather unique to tics is the ability of patients to suppress them, although this is usually associated with the development of discomfort in the body area involved in the production of the phenomenon. The majority of patients with tics present with simple movements concentrated in the rostral part of the body. Examples are excessive blinking, grimacing, and head jerking. Phonic tics are also simple vocalizations, such as sniffing and throat clearing, in most patients. However, more severe cases, comprising a minority of subjects, may have tics with a more widespread topographic distribution, complex pattern (e.g., sequence of movements during gait) of contractions, not rarely causing pain or even compressive myelopathy [8]. Vocalizations may also be complex with emission of sentences as well as repetition of other individuals’ statements (echolalia). A special case of complex phonic tics is coprolalia, emission of obscenities. It is not mandatory for the diagnosis of TS where it occurs in less than 25% of patients [9]. There is a strong association between TS and behavioral problems, particularly obsessive compulsive disorder and attention deficit and hyperactivity disorder. The long-term natural history of TS and related conditions is favorable, with spontaneous improvement or remission in up to 70% of individuals [10]. Rarely, tics may be secondary to an identifiable cause, such as structural brain lesions (encephalitis, trauma, stroke etc), toxic lesions, degenerative diseases and chromosomal disorders. In this case the term tourettism is used to describe the condition [11]. 3. Dystonia Primary dystonias, defined as those without a structural lesion of the nervous system, are usually idiopathic or have a genetic cause [3]. They account for at least two thirds of the cases of dystonia among children. Although a large number of genetic forms of dystonia has already been identified [12], in this article focus will be given to Oppenheim’s dystonia (DYT1) and dopa-responsive dystonia (DYT5). DYT1, or Oppenheim’s dystonia, an autosomal dominant condition with variable penetrance and expression, is the most common cause of generalized dystonia in patients under the age of 26 years. Typically, the onset is in the first decade of life with unilateral dystonia of the foot induced by gait. This is followed by gradual spreading of the movement disorder with involvement of the contralateral lower limb, trunk and even upper limbs, neck and face. Severe forms leading patients to become wheelchair bound are rare but may occur [3,12]. With the availability of the molecular diagnosis of DYT1 after the discovery that the gene is located on chromosome 9q [13], there is a better understanding of the phenomenology of this condition. Indeed, it is more common among Ashkenazi Jews and there is no obvious neurological abnormality other than dystonia (i.e., it is a primary dystonia). However, it is now known that in many subjects it has a mild presentation with focal and segmental forms of dystonia. Dopa-responsive dystonia (DYT5) is also known as Segawa’s disease after the Japanese physician who originally described it. Similarly to DYT1, it is an autosomal dominant condition with greater expression in females, with patients developing action dystonia of the foot during the first decade of life. Its prevalence is about 1/10 of DYT1 and many patients notice fluctuation of the symptoms, with increasing severity throughout the day and after exercising. Some subjects may have parkinsonian findings such as rigidity, bradykinesia and mild tremor. The presence of this additional phenomenology justifies the labeling of DYT5 as
belonging to the group of dystonia-plus conditions, although this term has often been criticized [3]. The unique distinguishing feature is the remarkable response to low-dose L-dopa that leads to complete disappearance of dystonia. Because it is a metabolic disease with impairment of the metabolism of dopamine and not a degenerative disease like Parkinson’s disease (PD), patients with DYT5 do not develop the long-term complications of the use of L-dopa seen in the latter [12,13]. Because of this response and the common difficulty in differentiating DYT5 from other forms of childhood-onset dystonia, it is mandatory to treat all these patients with L-dopa for at least 60 days. The most common form of secondary dystonia in children is cerebral palsy (CP). Unlike the two dystonias described in the preceding paragraphs, patients with CP display a myriad of movement disorders and other neurological findings: dystonia, chorea, tremor, myclonus, ataxia and spasticity. Unlike primary dystonias, the severity of dystonia in CP is greater in the upper half of the body and patients commonly have severe dysarthria. As already mentioned, many authors still use the term athetosis to describe the distal dystonic movements displayed by DP patients [14]. 4. Chorea The most common cause of acute chorea in children worldwide is Sydenham’s chorea (SC) [15,16]. It is a major manifestation of rheumatic fever, presumably caused by antibodies induced by b-hemolytic streptocci that cross-react with brain antigens [17]. The average age at onset is 9 years and it is more common in girls. In addition to chorea, that can be limited to one half of the body in 20% of patients, there are other motor and non-motor features: decreased muscle tone, vocalizations, emotional lability, obsessions and compulsions, attention deficit and hyperactivity, carditis, and others. It is worth mentioning that a cardiac lesion is the most important source of disability in patients with SC [15]. In at least one quarter of patients with SC, the disease has a protracted course, lasting two or more years, called persistent SC [18]. It is also well recognized that patients with a previous history of SC may develop recurrence later in life when becoming pregnant (chorea gravidarum) or if treated with oral contraceptive agents [19]. As there are no specific biological markers for SC, the diagnosis relies on the presence of typical clinical findings and ruling out alternative diseases. The most common source of diagnostic confusion is chorea associated to systemic lupus erythematosus (SLE), where up to 2% of patients may develop chorea. From a clinical point of view, the majority of subjects with this condition will have other non-neurologic manifestations such as arthritis, pericarditis, and other serositis as well as skin abnormalities. Moreover, the neurologic picture of SLE tends to be more complex and may include psychosis, seizures, other movement disorders, and even mental status and consciousness level changes. Only in rare instances will patients with SLE have chronic isolated chorea with a tendency for spontaneous remissions and recurrences. The difficulty in distinguishing lupus from SC is increased by the finding that up to 20% of patients with the latter display recurrence of the movement disorder. Eventually, patients with SLE will develop other features, meeting diagnostic criteria for this condition [20]. Primary antiphospholipid antibody syndrome is differentiated from SC by the absence of other clinical and laboratory features of rheumatic fever as well as the usual association with repeated abortions, venous thrombosis, other vascular events, and the presence of typical laboratory abnormalities [15]. It is important to emphasize that Huntington’s disease (HD) is not a differential diagnosis of SC since the childhood or juvenile form of HD (the Westphall variant) is characterized by a rigid-akinetic syndrome and not chorea.
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Benign hereditary chorea (BHC) is most likely the main cause of isolated genetic chorea in children. It is an autosomal dominant illness with mutation in the TITF1/NKX2-1 gene, which codes for a transcription factor essential for the organogenesis of the lung, thyroid, and basal ganglia [21]. The clinical picture of patients with BHC is characterized by a variable combination of chorea, mental retardation, congenital hypothyroidism, and chronic lung disease, hence the term brain–thyroid–lung syndrome proposed for this disease [22]. New studies with clinical–genetic correlation have helped to demonstrate that the clinical spectrum of benign hereditary chorea is wider than previously thought, including decreased muscle tone, dystonia, myoclonus, tics, attention deficit hyperactivity disorder, psychosis and short stature [22–24]. 5. Tremor Clinical practice suggests that physiological tremor enhanced by drugs is the most common cause of tremor in childhood. The list of offending medications is long, encompassing not only agents used to treat neuropsychiatric conditions, such as stimulants, neuroleptics, antiepileptic drugs and antidepressants, but also medications commonly prescribed to manage non-neurologic problems such as asthma and cardiac arrhythmia [25]. The clinical presentation is characterized by a high-frequency postural and kinetic tremor of the upper limbs that only rarely is disabling, causing difficulties in tasks such as handwriting and eating. Essential tremor (ET) is often regarded as the most common movement disorder among adults, with studies suggesting that up to 5% of people older than 40 years have this condition [26]. Although community-based studies of ET in children are lacking, surveys of adults indicate that up to 30% of them already had tremor during childhood with a mean age of onset of 6 years [27]. As the clinical features are similar to those found in enhanced physiologic tremor and there is no biological marker of ET, the diagnosis is solely based on clinical grounds. In the context of emergency units, psychogenic tremor is the most common cause of tremor in children [28]. Features suggestive of psychogenic nature of a movement disorder, including tremor, are acute onset, paroxysmal nature, irregular frequency and amplitude, entraining, disappearance with distractability, coexistence with obvious non-neurologic signs and symptoms, and co-existent psychiatric disorders. As to the latter, it is worth mentioning that in up to one third of subjects with defined psychogenic movement disorder there is no psychiatric diagnosis.
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study demonstrated that patients with RS have hand stereotypies with hand clapping that is continuous and predominant at the midline whereas in autism they are intermittent, away from the body, involve objects and hand gaze [29]. To conclude this session, stereotypies in children can be seen as part of the normal development as well as side effects of drugs. 7. Parkinsonism Parkinsonian syndrome (PS) is uncommon in children. In contrast to adults, where Parkinson’s disease is by far the most frequent cause of parkinsonism, this is an exceedingly rare condition in the first two decades of life. In most instances, PS in children is either associated with infectious or auto-immune encephalitis or drug-induced [28]. Of note, a rigid-akinetic syndrome without tremor often characterizes the clinical presentation. In the instances where the cause is encephalitis, PS is usually combined with other phenomena such as decrease of awareness level, behavioral disturbances, seizures, pyramidal signs and other movement disorders [1]. 8. Conclusions Movement disorders are common in children but have etiology and phenomenology different than in adult patients. Tics are the most common phenomena although in most instances they are mild and have a favorable long-term prognosis. Dystonia is less common than tics but when present it is usually genetic or idiopathic and causing meaningful disability. SC remains the most common cause of chorea in children worldwide. Although SLE is much rarer, it is always to be ruled out in children with acute-onset chorea given the lack of a specific diagnostic marker of SC. Tremor is regarded as a rather uncommon movement disorder. However, one may speculate that it is much more frequent than currently thought; arguably, most pediatric patients with tremor do not seek medical attention because of the lack of disability. Stereotypies are relatively uncommon but their recognition is clinically relevant since they are usually associated with severe conditions such as autism and Rett syndrome. Parkinsonism is quite rare in children and either results from encephalitis or is a side effect of medications. Finally, although WD is an uncommon condition, it is mandatory to rule it out in every child with a movement disorder given the existence of effective treatment and very poor prognosis if left untreated. Conflict of interests
6. Stereotypy Autism is the most common cause of stereotypies in children. In the context of classical autism, there are motor and vocal (phonic) stereotypies. In this context, the usual phenomenology is pronation and supination of hands with elbows kept in flexion (“flapping”), finger wiggling, trunk rocking, pacing, skipping and shouting of simple sounds. Less often, they can be more complex such as shaking or tapping objects, jumping or running and shouting complete sentences. Importantly, however, in all instances they are performed repeatedly, can be suppressed voluntarily and tend to disappear with distraction [4,29]. Rett syndrome (RS) is another neurodevelopmental disorder of childhood onset but occurring in girls, usually associated with MECP2 mutations and having a very poor prognosis. The clinical features of RS include developmental arrest and regression, poor sociability, lack of communication, irritability, anxiety, dystonia, respiratory pauses, loss of hand skills, deceleration of head growth, progressive motor deterioration and stereotypies. The phenomenology of the latter, particularly when occurring in the hands, can overlap with autism. However, a
The author is secretary of the International Parkinson and Movement Disorders Society, delegate of the Brazilian Academy of Neurology to WFN, and member of the Editorial Board of Parkinsonism and Related Disorders; he has received a research grant from FAPEMIG and honoraria from Roche and Medtronic. References [1] Machado A, Chien HF, Deguti MM, Cancado ¸ E, Azevedo RS, Scaff M, et al. Neurological manifestations in Wilson’s disease: Report of 119 cases. Mov Disord 2006;21:2192–6. [2] Sanger TD, Chen D, Fehlings DL, Hallett M, Lang AE, Mink JW, et al. Definition and classification of hyperkinetic movements in childhood. Mov Disord 2010; 25:1538–49. [3] Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, et al. Phenomenology and classification of dystonia: A consensus update. Mov Disord 2013;28:863–73. [4] Edward MJ, Lang AE, Bhatia KP. Stereotypies: A critical appraisal and suggestion of a clinically useful definition. Mov Disord 2012;27:179–85. [5] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–4.
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[6] Cubo E, Gabriel y Galan ´ JM, Villaverde VA, Velasco SS, Benito VD, Macarron ´ JV, et al. Prevalence of tics in schoolchildren in central Spain: a population-based study. Pediatr Neurol 2011;45:100–8. [7] Kurlan R, McDermott MP, Deeley C, Como PG, Brower C, Eapen S, et al. Prevalence of tics in school children and association with placement in special education. Neurology 2001;57:1383–8. [8] Isaacs JD, Adams M, Lees AJ. Noncompressive myelopathy associated with violent axial tics of Tourette syndrome. Neurology 2010;74:697–8. [9] Cardoso F, Veado CC, de Oliveira JT. A Brazilian cohort of patients with Tourette’s syndrome. J Neurol Neurosurg Psychiatry 1996;60:209–12. [10] Pappert EJ, Goetz CG, Louis ED, Blasucci L, Leurgans S. Objective assessments of longitudinal outcome in Gilles de la Tourette’s syndrome. Neurology 2003; 61:936–40. [11] Mejia NI, Jankovic J. Secondary tics and tourettism. Rev Bras Psiquiatr 2005;27: 11–7. [12] Lohmann K, Klein C. Genetics of dystonia: What’s known? What’s new? What’s next? Mov Disord 2013;28:899–905. [13] Kwiatkowski DJ, Ozelius L, Kramer PL, Perman S, Schuback DE, Gusella JF, et al. Torsion dystonia genes in two populations confined to a small region on chromosome 9q32–34. Am J Hum Genet 1991;49:366–71. [14] Przekop A, Sanger TD. Birth-related syndromes of athetosis and kernicterus. Handb Clin Neurol 2011;100:387–95. [15] Cardoso F, Seppi K, Mair KJ, Wenning GK, Poewe W. Seminar on choreas. Lancet Neurol 2006;5:589–602. [16] Zomorrodi A, Wald ER. Sydenham’s chorea in western Pennsylvania. Pediatrics 2006;117:e675–9. [17] Doyle F, Cardoso F, Lopes L, Mendes M, Dias F, Cruz L, et al. Infusion of Sydenham’s chorea antibodies in striatum with up-regulated dopaminergic receptors: a pilot study to investigate the potential of SC antibodies to increase dopaminergic activity. Neurosci Lett 2012;15;523:186–9.
[18] Cardoso F, Vargas AP, Oliveira LD, Guerra AA, Amaral SV. Persistent Sydenham’s chorea. Mov Disord 1999;14:805–7. [19] Maia DP, Fonseca PG, Camargos ST, Pfannes C, Cunningham MC, Cardoso F. Pregnancy in patients with Sydenham’s chorea. Parkinsonism Relat Disord 2012;18:458–61. [20] Bakdash T, Goetz CG, Singer HS, Cardoso F. A child with recurrent episodes of involuntary movements. Mov Disord 1999;14:146–54. [21] Kleiner-Fisman G, Rogaeva E, Halliday W, Houle S, Kawarai T, Sato C, et al. Benign hereditary chorea: clinical, genetic, and pathological findings. Ann Neurol 2003; 54:244–7. [22] Inzelberg R, Weinberger M, Gak E. Benign hereditary chorea: An update. Parkinsonism Relat Disord 2011;17:301–7. [23] Kleiner-Fisman G, Lang AE. Benign hereditary chorea revisited: a journey to understanding. Mov Disord 2007;22:2297–305. [24] Gras D, Jonard L, Roze E, Chantot-Bastaraud S, Koht J, Motte J, et al. Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. J Neurol Neurosurg Psychiatry 2012;83:956–62. [25] Keller S, Dure S. Tremor in childhood. Semin Pediatr Neurol 2009;16:60–70. [26] Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord 2010;25:534–41. [27] Ferrara J, Jankovic J. Epidemiology and management of essential tremor in children. Paediatr Drugs 2009;11:293–307. [28] Dale RC, Singh H, Troedson C, Pillai S, Gaikiwari S, Kozlowska K. A prospective study of acute movement disorders in children. Dev Med Child Neurol 2010; 52:739–48. [29] Goldman S, Temudo T. Hand stereotypies distinguish Rett syndrome from autism disorder. Mov Disord 2012;27:1060–2.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Movement disorders in childhood Francisco Cardoso * Professor of Neurology, Movement Disorders Unit, Neurology Service, Internal Medicine Department, UFMG, Belo Horizonte, MG, Brazil
article info
summary
Keywords: Children Movement Disorders Tic Dystonia Tremor Chorea Stereotypy Parkinsonism
The aim of this article is to review movement disorders in children. They are common but have etiology and phenomenology different than in adults. Tics are the most common phenomena although in most instances they are mild and have a favorable long-term prognosis. Dystonia is the second most common phenomena but when present it is usually genetic or idiopathic and causes meaningful disability. Sydenham’s chorea is the most common cause of chorea in children worldwide. Systemic lupus erythematosus is a much rarer cause of chorea but it is always to be ruled out given the lack of a specific diagnostic marker for Sydenham’s chorea. Tremor, usually caused by drugs or essential tremor, is regarded as rather uncommon in children. Arguably, most pediatric patients with tremor do not seek medical attention because of the lack of disability. Stereotypies are relatively uncommon but their recognition is clinically relevant since they are usually associated with severe conditions such as autism and Rett syndrome. Parkinsonism is quite rare in children and either results from encephalitis or is a side effect of medications. Wilson’s disease must be ruled out in all children with movement disorders. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction The aim of this article is to provide an overview of the phenomenology of the main causes of movement disorders in children, tackling them by order of frequency. The focus of the review is on conditions where movement disorders are isolated or the predominant phenomena. For this reason, Wilson’s disease (WD), an autosomal recessive illness characterized by copper accumulation in the liver, cornea, brain and other organs, will not be described in further detail. Nevertheless, one must always bear in mind that WD needs to be ruled out in every single child with a movement disorder since if left untreated it inexorably leads to death [1]. In general, definitions will use a published consensus resulting from a meeting of specialists [2]. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. It should be added that in addition to motor tics there are also phonic ones that have the same features although of course they are sounds rather than movements [2]. Dystonia is defined according to the International Parkinson and Movement Disorders Society criteria, i.e., a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both [3]. Although there are authors who characterize * Correspondence: Francisco Cardoso MD PhD, Professor of Neurology, Av Pasteur 89/1107, 30150–290 Belo Horizonte MG, Brazil. Tel.: +55 31 3213 1055. E-mail address: [email protected] (F. Cardoso). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
athetosis as a separate phenomenon, the present author’s opinion is that it is merely a form of distal dystonia, often associated with cerebral palsy. The consensus meeting defined tremor as a rhythmic back-and-forth or oscillating involuntary movement about a joint axis [2]. The same group considers chorea as an ongoing randomappearing sequence of one or more discrete involuntary movements or movement fragments. Stereotypy, a controversial topic, has recently been defined as a non-goal-directed movement pattern that is repeated continuously for a period of time in the same form and on multiple occasions, and which is typically distractible [4]. Parkinsonism is defined as a combination of bradykinesia and at least one more of the additional cardinal signs: rigidity, tremor and postural instability [5]. Children often present with myoclonus but this phenomenon is beyond the scope of this article since in the majority of childhood cases it has an epileptic origin. 2. Tics Tics are the most common movement disorder in children. Several studies in different parts of the world report that near one fifth of students in elementary school have tics [6]. There is a clear association of tics with placement in special education: for instance, a study in Rochester, NY, found that 18.5% of students in regular education have tics whereas this figure increased to 23.4% among students of special education [7]. Tourette’s syndrome (TS) and its variants, such as chronic motor or vocal tics as well as transient tic of childhood, account for almost all cases of tics in children. This group of conditions usually have onset around age 8 years and are more common in boys. TS is defined
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by the presence of multiple motor tics, at least one phonic tic, duration of at least one year and onset before age 21 years. The etiology remains to be determined although these conditions are thought to result from a combination of genetic predisposition and environmental factors. A feature rather unique to tics is the ability of patients to suppress them, although this is usually associated with the development of discomfort in the body area involved in the production of the phenomenon. The majority of patients with tics present with simple movements concentrated in the rostral part of the body. Examples are excessive blinking, grimacing, and head jerking. Phonic tics are also simple vocalizations, such as sniffing and throat clearing, in most patients. However, more severe cases, comprising a minority of subjects, may have tics with a more widespread topographic distribution, complex pattern (e.g., sequence of movements during gait) of contractions, not rarely causing pain or even compressive myelopathy [8]. Vocalizations may also be complex with emission of sentences as well as repetition of other individuals’ statements (echolalia). A special case of complex phonic tics is coprolalia, emission of obscenities. It is not mandatory for the diagnosis of TS where it occurs in less than 25% of patients [9]. There is a strong association between TS and behavioral problems, particularly obsessive compulsive disorder and attention deficit and hyperactivity disorder. The long-term natural history of TS and related conditions is favorable, with spontaneous improvement or remission in up to 70% of individuals [10]. Rarely, tics may be secondary to an identifiable cause, such as structural brain lesions (encephalitis, trauma, stroke etc), toxic lesions, degenerative diseases and chromosomal disorders. In this case the term tourettism is used to describe the condition [11]. 3. Dystonia Primary dystonias, defined as those without a structural lesion of the nervous system, are usually idiopathic or have a genetic cause [3]. They account for at least two thirds of the cases of dystonia among children. Although a large number of genetic forms of dystonia has already been identified [12], in this article focus will be given to Oppenheim’s dystonia (DYT1) and dopa-responsive dystonia (DYT5). DYT1, or Oppenheim’s dystonia, an autosomal dominant condition with variable penetrance and expression, is the most common cause of generalized dystonia in patients under the age of 26 years. Typically, the onset is in the first decade of life with unilateral dystonia of the foot induced by gait. This is followed by gradual spreading of the movement disorder with involvement of the contralateral lower limb, trunk and even upper limbs, neck and face. Severe forms leading patients to become wheelchair bound are rare but may occur [3,12]. With the availability of the molecular diagnosis of DYT1 after the discovery that the gene is located on chromosome 9q [13], there is a better understanding of the phenomenology of this condition. Indeed, it is more common among Ashkenazi Jews and there is no obvious neurological abnormality other than dystonia (i.e., it is a primary dystonia). However, it is now known that in many subjects it has a mild presentation with focal and segmental forms of dystonia. Dopa-responsive dystonia (DYT5) is also known as Segawa’s disease after the Japanese physician who originally described it. Similarly to DYT1, it is an autosomal dominant condition with greater expression in females, with patients developing action dystonia of the foot during the first decade of life. Its prevalence is about 1/10 of DYT1 and many patients notice fluctuation of the symptoms, with increasing severity throughout the day and after exercising. Some subjects may have parkinsonian findings such as rigidity, bradykinesia and mild tremor. The presence of this additional phenomenology justifies the labeling of DYT5 as
belonging to the group of dystonia-plus conditions, although this term has often been criticized [3]. The unique distinguishing feature is the remarkable response to low-dose L-dopa that leads to complete disappearance of dystonia. Because it is a metabolic disease with impairment of the metabolism of dopamine and not a degenerative disease like Parkinson’s disease (PD), patients with DYT5 do not develop the long-term complications of the use of L-dopa seen in the latter [12,13]. Because of this response and the common difficulty in differentiating DYT5 from other forms of childhood-onset dystonia, it is mandatory to treat all these patients with L-dopa for at least 60 days. The most common form of secondary dystonia in children is cerebral palsy (CP). Unlike the two dystonias described in the preceding paragraphs, patients with CP display a myriad of movement disorders and other neurological findings: dystonia, chorea, tremor, myclonus, ataxia and spasticity. Unlike primary dystonias, the severity of dystonia in CP is greater in the upper half of the body and patients commonly have severe dysarthria. As already mentioned, many authors still use the term athetosis to describe the distal dystonic movements displayed by DP patients [14]. 4. Chorea The most common cause of acute chorea in children worldwide is Sydenham’s chorea (SC) [15,16]. It is a major manifestation of rheumatic fever, presumably caused by antibodies induced by b-hemolytic streptocci that cross-react with brain antigens [17]. The average age at onset is 9 years and it is more common in girls. In addition to chorea, that can be limited to one half of the body in 20% of patients, there are other motor and non-motor features: decreased muscle tone, vocalizations, emotional lability, obsessions and compulsions, attention deficit and hyperactivity, carditis, and others. It is worth mentioning that a cardiac lesion is the most important source of disability in patients with SC [15]. In at least one quarter of patients with SC, the disease has a protracted course, lasting two or more years, called persistent SC [18]. It is also well recognized that patients with a previous history of SC may develop recurrence later in life when becoming pregnant (chorea gravidarum) or if treated with oral contraceptive agents [19]. As there are no specific biological markers for SC, the diagnosis relies on the presence of typical clinical findings and ruling out alternative diseases. The most common source of diagnostic confusion is chorea associated to systemic lupus erythematosus (SLE), where up to 2% of patients may develop chorea. From a clinical point of view, the majority of subjects with this condition will have other non-neurologic manifestations such as arthritis, pericarditis, and other serositis as well as skin abnormalities. Moreover, the neurologic picture of SLE tends to be more complex and may include psychosis, seizures, other movement disorders, and even mental status and consciousness level changes. Only in rare instances will patients with SLE have chronic isolated chorea with a tendency for spontaneous remissions and recurrences. The difficulty in distinguishing lupus from SC is increased by the finding that up to 20% of patients with the latter display recurrence of the movement disorder. Eventually, patients with SLE will develop other features, meeting diagnostic criteria for this condition [20]. Primary antiphospholipid antibody syndrome is differentiated from SC by the absence of other clinical and laboratory features of rheumatic fever as well as the usual association with repeated abortions, venous thrombosis, other vascular events, and the presence of typical laboratory abnormalities [15]. It is important to emphasize that Huntington’s disease (HD) is not a differential diagnosis of SC since the childhood or juvenile form of HD (the Westphall variant) is characterized by a rigid-akinetic syndrome and not chorea.
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Benign hereditary chorea (BHC) is most likely the main cause of isolated genetic chorea in children. It is an autosomal dominant illness with mutation in the TITF1/NKX2-1 gene, which codes for a transcription factor essential for the organogenesis of the lung, thyroid, and basal ganglia [21]. The clinical picture of patients with BHC is characterized by a variable combination of chorea, mental retardation, congenital hypothyroidism, and chronic lung disease, hence the term brain–thyroid–lung syndrome proposed for this disease [22]. New studies with clinical–genetic correlation have helped to demonstrate that the clinical spectrum of benign hereditary chorea is wider than previously thought, including decreased muscle tone, dystonia, myoclonus, tics, attention deficit hyperactivity disorder, psychosis and short stature [22–24]. 5. Tremor Clinical practice suggests that physiological tremor enhanced by drugs is the most common cause of tremor in childhood. The list of offending medications is long, encompassing not only agents used to treat neuropsychiatric conditions, such as stimulants, neuroleptics, antiepileptic drugs and antidepressants, but also medications commonly prescribed to manage non-neurologic problems such as asthma and cardiac arrhythmia [25]. The clinical presentation is characterized by a high-frequency postural and kinetic tremor of the upper limbs that only rarely is disabling, causing difficulties in tasks such as handwriting and eating. Essential tremor (ET) is often regarded as the most common movement disorder among adults, with studies suggesting that up to 5% of people older than 40 years have this condition [26]. Although community-based studies of ET in children are lacking, surveys of adults indicate that up to 30% of them already had tremor during childhood with a mean age of onset of 6 years [27]. As the clinical features are similar to those found in enhanced physiologic tremor and there is no biological marker of ET, the diagnosis is solely based on clinical grounds. In the context of emergency units, psychogenic tremor is the most common cause of tremor in children [28]. Features suggestive of psychogenic nature of a movement disorder, including tremor, are acute onset, paroxysmal nature, irregular frequency and amplitude, entraining, disappearance with distractability, coexistence with obvious non-neurologic signs and symptoms, and co-existent psychiatric disorders. As to the latter, it is worth mentioning that in up to one third of subjects with defined psychogenic movement disorder there is no psychiatric diagnosis.
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study demonstrated that patients with RS have hand stereotypies with hand clapping that is continuous and predominant at the midline whereas in autism they are intermittent, away from the body, involve objects and hand gaze [29]. To conclude this session, stereotypies in children can be seen as part of the normal development as well as side effects of drugs. 7. Parkinsonism Parkinsonian syndrome (PS) is uncommon in children. In contrast to adults, where Parkinson’s disease is by far the most frequent cause of parkinsonism, this is an exceedingly rare condition in the first two decades of life. In most instances, PS in children is either associated with infectious or auto-immune encephalitis or drug-induced [28]. Of note, a rigid-akinetic syndrome without tremor often characterizes the clinical presentation. In the instances where the cause is encephalitis, PS is usually combined with other phenomena such as decrease of awareness level, behavioral disturbances, seizures, pyramidal signs and other movement disorders [1]. 8. Conclusions Movement disorders are common in children but have etiology and phenomenology different than in adult patients. Tics are the most common phenomena although in most instances they are mild and have a favorable long-term prognosis. Dystonia is less common than tics but when present it is usually genetic or idiopathic and causing meaningful disability. SC remains the most common cause of chorea in children worldwide. Although SLE is much rarer, it is always to be ruled out in children with acute-onset chorea given the lack of a specific diagnostic marker of SC. Tremor is regarded as a rather uncommon movement disorder. However, one may speculate that it is much more frequent than currently thought; arguably, most pediatric patients with tremor do not seek medical attention because of the lack of disability. Stereotypies are relatively uncommon but their recognition is clinically relevant since they are usually associated with severe conditions such as autism and Rett syndrome. Parkinsonism is quite rare in children and either results from encephalitis or is a side effect of medications. Finally, although WD is an uncommon condition, it is mandatory to rule it out in every child with a movement disorder given the existence of effective treatment and very poor prognosis if left untreated. Conflict of interests
6. Stereotypy Autism is the most common cause of stereotypies in children. In the context of classical autism, there are motor and vocal (phonic) stereotypies. In this context, the usual phenomenology is pronation and supination of hands with elbows kept in flexion (“flapping”), finger wiggling, trunk rocking, pacing, skipping and shouting of simple sounds. Less often, they can be more complex such as shaking or tapping objects, jumping or running and shouting complete sentences. Importantly, however, in all instances they are performed repeatedly, can be suppressed voluntarily and tend to disappear with distraction [4,29]. Rett syndrome (RS) is another neurodevelopmental disorder of childhood onset but occurring in girls, usually associated with MECP2 mutations and having a very poor prognosis. The clinical features of RS include developmental arrest and regression, poor sociability, lack of communication, irritability, anxiety, dystonia, respiratory pauses, loss of hand skills, deceleration of head growth, progressive motor deterioration and stereotypies. The phenomenology of the latter, particularly when occurring in the hands, can overlap with autism. However, a
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