Annemieke I. Buizer

Effects of Chemotherapy on Neurocognitive Function in Children With Acute Lymphoblastic Leukemia: A Critical Review of the Literature

Chemotherapy‐only treatment has increasingly become the standard of treatment for childhood acute lymphoblastic leukemia (ALL). The objective of this review is to assess the present state of knowledge of the neurocognitive effects of central nervous system (CNS)‐directed chemotherapy in children with ALL, and to formulate directions for future research. We performed a review of studies published since 1997, that included an ALL group treated with chemotherapy only and a control group. Twenty‐one studies met our inclusion criteria. There is evidence of subtle long‐term neurocognitive deficits survivors of childhood ALL after treatment with chemotherapy only. These involve mainly processes of attention and of executive functioning, while global intellectual function is relatively preserved. Young age at diagnosis and female sex emerged as risk factors. Pediatr Blood Cancer 2009;52:447–454.

Chemotherapy and attentional dysfunction in survivors of childhood acute lymphoblastic leukemia: Effect of treatment intensity

Central nervous system (CNS) directed chemotherapy is replacing prophylactic cranial irradiation in treatment protocols for childhood acute lymphoblastic leukemia (ALL), mainly to reduce long‐term neuropsychological sequelae. We evaluated the effects of chemotherapy on attentional function in survivors of ALL and examined whether possible deficits are related to treatment intensity.

Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

Treatment for childhood acute lymphoblastic leukemia (ALL), which includes CNS prophylaxis, is associated with central and peripheral neurotoxicity. The purpose of the present study was to analyze the effects of chemotherapy on various levels of visuomotor control in survivors of childhood ALL treated without cranial irradiation, and to identify risk factors for possible deficits. Visuomotor function was compared between children after treatment for ALL (n = 34), children after treatment for Wilms tumor, which consists of non-CNS directed chemotherapy (n = 38), and healthy controls (n = 151). Three tasks were administered: a simple visual reaction time task and two tasks measuring visuomotor control with one requiring a higher level of cognitive control than the other. Visuomotor deficits were detected only in the ALL group, with poorer performance restricted to the condition requiring the highest level of control. Significant risk factors for poorer performance were female gender and a short time since end of treatment, and a trend was found for a young age at diagnosis. A high cumulative methotrexate dose was an adverse predictive factor in girls. The results indicate that chemotherapy-induced central neurotoxicity in childhood ALL treatment is associated with higher order visuomotor control deficits. Girls appear to be particularly vulnerable.

The Effects of Varying Ankle Foot Orthosis Stiffness on Gait in Children with Spastic Cerebral Palsy Who Walk with Excessive Knee Flexion.

Introduction Rigid Ankle-Foot Orthoses (AFOs) are commonly prescribed to counteract excessive knee flexion during the stance phase of gait in children with cerebral palsy (CP). While rigid AFOs may normalize knee kinematics and kinetics effectively, it has the disadvantage of impeding push-off power. A spring-like AFO may enhance push-off power, which may come at the cost of reducing the knee flexion less effectively. Optimizing this trade-off between enhancing push-off power and normalizing knee flexion in stance is expected to maximize gait efficiency. This study investigated the effects of varying AFO stiffness on gait biomechanics and efficiency in children with CP who walk with excessive knee flexion in stance. Fifteen children with spastic CP (11 boys, 10±2 years) were prescribed with a ventral shell spring-hinged AFO (vAFO). The hinge was set into a rigid, or spring-like setting, using both a stiff and flexible performance. At baseline (i.e. shoes-only) and for each vAFO, a 3D-gait analysis and 6-minute walk test with breath-gas analysis were performed at comfortable speed. Lower limb joint kinematics and kinetics were calculated. From the 6-minute walk test, walking speed and the net energy cost were determined. A generalized estimation equation (p<0.05) was used to analyze the effects of different conditions. Compared to shoes-only, all vAFOs improved the knee angle and net moment similarly. Ankle power generation and work were preserved only by the spring-like vAFOs. All vAFOs decreased the net energy cost compared to shoes-only, but no differences were found between vAFOs, showing that the effects of spring-like vAFOs to promote push-off power did not lead to greater reductions in walking energy cost. These findings suggest that, in this specific group of children with spastic CP, the vAFO stiffness that maximizes gait efficiency is primarily determined by its effect on knee kinematics and kinetics rather than by its effect on push-off power. Trial Registration Dutch Trial Register NTR3418

The effect of intrathecal baclofen treatment on activities of daily life in children and young adults with cerebral palsy and progressive neurological disorders

INTRODUCTION Intrathecal baclofen (ITB) treatment is applied in patients with spastic cerebral palsy (SCP), dystonic cerebral palsy (DCP) and progressive neurological disease (PND). Our aim was to investigate whether ITB treatment has a different effect on activities of daily life (ADL) in these groups. METHOD A retrospective and cross-sectional survey was conducted using a questionnaire to assess the qualitative effect of ITB (Likert scale) on different domains of functioning (mobility, personal care, communication, comfort) and satisfaction with the results. Groups were compared using non-parametric statistics. RESULTS Questionnaires were completed for 68 patients (39 SCP, 13 DCP, 16 PND). Satisfaction scores were relatively high in all groups (7-8) and the positive effect on personal care and communication was similar in all groups. The PND group had the shortest follow-up and scored significantly less favourably for the effect on mobility and comfort. DISCUSSION This is the first study to show that ITB treatment has similar effects on personal care and communication in stable and progressive neurological disease. The decrease in mobility in the PND group is likely due to the progressive nature of the disease. The different effect on comfort between groups is mainly due to the smaller effect on startles in the PND group.

Kinetic comparison of walking on a treadmill versus over ground in children with cerebral palsy.

Kinetic outcomes are an essential part of clinical gait analysis, and can be collected for many consecutive strides using instrumented treadmills. However, the validity of treadmill kinetic outcomes has not been demonstrated for children with cerebral palsy (CP). In this study we compared ground reaction forces (GRF), center of pressure, and hip, knee and ankle moments, powers and work, between overground (OG) and self-paced treadmill (TM) walking for 11 typically developing (TD) children and 9 children with spastic CP. Considerable differences were found in several outcome parameters. In TM, subjects demonstrated lower ankle power generation and more absorption, and increased hip moments and work. This shift from ankle to hip strategy was likely due to a more backward positioning of the hip and a slightly more forward trunk lean. In mediolateral direction, GRF and hip and knee joint moments were increased in TM due to wider step width. These findings indicate that kinetic data collected on a TM cannot be readily compared with OG data in TD children and children with CP, and that treadmill-specific normative data sets should be used when performing kinetic gait analysis on a treadmill.

European consensus on the concepts and measurement of the pathophysiological neuromuscular responses to passive muscle stretch

To support clinical decision‐making in central neurological disorders, a physical examination is used to assess responses to passive muscle stretch. However, what exactly is being assessed is expressed and interpreted in different ways. A clear diagnostic framework is lacking. Therefore, the aim was to arrive at unambiguous terminology about the concepts and measurement around pathophysiological neuromuscular response to passive muscle stretch.

Freehand three‐dimensional ultrasound to assess semitendinosus muscle morphology

In several neurological disorders and muscle injuries, morphological changes of the m. semitendinosus (ST) are presumed to contribute to movement limitations around the knee. Freehand three‐dimensional (3D) ultrasound (US), using position tracking of two‐dimensional US images to reconstruct a 3D voxel array, can be used to assess muscle morphology in vivo. The aims of this study were: (i) to introduce a newly developed 3D US protocol for ST; and (ii) provide a first comparison of morphological characteristics determined by 3D US with those measured on dissected cadaveric muscles. Morphological characteristics of ST (e.g. muscle belly length, tendon length, fascicle length and whole muscle volume, and volumes of both compartments) were assessed in six cadavers using a 3D US protocol. Subsequently, ST muscles were removed from the body to measure the same morphological characteristics. Mean differences between morphological characteristics measured by 3D US and after dissection were smaller than 10%. Intra‐class correlation coefficients (ICCs) were higher than 0.75 for all variables except for the lengths of proximal fascicles (ICC = 0.58). Measurement of the volume of proximal compartment by 3D US was not feasible, due to low US image quality proximally. We conclude that the presented 3D US protocol allows for reasonably accurate measurements of key morphological characteristics of ST muscle.

The validity and reliability of modelled neural and tissue properties of the ankle muscles in children with cerebral palsy

Spastic cerebral palsy (CP) is characterized by increased joint resistance, caused by a mix of increased tissue stiffness, as well as involuntary reflex and background muscle activity. These properties can be quantified using a neuromechanical model of the musculoskeletal complex and instrumented assessment. The construct validity of the neuromechanical parameters was examined (i.e. the internal model validity, effect of knee angle, speed and age, sensitivity to patients versus controls, spasticity severity and treatment), together with the repeatability. We included 38 children with CP and 35 controls. A motor driven footplate applied two slow (15°/s) and two fast (100°/s) rotations around the ankle joint, at two different knee angles. Ankle angle, torque and EMG of the gastrocnemius (GA), soleus (SO) and tibialis anterior (TA) muscle were used to optimize a nonlinear neuromuscular model. Outcome measures were tissue stiffness, reflex and background activity for GA, SO and TA. The internal model validity showed medium to high parameter confidence and good model fits. All parameter could discriminate between patients with CP and controls according to CP pathology. Other measures of external model validity (effect of test position, speed and age) showed behaviour along the lines of current knowledge of physiology. GA/SO background activity was sensitive to spasticity severity, but reflex activity was not. Preliminary data indicated that reflex activity was reduced after spasticity treatment. The between-trial and -day repeatability was moderate to good. The large variance between patients in the ratio of stiffness and neural resistance indicates that the method could potentially contribute to patient-specific treatment selection.

Optimising Ankle Foot Orthoses for children with cerebral palsy walking with excessive knee flexion to improve their mobility and participation; protocol of the AFO-CP study.

BackgroundAnkle-Foot-Orthoses with a ventral shell, also known as Floor Reaction Orthoses (FROs), are often used to reduce gait-related problems in children with spastic cerebral palsy (SCP), walking with excessive knee flexion. However, current evidence for the effectiveness (e.g. in terms of walking energy cost) of FROs is both limited and inconclusive. Much of this ambiguity may be due to a mismatch between the FRO ankle stiffness and the patient’s gait deviations.The primary aim of this study is to evaluate the effect of FROs optimised for ankle stiffness on the walking energy cost in children with SCP, compared to walking with shoes alone. In addition, effects on various secondary outcome measures will be evaluated in order to identify possible working mechanisms and potential predictors of FRO treatment success.Method/DesignA pre-post experimental study design will include 32 children with SCP, walking with excessive knee flexion in midstance, recruited from our university hospital and affiliated rehabilitation centres. All participants will receive a newly designed FRO, allowing ankle stiffness to be varied into three configurations by means of a hinge. Gait biomechanics will be assessed for each FRO configuration. The FRO that results in the greatest reduction in knee flexion during the single stance phase will be selected as the subject’s optimal FRO. Subsequently, the effects of wearing this optimal FRO will be evaluated after 12–20 weeks. The primary study parameter will be walking energy cost, with the most important secondary outcomes being intensity of participation, daily activity, walking speed and gait biomechanics.DiscussionThe AFO-CP trial will be the first experimental study to evaluate the effect of individually optimised FROs on mobility and participation. The evaluation will include outcome measures at all levels of the International Classification of Functioning, Disability and Health, providing a unique set of data with which to assess relationships between outcome measures. This will give insights into working mechanisms of FROs and will help to identify predictors of treatment success, both of which will contribute to improving FRO treatment in SCP in term.Trial registrationThis study is registered in the Dutch Trial Register as NTR3418.