Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.

OBJECTIVE: To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use. SUBJECTS DESIGN: Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland). RESULTS: R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children. CONCLUSION: The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age.

Sexual functioning in adolescents and young adults with spina bifida.

OBJECTIVE: To assess sexual education and sexual functioning in adolescents and young adults with spina bifida. DESIGN: Survey, inception cohort. SETTING: The community. PARTICIPANTS: A cohort of adolescents and young adults (N=121; range, 15-35 y; 58% women) enrolled in a longitudinal pediatric database. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Questions on sexual function, reproductive function, bladder and bowel continence, the Perceived Quality of Life Scale, and the Satisfaction With Life Scale. RESULTS: Almost all adolescents and young adults with spina bifida in our study received sexual education at school, less at home, or by physicians. Twenty-five percent of men and 68% of women were informed about reproductive function by their physicians. Participants who reported that they smoked were 10 times more likely to report being sexually active and women were 2.3 times more likely to be sexually active than men. Hydrocephalus was a significant predictor of sexual activity among women but not men. Participants with urinary incontinence were less likely to be sexually active. Women without hydrocephalus were significantly more satisfied with life than women with hydrocephalus. CONCLUSIONS: Adolescents and young adults with spina bifida in this sample were only slightly satisfied with life and sexual activity was only associated with life satisfaction among women. Dissatisfaction with life often leads to engagement in health-risk behaviors, which may, in part, account for the association between sexual activity and smoking behavior observed in these data. Further studies of health risk behaviors among youth with spina bifida are warranted and interventions aimed at reducing health risk behaviors among adolescents and young adults should specifically include spina bifida as a target group.

Ambulatory physical activity performance in youth with cerebral palsy and youth who are developing typically.

BACKGROUND AND PURPOSE: Assessment of walking activity in youth with cerebral palsy (CP) has traditionally been "capacity-based." The purpose of this study was to describe the day-to-day ambulatory activity "performance" of youth with CP compared with youth who were developing typically. SUBJECTS: Eighty-one youth with CP, aged 10 to 13 years, who were categorized as being in Gross Motor Function Classification System (GMFCS) levels I to III and 30 age-matched youth who were developing typically were recruited. METHODS: Using a cross-sectional design, participants wore the StepWatch monitor for 7 days while documenting average daily total step counts, percentage of time they were active, ratio of medium to low activity levels, and percentage of time at high activity levels. RESULTS: The youth with CP demonstrated significantly lower levels of all outcomes than the comparison group. DISCUSSION AND CONCLUSION: Daily walking activity and variability decreased as functional walking level (GMFCS level) decreased. Ambulatory activity performance within the context of the daily life for youth with CP appears valid and feasible as an outcome for mobility interventions in CP.

Long-term intrathecal baclofen therapy for severe spasticity of cerebral origin.

OBJECT: The goal of this study was to ascertain the long-term effectiveness and safety of intrathecal baclofen (ITB) in the treatment of spasticity of cerebral origin in children and young adults. METHODS: A prospective, multicenter study was conducted in 68 patients who had been enrolled in the initial evaluation of ITB therapy and were willing to participate in long-term surveillance. Seventy-three percent of the patients were younger than 16 years of age at the time of study entry. The patients were examined at least every 3 months and were observed for an average of 70 months. At each follow-up visit, spasticity in the upper and lower extremities was evaluated by applying Ashworth scores. All adverse events and complications were recorded on standardized data forms. Spasticity in both upper and lower extremities decreased significantly (p < 0.005) and remained decreased up to 10 years. The dosage of ITB increased from a mean of 157 microg/day 3 months after pump insertion to 300 microg/day at 2 years postimplantation, and remained relatively stable thereafter. There were no significant differences in ITB dosage in children of different ages. Adverse events potentially related to ITB therapy occurred in 50% of patients within 2 months after pump insertion and in 50% of patients thereafter; hypotonia and lethargy were the two most common adverse events. The most common complications of surgery were catheter-related problems (31%), seromas (24%), and cerebrospinal fluid leaks (15%). CONCLUSIONS: Intrathecal baclofen provides effective long-term treatment of spasticity of cerebral origin and its effects do not appear to diminish with time. This therapy is frequently associated with adverse side effects that usually can be alleviated by adjustments in dosage.

The route to extinction: population dynamics of a threatened butterfly.

We compare results of field study and model analysis of two butterfly populations to evaluate the importance of alternative mechanisms causing changes in abundance. Although understanding and predicting population fluctuations is a central goal of population ecology, it is not often achieved because long-term abundance data are available for few populations in which mechanisms causing fluctuations also are known. Both kinds of information exist for two populations of the checkerspot butterfly, Euphydryas editha bayensis, which are matched in most ways except for habitat area and topography. We applied results from field study to make predictions about the dynamics of the two populations. Then we tested these predictions using nonlinear modeling of abundance data. Models included endogenous factors, exogenous effects of weather, or both. Results showed that the populations differed in variability and responses to endogenous and exogenous factors. The population in the more homogeneous habitat varied more widely, went extinct first, and fluctuated more severely with climate. Dynamics of the population occupying the topographically diverse habitat were more complex, containing damped oscillations and weaker influences of weather. We draw four main conclusions. First, the routes to extinction for E. e. bayensis populations in protected habitat were random walks driven by climatic variability. Climatic influences dominated both populations, but the timing and functional forms of climatic effects differed between populations. Second, topographic diversity reduced weather-induced population variability and increased persistence time. Third, one must explicitly consider both endogenous and exogenous components to fully understand population dynamics. Fourth, resolving the debate over population regulation requires integrating long-term population sampling, model analysis, and investigation of mechanisms in the field.

Hip status in cerebral palsy after one year of continuous intrathecal baclofen infusion.

The purpose of this study was to assess whether reduction of muscle tone by continuous intrathecal baclofen infusion affects the progression of hip subluxation in persons with cerebral palsy. This prospective, open-label, case series was conducted at multiple specialty referral centers. There were 33 subjects, ages 4 to 31 years. All had a pretreatment lower extremity Ashworth score of >/=3; all subjects had a significant reduction in tone after a bolus injection of intrathecal baclofen and received an implanted pump for continuous delivery of intrathecal baclofen. Subjects had hip x-rays before and 1 year after pump implantation. The primary outcome measure was change in absolute hip migration percentage. One third of the hips had an increase of absolute migration percentage of 5% or more; 12% of the hips had a decrease of migration percentage of 5% or more. Change of migration percentage class was used as a second outcome criterion. 90.9% of hips manifested no deterioration or had improvement of their migration percentage class during the year of intrathecal baclofen therapy. The observed changes were not associated with the subject's age or the severity of cerebral palsy.

Survey of the use of massage for children with cerebral palsy.

BACKGROUND: Conventional medicine and complementary and alternative medicine (CAM) are merging into the broader field of "integrative medicine." Massage is no longer considered complementary or alternative in some conventional medical circles today. PURPOSE: We aimed to determine the prevalence of massage use among children with cerebral palsy (CP) in the Pacific Northwest in the United States, the reasons that massage is being used, and the limits of recruitment for a future randomized controlled trial. METHODS: This study, the first step in a three-stage research plan, was conducted at the Neurodevelopmental and Neurology clinics at Seattle Children's Hospital, a tertiary pediatric hospital that provides service to patients primarily from Washington, Alaska, Montana, and Idaho. As a feasibility study (stage one), it precedes a planned pilot study (stage two), and subsequently, a full-scale randomized controlled trial (stage three) of whether massage can improve the health of children with CP. The study subjects-104 families with a child with CP ranging in age from 17 months to 21 years-were surveyed by the principal investigator and a research assistant in exam rooms at the hospital. RESULTS: In the families surveyed, 80% of the children had received massage at some point. Massage was currently being used in 51%, and trained professionals were providing the massage in 23%. Most families use massage for musculoskeletal relaxation, to improve quality of life, and to help their children sleep. Lower maternal income was associated with relatives as compared with professional massage therapists providing the massage. Massage therapy use by the mother and more severe CP were significantly associated with current use of massage for the child. CONCLUSIONS: Most children with CP in the Pacific Northwest have used massage. Most parents surveyed believe that massage is helpful to their child. Additional research is needed to determine whether massage should be routinely recommended for children with CP.

Botulinum toxin for spasticity in children with cerebral palsy: a comprehensive evaluation.

BACKGROUND: Spasticity is a prevalent disabling clinical symptom for children with cerebral palsy. Treatment of spasticity with botulinum toxin in children with cerebral palsy was first reported in 1993. Botulinum toxin provides a focal, controlled muscle weakness with reduction in spasticity. Interpretation of the literature is difficult because of the paucity of reliable measures of spasticity and challenges with measuring meaningful functional changes in children with disabilities. OBJECTIVE: This study documents the effects of botulinum toxin A injections into the gastrocnemius muscles in children with spastic diplegia. Outcomes are evaluated across all 5 domains of the National Centers for Medical and Rehabilitation Research domains of medical rehabilitation. METHODS: A randomized, double-masked, placebo-controlled design was applied to 33 children with spastic diplegia with a mean age of 5.5 and Gross Motor Function Classification System Levels of I through III. Participants received either 12 U/kg botulinum toxin A or placebo saline injections to bilateral gastrocnemius muscles. Outcomes were measured at baseline and 3, 8, 12, and 24 weeks after injection. RESULTS: Significant decreases in the electromyographic representation of spasticity were documented 3 weeks after botulinum toxin A treatment. A significant decrease in viscoelastic aspects of spasticity was present at 8 weeks, and subsequent increases in dorsiflexion range were documented at 12 weeks for the botulinum toxin A group. Improvement was found in performance goals at 12 weeks and in maximum voluntary torque and gross motor function at 24 weeks for the botulinum toxin A. There were no significant differences between groups in satisfaction with performance goals, energy expenditure, Ashworth scores, or frequency of adverse effects. CONCLUSIONS: The safety profile of 12 U/kg of botulinum toxin A is excellent. Although physiologic and mechanical effects of treatment with botulinum toxin A were documented with functional improvement at 6 months, family satisfaction with outcomes were no different. Communication is needed to ensure realistic expectations of treatment.

Lower extremity sensory function in children with cerebral palsy.

OBJECTIVES: (1) To determine the feasibility of qualitative sensory testing in the lower extremities (LE) of children with cerebral palsy (CP), especially spastic diplegia. (2) To determine if there is a detectable difference in qualitative LE sensory function in children with CP compared to typical children. (3) To determine if dorsal rhizotomy results in detectable changes in LE sensory function in children with spastic diplegia. DESIGN: Objectives 1 and 2: Prospective observational cohort study. Objective 3: Add-on to prospective interventional studies. SETTING: Regional tertiary children's hospital. PARTICIPANTS: Objectives 1 and 2: 62 children with CP and 65 typical children between 3-18 years of age. Objective 3: 34 children with spastic diplegia. INTERVENTIONS: Objectives 1 and 2: None. Objective 3: Dorsal rhizotomy. MAIN OUTCOME MEASURES: Pain, light touch, direction of scratch, vibration, toe position and knee position using standard qualitative techniques. RESULTS: Objective 1: 32 (52%) children with CP and 55 (85%) typical children completed all items (p = 0.09). Objective 2: Summary scores for separate LE sensory modalities were lower in children with CP for direction of scratch (p < 0.001), toe position (p = 0.01) and vibration sense (p = 0.01). Objective 3: No changes of LE sensory function. CONCLUSIONS: LE sensory testing in young children with CP is feasible. There is a qualitative sensory deficit in this sample of children with CP and specifically in children with spastic diplegia that is traditionally associated with dorsal column sensory modalities. A conservative dorsal rhizotomy does not produce a measurable change in LE sensory function in this sample of children with spastic diplegia.

GMFM 1 year after continuous intrathecal baclofen infusion.

The purpose of this study was to assess whether there is an improvement in motor function in persons with cerebral palsy (CP) who have had a reduction of muscle tone by continuous intrathecal baclofen infusion. This was a prospective, open label, non-blinded case series without a control group, conducted at multiple centres. There were 31 subjects, aged 4-29 years. All had a pre-treatment mean lower extremity Ashworth scores of >or= 3 and a significant reduction in tone after a bolus injection of intrathecal baclofen (ITB) and received an implanted pump for continuous delivery of ITB. Motor function was assessed by the Gross Motor Function Measure (GMFM) prior to and 1 year following pump implantation. Significant improvement (p < 0.05) in mean GMFM scores was seen in subjects < 8 years (mean change 4.1) and in those from 8-18 years (mean change 3.7) and in subjects with CP Classes 2 and 5 (mean changes 6.2 and 2.9). There was a statistically significant decrease (p < 0.05) in Ashworth scores in CP classes 2-5. Subjects or their caregivers that completed a survey about perceived changes stated that motor control, positioning and endurance improved.

Climate change hastens population extinctions.

Climate change is expected to alter the distribution and abundance of many species. Predictions of climate-induced population extinctions are supported by geographic range shifts that correspond to climatic warming, but few extinctions have been linked mechanistically to climate change. Here we show that extinctions of two populations of a checkerspot butterfly were hastened by increasing variability in precipitation, a phenomenon predicted by global climate models. We model checkerspot populations to show that changes in precipitation amplified population fluctuations, leading to rapid extinctions. As populations of checkerspots and other species become further isolated by habitat loss, climate change is likely to cause more extinctions, threatening both species diversity and critical ecosystem services.

Long-term safety and efficacy of continuous intrathecal baclofen.

Long-term continuous intrathecal baclofen (CITB) infusion is a treatment option used to manage otherwise intractable spasticity and is delivered via an implantable pump. The purpose of this single-center multidisciplinary review was to report on the long-term safety and efficacy of CITB in the treatment of 21 children with intractable severe spasticity of cerebral origin. Nineteen recipients had spastic quadriplegia and two had spastic diplegia. Seven recipients had level IV severity on the Gross Motor Functional Classification System and 14 had level V. Median age at implantation was 12 years (range 4 to 20). Fifteen recipients were male, 6 were female. Seventeen recipients were alive at the end of the follow-up period (31 to 78 months; mean 53, SD 4). The Ashworth scale showed a substantial decrease in spasticity in the upper and lower extremities at 6 months and at the most recent follow-up. The Gross Motor Function Measure and Pediatric Evaluation of Disability Inventory showed no functional change. Most treatment goals were at least partly achieved. Caregivers reported a reduction in use of oral medication for spasticity, and improvements in comfort, function, and ease of care. Caregiver satisfaction was high. During 80 recipient-years of pump operation, 153 treatment-associated adverse events occurred: 27 of these were device-related. There were four deaths unrelated to CITE, including one from acute pancreatitis. Our findings might assist in establishing patient selection criteria and treatment goals, improving patient follow-up, and monitoring adverse events.

Oral motor, communication, and nutritional status of children during intrathecal baclofen therapy: a descriptive pilot study.

OBJECTIVE: To describe the oral motor, communication, and nutritional status of children receiving intrathecal baclofen (ITB) therapy for spasticity of cerebral origin. DESIGN: Observational cross-sectional design. SETTING: Tertiary-care regional children's hospital. PARTICIPANTS: Thirty children with spasticity of cerebral origin receiving ITB therapy. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: One interviewer administered a structured in-person interview tool designed for this pilot study, data from which were collapsed into 4 change categories: communication and speech, feeding and nutrition, oral motor function, and gastrointestinal function. Functional severity was ranked with the Gross Motor Function Classification System (GMFCS). RESULTS: Speech: 10 improved (5 in GMFCS level V) and 2 worsened. Use of assistive technology to communicate: 6 improved (5 in GMFCS level V). Appetite: 10 improved (6 in GMFCS level V) and 4 worsened. Self-feeding: 9 improved (2 in GMFCS level III, 4 in level IV, 3 in level V) and 2 worsened. Saliva control: 10 improved (1 in GMFCS level III, 1 in level IV, 8 in level V) and 8 worsened. Cup drinking: 12 improved (5 in GMFCS level V) and 2 worsened. Indicates thirst: 9 improved (4 in GMFCS level IV, 5 in level V) and none worsened. Stool frequency: 8 improved (8 in GMFCS level V) and 14 worsened. CONCLUSIONS: Some aspects of speech, communication, and saliva control seemed to have improved, with bowel movement frequency decreased in some children receiving ITB. Fewer changes in feeding and nutritional status were reported. On the basis of this pilot study, prospective management guidelines are proposed that relate objective outcome measures of oral motor function, communication, and nutrition to changes in spasticity with ITB.