Treatment of Gait Disorders in Children With Dravet Syndrome
Condition: Dravet Syndrome; Severe Myoclonic Epilepsy of Infancy
MeSH terms: Epilepsy; Epilepsies, Myoclonic; Syndrome
Study type: Observational

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.
    

Intervention name(s): Clinical gait analysis
Intervention type(s): Diagnostic Test
Intervention description(s): Three dimensional gait analysis consisting of joint kinematics, kinetics and dynamic EMG data will be introduced into the diagnostic scheme
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
      
Keywords: Dravet syndrome; severe myoclonic epilepsy of infancy; intellectual disabilities; movement disorders; gait; biomechanics