Medication use in childhood dystonia

Accepted Manuscript Medication Use in Childhood Dystonia Daniel E. Lumsden, Margaret Kaminska, Stephen Tomlin, Jean-Pierre Lin PII:

S1090-3798(16)00036-2

DOI:

10.1016/j.ejpn.2016.02.003

Reference:

YEJPN 2012

To appear in:

European Journal of Paediatric Neurology

Received Date: 1 December 2015 Revised Date:

5 January 2016

Accepted Date: 8 February 2016

Please cite this article as: Lumsden DE, Kaminska M, Tomlin S, Lin J-P, Medication Use in Childhood Dystonia, European Journal of Paediatric Neurology (2016), doi: 10.1016/j.ejpn.2016.02.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title:

Medication Use in Childhood Dystonia

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Authors

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Daniel E Lumsdena*, Margaret Kaminskaa, Stephen Tomlinb, Jean-Pierre Lina

a

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Complex Motor Disorder Service, Evelina Children’s Hospital, Guy’s and St

Thomas’ NHS Foundation Trust, London b

Paediatric Pharmacy, Evelina Children’s Hospital, Guy’s and St Thomas’

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NHS Foundation Trust, London

*

Corresponding Author:

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[email protected]

Complex Motor Disorder Service, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, Westminister Bridge Road, London SE1 7EH

Tel: +44 (0) 207 188 7188 Ext 8533 Fax: + 44 (0) 207 188 0851

ACCEPTED MANUSCRIPT Running Title: Medication Use in Childhood Dystonia

Number of references: 19

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Key Words: dystonia, medication, complications, childhood

Number of Figures: 1

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Number of Tables: 3

Abstract

ACCEPTED MANUSCRIPT Background Data around current prescription practices in childhood dystonia is limited. Medication use may be limited by side effects, the incidence of which is

aimed to:

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uncertain. For a large cohort assessed by our supra-regional service we

Review medications used at the point of referral

ii)

Determine the prevalence of adverse drug responses (ADR) resulting in discontinuation of drug use

iii)

Identify clinical risk factors for ADR.

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Methods:

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i)

Case note review of 278 children with dystonia referred to our service. Data collected on medications, ADR, dystonia aetiology, Gross Motor Function Classification System (GMFCS) level and motor phenotype (pure

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dystonia/mixed dystonia-spasticity). Logistic regression analysis was used to

Results:

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identify risk factors for ADR.

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At referral 82/278 (29.4%) children were taking no anti-dystonic medication. In the remainder the median number of anti-dystonic medications was 2 (range 1-5). Medications use increased with worsening GMFCS level. The commonest drugs used were baclofen (118/278: 42.4%), trihexyphenidyl (98/278: 35.2%), L-Dopa (57/278: 20.5%) and diazepam (53/278: 19%). Choice of medication appeared to be influenced by dystonia aetiology.

ACCEPTED MANUSCRIPT ADR had been experienced by 171/278 (61.5%) of children. The commonest drugs responsible for ADR were trihexyphenidyl (90/171: 52.3%), baclofen (43/171: 25.1%) and L-Dopa (26/171: 15.2%). Binary logistic regression

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demonstrated no clinical risk factors for ADR.

Conclusions:

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ADR is commonly experienced by children with dystonia, regardless of dystonia severity or aetiology. A wide variation in drug management of

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dystonia was identified. Collectively these findings highlight the need for a rational approach to the pharmacological management of dystonia in

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childhood.

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Introduction:

Dystonia in childhood may be defined as “A movement disorder in which

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involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both.”1 Childhood dystonia is frequently secondary in aetiology, may be associated with spasticity 2, 3 and

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expressed on the background of a maturing central nervous system, potentially altering the response to pharmacological agents4, 5. Childhood

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dystonia is unlikely to remit spontaneously3, 6 and negatively affects a child’s life including activity and participation 7.

The evidence-base for pharmacological managements of dystonia is limited, with the exception of botulinum toxin and trihexyphenidyl8. Recently guidelines for the treatment of childhood dystonia are based largely upon expert opinion4, 9.

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Although clinicians recognize that the use of the common anti-dystonic agents maybe limited by adverse drug reactions (ADR), the frequency of these reactions remains to be established. A better understanding of ADR is

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required to counsel parents and carers on medication choices. We aimed for

centre to:

Review medications used at referral

ii)

Determine the prevalence of ADR

iii)

Identify clinical risk factors for ADR.

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i)

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a cohort of children with dystonic movement disorders referred to our tertiary

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Methods

Data were collected retrospectively from the clinical notes of Children and Young People (CAYP) referred to the Complex Motor Disorders Service

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between July 2005 and January 2012. Clinical notes were available for

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294/315 (93.3%) CAYP, with 16 subsequently excluded (15 having a pure spastic phenotype on clinical examination and 1 insufficient information documented on medication use at baseline). This left 278 CAYP for study. Demographic features of children included in this cohort have previously been reported3. A pro-forma procedure was used to record patient details at initial contact to our service, including age at presentation, aetiological classification of dystonia6, presence of spasticity, functional classification as measured by Gross Motor Function Classification System (GMFCS)10,duration of dystonia,

ACCEPTED MANUSCRIPT proportion of life lived with dystonia (calculated by normalizing duration of dystonia to age) and source of referral. Regular maintenance medication use at presentation, previous history of medication use, and the occurrence of ADR. In case ADR had occurred, it

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was recorded to what medication ADR had been attributed. ADR was defined as an adverse side effect to the medication sufficiently severe to result in

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discontinuation of the medication.

Statistical analysis was performed using SPSS version 17.0 (SPSS Inc.,

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Chicago, IL, USA). Differences in the number of medications used across aetiological classifications and functional level was measured using the Kruskal-Wallis test. Differences in the occurrence of ADR between aetiological classifications or functional level were assed by Chi-squared

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testing. In both cases a P-value <0.05 was considered statistically significant. Ordinal regression with a logit link function was used to explore which factors independently related to number of medications at presentation. Binary

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logistic regression was performed to explore possible factors relating to ADR.

Results:

Median age at presentation was 9.75 years (6.6 to 13.0, 25th-75th centile), with a median duration of dystonia of 7.75 years (4.6 to 10.9, 25th-75th centile). The median proportion of life lived with dystonia was 0.95 (0.80 to 0.99, 25th50th centile). Dystonia was classified as primary for 30/278 (10.8%), Secondary 200/278

ACCEPTED MANUSCRIPT (71.9%), Heredodegenerative 29/278 (10.4%) and Primary-Plus 19/278 (6.8%). GMFCS levels were I=26, II=26, III=14, IV=40 and V=172. For 79/278 (28.4%) of the cohort spasticity was found coincident with dystonia.

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The commonest source of referral (123/278) was tertiary paediatric

neurologists, followed by Consultants in Paediatric Neurodisability (78/278).

Remaining referrals were received from General Paediatric Services (41/278),

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Community Paediatric Services (34/278), with 1 case referred by an

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Orthopaedic Surgeon and 1 further case referred from General Practice.

A total of 18 different anti-dystonic medications were identified at the point of referral. Across the cohort as a whole, the 3 commonest anti-dystonic medications were baclofen (118/278, 42.5%), trihexyphenidyl (98/278, 35.3%)

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and L-DOPA (57/278, 20.5%) (Table 1, Figure 1). The profile of medication use differed by dystonia aetiology. In the secondary and heredodegenerative group the commonest 2 anti-dystonic medications used were baclofen and

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trihexyphenidyl, in the primary group L-DOPA followed by trihexyphenidyl,

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with more limited medication use in the Primary-Plus group. The number of anti-dystonic medications varied across the group from 0-5 (median 2). No anti-dystonic medication was in used for 82/278 (29.5%) CAYP. A greater number of anti-dystonic medications were used by those CAYP with lower function, i.e. higher GMFCS level, (Chi-squared P<0.001) (Table 2). Medication use also differed by aetiology, with greater medication use in the Secondary and Heredodegenerative dystonia group (Kruskal-Wallis test, P=001). The number of medications used did not differ between those

ACCEPTED MANUSCRIPT children with or without spasticity (Mann-Whitney U-test, P=0.241). Baclofen use was higher in CAYP with co-incident spasticity (50/79 or 63% with spasticity, 68/179 or 37.9% without spasticity, Chi-squared test P<0.001)).

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ADR had been experienced by 171/278 (61.5%) CAYP, caused by 11

different medications. For the cohort as a whole, and regardless of aetiology, the drug most commonly causing ADR was trihexyphenidyl. Baclofen was the

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drug next most commonly reported as causing ADR, except in the primary

dystonia and primary-plus dystonia groups, where L-DOPA and clonazepam

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respectively were the second most common drugs. Experience of ADR did not differ by dystonia aetiological (Chi-squared, P=0.302) (Table 3), GMFCS level (Chi-squared, P=0.079), Proportion of life lived with dystonia (Kruskal-Wallis, P=0.42) or presence/absence of co-incident spasticity (Chi-squared, P=0.28).

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Logistic regression found no relationship between ADR any of the potential

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Discussion

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explanatory variables.

In a large cohort of children referred to our specialist Complex Motor Disorders Service a wide range of medications were used in the management of dystonia, with a high frequency of previous ADR. The commonest medications used in this cohort were baclofen and trihexyphenidyl. Baclofen is a gamma-aminobutyric acid (GABA) B receptor agonist, used in the management of most forms of high tone. Evidence to support the use of oral baclofen in childhood dystonia is limited, despite widespread use4. Few

ACCEPTED MANUSCRIPT studies of oral therapy are available, limited to retrospective reports now several years old11-13. In our cohort, the proportion of CAYP receiving baclofen was significantly higher in children with co-incident spasticity, though

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in all cases dystonia was considered the predominant symptom.

A more robust evidence-base supports the use of trihexyphenidyl in the

management of childhood dystonia4, 8. Trihexyphenidyl is an anti-cholinergic

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agent, with evidence to suggest that best results are seen within 5 years of onset of primary dystonia14. Trihexyphenidyl also appears to offer more

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benefits and is better tolerated when initiated earlier in life for children with cerebral palsy15.

L-DOPA use was used commonly in our cohort, particularly in the primary

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dystonia group. Some authors have suggested L-DOPA as first line therapy for dystonia management in childhood, given the dramatic responses which may be seen in patients with Dopa-Responsive dystonia4. Less dramatic

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responses may be seen with other forms of dystonia, or even a worsening of

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symptoms, e.g. as appears to occur in Lesch-Nyhan Disease16.

At the time of referral ~2/3 children had experienced ADR to medications prescribed to reduce dystonia. Experience of ADR did not appear to relate to dystonia severity, aetiology or presence/absence of spasticity. No particular risk factor was identified.

In the absence of a clear evidence-base it is not possible to provide

ACCEPTED MANUSCRIPT prescriptive guidance for medication use in childhood dystonia. For most children with dystonia, anti-dystonic medications are unlikely to fully abolish abnormal muscle contractions. Decisions regarding medication must therefore be made at the individual level on the basis of functional goals agreed by

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carers and clinicians. Use of multiple medications places significant burden to carers with respect to the administration of these medications, and also the

attendant risks of polypharmacy. It is notable that 60 children where receiving

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3 or more anti-dystonic medications at the time of referral to our service. This higher number of medications had not resulted in sufficient dystonia control to

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prevent referral for consideration for potential neurosurgical intervention. In recent years there has been a considerable rationalizing of the pharmacological management of epilepsy, another common neurological condition seen in childhood. Evidenced-based guidelines exist for epilepsy in

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childhood, covering when to initiate medication, choice of first and subsequent medications and the limits to the number of antiepileptic medications a child should be prescribed concurrently17. It is unlikely that this level of

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sophistication will be achieved for childhood dystonia. One particularly

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question is how many medications should be used at a given time? The restriction to 2-3 medications suggested in the management of epilepsy are based on the observation that additive benefits are not seen with additional medications in terms of significantly reducing seizure frequency. Dystonia differs from epilepsy in that the main symptom is fluctuating level of abnormal tone and/or movement, rather then discrete episodic events in the majority of cases. Additional medications may be justified if even a small amount of reduction of discomfort is achieved. For most children with childhood dystonia,

ACCEPTED MANUSCRIPT exempting those with Dopa-Responsive Dystonia, anti-dystonic medications are unlikely to fully abolish abnormal muscle contractions. Decisions regarding medication must therefore be made at the individual level on the basis of functional goals agreed by carers and clinicians. Discussion is

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required by clinicians managing children with complex dystonia regarding the benefits of additional pharmacological intervention if dystonia is not controlled by 1-2 medications. Increasing medication use exposes patients to greater

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risks of side effects, and also of more drug interactions.

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Our current study has a number of limitations, related to the retrospective collection of data. Whilst data was available for medication use at the time of referral, comprehensive records of the order and timing of introduction of previous medications was not available for sufficient cases to allow further

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exploration. Whilst data was available as to whether previous ADR had occurred, details of ADR were limited, and it was not possible to explore the types of reactions experienced. When documentation on the nature of the

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ADR was available, it most frequently appeared to relate to the expected side

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effects of the medication taken, e.g. anti-muscarinic effects with trihexyphenidyl, drowsiness and clouded thinking with benzodiazepines. Similarly, details of the timing/age of introduction of drugs provoking ADR, polypharmacy at the time of introduction or dosage details at the time could not be commented on. It was not possible to measure the harm caused by ADR. Furthermore, as a tertiary referral centre, our cohort represents a biased population (reflected in the sources of referral to our service), likely to have a more severe and/or difficult to manage dystonia than may be seen in the

ACCEPTED MANUSCRIPT general population, such case-complexity in part prompting referral.

A pragmatic definition of ADR was used. CAYP may, however, have experienced adverse responses to medication which were not sufficient to

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result in the discontinuation of medication, though still were important to the both patient and family/carers. We may have consequently underestimated

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the true incidence of ADR.

We have used GMFCS level as a measure of motor impairment in this study,

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and as a proxy measure of dystonia severity, in place of a more dystonia specific scale, e.g. the BFMDRS18. We have, however, recently demonstrated a strong correlation between BFMDRS and GMFCS score for a mixed cohort

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of CAYP with dystonial19.

In conclusion, considerable heterogeneity exists in the pharmacological management of childhood dystonia. Previous ADR was commonly seen in our

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cohort, and children appear at equal risk, regardless of dystonia severity or

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aetiology. Further studies and a rational approach to pharmacological management of childhood dystonia are required, to enable informed decisions to be made by clinicians in partnership with patients and carers. Over the last decade, considerable progress has been made towards understanding the role of neurosurgical interventions in the management of childhood dystonia. It is important in the next decade that robust exploration of the role of existing and emerging medications is not abandoned, as these will remain the mainstay of management for the majority of CAYP with dystonia.

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Funding/Competing Interests: DEL has bee partly supported by a Dystonia Society UK grant 01/2011. J-PL has held grants from the Guy's and St

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Thomas Charity (grant G060708), the Dystonia Society UK (grant 01/2011 and 07/2013) and Action Medical Research (grant GN2097). J-PL, DEL and MK have received unrestricted educational support from Medtronic Ltd. J-PL

has acted as a consultant for Medtronic Ltd. ST reports no funding or conflicts

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of interest in relation to this work.

Financial Disclosures for the Previous 12 months

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All authors have no disclosures to report

Figure 1:

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Figure Legends

Bar chart summarizing frequency of anti-dystonic medication use and frequency of previous Adverse Drug Reaction (ADR) to each medication at

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the time of referral to our service. Numbers indicated numbers of children and young people (CAYP) reporting use of medication (blue) or previous ADR with

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each medication (red).

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References

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1. Sanger TD, Chen D, Fehlings DL, et al. Definition and classification of hyperkinetic movements in childhood. Mov Disord 2010;25(11):1538-1549. 2. Roubertie A, Rivier F, Humbertclaude V, et al. [The varied etiologies of childhood-onset dystonia]. Rev Neurol (Paris) 2002;158(4):413-424. 3. Lin JP, Lumsden DE, Gimeno H, Kaminska M. The impact and prognosis for dystonia in childhood including dystonic cerebral palsy: a clinical and demographic tertiary cohort study. J Neurol Neurosurg Psychiatry 2014;85(11):1239-1244. 4. Roubertie A, Mariani LL, Fernandez-Alvarez E, Doummar D, Roze E. Treatment for dystonia in childhood. Eur J Neurol 2012. 5. Mink JW. Special concerns in defining, studying, and treating dystonia in children. Mov Disord 2013;28(7):921-925. 6. Bressman SB. Dystonia genotypes, phenotypes, and classification. Adv Neurol 2004;94:101-107. 7. Gimeno H, Gordon A, Tustin K, Lin JP. Functional priorities in daily life for children and young people with dystonic movement disorders and their families. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 2012. 8. Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and other cure options. Eur J Neurol 2004;11(6):361-370. 9. Tickner N, Apps JR, Keady S, Sutcliffe AG. An overview of drug therapies used in the treatment of dystonia and spasticity in children. Arch Dis Child Educ Pract Ed 2012;97(6):230-235. 10. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39(4):214-223. 11. Greene PE, Fahn S. Baclofen in the treatment of idiopathic dystonia in children. Mov Disord 1992;7(1):48-52. 12. Greene P. Baclofen in the treatment of dystonia. Clin Neuropharmacol 1992;15(4):276-288.

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13. Anca MH, Zaccai TF, Badarna S, Lozano AM, Lang AE, Giladi N. Natural history of Oppenheim's dystonia (DYT1) in Israel. J Child Neurol 2003;18(5):325-330. 14. Burke RE, Fahn S. Double-blind evaluation of trihexyphenidyl in dystonia. Adv Neurol 1983;37:189-192. 15. Hoon AH, Jr., Freese PO, Reinhardt EM, et al. Age-dependent effects of trihexyphenidyl in extrapyramidal cerebral palsy. Pediatr Neurol 2001;25(1):5558. 16. Visser JE, Schretlen DJ, Bloem BR, Jinnah HA. Levodopa is not a useful treatment for Lesch-Nyhan disease. Mov Disord 2011;26(4):746-749. 17. Nunes VD, Sawyer L, Neilson J, Sarri G, Cross JH. Diagnosis and management of the epilepsies in adults and children: summary of updated NICE guidance. BMJ 2012;344:e281. 18. Burke RE, Fahn S, Marsden CD, Bressman SB, Moskowitz C, Friedman J. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 1985;35(1):73-77. 19. Elze MC, Gimeno, H., Tustin, K., Baker, L., Lumsden, D.E., Hutton, J.L., Lin, JP. Burke-Fahn-Marsden dystonia severity, Gross Motor, Manual Ability and Communication Function Classification Scales in childhood hyperkinetic movement disorders including cerebral palsy: a Rosetta Stone study. Dev Med Child Neurol 2015;In Press.

ACCEPTED MANUSCRIPT Table 1: Medications Used at the Point of Referral

Medication

Number of Cases Receiving Primary

Secondary Heredodegenerati

Primary-Plus

Cohort

Dystonia

Dystonia

ve Dystonia

Dystonia

(N=278)

(N=30)

(N=200)

(N=29)

(N=19)

118

6

97

13

1

Trihexyphenidyl 98

9

76

11

Chloral Hydrate

26

4

17

5

Diazepam

53

2

39

L-DOPA

57

11

7

Nitrazepam

9

0

Clonidine

9

1

Tetrabenazine

6

3

Triclofos

8

0

Tizanidine

3

0

Clonazepam

16

Clobazam

7

Midazolam

4

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3 1 1

3

2

14

2

0

7

1

0

1

2

0

6

2

0

0

2

0

0

14

2

1

0

6

1

0

1

3

0

0

Levetiracetam

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9

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Baclofen

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Total

0

2

0

0

Carbamazepine 3

0

1

1

0

Pramipexole

1

0

1

0

0

Dantrolene

4

0

2

1

0

Amantidine

1

0

0

0

1

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2

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Table 2: Number of medications used by functional level and by Dystonia aetiology

0

1

2

3

1

16

8

2

0

2

10

6

9

1

3

6

7

0

1

4

18

12

6

5

32

42

44

Primary

8

Secondary

54

Heredodegenerative 6 14

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0

0

0

0

0

0

3

1

0

33

18

3

11

6

4

1

0

53

50

30

11

2

8

5

3

7

0

3

0

1

0

1

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Primary-Plus

5

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Aetiology

4

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GMFCS

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Number of Anti-dystonic Medications

ACCEPTED MANUSCRIPT Table 3: Medications Causing Adverse Drug Reactions (ADRs)

Medication

Number of Cases Reporting previous aDR Primary

Secondary Heredodegenerati

Primary-Plus

Cohort

Dystonia

Dystonia

ve Dystonia

Dystonia

(N=278)

(N=30)

(N=200)

(N=29)

(N=19)

43

4

33

4

2

Trihexyphenidyl 90

13

62

11

Diazepam

4

1

3

0

L-DOPA

26

5

16

3

Nitrazepam

2

0

2

Clonidine

2

0

1

Tetrabenazine

5

1

Tizanidine

2

0

Clonazepam

6

1

Levetiracetam

3

1

Dantrolene

1

0

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4

0

2

0

0

0

1

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Baclofen

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Total

4

0

0

2

0

0

2

0

3

2

0

0

1

0

0

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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Highlights

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Anti-dystonic medication use is reported in a cohort of 278 children and young people with dystonia

and young people with dystonia •

The commonest drugs used in the treatment of dystonia were baclofen (118/278) and trihexyphenidyl

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Choice of medication appeared to be influenced by dystonia aetiology

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and co-incidence of spasticity

No clinical risk factors for adverse drug response were identified

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Adverse drug responses had been experienced by 171/278 children

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•