Moving forward in childhood-onset movement disorders Eggink, Hendriekje

Moving forward in childhood-onset movement disorders Eggink, Hendriekje

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10.33612/diss.94395271

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Eggink, H. (2019). Moving forward in childhood-onset movement disorders: a multidisciplinary approach to diagnosis and care. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.94395271

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Moving forward in childhood-onset movement disorders A multidisciplinary approach to diagnosis and care

Hendriekje (Wieke) Eggink

The research of this thesis was supported by a MD/PhD grant from the University Medical Center Groningen and the Phelps Stichting voor Spastici.

Publication of this thesis was generously supported by the University of Groningen, Stichting Beatrixoord Noord Nederland, University Medical Center Groningen, Research School of Behavioural and Cognitive Neurosciences, Merz Pharma Benelux and Ipsen Farmaceutica.

Lay-out: Jules Verkade, persoonlijkproefschrift.nl

Cover: Tim Valkeman

Printed by: Ipskamp Printing, proefschriften.net ISBN printed version: 978-94-034-1797-4

ISBN digital version: 978-94-034-1796-7

A multidisciplinary approach to diagnosis and care

Proefschrift

ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen

op gezag van de

rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College van Promoties.

De openbare verdediging zal plaatsvinden op

woensdag 11 september 2019 om 16:15 uur

door

Hendriekje Eggink

geboren op 4 oktober 1988

te Markelo

Prof. dr. M.A.J. de Koning-Tijssen

Copromotores

Dr. D.A. Sival Dr. T.J. de Koning

Beoordelingscommissie

Prof. dr. J.G. Becher

Prof. dr. J.M. Spikman

Prof. dr. J. Vermeulen

Ontworpen door Tim Valkeman

Op de omslag van dit proefschrift ziet u hoe een groep wielrenners samen een jongen met een bewegingsstoornis (dystonie) de Mont Ventoux omhoog brengt. Dit symboliseert hoe het werken in teamverband de zorg voor patiënten verder kan brengen.

Gerben is de inspiratie voor deze omslag. Hij was de allereerste jongen die meedeed aan

mijn onderzoek en de reden waarom ik in 2016 zelf de Mont Ventoux heb mogen beklim-

men met de stichting Join4Energy.

Jeannette Gelauff

Maaike Wevers

PART I — Recognition and diagnosis of childhood-onset movement disorders

Chapter 2 Crossing barriers: a multidisciplinary diagnostic approach to children and adults with young-onset movement disorders

Journal of Clinical Movement Disorders. 2018; 5: 3.

20

Chapter 2a Patience is the key: Contraceptive induced chorea in a girl with Down Syndrome European Journal of Paediatric Neurology. 2016 ;20(4): 671-673.

36

Chapter 2b Dystonia-deafness syndrome caused by a β-actin gene mutation and response to deep brain stimulation

Movement Disorders. 2017; 32(1): 162-165.

44

Chapter 3 Spasticity, dyskinesia and ataxia in cerebral palsy: Are we sure we can differentiate them?

European Journal of Paediatric Neurology. 2017; 21(5):703-706.

52

PART II — Impact upon health-related quality of life

Chapter 4 Rare inborn errors of metabolism with movement disorders: a case study to evaluate the impact upon quality of life and adaptive functioning

Orphanet Journal of Rare Diseases. 2014; 9: 177.

64

Chapter 5 Motor and non-motor determinants of health-related quality of life in children and young adults with dystonia

Parkinsonism & Related Disorders. 2019; 58: 50-55.

80

PART III — Measuring the effectiveness of treatment in dystonia

Chapter 6 Non-motor effects of deep brain stimulation in dystonia: A systematic review Parkinsonism & Related Disorders. 2018; 55: 26-44.

102

Chapter 7 A patient-centered approach to measure the effectiveness of deep brain stimulation in dystonia: a prospective pilot study

Article submitted

142

Chapter 8 Summary and general discussion 152

Appendices Nederlandse samenvatting 170

List of abbrevations 176

List of Publications 178

Curriculum vitae 182

Dankwoord 184

1

This thesis focuses on neurological movement disorders (MDs) in children and young adults, with special attention to hyperkinetic MDs, including dystonia. Childhood-onset MDs are a relatively new area of specialization within the field, differing considerably from those manifesting in adulthood. This thesis on childhood-onset MDs deals with the following topics: 1) how do we recognise them, 2) what is their impact on health-related quality of life (HR-QoL) and finally, 3) how can we measure the effect of treatment interventions.

Neurological MDs comprise a spectrum of clinical syndromes leading to a disruption in the execution of movements. They are subdivided into hyperkinetic (excess in move- ments), hypokinetic (decrease in movements) and ataxia (disturbance in the execution of coordinated actions). The exact pathophysiology of MDs is not fully clear, but the general consensus is that a dysfunctional signalling within the cortico/basal-ganglia/cerebellar network is involved. The subcortical nuclei and the cerebellum are densely connected with cortical areas of the brain, fulfilling a prominent role in motor control as well as in executive functioning and regulation of emotion and behaviour.[1,2] A disruption or dysfunction within the networks may therefore induce both motor and non-motor symptoms.

CHILDHOOD-ONSET MOVEMENT DISORDERS

There are three main elements in the approach to childhood-onset MDs that are charac- terized by three questions. The first is: ‘what symptom(s) do we see?’. This leads to two other, namely ‘what is the cause?’ and ‘what is the best treatment?’.

When referring to `what do we see?’, it is important to realize that childhood-onset MDs are considerably different from adulthood-onset manifestations. First, in childhood-onset MDs symptoms occur in a developing nervous system, which is important for the inter- pretation of the clinical picture. Immature motor behavior in healthy children is known to mimic features of MDs, such as ataxic or dystonic MD-like characteristics which are physiologically present until the age of twelve and sixteen years respectively.[3–7] Second, the prevalence of the MD subtypes differs between childhood and adulthood-onset MDs.

[5] Hypokinetic MDs, such as parkinsonism, are rarely observed in children. Childhood

hyperkinetic MDs are more common and can be classified as tics, dystonia, chorea,

myoclonus, tremor and stereotypies, and form the majority. Third, childhood-onset MDs

are often embedded in a complex clinical picture, not only involving mixed phenotypes with

multiple MDs, but other neurological and non-neurological features as well (e.g. mental

retardation, seizures, dysmorphias or deafness).[5]

With regards to the question ‘what is the cause?’, identification of the underlying etiology in childhood-onset MDs is of great importance. For instance, in treatable MDs, early adequate therapeutic intervention may minimize or even prevent the onset of symptoms.[8]

In addition, identification of the cause will allow proper prognostic and genetic counselling of the patients and their families. The rapidly developing diagnostic techniques have led to a large, yet still expanding number of etiologies that can cause childhood-onset MDs in the acquired (e.g. ischemic, infectious, auto-immune, toxic, drug-related, or structural causes) and the genetic domain (e.g., metabolic, mitochondrial or neurodegeneration).[5,8,9]

The selection of the optimal treatment is the third aspect in the care for patients with childhood-onset MDs. Despite increasing pathophysiologic insights, treatment is mainly targeted at the presented symptomatology.[9] Randomized controlled interventional studies are lacking and existing literature, suggests that all MDs may require a different approach regarding pharmacological or surgical treatment.[9]

Altogether, these aspects may impose unique challenges to the doctors, parents and caretakers of patients with childhood-onset MDs. This highly heterogeneous population of patients warrants a broad expertise regarding (ab)normal development, MD charac- terization, interpretation of concurring neurological and non-neurological features and the wide spectrum of possible acquired and genetic etiologies.[10] In daily practice, this complexity may lead to diagnostic delays and uncertainty for the patients and their families.

Analogous to other complex neurological syndromes (including epilepsy, neurovascular- and neuromuscular disorders), a multidisciplinary approach could be beneficial for the diagnostic procedure, treatment and surveillance of patients.[11-13] This enables clinicians from different backgrounds to combine their expertise in order to optimize the diagnosis and management of patients with complex disorders.

THE CONCEPT OF DYSTONIA

Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, abnormal posturing, or both.[14] Oppenheim introduced the term in 1911 to describe a clinical picture in four children.[15] Between then and now, it has become clear that dystonia is an umbrella term covering a broad range of syndromes secondary to acquired, hereditary, and idiopathic causes.[14]

1

The multifaceted nature of dystonia requires a clinical and etiological classification system.

[14] The first distinguishing clinical parameter is ‘age of onset’. In addition, patients are classified according to the anatomical distribution of symptoms (focal to generalized), temporal pattern (disease course and variability over the day), and the presence of asso- ciated features including other MDs and neurological or systemic manifestations. Etiology subdivides patients according to nervous system pathology (degeneration, structural lesions or no pathology) and mode of inheritance (inherited, acquired or idiopathic).[14]

Childhood-onset dystonia

After tics, dystonia is recognized as the second most common childhood-onset MD.[16]

In contrast to adulthood-onset dystonia, childhood-onset dystonia has a tendency to spread to generalized dystonia. Moreover, as already explained, childhood-onset dystonia is often presented as a mixed and complex phenotype with additional (non-) neurological features. Etiologically, childhood-onset dystonia is more likely to have a detectable acquired or genetic cause compared to the mainly idiopathic forms of adult dystonia. The most common cause is hypoxic-ischemic encephalopathy (e.g. cerebral palsy; CP). In addition, there are numerous other etiologies including metabolic diseases. The wide spectrum of possible etiologies (genetic heterogeneity), and the fact that one etiology can lead to different clinical pictures (phenotypic pleiotropy), gives rise to a very heterogeneous patient population of childhood-onset dystonia.

The phenotype of dystonia

The term phenotype is derived from the Greek words ‘phainein’ (to show) and ‘typos’

(type) and refers to observable traits of a person, including appearance, development, and behavioral traits. The phenotype is the result of the genotype, environmental factors, and the interaction between the two, resulting in both motor and non-motor traits.

Motor symptoms

Accurate phenotyping (what do we see) of young patients with dystonia is essential for diag-

nosis and treatment aspects. A careful medical history and recognition and correct classifi-

cation of the symptoms are crucial steps in search of the underlying etiology.[10,17] Moreover,

management of dystonia predominantly involves symptomatic treatment, targeted at the

symptoms.[18] Thus, irrespective of whether the etiological diagnosis is known, reliable

phenotyping has consequences for the selection of an adequate treatment strategy.

However, the recognition of dystonia can be challenging. In adult dystonic patients, it has been indicated that MD experts only moderately agree on the classification of hyperkinetic MDs.[19,20] In children, such inter-observer study data on MD recognition are sparse.

One pediatric pilot study reported a moderate agreement on the phenotypic recognition of early-onset ataxia.[21] Regarding the ongoing dispute that pediatric dystonia is often mistaken for spasticity in children with CP, one could anticipate that the agreement on pediatric dystonia recognition is limited too.[22] These findings give rise to the question whether clinicians can reliably distinguish MD symptoms and whether MD specialists speak the same language when they describe a MD phenotype in children.

Non-motor symptoms

Although dystonia is primarily defined by the distinct motor symptoms, there is an increasing interest for non-motor symptoms associated with dystonia. These comprise psychiatric disturbances, pain, sleep problems, and cognitive deficits.[23,24] Interestingly, it is now known in other basal ganglia disorders such as Parkinson´s or Huntington´s disease that non-motor symptoms are an integral part of the disease phenotype. In dystonia, the presence of non-motor symptoms is also not entirely explainable as a consequence of the motor symptoms.[25] In adult dystonia, this is underscored by only a weak relationship between non-motor and motor symptoms, as well as by the fact that non-motor features may already become manifest prior to motor features.[23,24,26] A possible explanation could be provided by the network connections between the basal ganglia, prefrontal cortex, hippocampus, limbic and paralimbic cortices.[2] These circuits underlie complex behavior, such as executive functioning and emotion regulation. In this perspective, it is important to elucidate all aspects of the dystonic phenotype, including the mixture of motor and non-motor features.

Health-related quality of life in dystonia

Over the past decades, self- or parent/proxy-reported HR-QoL has emerged as a mean- ingful way to measure the impact of a chronic condition upon physical and psychosocial domains of functioning.[27] To date, knowledge regarding HR-QoL in childhood-onset dystonia is scarce. Adulthood-onset forms of focal and generalized dystonia are known to negatively impact the HR-QoL.[25,28] Interestingly, the association between HR-QoL and dystonia severity is only modest. This could be explained by the fact that non-motor features, such as pain and psychiatric issues, are at least as important for the HR-QoL as motor features. Thus, recognition of non-motor symptoms is important for the perceived disease burden and quality of life of the dystonic patient.[25]

1

HR-QoL studies solely focusing on childhood-onset dystonic syndromes are lacking so far.

In children with tic disorders, non-motor features have been shown to affect the HR-QoL.

[29,30] In addition, it has been shown that children with cerebral palsy (CP), the most common cause of childhood dystonia, may suffer from a lower HR-QoL than children with other chronic childhood disorders.[31] Altogether, in childhood-onset dystonia, these data may implicate that systematic assessment of both motor and non-motor symptoms could contribute to the treatment and clinical surveillance of the patient.

EFFECTIVENESS OF TREATMENT IN DYSTONIA

Over the past several decades, pharmacological, surgical, and paramedical treatment options have been developed for dystonia. These treatment options mainly focus on diminishing motor symptoms and their efficacy is mainly assessed with dystonia rating scales (e.g. Burke-Fahn Dystonia Rating Scale (BFMDRS)).[32-34] One of the limitations of these scales is that they do not assess non-motor symptoms. This may implicate that not all therapeutic effects of an intervention would be measured when the BFMDRS would be the solitary outcome. Until now, it is still unclear how motor symptom reduction can be translated in terms of HR-QoL or other aspects of daily functioning important to patients and their caregivers. Furthermore, in a heterogeneous population such as childhood-onset dystonia, one might question whether a single rating scale can adequately capture mean- ingful changes for the full range of syndromes.[35,36]

A suitable example in the abovementioned discussion is deep brain stimulation of the globus pallidus internus (GPi-DBS). GPi-DBS comprises the neurosurgical insertion of one unilateral or two bilateral electrodes into the GPi nucleus of the basal ganglia. A subcuta- neously located neuro-stimulator generates regular pulses from the electrodes. Although the exact mechanism of GPi-DBS is unknown, it has emerged as a safe treatment option.

In patients with isolated dystonia, it exerts an overall good response (40-90% symptom relief), but in patients with acquired or lesional forms of dystonia, the response is more variable. Remarkably, in spite of the significance of non-motor symptoms in dystonia, the effect of GPi-DBS on these symptoms is not well established.

There are repeatedly reported discrepancies between the ‘objective’ effect measured with

the BFMDRS and the ‘subjective’ improvement experienced by patients after GPi-DBS,

especially in lesional or secondary dystonia.[37] For example, a minimal BFMDRS change

in a patient being able to independently steer an electric wheelchair after DBS. Despite

limited rating scale improvement, it is important to realize that a functional effect may still be important for the quality of daily living. Furthermore, the final outcome should be interpreted from both motor and non-motor changes.

To elucidate the real clinical effect of interventions, it may be important to re-define outcome parameters to establish effectiveness -- for example, by setting individual treat- ment goals, which is already routinely done in rehabilitation medicine. This does not only provide a unique insight into the priorities of the patient, but also helps the clinician to select the most appropriate treatment strategy.[38]

OBJECTIVES

This thesis aims to contribute to the clinical care of patients with childhood-onset MDs through the assessment of the recognition of the phenotypes, the impact of motor and non-motor features upon HR-QoL, and the evaluation of meaningful outcome parameters.

In the first part, Chapter 2 reports how a multidisciplinary approach may facilitate diagnosis and treatment of complex MDs in children and young adults. Chapter 2a and 2b serve as examples to underscore the benefits of this multidisciplinary approach. Chapter 3 studies how clinicians describe and agree with each other and themselves on phenotyping children with CP, the most common cause of childhood-onset dystonia.

The second part of the thesis focuses on the impact of childhood-onset dystonic syn- dromes upon HR-QoL. In Chapter 4 the impact of MDs in children with inborn errors of metabolism (IEM) on HR-QoL and adaptive functioning is discussed. Chapter 5 provides a systematic evaluation of motor and non-motor symptoms and their impact on HR-QoL in patients with childhood onset dystonia.

The third part focuses on the efficacy of GPi-DBS as treatment strategy in patients with dystonia. Chapter 6 comprises a systematic review of the existing literature regarding non-motor outcome of GPi-DBS. Finally, Chapter 7 addresses the GPi-DBS treatment effect by elucidating how different outcome parameters (dystonia rating scale scores and patient-set priorities) can influence the interpretation of effectiveness.

1

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[15] Oppenheim H. Über eine eigenartige Krampfkrankheit des kindlichen und jugendlichen Alters (Dysbasia lordotica progressiva, Dystonia musculorum deformans). Neurol Cent 1911;30.

[16] Delgado MR, Albright AL. Movement disorders in children: definitions, classifications, and grading systems. J Child Neurol 2003;18Suppl1:S1-8.

[17] van Egmond ME, Kuiper A, Eggink H, Sinke RJ, Brouwer OF, Verschuuren-Bemelmans CC, et al. Dystonia in children and adolescents:

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[19] Logroscino G, Livrea P, Anaclerio D, Aniello MS, Benedetto G, Cazzato G, et al. Agreement among neurologists on the clinical diagnosis of dystonia at different body sites. J Neurol Neurosurg Psychiatry 2003;74:348–350.

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[28] Page D, Butler A, Jahanshahi M. Quality of life in focal, segmental, and generalized dystonia. Mov Disord 2007;22:341–347.

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[30] Cutler D, Murphy T, Gilmour J, Heyman I. The quality of life of young people with Tourette syndrome. Child Care Health Dev 2009;35:496–504.

[31] Varni JW, Limbers CA, Burwinkle TM. Impaired health-related quality of life in children and adolescents with chronic conditions: a comparative analysis of 10 disease clusters and 33 disease categories/severities utilizing the PedsQL 4.0 Generic Core Scales. Health Qual Life Outcomes 2007;5:43.

[32] Roubertie A, Mariani LL, Fernandez-Alvarez E, Doummar D, Roze E. Treatment for dystonia in childhood. Eur J Neurol 2012;19:1292–1299.

[33] Jahanshahi M, Czernecki V, Zurowski AM.

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[34] Castrioto A, Lhommée E, Moro E, Krack P.

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[35] Gimeno H, Gordon A, Tustin K, Lin J-P. Functional priorities in daily life for children and young people with dystonic movement disorders and their families. Eur J Paediatr Neurol 2013;17:161-168.

[36] Lumsden DE, Gimeno H, Tustin K, Kaminska M, Lin J-P. Interventional studies in childhood dystonia do not address the concerns of children and their carers. Eur J Paediatr Neurol 2015;19:327–336.

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1

PART I

RECOGNITION AND DIAGNOSIS OF

CHILDHOOD-ONSET MOVEMENT DISORDERS

2

DIAGNOSTIC APPROACH TO CHILDREN AND ADULTS WITH YOUNG-ONSET MOVEMENT DISORDERS

HENDRIEKJE EGGINK*

MARTJE E. VAN EGMOND*

ANOUK KUIPER DEBORAH A. SIVAL

CORIEN C. VERSCHUUREN-BEMELMANS MARINA A.J. TIJSSEN

TOM J. DE KONING

* CONTRIBUTED EQUALLY

ABSTRACT

Background: Diagnosis of less common young-onset movement disorders is often chal- lenging, requiring a broad spectrum of skills of clinicians regarding phenotyping, normal and abnormal development and the wide range of possible acquired and genetic etiologies.

This complexity often leads to considerable diagnostic delays, paralleled by uncertainty for patients and their families. Therefore, we hypothesized that these patients might benefit from a multidisciplinary approach. We report on the first 100 young-onset movement disorders patients who visited our multidisciplinary outpatient clinic.

Methods: Clinical data were obtained from the medical records of patients with disease-on- set before age 18 years. We investigated whether the multidisciplinary team, consisting of a movement disorder specialist, pediatric neurologist, pediatrician for inborn errors of metabolism and clinical geneticist, revised the movement disorder classification, etiological diagnosis, and/or treatment.

Results: The 100 referred patients (56 males) had a mean age of 12.5 ± 6.3 years and mean disease duration of 9.2 ± 6.3 years. Movement disorder classification was revised in 58/100 patients. Particularly dystonia and myoclonus were recognized frequently and supported by neurophysiological testing in 24/29 patients. Etiological diagnoses were made in 24/71 (34%) formerly undiagnosed patients, predominantly in the genetic domain.

Treatment strategy was adjusted in 60 patients, of whom 43 (72%) reported a subjective positive effect.

Conclusions: This exploratory study demonstrates that a dedicated tertiary multidisci-

plinary approach to complex young-onset movement disorders may facilitate phenotyp-

ing and improve recognition of rare disorders, with a high diagnostic yield and minimal

diagnostic delay. Future studies are needed to investigate the cost-benefit ratio of a

multidisciplinary approach in comparison to regular subspecialty care.

BACKGROUND

Young-onset movement disorders (YMDs) is a relatively new field in neurology, comprising clinical neurological syndromes presenting with involuntary movements manifesting before the age of 18. As with movement disorders (MDs) in adults, YMDs are subdivided into hyperkinetic movements (dystonia, myoclonus, chorea, ballism, tremor and tics), hypoki- netic movements (parkinsonism), and ataxia.[1–5] Recognition of common YMDs, such as tics and stereotypies, is usually straightforward for most clinicians. However, diagnosis of less common and more complex YMDs, such as disorders presenting primarily with myoclonus or dystonia, is often difficult, both for pediatric and adult neurologists.[1,6,7]

The recognition and classification of YMDs present some unique challenges. Firstly, YMDs are often embedded in a complex clinical phenotype. For example, the occurrence of mixed MDs (more than one MD present) or co-existence of a variety of symptoms such as psychomotor retardation or behavioral abnormalities are commonly seen.[5,8,9]

Secondly, in young children the developing nervous system may produce a variety of motor patterns that would be labelled as pathologic in older children and adults, but are simply a manifestation of brain immaturity in younger patients.[1] For instance, chorea is a normal feature in healthy infants and toddlers, and (subtle) signs of overflow dystonia and ataxia are found in healthy children up till the age of 12 years or even older.[10,11] Finally, YMDs can be caused by a broad spectrum of both acquired and genetic disorders, including infections, auto-antibody and auto-immune disorders, as well as rare metabolic disorders and other inherited defects.[7,12–14]

The complexity of the diagnosis and management of YMDs is becoming increasing clear, which has resulted in a growing number of specialized pediatric neurologists. Despite this development, the diagnostic process in complex YMDs often remains challenging, a burden for patients and their families, and costly for our health care system as patients often remain undiagnosed for many years.[1,6,7,14,15] This has been reflected in a recent study in a tertiary referral center that showed a mean delay of diagnosis of 11.1 ± 12,5 years in a cohort of 260 patients with non-tic YMDs.[7]

In other heterogeneous or rare diseases in children such as epilepsy or neuromuscular disorders, a beneficial effect of a multidisciplinary approach has been reported.[16–20]

We hypothesized that such an approach might be a possibility to tackle the complexity of children and young adults with MDs. A multidisciplinary team may enable to overcome the

2

three difficulties experienced in this patient group: a complex clinical phenotype (movement disorder specialist), the variety of motor patterns produced by the developing brain (pediat- ric neurologist), and a broad spectrum of both acquired and genetic disorders (pediatrician for inborn errors of metabolism and a clinical geneticist).

In this exploratory study, we report on the first 100 patients with YMDs who visited our multidisciplinary outpatient clinic. Our aim was to share our experience of a new multidis- ciplinary approach in terms of changes in MD classification, diagnostic yield and targeted treatment strategies.

METHODS

Design and setting of the study

In this retrospective, single center, observational study we evaluated the first 100 patients who visited our multidisciplinary outpatient clinic for YMDs. It was situated in a tertiary referral center, the University Medical Center Groningen, in the Netherlands. The study was performed according to the ethical standards and regulations of our institute.

Patients

All patients had a confirmed or suspected MD with an onset before the age of 18 years and were referred for an expert opinion regarding MD classification, etiology or treatment of involuntary movements (Table 1).

Multidisciplinary outpatient clinic

The clinic was initiated in 2012 with a team consisting of an adult neurologist specialized in MDs (MT), a pediatric neurologist specialized in developmental neurology and YMDs especially ataxia (DS), a pediatrician specialized in inborn errors of metabolism (TK) and a clinical neuro-geneticist (CV). In addition, clinical fellows in movement disorders and resi- dents attend the clinic to gain skills and knowledge from the different medical specialties involved as part of their clinical training.

The pediatrician for inborn errors of metabolism received the referrals as the coordi-

nating medical specialist, which were subsequently discussed within the team. Prior to

the consultation, referral letters and medical reports containing previous diagnostic and

treatment strategies were read carefully by the clinical fellow, who sent a summary to all

team members.

During the consultation, patients were seen by all team members at once. In a separate meeting, the team members reviewed the video images, discussed the movement disorder classification and the results of the additional investigations, and developed joint diagnostic and therapeutic recommendations. In all cases the team members reached consensus.

The main diagnostic steps were laboratory investigations, (neuro-)imaging, clinical neu- rophysiology or genetic testing. The key therapeutic options comprised pharmacological treatment, botulinum toxin injections, paramedical interventions (e.g. physiotherapy, occupational therapy, speech therapy), ketogenic diet, and deep brain stimulation.

The primary purpose of the multidisciplinary team was not to take over the clinical care provided by the referring medical specialist, but preferably to see a patient once and provide an all-in-one expert opinion. The presence of the clinical geneticist enabled direct genetic counseling in case genetic testing was considered. Results of additional investigations and genetic diagnostics were shared with the patient or caregivers by one of the team members via a follow-up consult or, if preferred by the family, by a telephone consultation. The team aimed to leave further management and follow-up to the referring specialist, but in case of unresolved issues patients were welcome to return to the multidisciplinary outpatient clinic.

Data collection

We evaluated the first 100 patients who visited our multidisciplinary clinic for YMDs between June 2012 and May 2014. Medical records were reviewed for patient characteristics and previous phenotypical classifications. The severity of the YMDs present was assessed by the team members using the global clinical impression scale of severity (GCI-S). This commonly used 7-point scale enables a clinician to rate the extent of movement disorders with no movement disorder (1), slight (2), mild (3), moderate (4), marked (5), severe (6), and among the most severest (7).[21] We compared the classification of the most prominent MD and etiological diagnosis before and after assessment by the multidisciplinary team. In addition, we studied the treatment strategies and whether the patients or their caregivers reported any positive effects of therapies 3–6 months after initiation. Since many patients were not under our primary care, and/or living at a distance from our center, we performed follow-up using a semi-structured interview during a telephone consultation. Patients and/or caregivers were asked (1) whether they experienced benefit with regard to motor symptoms, (2) since when they experienced this, (3) extent of improvement (none/slight/

moderate/good), and (4) if any adverse effects were present.

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RESULTS

Patient characteristics

A total of 56 male and 44 female patients visited the multidisciplinary clinic (Table 1).

Patients had a mean age of 12.5 years (SD 6.3) and a mean duration of symptoms of 9.2 years (SD 6.3). Referring specialists were predominantly pediatric neurologists, pediatri- cians and physiatrists (rehabiliation physicians) with questions concerning the MD clas- sification, etiology or treatment options. We had 36 patients referred with an unclassified MD, documented as dyskinesias, trembling, involuntary movements, or restlessness. A confirmed etiological diagnosis (17 inherited, 12 acquired) already explained the phenotype of 29 patients upon referral.

Table 1. Baseline characteristics Characteristics

Patient characteristics

Sex (male/female) 56/44

Age (years)* 12.5 ± 6.3; 1-33

Age at symptom-onset (years)* 3.3 ± 4.6; 0-19

Duration of symptoms (years)* 9.2 ± 6.3; 1-32

Referral questions

Movement disorder classification 50

Etiology 38

Treatment 42

MD classification

Ataxia 9

Dystonia 32

Myoclonus 11

Other** 12

Unclassified 36

Etiological diagnosis

Inherited etiologies 17

Monogenic

ARX mutation 1

Ataxia telangiectasia 1

Coffin Lowry syndrome 1

Glutaric aciduria type 1 2

GLI2 mutation 1

GOSR2 mutation 1

GTPCH deficiency (DYT5) 1

Table 1. (continued) Characteristics

Proprionacidemia 1

SCN1A mutation 2

THAP1 mutation (DYT6) 2

TITF1 mutation 1

Structural chromosomal abnormality

Microdeletion 19p13.2p13.13 (NFIX and CACNA1A gene) 1

Partial deletion chromosome 7q (SCGE gene) 1

Uniparental disomia chromosome 7 (SCGE gene) 1

Acquired etiologies 12

Infectious 2

Perinatal asphyxia 9

Functional 2

* Age in years ± standard deviation; range;

** Chorea, tics, tremor, parkinsonism and if no MD was present

Abbreviations: ARX, Aristaless related homeobox; GOSR2, Golgi SNAP receptor complex member 2; GTPCH, Guanosine Triphosphate Cyclohydrolase; SCN1A, sodium channel voltage gated type I alpha subunit; TITF1, Thyroid transcription factor-1; NFIX, nuclear factor I/X; CACNA1A, calcium channel voltage-dependent, P/Q type, alpha 1A subunit; SCGE, epsilon-sarcoglycan.

Movement disorder classification

Mean severity of the MDs present was 4.3 ± 1.7 on the GCI-s (range 1–7), corresponding with a moderate to marked MD severity. The multidisciplinary team revised the initial clas- sification in 58/100 patients (Table 2). These revisions reduced the number of patients with an unclassified MD from 36 down to 4. Compared to the referring clinicians, the team more frequently classified the patients’ involuntary movements as dystonia (from 32 to 41) and myoclonus (from 11 to 31). The number of ataxic and tremor patients dropped (from 9 to 1 and 6 to 1, respectively), whereas the number of patients with chorea increased (from 4 to 6). The multidisciplinary team observed no MDs in eleven patients (e.g. the movements were related to agitation or caused by behavioral abnormalities). Simultaneous non-inva- sive surface electroencephalography/electromyography (EEG/EMG) was performed in 29 predominantly myoclonic patients and this confirmed or supported the MD classification observed by the team in 24/29 patients. In the remaining five cases, EEG/EMG was not conclusive due to an absence of symptoms during registration (n = 3) or the patient being unable to comply with the registration protocol (n = 2).

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Table 2. Overview of classification of most prominent MD before and after visiting the multidisciplinary outpatient clinic

Observed MD classification by the multidisciplinary team

Re fe rr al M D c la ss ifi ca tio n Dystonia Myoclonus* Ataxia Other** Unclassified Total

Dystonia 26 1 0 4 1 32

Myoclonus* 0 10 0 1 0 11

Ataxia 0 8 0 1 0 9

Other** 2 5 0 5 0 12

Unclassified 13 7 1 12 3 36

Total 41 31 1 23 4 100

* Isolated myoclonus, myoclonus ataxia and myoclonus dystonia;

** Comprises chorea, tics, tremor, parkinsonism and if no MD was present

Associated neurological and non-neurological features

Only 26/100 patients presented with a (mixed) MD without associated features, whereas the majority of patients also had additional neurological symptoms (n = 35), non-neuro- logical symptoms (n = 9) or both (n = 30). The most important additional features were intellectual disability, epilepsy, spasticity, skin abnormalities, deafness, dysmorphias, and skeletal and growth abnormalities.

Etiological diagnosis

At presentation, 29/100 patients had a confirmed genetic or acquired cause explaining their phenotype (Table 1). The multidisciplinary team established a diagnosis in 24 additional patients (Table 3), particularly in the genetic domain, where the number of diagnoses more than doubled from 17 to 37. Monogenetic etiologies were found using single-gene testing in nine cases, by targeted resequencing in three cases and using whole exome sequencing in five cases. Biochemical testing led to a diagnosis of non-ketotic hyperglycinemia in one case in which confirmation of the molecular defect is still pending.

Table 3. Confirmed etiological diagnoses after assessment by the multidisciplinary team

Diagnosis N

Inherited etiologies 20

Monogenic

ACTB mutation 1

CTNNB1 mutation 1

GLRA1 mutation 1

GOSR2 mutation 6

HSD17B10 mutation 1

MECP2 mutation 1

Table 3. (continued)

Diagnosis N

OFD-1 mutation 1

OTC-deficiency 1

PRRT2 mutation 1

SPTBN2 mutation 1

TH mutation 1

TITF-1 mutation 1

Laboratory abnormalities

Non-ketotic hyperglycinemia 1

Syndrome diagnosis

Gilles de la Tourette 1

Linear naevus syndrome 1

Acquired etiologies 4

Drug-induced 1

Functional 3

Abbreviations: ACTB, beta-actin; CTNNB1, catenin (cadherin-associated protein) beta 1; GLRA1, glycine receptor alpha 1; GOSR2, Golgi SNAP receptor complex member 2; HSD17B10, 17beta-hydroxysteroid dehydrogenase type 10; MECP2, methyl CpG binding protein 2; OFD-1, oral-facial-digital syndrome 1; OTC, ornithine

carbamoyltransferase; PRRT2, proline-rich transmembrane protein 2; SPTBN2, spectrin beta non-erythrocytic 2; TH, tyrosine hydroxylase; TITF1, thyroid transcription factor-1; HSD17B10 or 2-methyl-3-hydroxybytyryl-CoA dehydrogenase deficiency

Among the acquired causes, oral contraceptive-induced chorea was diagnosed in one patient and three patients turned out to have functional MDs. Despite an increase in confirmed etiological diagnoses from 29 to 53, we still had 35 patients categorized with a suspected genetic diagnosis (defined as strong suspicion of a genetic cause based on a severe clinical phenotype, early onset, family history, and absence of any of the known acquired causes). In these cases, multiple genetic tests, including whole exome sequenc- ing, have not yet revealed a causative molecular defect. For 21 of these 35 patients we are awaiting elucidation of the causal mutation in a research setting, the other 14 patients (or their caregivers) decided not to participate in this research.

Treatment strategies

More than half of the 100 patients (61%) had not been given any specific treatment for their MD before visiting our clinic. The multidisciplinary team initiated or changed the treatment strategy in 60/100 of the patients. Table 4 gives an overview of changes in the treatment strategy, categorized by MD type. In 30/60 cases (50%), the new treatment strategy was based on the revised MD classification. In the other 30 patients the team initiated or

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adjusted the treatment strategy, despite an unchanged MD classification: for example symptomatic treatment with trihexyphenidyl in dystonic cerebral palsy. We advised six patients to stop their medication, which led to unchanged clinical symptoms in two patients and an improvement of symptoms in three others. An example of the latter was advice to stop taking oral contraceptives, which led to an almost complete disappearance of adolescent-onset chorea. In the group of 60 patients who had new or adjusted treatment, 72% of them or their caregivers reported a positive effect therapy after 3–6 months. Five patients were advised to stop their medication at the 3–6 months evaluation, because of limited benefit and or potential aggravation of other symptoms and side effects, such as effects on mood, behavior or constipation.

Table 4. Overview of treatment strategies that were changed by the multidisciplinary team

Movement disorder Treatment category Treatment specifics N Positive effect (N)

Dystonia Pharmacological Clonazepam 1 1

Gabapentin 3 3

L-dopa 2 1

Trihexyphenidyl 8 3

Cessation of drug 1 1

Botulinum toxin 5 5

Deep brain stimulation 5 4

Paramedical 2 2

Total dystonia 27 20

Myoclonus Pharmacological Clonazepam 10 10

Ketogenic diet 4 1

Paramedical 4 2

Total myoclonus 18 12

Other Pharmacological L-dopa 4 4

Acetozolamide 1 1

Cessation of drug 4 2

Botulinum toxin 1 1

Paramedical 3 2

Total other 13 10

Difficult to classify Pharmacological L-dopa 2 1

Total 60 43

DISCUSSION

To our knowledge, this is the first study describing the experience with a multidisciplinary team approach towards children and adults with YMDs. Based on the results, it is likely that patients with YMDs benefit from a multidisciplinary team strategy with regard to MD classification, diagnostic yield and targeted treatment strategies.

The multifaceted nature of YMDs served as an impulse for setting up our multidisciplinary outpatient clinic, because the complexity of YMDs often leads to a time-consuming and burdensome diagnostic process.[1,6,7] This issue is reflected by a mean symptom duration of 74% of our patients’ life spans, which is in line with the results of a previous study.[7]

In 58% of the patients, the team revised the MD classification or defined another MD as the most prominent clinical symptom. We think this high percentage of revisions may be due to the combined expertise of a pediatric neurologist, trained to distinguish normal developmental from abnormal movements, and a movement disorder specialist, trained to establish the phenomenology of clinical MD syndromes.[1,8] Although we are aware that there is no gold standard for clinical MD classification, additional investigations such as EEG/EMG for myoclonus confirmed the clinical diagnosis in 24/29 of our cases.[22]

The presence of non-neurological features in 39% of our YMD cohort underscores the complexity of the clinical presentations in a significant part of this population, and the combined expertise of a pediatrician and a clinical geneticist to include all symptoms, facilitated the diagnostic process.

The team identified a etiological diagnosis in 24/71 (34%) previously undiagnosed patients, of which 17 were found to have monogenetic disorders. In contrast, in a study with 260 patients non-tic YMDs patients, who were referred to a neurologist specialized in YMDs between 2004 and 2013, a definitive genetic diagnosis was made in 17%.[7] We realize that the genetic advances of the past decade are likely to have contributed to the higher yield in our sample, however we hypothesize that the team’s broad and combined expertise has also been an important contributing factor. Furthermore, the diagnostic yield was obtained in a relatively short period of time, as a multidisciplinary team strategy facilitates immediate decision-making in comparison to the normal serial process involving multiple referrals, therefore minimizing the burden for the patients and their families.

After critical appraisal of phenotype and etiology, therapeutic strategies were considered and tailored to individual patient needs. The team gave specific advice on treatment in 60%

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of the patients, with 72% (n = 42) of them or their caregivers reporting a subjective positive effect of the suggested treatment on follow-up. The effectiveness of treatment was only assessed through a semi-structured questionnaire and it was therefore not possible to draw more detailed conclusions on objective and/or long-term outcome measures of its effectiveness. Nevertheless, the large number of patients in which treatment was initiated at our clinic may reflect a potential under-treatment of YMDs, likely to significantly impact the patient’s quality of life. The low number of patients that were already treated for their MD is remarkable, in particular when taking into account that the mean MD severity of these 60 cases was significant (5 on a scale of 7). Low treatment rates and potential under-treatment have also been reported in MDs in children with inborn errors of metabolism, despite the fact that it has been shown that symptomatic treatment may significantly improve patients’

daily functioning and quality of life.[13,14,23,24]

The results of this exploratory study indicate that YMDs patients might benefit from a multidisciplinary team approach in terms of diagnosis and treatment in comparison to the referring specialists. However, interpretation of the results is limited by the lack of a control group of patients’ receiving assessment by a pediatric movement disorder specialist, or in comparison to assessments by an alternative team consisting of two or three specialists.

Inclusion of such a control group was not feasible in our center. Nevertheless, we think that this single-institution experience indicates that a dedicated multidisciplinary approach to YMDs disorders may facilitate phenotyping and improve recognition of rare disorders.

Notably, in this study, the age at presentation at our outpatient clinic ranged from 1 to 33

years, which is beyond the standard upper limit of 18 years for pediatric care. Distinguishing

early-onset from later-onset MDs is useful for diagnostic purposes.[3,4] However, we believe

that the age of symptom-onset in these patients is a more important inclusion criterion

than the age at time of referral, especially because long delays between symptom-onset

and diagnosis have been reported.[7] Therefore, we propose to consider patients with YMDs

as a spectrum, irrespective of the age of referral, and to allow all complex YMD patients to

benefit from the combined expertise of a multidisciplinary team, crossing barriers between

pediatric and adult neurology.

CONCLUSION

In summary, our results suggest that a multidisciplinary approach might help tackle the complexity of diagnosis and managing complex YMDs. Our experience indicates that this approach may improve recognition of rare disorders, with a good diagnostic yield and a minimal diagnostic delay. Future studies are needed to investigate the cost-benefit ratio of a multidisciplinary approach in comparison to regular subspecialty care, preferably using a prospective study design with standardized clinical assessments to systematically evaluate treatment effects.

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REFERENCES

[1] Singer HS, Mink JW, Gilbert DL, Jankovic J.

Movement Disorders in Childhood. 2nd ed.

Philadelphia: Saunders Elsevier 2016.

[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;25:1538–1549.

[3] Fahn S. Classification of movement disorders.

Mov Disord 2011;26:947–957.

[4] Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung V, et al. Phenomenology and classification of dystonia: a consensus update.

Mov Disord 2013;28:863–873.

[5] Delgado MR, Albright AL. Movement disorders in children: definitions, classifications and grading systems. J Child Neurol 2003;15(Suppl):1–8.

[6] van Egmond ME, Kuiper A, Eggink H, Sinke RJ, Brouwer OF, Verschuuren-Bemelmans CC, et al. Dystonia in children and adolescents:

a systematic review and a new diagnostic algorithm. J Neurol Neurosurg Psychiatry 2015;86:774–781.

[7] Bäumer T, Sajin V, Münchau A. Childhood-onset movement disorders: a clinical series of 606 cases. Mov Disord Clin Prac 2017;4:437–440.

[8] Abdo WF, van de Warrenburg BPC, Burn DJ, Quinn NP, Bloem BR. The clinical approach to movement disorders. Nat Rev Neurol 2010;6:29–37.

[9] 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;25:1538–1549.

[10] Brandsma R, Spits AH, Kuiper MJ, Lunsing RJ, Burger H, Kremer HP, et al. Ataxia rating scales are age-dependent in healthy children. Dev Med Child Neurol 2014;56:556–563.

[11] Kuiper MJ, Vrijenhoek L, Brandsma R, Lunsing RJ, Burger H, Eggink H, et al. The Burke-Fahn- Marsden Dystonia Rating Scale is Age-Dependent in Healthy Children. Mov Disord Clin Pract 2015;3:580–586.

[12] Gascon GG, Ozand PT, Brismar J. Movement disorders in childhood organic acidurias. Clinical, neuroimaging, and biochemical correlations.

Brain & Development 1994;16(Suppl):94–103.

[13] García-Cazorla A, Wolf NI, Serrano M, Pérez- Dueñas B, Pineda M, Campistol J, et al. Inborn errors of metabolism and motor disturbances in children. J Inherit Metab Dis 2009;32:618–629.

[14] Eggink H, Kuiper A, Peall KJ, Contarino MF, Bosch AM, Post B, et al. Rare inborn errors of metabolism with movement disorders: a case study to evaluate the impact upon quality of life and adaptive functioning. Orphanet J Rare Dis 2014;9:177.

[15] Bertram KL, Williams DR. Diagnosis of dystonic syndromes – a new eightquestion approach. Nat Rev Neurol 2012;8:275–283.

[16] Shapiro BS, Cohen DE, Covelman KW, Howe CJ, Scott SM. Experience of an interdisciplinary pediatric pain service. Pediatrics 1991;88:1226–1232.

[17] Bent N, Tennant T, Swift T, Posnett J, Scuffham P, Chamberlain MA, et al. Team approach versus ad hoc health services for young people with physical disabilities: a retrospective cohort study.

Lancet 2002;360:1280–1286.

[18] Ladner TR, Mahdi J, Attia A, Froehler MT, Le TM, Lorinc AN, et al. A multispecialty pediatric neurovascular conference: a model for interdisciplinary management of complex disease. Pediatric Neurol 2016;52:165–173.

[19] Geerlings R, Aldenkamp AP, Gottmer-Welschen LM, van Staa AL, de Louw AJ. Long-term effects of a multidisciplinary transition intervention from paediatric to adult care in patients with epilepsy.

Seizure 2016;38:46–53.

[20] Paganoni S, Nicholson K, Leigh F, Swoboda K, Chad D, Drake K, et al. Developing multidisciplinary clinics for neuromuscular care and research. Muscle Nerve 2017;56(5):848–858.

[21] Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry (Edgmont) 2007;4:28–37.

[22] Zutt R, van Egmond ME, Elting JW, van Laar PJ,

Brouwer OF, Sival DA, et al. A novel diagnostic

approach to patients with myoclonus. Nat Rev

Neurol 2015;12:687–697.

[23] Egmond ME, Elting JWJ, Kuiper A, Zutt R, Heineman KR, Brouwer OF, et al. Myoclonus in childhood-onset neurogenetic disorders: The importance of early identification and treatment.

Eur J Paediatr Neurol 2015;19:726–729.

[24] Liow NY, Gimeno H, Lumsden D, Marianczak J, Kaminska M, Tomlin S, et al. Gabapentin can significantly improve dystonia severity and quality of life in children. Eur J Paediatr Neurol 2016;20:100–107.

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INDUCED CHOREA IN A GIRL WITH DOWN SYNDROME

HENDRIEKJE EGGINK ANOUK KUIPER

CATHÉRINE C.S. DELNOOZ DEBORAH A. SIVAL

TOM J. DE KONING

MARINA A.J. TIJSSEN

ABSTRACT

Background: Isolated (sub)acute chorea in young patients is a relatively rare movement disorder with a broad differential diagnosis, including drug-induced, post-infectious, auto- immunological and vascular etiologies.

Case presentation: We describe an adolescent girl with Down’s syndrome presenting with chorea due to oral contraceptive usage. After discontinuation of the oral contracep- tive it took several months before the symptoms disappeared. Although generally well recognised, it is important to realise this delayed effect. Rejecting the diagnosis too soon may lead to unnecessary treatment for other possible underlying etiologies, especially in patients with Down Syndrome, known to be vulnerable for autoimmune disorders.

Conclusion: We plead for discontinuation for at least three months before exclusion of

oral contraceptives as cause of chorea.

INTRODUCTION

Isolated chorea is a relatively rare movement disorder in young patients, presenting with continuous, non-patterned, involuntary movements which are unpredictable in rate and direction.[1] In addition to post-streptococcal, autoimmune, encephalopathic and vascular etiologies, drug-induced chorea (e.g. dopamine agonists, neuroleptics, anticonvulsants) form an important, reversible group.[1,2] In adolescents, the use of oral contraceptives (OCP) accounts for another possible cause of chorea.[3,4] Although OCP-induced chorea is generally well-recognized, it may take several months for the symptoms to disappear after cessation. To illustrate this, we report on an adolescent girl with Down Syndrome.

CLINICAL PRESENTATION

A 19-year-old adolescent with Down Syndrome was referred to our tertiary outpatient clinic with subacute generalized chorea (see video 1)*. Her medical history revealed recurrent throat and ear infections and a negative family history for involuntary movements. The chorea had started acutely two years earlier, initially in her left arm and leg with gener- alization to the other side of her body in the subsequent six months. The severity of the symptoms fluctuated in the first year and remained stable after that. Due to the involuntary movements, she had marked difficulties with fine motor skills, such as writing and using cutlery. In addition, her parents reported severe fatigue, loss of appetite and behavioral changes in the form of increased irritability.

Symptoms manifested three months after initiation of OCP for irregular menstruations.

Cessation of OCP for one month had not led to improvement of the symptoms in the past.

Therefore, a broad range of diagnostic tests was conducted. Throat cultures showed no abnormalities and laboratory tests detected no raised anti-streptolysin-O titre or abnormal auto-antibodies (thyroxine-binding globulin, antihuman thyroglobulin, thyrotropin binding inhibiting immunoglobulins, anti-thyroid peroxidase, anti-cardiolipin antibodies, anti-double stranded DNA, lupus anticoagulant, anti-transglutaminase antibodies, anti-gliadin IgG, antiglutamic acid decarboxylase 65, anti-basal ganglia antibodies, anti-DNAse B and anti- N-methyl-D-aspartate antibodies). Magnetic resonance imaging of the brain was normal, especially no signs suggestive of recent or old ischemic events were found. Due to the possible anamnestic association with throat infections, she had been treated with 1 mg/

kg prednisolone twice for several weeks and pheneticillin for three months for Sydenham’s chorea (SC). This only led to a temporal reduction of two weeks. Treatment with intravenous

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immunoglobulins was considered, but her treating physician decided to first refer her to our tertiary clinic for advice on a possible etiology.

When visiting our clinic, we decided to stop the OCP for several months because of the strong relationship between initiation of OCP and onset of chorea. Follow-up on a monthly basis revealed reduction after three months of cessation and almost complete disappearance of the involuntary movements after four months (see video 2)*. Moreover, parents reported she regained her appetite and energy and did not show any irritable behavior anymore. She was referred to a gynaecologist for further treatment of her irregular menstruations.

DISCUSSION

With a significant percentage of adolescent girls using OCP for contraception or other purposes, OCP-induced chorea is an important cause to consider. This is regardless of the type of OCP.[3-5] Both unilateral and bilateral symptoms have been described.[3] The close relation in time appears to be the strongest diagnostic clue, as onset of symptoms is usually shortly after initiation of OCP.[3]

Although the pathophysiology remains unknown, several hormonal and (auto)immunolog-

ical theories have been proposed. Oestrogens have been repeatedly considered as having

a complex, possibly enhancing effect on the dopaminergic pathways.[6,7] Immunological

theories are supported by the association of OCP-induced chorea with SC or an autoim-

mune disease (systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome

(APS), anti-basal ganglia antibodies).[3] To our knowledge, this is the first report of

OCP-induced chorea in a Down Syndrome patient. Down Syndrome is associated with

a higher incidence of autoimmune diseases, possibly leading to a higher vulnerability for

OCP-induced chorea.[8] Down Syndrome patients have a 26-fold higher prevalence of the

moyamoya syndrome in comparison to the general population.[9] Moyamoya syndrome

is a rare cerebrovascular occlusive disease, resulting in a presentation with (transient)

cerebral ischaemia. The classical clinical manifestation include paralysis, headaches or

convulsions, but there is one report of a Down Syndrome patient presenting with chorea

as initial sign.[10] Moyamoya syndrome should be considered in acute chorea, especially

in a Down Syndrome patient, although in our patient the likelihood was minimized by a

normal MRI scan of the brain.

Most importantly, we would like to underscore that it may require patience for both patient and doctor to confirm the diagnosis of OCP-induced chorea. This case report shows that it sometimes takes several months before symptoms diminish after cessation. The differen- tial diagnosis of (sub)acute chorea in young patients is broad, including serious causes or etiologies requiring specific treatment, for instance SLE, APS, SC or moyamoya syndrome.

It seems therefore rational to perform additional investigations while awaiting the effect of OCP cessation. However, rejecting the diagnosis too soon may lead to unnecessary treatments for other causes as in our patient. We emphasise that OCP should be discon- tinued for a minimum of three months before excluding this benign diagnosis of chorea.

* Videos can be found at http://dx.doi.org/10.1016/j.ejpn.2016.03.004.

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REFERENCES

[1] Singer HS, Mink JW, Gilbert DL, Jankovic J.

Movement disorders in childhood. Saunders Elsevier 2010;76.

[2] Kirkham FJ, Haywood P, Kashyape P, Borbone J, Lording A, Pryde K, et al. Movement disorder emergencies in childhood. Eur J Paediatr Neurol 2011;15:390-404.

[3] Miranda M, Cardoso F, Giovannoni G, Church A. Oral contraceptives Induced chorea: another associated with anti-basalganglia antibodies. J Neurol Neurosurg Psychiatry 2004;75:327-328.

[4] Vela L, Sfakianakis GN, Heros D, Koller W, Singer C. Chorea and contraceptives: case report with PET study and review of the literature. Mov Disord 2004;19(3):349-352.

[5] Finer LB, Philbin JM. Sexual initiation, contraceptive use, and pregnancy among young adolescents. Pediatrics 2013;131(5):886-891.

[6] Nausieda PA, Koller WC, Weiner WJ, Klawans HL. Chorea induced by oral contraceptives.

Neurology 1979;29:1605-1609.

[7] Cardoso F. Chorea gravidarum. Arch Neurol 2002;59:868-870.

[8] Gimenez-Barcons M, Caster as A, Armengol Mdel P, Porta E, Correa PA, Marin A, et al.

Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J Immunol 2014;193(8):3872-3879.

[9] Kainth DS, Chaudhry SA, Kainth HS, Suri FK, Qureshi AI. Prevalence and characteristics of concurrent down syndrome in patients with moyamoya disease. Neurosurgery 2013;72:210-215.

[10] Takanashi J, Sugita K, Honda A, Niimi H.

Moyamoya syndrome in a patients with Down

syndrome presenting with chorea. Pediatr Neurol

1993;9(5):396-398.

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BY A β-ACTIN GENE MUTATION AND

RESPONSE TO DEEP BRAIN STIMULATION

HENDRIEKJE EGGINK MARTJE E. VAN EGMOND

CORIEN C. VERSCHUUREN-BEMELMANS MARLEEN C. SCHÖNHERR

TOM J. DE KONING

D.L. MARINUS OTERDOOM J. MARC C. VAN DIJK

MARINA A.J. TIJSSEN