Treatment of Gait Disorders in Children With Dravet Syndrome

NCT ID: NCT03857451

Last Updated: 2022-04-14

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 50 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-01-01
• Study Completion Date: 2020-12-31

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.

Conditions

Dravet Syndrome; Severe Myoclonic Epilepsy of Infancy

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Interventions

Clinical gait analysis

Three dimensional gait analysis consisting of joint kinematics, kinetics and dynamic EMG data will be introduced into the diagnostic scheme

Intervention Type: DIAGNOSTIC_TEST

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

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Antwerp

OTHER

Sponsor Role: collaborator

KU Leuven

OTHER

Sponsor Role: collaborator

Universitaire Ziekenhuizen KU Leuven

OTHER

Sponsor Role: collaborator

Research Foundation Flanders

OTHER

Sponsor Role: collaborator

Universiteit Antwerpen

OTHER

Sponsor Role: lead

Responsible Party

Ann Hallemans

Assistent Professor, Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Science, Head of the Multidisciplinary Motor Center Antwerp

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ann Hallemans, PhD

Role: PRINCIPAL_INVESTIGATOR

Rehabilitation Sciences and Physiotherapy, University of Antwerp

Locations

University Hospital Antwerp

Antwerp, , Belgium

University of Antwerp

Antwerp, , Belgium

KU Leuven

Leuven, , Belgium

Countries

Belgium

References

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.

Reference Type: BACKGROUND

PMID: 18703958 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22409937 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22704920 (View on PubMed)

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.

Reference Type: RESULT

PMID: 33445140 (View on PubMed)

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.

Reference Type: RESULT

PMID: 33230827 (View on PubMed)

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.

Reference Type: RESULT

PMID: 34666230 (View on PubMed)

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.

Reference Type: RESULT

PMID: 33445141 (View on PubMed)

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.

Reference Type: RESULT

PMID: 30940509 (View on PubMed)

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.

Reference Type: RESULT

PMID: 31582194 (View on PubMed)

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.

Reference Type: RESULT

PMID: 30644536 (View on PubMed)

Provided Documents

Document Type: Study Protocol

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Document Type: Informed Consent Form

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Other Identifiers

T003116N

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

34264

Identifier Type: -

Identifier Source: org_study_id