Clinical trial NCT03857451: Treatment of Gait Disorders in Children With Dravet Syndrome
Official title: Treatment of Gait Disorders in Children With Dravet Syndrome
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Dravet Syndrome
Severe Myoclonic Epilepsy of Infancy
Keywords: Dravet syndrome
severe myoclonic epilepsy of infancy
intellectual disabilities
movement disorders
gait
biomechanics
Lead sponsor: Universiteit Antwerpen
Sponsor class: OTHER
Collaborators: name: University Hospital, Antwerp
name: KU Leuven
name: Universitaire Ziekenhuizen KU Leuven
name: Research Foundation Flanders
First posted: 2019-02-28
Enrollment: 50
Sex: ALL
Minimum age (years): 3
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All children and adolescents with Dravet syndrome living in Flanders and the Netherlands

Brief summary: Dravet syndrome is a severe infantile onset epilepsy syndrome with a prevalence of 1/15.000 to 1/30.000. An infant with an apparently normal development presents around 6 months of age with a convulsive status epilepticus. Seizures can be triggered by fever, illness or vaccination. Because of its drug-resistance, in the past, most attention has been paid to seizure control. However, developmental and behavioural problems also become a serious concern during the second year of life. Outcome is poor, with intellectual disability and ongoing seizures. On the long term, the deterioration in gait is very characteristic. A crouch gait pattern develops that largely impacts the daily life functioning. Most children maintain the ability to walk around the house, but for longer distances they must rely on wheelchair use, which further negatively affects their mobility. Gait analysis, when combined with physical examination, provides quantitative information to guide treatment of gait disorders and assess its outcome. The goal of this project is the development of a clinical decision framework based upon 3D gait analysis to diagnose and treat mobility problems in children with Dravet syndrome. Two major university hospitals in Flanders (UZA and UZ Leuven) are partners in this project. The parent organisation "Stichting Dravetsyndroom Nederland/Vlaanderen" will also participate, as intermediate partner to facilitate contacts between all parties being patients and their caregivers, clinical gait labs and treating physicians.

Detailed description: The problem under investigation is the reduced functional mobility of patients with Dravet syndrome resulting from a crouch gait pattern. The solution, proposed in this research project, is the development of a decision framework based upon clinical gait analysis to identify the main problems and subsequently use this knowledge to select the appropriate treatment for the observed gait disorder.

Dravet syndrome is a severe infantile onset epilepsy syndrome with a prevalence of 1/15.000 to 1/30.000. In 80% of the cases it is associated with mutations in the gene encoding the alpha-subunit of the sodium channel SCN1A that is expressed in the frontal lobe, basal ganglia and cerebellum. An infant with an apparently normal development presents around 6 months of age with a convulsive status epilepticus. Seizures can be triggered by fever, illness or vaccination. Because of its drug-resistance, in the past, most attention has been paid to seizure control. However, developmental and behavioural problems also become a serious concern during the second year of life. Outcome is poor, with intellectual disability and ongoing seizures. On the long term, the deterioration in gait is very characteristic. A crouch gait pattern develops that largely impacts the daily life functioning. Most children maintain the ability to walk around the house, but for longer distances they must rely on wheel-chair use, which further negatively affects their mobility. In general, Dravet syndrome is a very severe epileptic encephalopathy with a negative impact on the health and quality of life of both the patients and their caregivers.

Crouch gait refers to a sustained flexion of the hip, knee and ankle throughout the stance phase of gait. This is a very inefficient walking pattern with increased energy expenditure. Crouch gait is also observed in children with cerebral palsy (CP). In this population, ankle-foot orthoses (AFOs) show effective in resolving the underlying biomechanical deviations and improving functional mobility. Similar benefits can be expected in children with Dravet. However, before AFOs can be routinely applied in clinical practice, more research is necessary to identify the cause of crouch gait in patients with Dravet syndrome. The hypothesis was formulated that the crouch pattern in children with Dravet might develop as a consequence of lever arm dysfunctions in the lower limbs resulting from skeletal malalignment in combination with muscle weakness. The first objective in this study is to confirm this hypothesis. The second objective is to determine the effectiveness of AFOs in relieving the biomechanical problems, thereby reducing crouch gait and improving functional mobility. Pilot work in 10 children show primary problems situated around the ankle joint, providing proof of concept for the use of AFOs. In the first phase of the project, two research questions will be addressed.

1. Which biomechanical problems contribute to the crouch gait in children with Dravet syndrome?
2. Can AFO improve musculoskeletal alignment and reduce knee flexion in children with Dravet syndrome?

Gait analysis, when combined with physical examination, provides quantitative information to guide treatment of gait disorders and assess its outcome. At the University of Antwerp a state-of-the-art gait lab, the Multidisciplinary Motor Center Antwerp (M²OCEAN) was established in 2010 by means of a Hercules grant type 2 (AUHA/09/006). Since the Dravet consultation follows 80% of the children with Dravet syndrome in Flanders, the University of Antwerp is best placed to incorporate clinical gait analysis in the diagnostic scheme of these children. However, as a result of the mental retardation observed in these children, lengthy and time consuming protocols are a problem that can negatively affect the attainability of a good measurement. The mental retardation also becomes a problem when the children do not understand the instructions during physical examination. The challenge is to develop adequate protocols for both data collection and processing that specifically target the problems faced in this population. These protocols need to be feasible and understandable in children with low intelligence quotient. Information from the first phase of this project serves as input for this second phase that aims at answering the following questions:

1. Which protocols for clinical gait analysis are most suitable in children with Dravet syndrome?
2. What are the mobility benefits of applying the selected protocols for 3D gait analysis in clinical practice for children with Dravet syndrome? This project consists of 2 phases. The first phase (month 1 - 36) is directed at scientific research to validate the proof of concept for treatment of crouch gait in children with Dravet syndrome. The second phase (month 12 - 48) is dedicated to methodological developments that will enhance the routinely application of clinical gait analysis in the diagnostic scheme of children with Dravet syndrome and will provide proof that clinical gait analysis is a useful tool to identify main gait problems and set appropriate treatment goals in children with Dravet syndrome.

The overall design of choice for the first phase is a mixed longitudinal design. A cohort of children with Dravet syndrome will be subjected to follow-up for a period of 3 years annually receiving a physical examination and instrumented 3D clinical gait analyses (kinematics, kinetics, EMG). Two age-matched control groups will be retrospectively included. Control groups consist of a sample of age-matched typically developing children and a sample of age-matched children with cerebral palsy walking without and with AFO.

The work is organised into four work packages. The first work package (WP1) is dedicated to data collection and comprises the longitudinal follow up of the cohort of children with Dravet syndrome and the retrospective data collection in the control groups. Data will be collected throughout the first 3 years of the project. Case - control studies related to scientific goals 1 and 2 are organised in the second work package (WP2) whereby WP2.1 focusses on the identification of the biomechanical factors that contribute to the development of crouch gait and WP2.2 is directed at providing evidence that AFO can improve gait. The third work package (WP3) occurs synchronously in time and is related to the third research goal aiming at providing evidence for the benefit of including clinical gait analysis in the diagnostic scheme of children with Dravet syndrome. The last work package (WP4), the protocol selection and optimization, can start when the main biomechanical problems are identified in WP2.1.

Eligibility criteria: Inclusion Criteria:

* diagnosed with Dravet syndrome according to the criteria of Ceulemans and Cras (2004)
* aged minimum 3 years and maximum 25 years at inclusion
* having minimum 1 year of walking experience

Exclusion Criteria:

* severe epileptic seizure (status epilepticus or tonic-clonic insult over 3 min) within the 24 hours before the assessment
* insufficient cooperation to perform 3D gait analysis
* comorbidities of other neurological and/or orthopedic disorders not linked to Dravet syndrome

Primary outcomes:
measure: Lower limb kinematics during walking in degrees
timeFrame: baseline (at intake in year 1 of the study, T0)
Secondary outcomes:
measure: Lower limb kinematics during walking in degrees
timeFrame: after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: Lower limb kinetics during walking
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: Muscle activation patterns during gait in microvolts
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: Functional strength on the Functional Strength Measurement.
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: Functional Mobility Scale
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: Mobility Questionnaire 28
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
Other outcomes:
measure: heigth in meters
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: body weigth in kilogram
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: passive joint range of motion in degrees
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: skeletal alignment in degrees
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: Muscle length in degrees
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
measure: Selective muscle strength on the Medical Research Council muscle scale
timeFrame: baseline (at intake in year 1 of the study, T0), after 12 months (T1), after 24 months (T2) and after 36 months (T3) from intake
Locations:
city: Antwerp
country: Belgium
facility: University Hospital Antwerp
city: Antwerp
country: Belgium
facility: University of Antwerp
city: Leuven
country: Belgium
facility: KU Leuven
Study officials:
affiliation: Rehabilitation Sciences and Physiotherapy, University of Antwerp
name: Ann Hallemans, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Figueiredo EM, Ferreira GB, Maia Moreira RC, Kirkwood RN, Fetters L. Efficacy of ankle-foot orthoses on gait of children with cerebral palsy: systematic review of literature. Pediatr Phys Ther. 2008 Fall;20(3):207-23. doi: 10.1097/PEP.0b013e318181fb34.
citation: Rodda JM, Scheffer IE, McMahon JM, Berkovic SF, Graham HK. Progressive gait deterioration in adolescents with Dravet syndrome. Arch Neurol. 2012 Jul;69(7):873-8. doi: 10.1001/archneurol.2011.3275.
citation: Scheffer IE. Diagnosis and long-term course of Dravet syndrome. Eur J Paediatr Neurol. 2012 Sep;16 Suppl 1:S5-8. doi: 10.1016/j.ejpn.2012.04.007. Epub 2012 Jun 16.
citation: Wyers L, Di Marco R, Zambelli S, Masiero S, Hallemans A, Van de Walle P, Desloovere K, Del Felice A. Foot-floor contact pattern in children and adults with Dravet Syndrome. Gait Posture. 2021 Feb;84:315-320. doi: 10.1016/j.gaitpost.2020.12.030. Epub 2021 Jan 6.
citation: Verheyen K, Wyers L, Del Felice A, Schoonjans AS, Ceulemans B, Van de Walle P, Hallemans A. Independent walking and cognitive development in preschool children with Dravet syndrome. Dev Med Child Neurol. 2021 Apr;63(4):472-479. doi: 10.1111/dmcn.14738. Epub 2020 Nov 23.
citation: Wyers L, Verheyen K, Ceulemans B, Schoonjans AS, Desloovere K, Van de Walle P, Hallemans A. Strength measurements in patients with Dravet Syndrome. Eur J Paediatr Neurol. 2021 Nov;35:100-110. doi: 10.1016/j.ejpn.2021.10.006. Epub 2021 Oct 15.
citation: Wyers L, Verheyen K, Ceulemans B, Schoonjans AS, Desloovere K, Van de Walle P, Hallemans A. The mechanics behind gait problems in patients with Dravet Syndrome. Gait Posture. 2021 Feb;84:321-328. doi: 10.1016/j.gaitpost.2020.12.029. Epub 2020 Dec 31.
citation: Wyers L, Van de Walle P, Hoornweg A, Tepes Bobescu I, Verheyen K, Ceulemans B, Schoonjans AS, Desloovere K, Hallemans A. Gait deviations in patients with dravet syndrome: A systematic review. Eur J Paediatr Neurol. 2019 May;23(3):357-367. doi: 10.1016/j.ejpn.2019.03.003. Epub 2019 Mar 22.
citation: Di Marco R, Hallemans A, Bellon G, Ragona F, Piazza E, Granata T, Ceulemans B, Schoonjans AS, Van de Walle P, Darra F, Dalla Bernardina B, Vecchi M, Sawacha Z, Scarpa B, Masiero S, Benedetti MG, Del Felice A. Gait abnormalities in people with Dravet syndrome: A cross-sectional multi-center study. Eur J Paediatr Neurol. 2019 Nov;23(6):808-818. doi: 10.1016/j.ejpn.2019.09.010. Epub 2019 Sep 21.
citation: Verheyen K, Verbecque E, Ceulemans B, Schoonjans AS, Van De Walle P, Hallemans A. Motor development in children with Dravet syndrome. Dev Med Child Neurol. 2019 Aug;61(8):950-956. doi: 10.1111/dmcn.14147. Epub 2019 Jan 15.