Moderate-severe Cerebral Palsy Research Articles

Live births with cerebral palsy at a tertiary maternity hospital: incidence and associated risk factors over a 17-year period

The aim of this retrospective study was to establish the incidence and associated risk factors for cerebral palsy (CP) at a tertiary maternity hospital in the UK between 2000–2016. We identified CP patients from our electronic coding system using ICD codes. Multiple independent variables for all live births born during this period were included in a univariate and multivariate logistic regression (LR) to identify associations between these and CP. We identified 130 CP children out of 87318 live births. Univariate LR determined male sex, birth weight <2500 g, gestational age of ≤36 weeks, Small-for-gestational-age, 1-and 5-minute Apgar score <9, neonatal intensive care unit (NICU) admission, multiple births, breech, emergency Caesarean section and delivery between 16.00–20.00 as significant risk factors. In the multivariate LG male sex, 1-minute Apgar <9, 5-minute Apgar <5 and admission to NICU remained as significant risk factors. The risk for delivery between 16.00–19.59 was nearly significant. There was a significant association between NICU admission and moderate-severe CP. Our CP incidence of 0.149% is at the lower end of the incidence spectrum of international comparisons. Impact Statement What is already known on this subject? The historic reported incidence of cerebral palsy (CP) ranges from 1.1 to 3.6 cases per 1000 live births, with birth weight <2500g, birth <28 weeks of gestation, Apgar scores ≤4 and male sex having been associated with an increased incidence. What do the results of this study add? This is a large series of live births from a tertiary maternity hospital with a comparative low CP incidence of 0.149%, despite the hospital dealing with many complex pregnancies and deliveries. We identified that already an Apgar score of <9 at 1 minute (significant) and births between 16.00–20.00 (non-significant) were associated with an increased risk to develop CP but not with a specific day of the week. What are the implications of these findings for clinical practice and/or future research? Our significant association between a 1-minute Apgar score of <9 and CP stresses the importance of immediate efficient resuscitation already for babies with a 1-minute score as high as 8. The increased CP risk for deliveries between 16.00–19.59 may be linked to staffing issues and needs further exploration. What this paper adds New data from a single maternity hospital Analysis of risk factors GMFCS distribution

Study protocol for Running for health (Run4Health CP): a multicentre, assessor-blinded randomised controlled trial of 12 weeks of two times weekly Frame Running training versus usual care to improve cardiovascular health risk factors in children and youth with cerebral palsy

IntroductionChildren and youth with moderate-severe (Gross Motor Function Classification System (GMFCS) levels II–V) cerebral palsy (CP) participate less frequently in physical activities compared with peers without CP and have elevated...

High-Risk Neighborhoods and Neurodevelopmental Outcomes in Infants Born Preterm

To study the association between neighborhood risk and moderate to severe neurodevelopmental impairment (NDI) at 22-26months corrected age in children born at <34weeks of gestation. We hypothesized that infants born preterm living in high-risk neighborhoods would have a greater risk of NDI and cognitive, motor, and language delays. We studied a retrospective cohort of 1291 infants born preterm between 2005 and 2016, excluding infants with congenital anomalies. NDI was defined as any one of the following: a Bayley Scales of Infant and Toddler Development-III Cognitive or Motor composite score <85, bilateral blindness, bilateral hearing impairment, or moderate-severe cerebral palsy. Maternal addresses were geocoded to identify census block groups and create high-risk versus low-risk neighborhood groups. Bivariate and regression analyses were run to assess the impact of neighborhood risk on outcomes. Infants from high-risk (n=538; 42%) and low-risk (n=753; 58%) neighborhoods were compared. In bivariate analyses, the risk of NDI and cognitive, motor, and language delays was greater in high-risk neighborhoods. Inadjusted regression models, the risks of NDI (OR, 1.43; 95% CI, 1.04-1.98), cognitive delay (OR, 1.62; 95% CI, 1.15-2.28), and language delay (OR, 1.58; 95% CI, 1.15-2.16) were greater in high-risk neighborhoods. Breast milk at discharge was more common in low-risk neighborhoods and was protective of NDI in regression analysis. High neighborhood risk provides an independent contribution to preterm adverse NDI, cognitive, and language outcomes. In addition, breast milk at discharge was protective. Knowledge of neighborhood risk may inform the targeted implementation of programs for socially disadvantaged infants.

Caregiver burden in patients with moderate-severe cerebral palsy. The influence of nutritional status

IntroductionPatients with moderate-severe cerebral palsy (CP) require the support of their caregivers to carry out the Activities of Daily Living (ADLs). Objectives: to describe the comorbidities, need for care in children with CP and to analyse the influence of the degree of motor involvement, nutritional status and other neurological disorders. MethodsCross-sectional and observational study. Patients with CP degrees III–IV–V according to the Gross Motor Function Classification System (GMFCS) have been studied. A record of comorbidities has been made and body composition has been studied using anthropometry and bioimpedance. In addition, a caregiver burden survey on ADLs has been carried out (10 items on the different actions: hygiene, clothing, transfers, sleeping and feeding). Which variables have the greatest influence on the perception of difficulty in performing ADLs have been studied. Results69 patients (50.7% women, mean age 10.46 ± 0.4 years) were analysed, with GMFCS grades: grade III 36.2% (N = 25), grade IV 29.0% (N = 20), grade V 34.8% (N = 24). A relationship was found between the caregiver burden score and GMFCS grade (p = 0.003) and intellectual disability (DI) (p < 0.001). However, regardless of the degree of GMFCS and DI, there is greater difficulty in performing ADLs in relation to lower values in weight (Z-score) (p = 0.028), fat mass (kilograms) (p = 0.035), fat mass (%) (p = 0.094), body mass index (Z-score) (p = 0.086). ConclusionsIn addition to the degree of clinical impairment, nutritional status is a factor that influences the caregiver's difficulty in performing the ADLs in CP patients on which we can act to improve this problem.

Blood Biomarkers and 6- to 7-Year Childhood Outcomes Following Neonatal Encephalopathy.

This study aimed to profile the cytokine/chemokine response from day 0 to 7 in infants (≥36 weeks of gestational age) with neonatal encephalopathy (NE) and to explore the association with long-term outcomes. This was a secondary study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network randomized controlled trial of whole body hypothermia for NE. Eligible infants with moderate-severe NE were randomized to cooling or normothermia. Blood spots were collected on days 0 to 1, 2 to 4, and 6 to 7. Twenty-four cytokines/chemokines were measured using a multiplex platform. Surviving infants underwent neurodevelopmental assessment at 6 to 7 years. Primary outcome was death or moderate-severe impairment defined by any of the following: intelligence quotient <70, moderate-severe cerebral palsy (CP), blindness, hearing impairment, or epilepsy. Cytokine blood spots were collected from 109 participants. In total 99 of 109 (91%) were assessed at 6 to 7 years; 54 of 99 (55%) developed death/impairment. Neonates who died or were impaired had lower early regulated upon activation normal T cell expressed and secreted (RANTES) and higher day 7 monocyte chemotactic protein (MCP)-1 levels than neonates who survived without impairment. Though TNF-α levels had no association with death/impairment, higher day 0 to 1 levels were observed among neonates who died/developed CP. On multiple regression analysis adjusted for center, treatment group, sex, race, and level of hypoxic ischemic encephalopathy, higher RANTES was inversely associated with death/impairment (odds ratio (OR): 0.31, 95% confidence interval [CI]: 0.13-0.74), while day seven MCP-1 level was directly associated with death/impairment (OR: 3.70, 95% CI: 1.42-9.61). Targeted cytokine/chemokine levels demonstrated little variation with hypothermia treatment. RANTES and MCP-1 levels in the first week of life may provide potential targets for future therapies among neonates with encephalopathy. · Elevation of specific cytokines and chemokines in neonates with encephalopathy has been noted along with increased risk of neurodevelopmental impairment in infancy.. · Cytokine/chemokines at <7 days were assessed among neonates in a trial of hypothermia for HIE.. · Neonates who died or were impaired at 6 to 7 years following hypoxic-ischemic encephalopathy had lower RANTES and higher MCP-1 levels than those who survived without impairment..

Carga del cuidador del paciente con parálisis cerebral moderada-grave: ¿influye el estado nutricional?

Patients with moderate-severe cerebral palsy require the support of their caregivers to carry out the activities of daily living (ADLs). To describe the comorbidities, need for care in children with cerebral palsy and to analyse the influence of the degree of motor involvement, nutritional status and other neurological disorders. Cross-sectional and observational study. Patients with cerebral palsy degrees III-IV-V according to the Gross Motor Function Classification System (GMFCS) have been studied. A record of comorbidities has been made and body composition has been studied using anthropometry and bioimpedance. In addition, a caregiver burden survey on ADLs has been carried out (10 items on the different actions: hygiene, clothing, transfers, sleeping and feeding). Which variables have the greatest influence on the perception of difficulty in performing ADLs have been studied. A total of 69 patients (50.7% women, mean age 10.46 ± 0.4 years) were analysed, with GMFCS grades: grade III 36.2% (N=25), grade IV 29.0% (N=20), grade V 34.8% (N=24). A relationship was found between the caregiver burden score and GMFCS grade (P=0.003) and intellectual disability (P<0.001). However, regardless of the degree of GMFCS and intellectual disability, there is greater difficulty in performing ADLs in relation to lower values in weight (Z-score) (P=0.028), fat mass (kg) (P=0.035), fat mass (%) (P=0.094), body mass index (Z-score) (P=0.086). In addition to the degree of clinical impairment, nutritional status is a factor that influences the caregiver's difficulty in performing the ADLs in cerebral palsy patients on which we can act to improve this problem.

Bone health impairment in patients with cerebral palsy.

To study the bone health of patients with CP and its relationship with neurological and nutritional status. Cerebral palsy (CP) is the most common cause of motor disability in pediatric age. Cross-sectional, observational, descriptive, and analytical study in which patients with CP between 4 and 5 years with Gross Motor Function Classification System (GMFCS) grades III-IV-V were included. It was carried out: survey, anthropometric study, bioimpedanciometry (BIA), and bone densitometry. Patients with low bone mineral density (BMD Z score less than - 2.0) underwent lumbar radiography looking for vertebral fractures to be diagnosed with osteoporosis. Total sample: 51 patients (51.0% women). Mean age: 11.0 ± 0.5 years. BMD Z score average: - 2.1 (95% CI - 2.5, - 1.7). BMD Z score according to GMFCS: grade III - 1.6 (- 2.2; - 1.), grade IV - 1.6 (- 2.4; - 0.9), grade V - 3.1 (- 3.9, - 2.2) (p = 0.013). Bone health classification according to the International Society for Clinical Densitometry was: 47.1% normal, 52.9% low BMD. Relationship between low BMD and low fat mass (p = 0.030) and low cell mass (p = 0.040) was found. Prevalence of vertebral fractures in lumbar radiography: 25.9%, increasing as the degree of neurological involvement. Vertebral fractures were found in 5/13 GMFCS grade V, 2/6 GMFCS grade IV, and 0/10 GMFCS grade III. Bone health in the pediatric population with CP is compromised in relation to the degree of neurological involvement and nutritional status. Those patients with moderate-severe cerebral palsy and low BMD seem to present an increased risk of fracture.

The Seated Postural & Reaching Control Test in Cerebral Palsy: A Validation Study

Aim: Children with moderate-severe cerebral palsy (CP) show postural control deficits that affect their daily activities, like reaching. The Seated Postural and Reaching Control test (SP&R-co) was developed to address the need for clinical measures that objectively identify dimensions of postural imbalance and corresponding reaching limitations in children with CP.Methods: SP&R-co documentation was designed for test validity and rater training. Rater and internal consistency were examined using Cronbach’s α. Reference SP&R-co score sheets of children and rater’s scores were used for absolute item-by-item, average inter-rater, and intra-rater reliability. Motor classification systems and performance tests were used for construct and concurrent validity.Results: The SP&R-co scoring showed acceptable-good consistency (α = 0.76–0.84). Interrelatedness of SP&R-co items was good-excellent (α = 0.82–0.97). The raters demonstrated fair, good, and excellent item-by-item reliability (ICC = 0.41–0.92). Inter-rater and intra-rater reliability of SP&R-co dimensions were good-excellent (ICC = 0.68–0.86 and ICC = 0.64–0.95, respectively). Construct and concurrent validity showed moderate-excellent correlations (r = 0.49–0.88).Conclusions: Results provide evidence that the SP&R-co is a reliable and valid test for therapists to objectively examine and quantify seated postural and reaching control in children with CP.

Intervention program to improve feeding, swallowing, and nutritional problems in children with cerebral palsy

Background Most children with cerebral palsy (CP) have feeding problems, which lead to long-term malnutrition and respiratory disease, decreasing the quality of life of children and caregivers and causing early mortality. In developed countries with sufficient resources, high-cost and low-cost medical interventions, ranging from gastrostomy tube feeding to parent training, are available. In Egypt, the former is not widely available, and the latter is both scarce and its effectiveness not evaluated. Aim The study aimed to design and implement a training program to evaluate the effectiveness of a training program, to improve the feeding practices of caregivers of children with CP, to observe the effect on the level of nutritional status, feeding skills, and distress caused during feeding. Patients and methods From Alexandria University Children’s Hospital and its outpatient clinics (neurology and physical medicine), 20 caregivers and their children aged 1–5 years with moderate-severe CP (Gross Motor Fine Classification System III–V) and feeding difficulties were invited to a 10-session training program over 5 days (two sessions/day). Before and after training measures (quantitative and qualitative) were taken during the evaluation session of all children in addition to giving brief advice for caregivers, and follow-up for 3 months was done to evaluate the effect of education on performance and skills of the caregivers. Results The percentage of children with appropriate feeding position was significantly higher in final evaluation (66.7%) compared with preliminary evaluation (5%), and the median meal time was significantly shorter in final evaluation (42.5 min) compared with preliminary evaluation (60 min). The percentage of children and their caregivers gaining new feeding skills was significantly higher in final evaluation (38.9%) compared with preliminary evaluation (0%) (P=0.016). The percentage of children using the utensils appropriately was significantly higher in final evaluation (66.7%) compared with preliminary evaluation (15%) (P=0.004). There was no significant difference in the number of feeding problems, eating and drinking ability classification system level, and the mean weight for age Z score between studied children in preliminary and final evaluations. Conclusion The training program has a beneficial effect on improving feeding practices of children with CP and their caregivers after ten training sessions, with positive consequences for both child and caregiver. Methods of providing cheap food supplementation need to be studied, and further steps must be taken to ensure that services have the motivation and capacity to address this area of need.

Magnesium sulfate, chorioamnionitis, and neurodevelopment after preterm birth.

To assess the neuroprotective effect of magnesium sulfate (MgSO4 ) in preterm children exposed to chorioamnionitis. A secondary analysis of a multicentre randomised controlled trial of antenatal MgSO4 administered to women at risk of preterm birth for the prevention of cerebral palsy (CP). Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24weeks of gestation, were selected. Cases were exposed to antepartum MgSO4 ; controls received placebo. Multicentre randomised controlled trial. Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at ≥24weeks of gestation. All data were analysed by intention to treat. Univariate and multivariate analyses were performed. Primary outcome was a composite of stillbirth, death by the age of 1year, or moderate or severe CP by the age of 2years. Secondary outcomes included a composite neonatal outcome as well as neurodevelopmental delay, defined as Bayley II mental and psychomotor developmental indices <70 at the age of 2years. Subgroup analysis assessed these outcomes in children born at <28weeks of gestation. A total of 396 children were included, with 192 (48.5%) randomised to MgSO4 . Maternal and delivery characteristics were similar between the groups. The primary outcome occurred in 14.1% of children exposed to MgSO4 and 12.7% of children exposed to placebo (relative risk, RR 1.29; 95% CI 0.70-2.38). Rates of stillbirth, death, moderate-severe CP, and neurodevelopmental delay did not differ between groups. In the subgroup analysis of children born at <28weeks of gestation, there was no difference in the rates of the primary outcome, nor in the secondary outcomes assessed. [Correction added on 02 March 2016 after online publication: There were errors in statistical data analysis and these have been corrected throughout the article.] Among children at risk for early preterm delivery exposed to chorioamnionitis, antenatal administration of MgSO4 was not associated with improved neurodevelopmental outcome. We do not recommend any change in the guidelines on the administration of MgSO4 for neuroprotection based on this study. MgSO4 was not associated with improved neurodevelopmental outcome in setting of chorioamnionitis.

Validation of a modified three-day weighed food record for measuring energy intake in preschool-aged children with cerebral palsy

Accurate energy intake (EI) determination in children with cerebral palsy (CP) is critical for nutritional management, however no valid measures exist. We aimed to validate a modified three-day weighed food record for measuring EI in preschool-aged children with CP. Thirty-one children with CP (61% male) of all functional abilities and 15 typically developing children (TDC) (63% male), median age 3.79 years participated. A three-day weighed food record was validated by comparing reported EI to measured total energy expenditure (TEE) via doubly labelled water, assuming a state of weight balance. Children with moderate-severe CP showed no difference between EI and TEE. Values for EI were less than TEE in children with mild CP and TDC (p<0.01, limits of agreement-2559 to 845kJ and-2524 to 350kJ respectively). The mean difference between EI and TEE as a percentage of measured TEE was 14.8% (mild CP), 4.3% (moderate-severe CP) and 16.8% (TDC), all less than data detailing typical within-subject variability in day-to-day EI. In contrast to previous literature, results demonstrated that a modified three-day weighed food record accurately measured EI in preschool-aged children with CP. This record can be used in clinical practice and future research to accurately determine EI in this population.

Feeding difficulties in children with cerebral palsy: low‐cost caregiver training in Dhaka, Bangladesh

The majority of children with cerebral palsy have feeding difficulties, which, if not managed, result in stressful mealtimes, chronic malnutrition, respiratory disease, reduced quality of life for caregiver and child, and early death. In well-resourced countries, high- and low-cost medical interventions, ranging from gastrostomy tube feeding to caregiver training, are available. In resource-poor countries such as Bangladesh, the former is not viable and the latter is both scarce and its effectiveness not properly evaluated. The aim of this study was to evaluate the effectiveness of a low-cost, low-technology intervention to improve the feeding practices of carers of children with moderate-severe cerebral palsy and feeding difficulties in Bangladesh. An opportunistic sample of 37 caregivers and their children aged 1-11 years were invited to a six-session training programme following an initial feeding assessment with brief advice. During home visits, pre- and post-measures of nutritional status, chest health and feeding-related stress were taken and feeding practices were observed. A control phase was evaluated for 20 of the participant pairs following initial assessment with advice, while awaiting full training. A minimum of four training sessions showed significant improvements in the children's respiratory health (P = 0.005), cooperation during mealtimes (P = 0.003) and overall mood (P < 0.001). Improvements in growth were inconsistent. Dramatic reductions were observed in caregiver stress (P < 0.001). A significant difference in the outcomes following advice only compared with advice plus training was also observed. In situations of poverty, compliance is restricted by lack of education, finances and time. Nonetheless, carers with minimal formal education, living in conditions of extreme poverty were able to change feeding practices after a short, low-cost training intervention, with highly positive consequences. The availability of affordable food supplementation for this population, however, requires urgent attention.

Magnesium sulfate therapy for the prevention of cerebral palsy in preterm infants: a decision-analytic and economic analysis

We sought to estimate the cost-effectiveness of magnesium neuroprophylaxis for all women at risk for preterm birth <32 weeks. A decision analytic and cost-effectiveness model was designed to compare use of magnesium for neuroprophylaxis vs no treatment for women at risk for preterm birth <32 weeks due to preterm premature rupture of membranes or preterm labor from 24-32 weeks. Outcomes included neonatal death and moderate-severe cerebral palsy. Effectiveness was reported in quality-adjusted life years. Magnesium for neuroprophylaxis led to lower costs ($1739 vs $1917) and better outcomes (56.684 vs 56.678 quality-adjusted life years). However, sensitivity analysis revealed the model to be sensitive to estimates of effect of magnesium on risk of moderate or severe cerebral palsy as well as neonatal death. Based on currently published evidence for efficacy, magnesium for neuroprophylaxis in women at risk to deliver preterm is cost-effective.

Seizures in Extremely Low Birth Weight Infants Are Associated with Adverse Outcome

To examine risk factors for neonatal clinical seizures and to determine the independent association with death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants. A total of 6499 ELBW infants (401-1000 g) surviving to 36 weeks postmenstrual age (PMA) were included in this retrospective study. Unadjusted comparisons were performed between infants with (n = 414) and without (n = 6085) clinical seizures during the initial hospitalization. Using multivariate logistic regression modeling, we examined the independent association of seizures with late death (after 36 weeks PMA) or NDI after controlling for multiple demographic, perinatal, and neonatal variables. Infants with clinical seizures had a greater proportion of neonatal morbidities associated with poor outcome, including severe intraventricular hemorrhage, sepsis, meningitis, and cystic periventricular leukomalacia (all P < .01). Survivors were more likely to have NDI or moderate-severe cerebral palsy at 18 to 22 months corrected age (both P < .01). After adjusting for multiple confounders, clinical seizures remained significantly associated with late death or NDI (odds ratio, 3.15; 95% CI, 2.37-4.19). ELBW infants with clinical seizures are at increased risk for adverse neurodevelopmental outcome, independent of multiple confounding factors.

Effects of Antenatal Exposure to Magnesium Sulfate on Neuroprotection and Mortality in Preterm Infants

To review the evidence regarding neuroprotective effects of antenatal exposure to magnesium sulfate. We conducted database searches of MEDLINE, the Cochrane Library and Controlled Trials Register, as well as the ClinicalTrials.gov and International Clinical Trials Register websites. Bibliographies of all relevant articles were reviewed. Randomized controlled trials comparing magnesium sulfate with placebo/other treatment in patients at risk of preterm delivery were evaluated for inclusion and methodological quality. The primary outcome was death or cerebral palsy by 18-24 months corrected age. Secondary outcomes were death, cerebral palsy, moderate-severe cerebral palsy, and death or moderate-severe cerebral palsy. Separate analyses were performed according to the gestational age (GA) at randomization (less than 32 to 34 weeks and less than 30 weeks) and for studies in which magnesium sulfate was used exclusively for fetal neuroprotection. Five randomized controlled trials were included (5,235 fetuses/infants). When analyzed by GA at randomization, in utero exposure to magnesium sulfate at less than 32-34 weeks did not reduce the rate of death or cerebral palsy (relative risk [RR] 0.92, 95% confidence interval [CI] 0.83-1.03). However, cerebral palsy (RR 0.70, 95% CI 0.55-0.89), moderate-severe cerebral palsy (RR 0.60, 95% CI 0.43-0.84), and death or moderate-severe cerebral palsy were significantly reduced, without an evident increase in the risk of death (RR 1.01, 95% CI 0.89-1.14). Similar results were obtained when the GA at randomization was less than 30 weeks. When only neuroprotection trials (four trials, 4,324 fetuses/infants) are analyzed, in utero exposure to magnesium sulfate additionally reduced the primary outcome of death or cerebral palsy. The number needed to treat to prevent one case of cerebral palsy among those who survive until age 18-24 months is 46 (95% CI 26-187) in infants exposed to magnesium sulfate in utero before 30 weeks, and 56 (95% CI 34-164) in infants exposed to magnesium sulfate in utero before 32 to 34 weeks. Fetal exposure to magnesium sulfate in women at risk of preterm delivery significantly reduces the risk of cerebral palsy without increasing the risk of death.

Brain activity and cognitive status in pediatric patients: development of a clinical assessment protocol.

The purpose of this study was to test the validity of a new computerized task to assess children's cognitive problem-solving skills using the brain event-related potentials. This event-related potential-computerized cognitive problem-solving task does not require a child to give a verbal or motor (ie, pointing) response. The event-related potential waveforms were recorded from 20 typically developing children. Two nonverbal, problem-solving tasks (tasks 1 and 2) were developed for each of two age groups (5 and 6 years). For each task, single pictures, taken from an existing standardized test of nonverbal problem solving, were individually and sequentially presented on a computer screen. One of the seven pictures was classified as incongruent or outside category; it did not belong with the other pictures. As predicted, the event-related potential amplitudes were significantly larger to the outside- versus within-category pictures. This effect was found for tasks 1 and 2 for the 5- and 6-year-old children. Children as young as 5 years of age reliably exhibit brain activity, which can be used to infer cognitive problem-solving skill. This assessment paradigm may eventually serve as a clinically useful adjunct to a thorough neurologic and neurodevelopmental assessment of selected pediatric populations, such as those presenting with moderate-severe cerebral palsy whose expressive language and motor skills are notably impaired.