This study is approved by the Medical Ethics Committee of the VU University Medical Center and by the Institutional Review Board of the Washington University in Saint Louis.
The specific inclusion and exclusion criteria are shown in Table . Briefly, participants are children with spastic CP having been treated for reduced ankle dorsiflexion in the past, but not needed to be treated at the moment they were included into this study. Children are excluded from the study if they have a history of surgery of the Gastrocnemius muscle and/or Soleus muscle and/or selective dorsal rhizotomy, if they have severe enough morbidity or mobility limitations that prevent them from walking far enough to complete a gait analysis, or if they are being treated with intrathecal baclofen therapy (i.e. they have a current, active pump).
Inclusion and exclusion criteria
Sample size calculation
Expecting a 5 degree change in ankle ROM (assumed as clinically relevant), with a standard deviation of 4.5 degrees, a significance level (α) of 0.05 that is corrected for comparisons between three groups using a Bonferroni correction (α = 0.0167), and a power level of 80%, 13 children in each group will be sufficient. The calculation takes five repeated measurements with a correlation coefficient of ρ = 0.7 into account. In this study, 66 participants (22 in each group) will be recruited to allow drop outs.
Subjects will be recruited from three centers: 1) the VU University medical center in the Netherlands (N = 18), 2) "Rehabilitation Medical Center (RMC) Groot Klimmendaal" in the Netherlands (N = 18) and 3) the Pediatric Neurology Cerebral Palsy Center at Washington University School of Medicine and St. Louis Children's Hospital in the USA (N = 30). Eligible subjects will be identified by the physicians during clinical sessions or from review of patient's charts. The recruited children and their parents will receive a letter about procedures and content of the study, as well as an informed consent form. The potential subjects and their caregivers will be informed by the site investigators and physicians. Both parents/guardians and children being 12 years old are asked to sign and return the informed consent to agree on voluntary participation in the study.
Setting & design
A single blind randomized controlled trial will be performed at the three above mentioned centers. The participants will be assigned into 3 different groups. In addition to their regular treatment, two groups will be treated with a dynamic or static KAFO for one year to prevent for a reduction of ankle dorsiflexion at full knee extension and one group will be included as a control group without additional intervention. The morphological measurements will be performed only at Dutch participants at the VU University medical center.
Measurements will be performed at baseline and at 3, 6, 9 and 12 months after treatment allocation. In combination with those measurements, participants of the experimental groups will have a meeting with the orthotist and physician to check for complications with the KAFO.
The assessor and analyser are blinded for treatment allocation. The trial will be performed between January 2010 and December 2012.
Patients of the control group will receive their usual care which may include ankle-foot-orthoses (AFOs) that are worn during the day (for standing and walking), oral baclofen therapy or other tone-reducing medications, strength training, stretching exercises, physical therapy, occupational therapy etc. Changes in usual care during the study will be monitored using questionnaires. Children will drop out of the study if they need surgical treatment (orthopaedic and neurosurgical procedures affecting muscle tone and length), botulinum toxin A injections in the lower extremity or serial casting treatments in the lower extremity.
In addition to their usual care, patients of the experimental groups will be treated for one year with a static KAFO or with a dynamic KAFO using an Ultraflex® ankle power unit. Children will be asked to wear the KAFO at least 6 hours per night. They will be allowed to remove the KAFO during the night when the child is seriously uncomfortable after wearing the KAFO for at least 20 minutes or when the child wakes up at night with complaints concerning the KAFO. When children do not wear the KAFO for 6 hours per night, parents will be asked to increase wearing time by asking the child to wear the KAFO during rest activities in day time. In case of unilateral treatment, patients will sleep one night with and one night without a KAFO. In case of bilateral treatment, patients will wear a KAFO alternating on the right and left side each night.
Manufacturing the KAFO
The KAFO will be custom made by certified orthotists using polyethylene or polypropylene and foam (for a covered inside). Two transverse bars (polyethylene or polypropylene) above and below the knee will be used to reinforce and stiffen the KAFO. Bandages of nylon Velcro straps will be placed at three locations: 1) as high as possible on the thigh, 2) directly above the patella and 3) directly below the patella. A circular foot fixation, made of leather or soft polyethylene, will be used for foot fixation. This circular foot fixation will be closed with two velcro straps. One strap overlaps the patient's most convex part of the ankle and one strap will overlap the patient's foot proximal of the caput ossis metatarsal I and V. Deformity of the patient's foot will be corrected by the use of an internal three point pressure system (see Figure ).
Figure 2 Three point's pressure for correction of deformity. (a)The equines correction will be performed by exerting force on the dorsal side of the lower leg (just below the knee), on the instep of the foot and under the ball of the foot. (b)The valgus correction (more ...)
Static KAFO specification
The static KAFO will provide a fixed knee extension of 0° and a fixed ankle dorsiflexion angle of 0°.
Dynamic KAFO specification
The dynamic KAFO will also have a fixed knee extension of 0°, but will use an ultraflex® ankle power unit (Ultraflex Systems, Pottstown, PA, USA). The force of the power unit that provides variable ankle dorsiflexion angles will be set according to the prescription shown in Figure .
Manual for dynamic splint settings.
To measure the maximal ankle dorsiflexion angle at full knee extension, a Single Digital Inclinometer (Model ACU001, Acumar, Lafayette, IN, USA) will be used. This goniometer is attached to a torque wrench (Sensotork 713/6, Stahlwille, Germany). The goniometer-torque wrench combination is attached to an adjustable foot fixation. The foot fixation is constructed with a forefoot part and a calcaneal part. The two parts can be adjusted in rotation and in distance with respect to each other. With the adjustment in rotation, adjustments for fore foot adduction and supination can be made to stabilize instable valgus foot deformity. With the adjustment in distance, foot sizes can be accommodated from 150 to 240 mm. The calcaneal part has a heel support (width: 45 mm) and a point to attach the torque wrench. Both parts are equipped with Velcro straps for foot fixation [31
]. Figure shows a photograph of the measurement device attached to the foot. The ankle dorsiflexion angle will be measured as the angle between the footplate of the foot fixation and the tibia (γ(f-t)
Figure 4 Photographic illustration of the hand held dynamometer. The hand held dynamometer consists of an adjustable foot fixation, a torque wrench and a goniometer. The foot fixation has parts supporting the forefoot and calcaneus. These parts are connected by (more ...)
The children will be asked to lie prone on a bench, with both feet overhanging the edge. The lower leg will lie in such a way that the fibula head and the lateral malleolus of the fibula are on the same height. The foot will be firmly attached to the adjustable foot plate for fixation. The ankle will be plantar flexed by the researcher, applying an external plantar flexion moment of 4 Nm, as measured using the toque wrench. The corresponding γ(f-t) is measured (further described as the 4 Nm plantar flexion angle). Subsequently, this procedure is repeated for 1 Nm plantar flexion and, 0 Nm, 1 Nm dorsiflexion, 4 Nm dorsiflexion and 6 Nm dorsiflexion. All measurements will be repeated six times and each moment will be exerted for five seconds. The γ(f-t) will be read out from the inclinometer simultaneously at the end of these 5 seconds at the target ankle joint moment. Positive values refer to an external dorsal flexion moment (Nm) of the dynamometer and dorsal flexion angle (°) of the ankle joint. There will be five seconds rest between each repetition and two minutes rest between each condition. The conditions will always be applied in the described order.
Children have to relax their muscles and will be asked to lie quietly during the measurements. Muscle activity will be checked using the electromyography (EMG) signals of Tibialis anterior muscle
and lateral Gastrocnemius Muscle
. The maximal voluntary muscle contraction (MVC) will be recorded before the measurements. The EMG signal will be A-D converted at 1000 Hz. After sampling, the signal will be high-pass filtered at 20 Hz to remove movement artefacts. Then, the signal will be normalized with respect to the MVC-value and filtered low pass at 5 Hz. EMG signals have to remain below 10% MVC during the angle and moment measurements to ensure muscle relaxation. Skin preparation and electrode placement of EMG will be carried out according to SENIAM guidelines [32
The mean of the first 5 measurements for each condition in which the EMG signal remained below 10% MVC will be used for further analysis. The results will be used to create angle-moment plots in which, for example, the muscle tendon complex stiffness can be determined by calculating the slope of the line between the 0 Nm and 4 Nm (see Figure ). A change in ankle dorsiflexion ROM will be investigated by analysing the γ(f-t) measured with 4 Nm dorsiflexion.
Ankle-moment plots. This figure will be created from the values measured with the hand held dynamometer. The dotted line will be used to calculate the muscle tendon complex (MTC) stiffness by calculating the slope of that line.
In case of potential bilateral treatment, the full procedure will only be performed on the participant's most involved leg. For the other leg, only the 4 Nm condition without EMG measurement will be performed to check for exit criteria (see withdrawal paragraph below). In case of potential unilateral treatment, the primary outcome measure will only be measured for the participant's potentially treated leg.
Secondary outcome - gait analysis
Sagittal and frontal video-recordings of the patient's gait pattern will be made at 50 Hz. The subjects will walk 5 times barefoot and 5 times with shoes and AFO if applicable, along a 10 m walkway at self-selected comfortable speed. Walking speed will be calculated from the time to complete a part of the track (5 meters, measured with infra red detectors or with a stopwatch, depending on measurement location). For follow up measurements, the patient will be requested to walk at baseline walking speed (within a range of ± 5%). Video recordings of the involved leg(s) will be taken in the sagittal and frontal plane. Three representative steps will be chosen for the assessment of the knee angle in midstance, the minimum knee angle in stance (between midstance and second bipedal phase of foot contact) and the ankle flexion in midstance. For the video analysis, a custom-made software package will be used (the Moxie Viewer®
, VU University Medical Center, Amsterdam, the Netherlands, http://www.smalll.nl
), and a software tool, allowing on screen video measurements of sagittal lower extremity joint angles [33
]. For all participants, the gait related outcome measures will only be measured in the potentially treated legs.
Secondary outcome - mobility
The level of mobility will be quantified using the Gross Motor Function Measure 66 Item Set (GMFM-66 IS) [34
] by a certified assessor. GMFM-66 IS scores will be calculated with the corresponding software (Gross Motor Ability Estimator version 1.0) that calculates scores on an interval scale.
Patient characteristics will be recorded using an intake form and will include age, gender, race, ethnicity, weight, length, localisation of CP (uni- or bilateral) and Gross Motor Function Classification System (GMFCS) [35
] class. To asses problematic behaviour of the child, the strength and difficulties questionnaire (SDQ) [36
] will be filled in by the parents. In addition, questions will also be asked about the children's sport activities, current therapies and other treatments, as well as preference sleeping positions.
Physical examination will be performed by the assessor to evaluate the physical characteristics of the patient. Variables to be measured are: 1) Position of the foot in standing, 2) transmalleolar axis position [37
], 3) gait pattern classification according to Rodda [38
] and Becher [39
], 4) ROM of the ankle and knee joints, 5) spasticity, by measuring the angle of catch (AOC) [40
] of the ankle and knee, 5) selective motor control, using the Selective Control Assessment of the Lower Extremity (SCALE) [41
] and 6) lower leg length. For all participants, the physical examination related outcome measures will only be measured in the potentially treated legs.
Web based diaries will be used to record the protocol adherence and will be collected by a research assistant. These diaries will be filled in during the fourth week of each month and include questions regarding KAFO use, KAFO-related complaints, sleeping problems, the use of an ankle-foot orthosis (AFO) as well as questions regarding stretching exercises performed over the last month. Problems with KAFO use experienced by patient and/or parents will be monitored by specific diary questions. The research assistant will call the participants at least once a month to check if there are any problems with the KAFO or motor function of the participant. Reported problems will be solved as soon as possible.
Furthermore, to check the reliability of diary reported KAFO wearing time, wearing time of the splints (for a subgroup of 10 children, recruited at VU University Medical Center) will be determined on the basis of KAFO temperature measured using a TidBit temperature datalogger (UTBI-001, Onset Computer Corporation, Bourne, MA). The KAFO temperature will increase due to body heat when the KAFO is worn. A sample of KAFO temperature data will be recorded each 15 minutes during the treatment period. Parents and children are not informed about the purpose of this measurement.
To get an indication of the sustained muscle stretch that is applied by the KAFOs, two measurements will be added. 1) The ankle moment at a γ(f-t) of 0° to simulate the static KAFO condition. This condition will be performed before the handheld dynamometer protocol. 2) The ankle dorsiflexion angle that could be imposed by the dynamic KAFO will be estimated during consultation hours by the physician using a goniometer.
To determine muscle morphology related variables, 3D-ultrasound imaging will be performed on the medial Gastrocnemius muscle. This muscle, covered with an ultrasound gel, will be scanned along it's length (making multiple transverse cross-section images, see Figure ) using a 5-cm linear array probe (12,5 MHz) of a B-mode ultrasound device (Technos MPX, ESAOTE, Italy). Two sets of recordings of the medial Gastrocnemius muscle will be made for each session. During 3D-ultrasound measurements, the position of the probe with a cluster marker is recorded using an active 3D marker motion analysis system (Optotrak, Northern Digital, Waterloo, Canada). In addition, 6 anatomical landmarks (lateral malleolus, medial malleolus, medial femur condyle, lateral femur condyle, medial femur epicondyle and lateral femur epicondyle) are recorded before each experiment to gain an anatomical frame of reference for post experimental 3D image reconstruction. In a prone position, the children are lying quietly on a bench. Using the ankle dynamometer, the ankle is fixed at γ(f-t) corresponding to 0, 1 and 4 Nm net dorsal flexion moment. Muscle activity is checked using EMG during the ultra sound measurements as described above in the primary outcome section.
Figure 6 Path of the ultrasound probe during scanning the medial Gastrocnemius muscle (MGM). The probe follows the path over the black line. It starts proximal, with the probe perpendicular to the path. First, the probe will be guided from lateral to medial over (more ...)
The ultra sound images will be converted into a voxel array and 3D-reconstructions will be calculated using a custom made program in MATLAB software according to the method that was described by Bénard e.a.[42
]. Measurements are performed in the mid-longitudinal fascicle plane of the medial Gastrocnemius muscle
, being perpendicular to (the tangent of) the distal aponeurosis of the medial Gastrocnemius muscle
, selected from the voxel array (see Figure ). The use of the correct plane is essential for minimizing measurement errors of fascicle length, fascicle angle and muscle thickness [43
]. Measurements are performed five times because this number of repetitions has been shown to yield reliable results [43
Figure 7 The orientation of the mid-longitudinal fascicle plane. Three orientation items (*) were used to define the mid-longitudinal fascicle plane of the medial Gastrocnemius muscle (MGM) (shaded plane and inset): 1) The estimate of the origin of the medial (more ...)
The following variables will be measured: tendon length (t
,) muscle length (m
), fascicle length ((fasc)
), muscle thickness ((m th)
) and fascicle angles with the aponeuroses (γ(fasc))
Using trigonometry, the following variables will be calculated: length of medial Gastrocnemius muscle
intramuscular distal (i.e. deep) and proximal (i.e. superficial aponeuroses) (a
) and length component of the physiological cross-section (
, the added perpendicular diameters of fascicles within the mid-longitudinal fascicle plane, Figure ).
Figure 8 Measurement and calculation of muscle geometry of medial Gastrocnemius muscle within its mid-longitudinal fascicle plane. (A) The mid-longitudinal fascicle plane, determined with 3D ultrasound. The medial Gastrocnemius muscle (MGM) is covered by the subcutis (more ...)
In case of potential bilateral treatment, the morphological outcome measures will only be measured on the participant's most involved leg. In case of potential unilateral treatment, the morphological outcome measure will only be measured at the participant's potentially treated leg.
The investigator and/or clinician can decide to withdraw a subject from the study for urgent medical reasons. First, they have an ankle dorsiflexion angle with an extended knee, measured as the angle between tibia and footplate (γ(f-t)), of 10° plantar flexion or more when an external ankle dorsiflexion moment of 4 Nm is applied. In such a case, the assessor will refer the child to the clinician who will decide whether the reduction in ROM has to be treated or not (note that the net ankle dorsiflexion moment of 4 Nm applied by the assessors is lower than is typically applied in a clinical setting). These children will not undergo follow-up measurements as they will receive other treatment for impaired ROM. Second, children have irresolvable problems with KAFO use (pain, pressure sores, sleeping problems). These subjects will be asked to undergo measurements after withdrawal and will be included in the analyses. Third, children can decide to withdraw at any time for any reason. These children will be asked to undergo measurements after withdrawal as well and will also be included in the analyses.
Premature termination of the study
The effects of orthotic management in rest on ankle dorsiflexion at full knee extension will be evaluated as soon as measurements have been performed on 30 children regarding follow-up measurement of 6 months. If the children in the control group show significantly larger γ(f-t) reduction compared to the other groups, this group will also be treated with a knee-ankle-foot orthosis. If the knee-ankle-foot orthoses groups (static and/or dynamic) show significantly larger reductions in γ(f-t) than the control group, the study will be terminated.
Randomisation will be performed by block randomisation of 3, 6 or 9 subjects, with pre-stratification by center. A member of the project team (AJD) not being involved in the recruitment/inclusion procedure of the subjects and not being involved in measurements will randomly generate an allocation sequence before the start of the trial to perform the randomisation. The order of allocation of treatment will be noted by AJD and kept in numbered sealed envelopes. After checking the inclusion and exclusion criteria by a physician and after receiving informed consent of the participant's parents, treatment allocation will be established by the research assistant after opening the numbered envelope. Subjects will be informed about their allocation after performing their baseline measurement.
The researchers performing the measurements and analysing the data will be blinded with respect to the treatment allocation. The children and their parents will be instructed to give no information about their treatment to the assessors. Blinding will be evaluated at the end of the study by asking the researchers the question: "In which group is the subject allocated and do you know this for sure, or is this a guess?"
Statistical analysis will be performed according to an "intention to treat" principle. All relevant subject characteristics, such as age, body weight and length, gender, clinical diagnosis, will be described by their mean value and standard deviation, or percentages. Differences between groups at baseline will be tested using linear regression techniques or Chi-square statistics. The effect of the intervention will be analysed using a multi-level analysis, with the primary and secondary outcome measures as dependent variables and treatment group and time as independent variables. To test for any differences in the changes of variables between groups, a treatment*time interaction is included as independent variable. Analysis are adjusted for treatment site (Amsterdam, Arnhem or St Louis). Covariates will be: 1) KAFO wearing time, 2) lower leg growth, 3) use of an AFO by day, 4) stretching exercises and 5) level of spasticity. The α-value will be set at 0.05.