Risk Factors for Term-Born Spastic Diplegic Cerebral Palsy: A Case-Control Study.

BACKGROUND: To identify if a predetermined set of potential risk factors are associated with spastic diplegic cerebral palsy (SDCP) in term-born children. METHODS: This is a case-control study with cases (n = 134) extracted from the Canadian Cerebral Palsy Registry (CCPR) and controls (n = 1950) from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Our primary variable was the SDCP phenotype in term-born children. Possible risk factors were selected a priori and include extreme maternal age (<19 or >35 years), pregnancy complications, maternal disease, substance use, perinatal infection, mode of delivery, perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia), sex, and birth weight. Multivariable analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Multivariable analysis revealed associations between term-born SDCP and pregnancy complications (OR = 4.73; 95% CI = 1.91 to 10.56), maternal disease (OR = 2.52; 95% CI = 1.57 to 3.93), substance use (OR = 3.11; 95% CI = 2.10 to 4.55), perinatal infection (OR = 2.72; 95% CI 1.32 to 5.10), Caesarean section (OR = 2.35; 95% CI = 1.62 to 3.40), and perinatal adversity (OR = 2.91; 95% CI = 1.94 to 4.50). Multiple regression analysis revealed associations between SDCP and pregnancy complications (OR = 3.28; 95% CI 1.20 to 8.15), maternal disease (OR = 2.52; 95% CI 1.50 to 4.12), substance use (OR = 3.59; 95% CI 2.37 to 5.40), perinatal infection (OR = 3.78, 95% CI 1.71 to 7.72), Caesarean section (OR = 2.72; 95% CI 1.82 to 4.03), and perinatal adversity (OR = 4.16; 95% CI 2.67 to 6.70). INTERPRETATION: Antenatal (pregnancy complications, maternal disease, substance use) and perinatal (infections, Caesarean section, and perinatal adversity) risk factors are associated with an increased risk of SDCP in term-born children, suggesting variable interactions between risk factors to provide a clinicopathologic framework that is different from SDCP observed in preterm-born children.

Risk Factors and Outcomes for Cerebral Palsy With Hypoxic-Ischemic Brain Injury Patterns Without Documented Neonatal Encephalopathy.

BACKGROUND AND OBJECTIVES: Perinatal hypoxic-ischemic brain injury is a leading cause of term-born cerebral palsy, the most common lifelong physical disability. Diagnosis is commonly made in the neonatal period by the combination of neonatal encephalopathy (NE) and typical neuroimaging findings. However, children without a history of neonatal encephalopathy may present later in childhood with motor disability and neuroimaging findings consistent with perinatal hypoxic-ischemic injury. We sought to determine the prevalence of such presentations using the retrospective viewpoint of a large multiregional cerebral palsy registry. METHODS: Patient cases were extracted from the Canadian Cerebral Palsy Registry with gestational age >36 weeks, an MRI pattern consistent with hypoxic-ischemic injury (HII, acute total, partial prolonged, or combined), and an absence of postnatal cause for HII. Documentation of NE was noted. Maternal-fetal risk factors, labor and delivery, neonatal course, and clinical outcome were extracted. Comparisons were performed using χ2 tests and multivariable logistic regression with multiple imputation. Propensity scores were used to assess for bias. RESULTS: Of the 170 children with MRI findings typical for HII, 140 (82.4%, 95% confidence interval [CI] 75.7%-87.7%) had documented NE and 29 (17.0%, 95% CI 11.7%-23.6%) did not. The group without NE had more abnormalities of amniotic fluid volume (odds ratio [OR] 15.8, 95% CI 1.2-835), had fetal growth restriction (OR 4.7, 95% CI 1.0-19.9), had less resuscitation (OR 0.03, 95% CI 0.007-0.08), had higher 5-minute Apgar scores (OR 2.2, 95% CI 1.6-3.0), were less likely to have neonatal seizures (OR 0.004, 95% CI 0.00009-0.03), and did not receive therapeutic hypothermia. MRI was performed at a median 1.1 months (interquartile range [IQR] 0.67-12.8 months) for those with NE and 12.2 months (IQR 6.6-25.9) for those without (p = 0.011). Patterns of injury on MRI were seen in similar proportions. Hemiplegia was more common in those without documented NE (OR 5.1, 95% CI 1.5-16.1); rates of preserved ambulatory function were similar. DISCUSSION: Approximately one-sixth of term-born children with an eventual diagnosis of cerebral palsy and MRI findings consistent with perinatal hypoxic-ischemic brain injury do not have documented neonatal encephalopathy, which was associated with abnormalities of fetal growth and amniotic fluid volume, and a less complex neonatal course. Long-term outcomes seem comparable with their peers with encephalopathy. The absence of documented neonatal encephalopathy does not exclude perinatal hypoxic-ischemic injury, which may have occurred antenatally and must be carefully evaluated with MRI.

Early Biomarkers in the Prediction of Later Functional Impairment in Term Children with Cerebral Palsy.

AIM: To identify possible early biomarkers that could predict later functional capabilities in children at risk for cerebral palsy (CP). METHODS: Data from 869 term children with CP were extracted from the Canadian Cerebral Palsy Registry. Univariate analyses were conducted to measure the association between readily available objective early biomarkers (neonatal encephalopathy [NE], cord or first hour of life pH, magnetic resonance imaging [MRI]) and functional outcomes such as mobility and feeding status. Multivariable regressions were then modeled to study whether adding predictors would affect the strength of the observed association. RESULTS: Patients with NE have higher odds of having an assigned Gross Motor Function Classification Score level of IV to V (prevalence ratio [PR], 2.87; 95% confidence interval [CI], 2.07 to 3.97) and are more likely to require dependent tube feeding (PR, 2.09; 95% CI, 1.12 to 3.88); this was similarly seen in patients with MRI findings of deep gray matter injury, watershed injury, near-total brain injury, and/or cortical malformation (mobility status [PR, 5.13; 95% CI, 3.73 to 7.11] and feeding status [PR, 4.87; 95% CI, 2.57 to 9.75]). Patients with cord or first hour of life pH <7 were also more likely to predict dependent mobility status (PR, 2.86; 95% CI, 1.76 to 4.69), however, not significantly more likely to predict eventual dependent feeding status (PR, 1.47; 95% CI, 0.58 to 3.32). CONCLUSIONS: This retrospective cohort study demonstrates that NE, MRI findings and cord or first hour of life pH can reliably predict later CP related functioning. These associations can be used to inform and clarify early prognosis discussions between caregivers and health professionals.

Development of a Bedside Tool to Predict the Diagnosis of Cerebral Palsy in Term-Born Neonates.

Importance: Cerebral palsy (CP) is the most common abnormality of motor development and causes lifelong impairment. Early diagnosis and therapy can improve outcomes, but early identification of infants at risk remains challenging. Objective: To develop a CP prognostic tool that can be applied to all term neonates to identify those at increased risk of developing CP. Design, Setting, and Participants: This case-control study used data from the Canadian Cerebral Palsy Registry (data collected from January 2003 to December 2019) for children with CP and the Alberta Pregnancy Outcomes and Nutrition study (mothers enrolled from May 2009 to September 2012; data extracted in 2020) for controls. There were 2771 children with CP and 2131 controls evaluated; 941 and 144, respectively, were removed for gestational age less than 37 weeks at birth, 565 with CP removed for incomplete data, and 2 controls removed for a diagnosis of CP. Data were analyzed from April to August 2022. Exposures: Potential risk factors were selected a priori based on the literature, including maternal, intrapartum, and infant characteristics. Main Outcomes and Measures: Diagnosis of CP, defined as a disorder of motor function due to a nonprogressive brain abnormality before age 1 year and classified by Gross Motor Function Classification System levels I to V. Results: Of 3250 included individuals, 1752 (53.9%) were male, and the median (IQR) gestational age at birth was 39 (38-40) weeks. Encephalopathy was present in 335 of 1184 infants with CP (28%) and 0 controls. The final prediction model included 12 variables and correctly classified 75% of infants, with a sensitivity of 56% (95% CI, 52-60) and specificity of 82% (95% CI, 81-84). The C statistic was 0.74 (95% CI, 71-76). Risk factors were found to be additive. A proposed threshold for screening is probability greater than 0.3, with a sensitivity of 65% (95% CI, 61-68) and specificity of 71% (95% CI, 69-73). The prognostic tool identified 2.4-fold more children with CP than would have presented with encephalopathy (odds ratio, 13.8; 95% CI, 8.87-22.65; P < .001). Conclusions and Relevance: In this case-control study, a prognostic model using 12 clinical variables improved the prediction of CP compared with clinical presentation with encephalopathy. This tool can be applied to all term newborns to help select infants for closer surveillance or further diagnostic tests, which could improve outcomes through early intervention.

Medical and surgical treatment of epilepsy in older adults: A national survey.

OBJECTIVE: There are no clinical guidelines dedicated to the treatment of epilepsy in older adults. We investigated physician opinion and practice regarding the treatment of people with epilepsy aged 65 years or older. We also sought to study how our opinion and practice varied between geriatricians, general neurologists, and epilepsy neurologists (i.e., epileptologists). METHODS: We initially piloted our survey to measure test-retest reliability. Once finalized, we disseminated the survey via two rounds of facsimiles, and then conventional mail, to eligible individuals listed in a national directory of Canadian physicians. We used descriptive statistics such as stacked bar charts and tables to illustrate our findings. RESULTS: One hundred forty-four physicians (104 general neurologists, 25 geriatricians, and 15 epileptologists) answered our survey in its entirety (overall response rate of 13.2%). Levetiracetam and lamotrigine were the preferred antiseizure medications (ASMs) to treat older adults with epilepsy. Two thirds of epileptologists and almost half of general neurologists would consider prescribing lacosamide in >50% of people aged >65 years; only one geriatrician was of the same opinion. More than 40% of general neurologists and geriatricians erroneously believed that none of the ASMs mentioned in our survey was previously studied in randomized controlled trials specific to the treatment of epilepsy in older adults. Epileptologists were more likely as compared to general neurologists and geriatricians to recommend epilepsy surgery (e.g., 66.6% vs. 22.9%-37.5% among older adults). SIGNIFICANCE: Therapeutic decisions for older adults with epilepsy are heterogeneous between physician groups and sometimes misalign with available clinical evidence. Our surveyed physicians differed in their approach to ASM choice as well as perception of surgery in older adults with epilepsy. These findings likely reflect the lack of clinical guidelines dedicated to this population and the deficient implementation of best practices.

Association Between Frailty and Antiseizure Medication Tolerability in Older Adults With Epilepsy.

BACKGROUND AND OBJECTIVE: Frailty is an important aspect of biological aging, referring to the increased vulnerability of individuals with frailty to physical and psychological stressors. While older adults with epilepsy are an important and distinct clinical group, there are no data on frailty in this population. We hypothesize that frailty will correlate with the seizure frequency and especially the tolerability of antiseizure medications (ASMs) in older adults with epilepsy. METHODS: We recruited individuals aged 60 years or older with active epilepsy from 4 Canadian hospital centers. We reported the seizure frequency in the 3 months preceding the interview, while ASM tolerability was quantified using the Liverpool Adverse Events Profile (LAEP). We applied 3 measures of frailty: grip strength as a measure of physical frailty, 1 self-reported score (Edmonton frail score [EFS]), and 1 scale completed by a healthcare professional (clinical frailty scale [CFS]). We also administered standardized questionnaires measuring levels of anxiety, depression, functional disability, and quality of life and obtained relevant clinical and demographic data. RESULTS: Forty-three women and 43 men aged 60-93 years were recruited, 87% of whom had focal epilepsy, with an average frequency of 3.4 seizures per month. Multiple linear regression and zero-inflated negative binomial regression models showed that EFS and CFS scores were associated with decreased ASM tolerability, each point increase leading to 1.83 (95% CI: 0.67-4.30) and 2.49 (95% CI: 1.27-2.39) point increases on the LAEP scale, respectively. Neither the EFS and CFS scores nor grip strength were significantly associated with seizure frequency. The EFS was moderately correlated with depression, anxiety, quality of life, and functional disability, demonstrating the best construct validity among the 3 tested measures of frailty. DISCUSSION: The EFS was significantly, both statistically and clinically, associated with ASM tolerability. It also showed multiple advantages in performance while assessing for frailty in older adults with epilepsy, when compared with the 2 other measures of frailty that we tested. Future studies must focus on what role the EFS during epilepsy diagnosis may play in ASM selection among older adults with epilepsy.

Risk Factors for Term-Born Periventricular White Matter Injury in Children With Cerebral Palsy: A Case-Control Study.

OBJECTIVE: The aim of this study was to identify possible risk factors associated with term-born children with cerebral palsy (CP) and periventricular white matter injury (PVWMI) on imaging. METHODS: This is a case-controlled study restricted to term-born children with CP with the cases extracted from the Canadian Cerebral Palsy Registry and controls from Alberta Pregnancy Outcomes and Nutrition (APrON) study. A diagnosis of PVWMI was performed based on expert categorization of MRI reports. Risk factor variables were selected a priori; these included pregnancy complications, antenatal toxin exposure, perinatal infection, sex, small for gestational age, and perinatal adversity (i.e., neonatal encephalopathy presumably on the basis of intrapartum hypoxia-ischemia). We used multivariable analyses to calculate odds ratios (ORs) and their 95% CIs. RESULTS: A total of 160 cases (7.06% of the registry sample) were compared with 1,950 controls. Of the term-born PVWMI participants, 59.4% were male and 13.5% were born to mothers of extreme maternal age. Multivariable analysis of each risk factor controlled for weight showed PVWMI is associated with pregnancy complications (OR = 3.35; 95% CI = 2.23-4.94), antenatal toxin exposure (OR = 2.45; 95% CI = 1.67-3.55), perinatal infection (OR = 3.61; 95% CI = 1.96-6.29), and perinatal adversity (OR = 2.03; 95% CI = 1.42-2.94). Term-born male participants were not more likely to experience PVWMI compared with female participants (OR = 1.37; 95% CI = 0.98-1.93). Multiple regression analyses suggested independent associations between PVWMI and pregnancy complications (OR = 3.75; 95% CI 2.46-5.62), antenatal toxin exposure (OR = 2.80; 95% CI 1.88-4.12), perinatal infection (OR = 4.62; 95% CI 2.46-8.42), and perinatal adversity (OR = 2.49; 95% CI = 1.71-3.69). DISCUSSION: Risk factors such as pregnancy complications, antenatal toxin exposure, perinatal infection, and perinatal adversity are associated with PVWMI in term-born children, suggesting perhaps variable interactions between antenatal and perinatal factors to yield this under-recognized CP phenotype.

Sudden Death and Cardiac Arrythmia With Lamotrigine: A Rapid Systematic Review.

BACKGROUND AND OBJECTIVES: A recent Food and Drug Administration warning concerning an arrhythmogenic potential of lamotrigine created concern in the neurologic community. This warning was based on in vitro studies, but no clinically relevant risk was considered. This rapid systematic review aims to elucidate the risk of lamotrigine on sudden death or ECG abnormalities. METHODS: We conducted a systematic search of Ovid Medline and Ovid Embase, including randomized controlled trials and observational studies and studies of people with or without epilepsy, with the outcome measures sudden unexpected death in epilepsy (SUDEP) or sudden cardiac death as well as the development or worsening of ECG abnormalities. We evaluated the sudden death definitions used in all included studies, as some could have used unclear or overlapping definitions. We used the American Academy of Neurology risk of bias tool to evaluate the class of evidence and the GRADE approach to evaluate our confidence in the evidence. RESULTS: We included 26 studies with 24,962 participants, of whom 2,326 used lamotrigine. Twelve studies showed no significant risk of SUDEP for lamotrigine users. One study reporting on sudden cardiac death and 3 studies with unclear sudden death definitions did not report an elevated risk of death in lamotrigine users compared to controls. In 10 studies reporting on ECG measures, there was no statistically significant increased risk among lamotrigine users except in 2 studies. These 2 studies reported either "slight increases" in PR interval or an increased PQ interval that the primary study authors believed to be related to structural cardiac differences rather than an effect of lamotrigine. One study was rated Class II; all others were Class III or IV. We had very low confidence in the evidence following the GRADE assessment. None of the studies examined the risk of lamotrigine in people with preexisting cardiac conditions. DISCUSSION: There is insufficient evidence to support or refute that lamotrigine is associated with sudden death or ECG changes in people with or without epilepsy as compared to antiseizure medication or placebo, due to the high risk of bias in most studies and low precision and inconsistency in the reported results.

Understanding cardiovascular disease in older adults with epilepsy.

OBJECTIVE: This study was undertaken to investigate the distribution of social, lifestyle/behavior, and chronic disease risk factors for cardiovascular disease (CVD) in people with epilepsy as compared to the general population. We also measured the cross-sectional association between epilepsy and CVD in older adults, with and without adjustments for a history of stroke. METHODS: We analyzed data for 44 817 participants in the Canadian Longitudinal Study on Aging, including 751 individuals with a lifetime history of epilepsy. We modeled associations using ordinal and binomial logistic regression, as well as log-binomial regression, with multiple imputation for missing data. We measured the attributable fraction of CVD burden due to stroke. RESULTS: The majority of the CVD risk factors were significantly more prevalent in people with epilepsy as compared to the general population without epilepsy, independent of age and sex. After adjusting for a history of stroke, people with epilepsy had a significantly higher prevalence of heart disease (prevalence ratio [PR] = 1.27, 95% confidence interval [CI] = 1.02-1.57) and peripheral vascular disease (PR = 1.88, 95% CI = 1.50-2.36). Stroke accounted for 36% (95% CI = 19.85-48.76) of the increased prevalence of any CVD among people with epilepsy, similar to the 32% (95% CI = 27.82-36.25) among people without epilepsy. After adjustment for all other CVD risk factors, peripheral vascular disease remained significantly more prevalent (PR = 1.65, 95% CI = 1.28-2.12) in people with epilepsy as compared to those without. SIGNIFICANCE: CVD risk factors are more prevalent in people with epilepsy, independent of age and sex, and the association between epilepsy and CVD is independent of the association between epilepsy and stroke. The association between peripheral vascular disease and epilepsy may differ from the associations with other types of CVD. These findings are important steps in more comprehensively understanding the origins of CVD in people with epilepsy.