Pediatric epilepsy syndromes with associated developmental impairment.

In 2022, the International League Against Epilepsy revised their classification of epilepsy syndromes for clinicians to better understand the relationships between different epilepsy syndromes, their underlying causes, and their associated developmental and behavioral features. This review highlights portions of the current classification with an emphasis on epilepsy syndromes that readily present with developmental challenges and provides a unique framework, based on electroencephalography, to easily identify and understand these syndromes. Included in this review are a helpful categorization scheme with visual aid, descriptions of updated epilepsy syndromes, figures of relevant identifiers of syndrome and information regarding future directions toward treatment and research. Covered syndromes include developmental and epileptic encephalopathy, Dravet syndrome, Rasmussen syndrome, and infantile epileptic spasm syndrome, among others. WHAT THIS PAPER ADDS: The revised epilepsy syndrome classification by the International League Against Epilepsy aims to improve the outcomes for children with epilepsy. The electroencephalography features of epilepsy syndromes are grouped based on a categorization model. This model allows clinicians to understand overlapping phenotypes and aid with both identification and diagnosis.

Epilepsy Surgery for Cognitive Improvement in Epileptic Encephalopathy.

Epileptic encephalopathies are defined by the presence of frequent epileptiform activity that causes neurodevelopmental slowing or regression. Here, we review evidence that epilepsy surgery improves neurodevelopment in children with epileptic encephalopathies. We describe an example patient with epileptic encephalopathy without drug refractory seizures, who underwent successful diagnostic and therapeutic surgeries. In patients with epileptic encephalopathy, cognitive improvement alone is a sufficient indication to recommend surgical intervention in experienced centers.

Preliminary evidence of a relationship between sleep spindles and treatment response in epileptic encephalopathy.

OBJECTIVE: Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) is a challenging neurodevelopmental disease characterized by abundant epileptiform spikes during non-rapid eye movement (NREM) sleep accompanied by cognitive dysfunction. The mechanism of cognitive dysfunction is unknown, but treatment with high-dose diazepam may improve symptoms. Spike rate does not predict treatment response, but spikes may disrupt sleep spindles. We hypothesized that in patients with EE-SWAS: (1) spikes and spindles would be anti-correlated, (2) high-dose diazepam would increase spindles and decrease spikes, and (3) spindle response would be greater in those with cognitive improvement. METHODS: Consecutive EE-SWAS patients treated with high-dose diazepam that met the criteria were included. Using a validated automated spindle detector, spindle rate, duration, and percentage were computed in pre- and post-treatment NREM sleep. Spikes were quantified using a validated automated spike detector. The cognitive response was determined from a chart review. RESULTS: Spindle rate was anti-correlated with the spike rate in the channel with the maximal spike rate (p = 0.002) and averaged across all channels (p = 0.0005). Spindle rate, duration, and percentage each increased, and spike rate decreased, after high-dose diazepam treatment (p ≤ 2e-5, all tests). Spindle rate, duration, and percentage (p ≤ 0.004, all tests) were increased in patients with cognitive improvement after treatment, but not those without. Changes in spindle rate but not changes in spike rate distinguished between groups. INTERPRETATION: These findings confirm thalamocortical disruption in EE-SWAS, identify a mechanism through which benzodiazepines may support cognitive recovery, and introduce sleep spindles as a promising mechanistic biomarker to detect treatment response in severe epileptic encephalopathies.

Preliminary evidence of a relationship between sleep spindles and treatment response in epileptic encephalopathy.

Objective: Epileptic encephalopathy with spike wave activation in sleep (EE-SWAS) is a challenging neurodevelopmental disease characterized by abundant epileptiform spikes during non-rapid eye movement (NREM) sleep accompanied by cognitive dysfunction. The mechanism of cognitive dysfunction is unknown, but treatment with high-dose diazepam may improve symptoms. Spike rate does not predict treatment response, but spikes may disrupt sleep spindles. We hypothesized that in patients with EE-SWAS: 1) spikes and spindles would be anticorrelated, 2) high-dose diazepam would increase spindles and decrease spikes, and 3) spindle response would be greater in those with cognitive improvement. Methods: Consecutive EE-SWAS patients treated with high-dose diazepam that met criteria were included. Using a validated automated spindle detector, spindle rate, duration, and percentage were computed in pre- and post-treatment NREM sleep. Spikes were quantified using a validated automated spike detector. Cognitive response was determined from chart review. Results: Spindle rate was anticorrelated with spike rate in the channel with the maximal spike rate ( p =0.002) and averaged across all channels ( p =0.0005). Spindle rate, duration, and percentage each increased, and spike rate decreased, after high-dose diazepam treatment ( p≤ 2e-5, all tests). Spindle rate, duration, and percentage ( p ≤0.004, all tests) were increased in patients with cognitive improvement after treatment, but not those without. Changes in spike rate did not distinguish between groups. Interpretation: These findings confirm thalamocortical disruption in EE-SWAS, identify a mechanism through which benzodiazepines may support cognitive recovery, and introduce sleep spindles as a promising mechanistic biomarker to detect treatment response in severe epileptic encephalopathies.

Clinical Reasoning: An 8-Year-Old With Acute Onset Ataxia.

Acute ataxia is a common neurologic presentation in the pediatric population that carries a broad differential diagnosis. The tempo of the presentation, distribution of the ataxia (focal or diffuse), examination findings, and paraclinical testing may be helpful in guiding diagnosis and management. Although Guillain-Barré syndrome (GBS) and its variant, Miller Fisher syndrome (MFS), are well defined, frequently encountered acute autoimmune neuropathies, the GBS/MFS spectrum have at least 12 different phenotypes with distinct neurologic features, 4 of which include ataxia. These lesser-known variants can be diagnosed clinically, in the absence of conclusive laboratory or neuroimaging data, and should always be considered in an acute presentation of ataxia. In this article, we present a previously healthy 8-year-old with acute onset ataxia with associated hyporeflexia that occurred after resolution of a presumed viral infection. We discuss our approach to ataxia, the patient's neurodiagnostic odyssey, and highlight the final diagnosis of acute ataxic neuropathy without ophthalmoplegia-a rare incomplete MFS subtype. Owing to timely recognition of the condition, the patient was treated appropriately and recovered fully.

Multimorbidity in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results From a Longitudinal, Multicenter Data Linkage Study.

OBJECTIVE: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is considered a chronic, relapsing condition. To date, no studies have investigated multimorbidity in AAV nationally. This study was undertaken to characterize temporal trends in multimorbidity and report excess health care expenditures associated with multimorbidities in a national AAV cohort from Scotland. METHODS: Eligible patients with AAV were diagnosed between 1997 and 2017. Each patient was matched with up to 5 general population controls. Linked morbidity and health care expenditure data were retrieved from a Scottish national hospitalization repository and from published national cost data. Multimorbidity was defined as the development of ≥2 disorders. Prespecified morbidities, individually and together, were analyzed for risks and associations over time using modified Poisson regression, discrete interval analysis, and chi-square test for trend. The relationship between multimorbidities and health care expenditure was investigated using multivariate linear regression. RESULTS: In total, 543 patients with AAV (median age 58.7 years [range 48.9-68.0 years]; 53.6% male) and 2,672 general population controls (median age 58.7 years [range 48.9-68.0 years]; 53.7% male) were matched and followed up for a median of 5.1 years. AAV patients were more likely to develop individual morbidities at all time points, but especially <2 years after diagnosis. The highest proportional risk observed was for osteoporosis (adjusted incidence rate ratio 8.0, 95% confidence interval [95% CI] 4.5-14.2). After 1 year, 23.0% of AAV patients and 9.3% of controls had developed multimorbidity (P < 0.0001). After 10 years, 37.0% of AAV patients and 17.3% of controls were reported to have multimorbidity (P < 0.0001). Multimorbidity was associated with disproportionate increases in health care expenditures in AAV patients. Health care expenditure was highest for AAV patients with ≥3 morbidities (3.89-fold increase in costs, 95% CI 2.83-5.31; P < 0.001 versus no morbidities). CONCLUSION: These findings emphasize the importance of holistic care in patients with AAV, and may identify a potentially critical opportunity to consider early screening.

Characterizing infection in anti-neutrophil cytoplasmic antibody-associated vasculitis: results from a longitudinal, matched-cohort data linkage study.

OBJECTIVES: Infection exerts a major burden in ANCA-associated vasculitis (AAV), however, its precise extent and nature remains unclear. In this national study we aimed to longitudinally quantify, characterize and contextualize infection risk in AAV. METHODS: We conducted a multicentre matched cohort study of AAV. Complementary data on infections were retrieved via data linkage with the population-based Scottish microbiological laboratory, hospitalization and primary care prescribing registries. RESULTS: A total of 379 AAV patients and 1859 controls were followed up for a median of 3.5 years (interquartile range 1.9-5.7). During follow-up, the proportions of AAV patients with at least one laboratory-confirmed infection, severe infection and primary care antibiotic prescription were 55.4%, 35.6% and 74.6%, respectively. The risk of infection was higher in AAV than in matched controls {laboratory-confirmed infections: incidence rate ratio [IRR] 7.3 [95% confidence interval (CI) 5.6, 9.6]; severe infections: IRR 4.4 [95% CI 3.3, 5.7]; antibiotic prescriptions: IRR 2.2 [95% CI 1.9, 2.6]}. Temporal trend analysis showed that AAV patients remained at a higher risk of infections throughout the follow-up period, especially year 1. Although the Escherichia genus was the most commonly identified pathogen (16.6% of AAV, 5.5% of controls; P < 0.0001), AAV patients had the highest risk for Herpes [IRR 12.5 (95% CI 3.7, 42.6)] and Candida [IRR 11.4 (95% CI 2.4, 55.4)]. CONCLUSION: AAV patients have up to seven times higher risk of infection than the general population and the overall risk remains significant after 8 years of follow-up. The testing of enhanced short- to medium-term prophylactic antibiotic regimes should be considered.

How well do we know Gradenigo? A comprehensive literature review and proposal for novel diagnostic categories of Gradenigo's syndrome.

Gradenigo's Syndrome is a rare complication of otitis media and/or mastoiditis resulting in inflammation of the petrous apex of the temporal bone. Here, we highlight an interesting case from our institution, summarize available pediatric cases from the past fifty years to provide an updated diagnostic categorization for this rare condition with confusing nomenclature, and suggest guidance for diagnosis and management.

Pain and depression are associated with both physical and mental fatigue independently of comorbidities and medications in primary Sjögren's syndrome.

Objectives: To report on fatigue in patients from the United Kingdom primary Sjögren's syndrome (pSS) registry identifying factors associated with fatigue and robust to assignable causes such as comorbidities and medications associated with drowsiness. Methods: From our cohort (n = 608), we identified those with comorbidities associated with fatigue, and those taking medications associated with drowsiness. We constructed dummy variables, permitting the contribution of these potentially assignable causes of fatigue to be assessed. Using multiple regression analysis, we modelled the relationship between Profile of Fatigue and Discomfort physical and mental fatigue scores and potentially related variables. Results: Pain, depression and daytime sleepiness scores were closely associated with both physical and mental fatigue (all p ≤ 0.0001). In addition, dryness was strongly associated with physical fatigue (p ≤ 0.0001). These effects were observed even after adjustment for comorbidities associated with fatigue or medications associated with drowsiness. Conclusions: These findings support further research and clinical interventions targeting pain, dryness, depression and sleep to improve fatigue in patients with pSS.This finding is robust to both the effect of other comorbidities associated with fatigue and medications associated with drowsiness.

Functional Connectivity in Term Neonates With Hypoxic-Ischemic Encephalopathy Undergoing Therapeutic Hypothermia.

BACKGROUND: We investigated whether therapeutic hypothermia and rewarming impact functional connectivity using electroencephalography (EEG) as a measure in neonates with hypoxic-ischemic encephalopathy. We hypothesized that EEG coherence and voltage correlations would be lower and phase lag greater in infants with hypoxic-ischemic encephalopathy than control subjects and that functional connectivity would evolve during therapeutic hypothermia with the greatest improvement occurring during rewarming. METHODS: This study was a retrospective study of 14 term neonates (greater than 37 weeks) with moderate hypoxic-ischemic encephalopathy who underwent therapeutic hypothermia and rewarming. Continuous EEG and video monitoring was conducted for 96 hours during therapeutic hypothermia and rewarming. The primary quantitative EEG measures of functional connectivity were coherence, phase lag, and voltage correlations. These EEG parameters were compared with a cohort of normal age-matched neonates. RESULTS: Neonates with hypoxic-ischemic encephalopathy had marked decreases in power, coherences, and voltage correlation and increases in phase lag when compared with control neonates. However, there were no significant changes in these measures between therapeutic hypothermia and rewarming. CONCLUSIONS: Neonates with hypoxic-ischemic encephalopathy demonstrate significant abnormalities in functional connectivity compared with control subjects. These abnormalities persist through therapeutic hypothermia and rewarming and are not altered after rewarming. Although hypoxic-ischemic encephalopathy is associated with impaired functional brain connectivity, there is no evidence, using quantitative EEG measures, that therapeutic hypothermia or rewarming either improves or exacerbates these abnormalities in connectivity.

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials.

BACKGROUND: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. METHODS: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. FINDINGS: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, ß2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. INTERPRETATION: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. FUNDING: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. VIDEO ABSTRACT.

Comparison of ESSDAI and ClinESSDAI in potential optimisation of trial outcomes in primary Sjögren's syndrome: examination of data from the UK Primary Sjögren's Syndrome Registry.

OBJECTIVES: To assess the use of the Clinical EULAR Sjögren's Syndrome Disease Activity Index (ClinESSDAI), a version of the ESSDAI without the biological domain, for assessing potential eligibility and outcomes for clinical trials in patients with primary Sjögren's syndrome (pSS), according to the new ACR-EULAR classification criteria, from the UK Primary Sjögren's Syndrome Registry (UKPSSR). METHODS: A total of 665 patients from the UKPSSR cohort were analysed at their time of inclusion in the registry. ESSDAI and ClinESSDAI were calculated for each patient. RESULTS: For different disease activity index cut-off values, more potentially eligible participants were found when ClinESSDAI was used than with ESSDAI. The distribution of patients according to defined disease activity levels did not differ statistically (chi2 p = 0.57) between ESSDAI and ClinESSDAI for moderate disease activity (score ≥5 and <14; ESSDAI 36.4%; ClinESSDA 36.5%) or high disease activity (score ≥14; ESSDAI 5.4%; ClinESSDAI 6.8%). We did not find significant differences between the indexes in terms of activity levels for individual domains, with the exception of the articular domain. We found a good level of agreement between both indexes, and a positive correlation between lymphadenopathy and glandular domains with the use of either index and with different cut-off values. With the use of ClinESSDAI, the minimal clinically important improvement value was more often achievable with a one grade improvement of a single domain than with ESSDAI. We observed similar results when using the new ACR-EULAR classification criteria or the previously used American-European Consensus Group (AECG) classification criteria for pSS. CONCLUSIONS: In the UKPSSR population, the use of ClinESSDAI instead of ESSDAI did not lead to significant changes in score distribution, potential eligibility or outcome measurement in trials, or in routine care when immunological tests are not available. These results need to be confirmed in other cohorts and with longitudinal data.

Subjective and Objective Measures of Dryness Symptoms in Primary Sjögren's Syndrome: Capturing the Discrepancy.

OBJECTIVE: To develop a novel method for capturing the discrepancy between objective tests and subjective dryness symptoms (a sensitivity scale) and to explore predictors of dryness sensitivity. METHODS: Archive data from the UK Primary Sjögren's Syndrome Registry (n = 688) were used. Patients were classified on a scale from -5 (stoical) to +5 (sensitive) depending on the degree of discrepancy between their objective and subjective symptoms classes. Sensitivity scores were correlated with demographic variables, disease-related factors, and symptoms of pain, fatigue, anxiety, and depression. RESULTS: Patients were on average relatively stoical for both types of dryness symptoms (mean ± SD ocular dryness -0.42 ± 2.2 and -1.24 ± 1.6 oral dryness). Twenty-seven percent of patients were classified as sensitive to ocular dryness and 9% to oral dryness. Hierarchical regression analyses identified the strongest predictor of ocular dryness sensitivity to be self-reported pain and that of oral dryness sensitivity to be self-reported fatigue. CONCLUSION: Ocular and oral dryness sensitivity can be classified on a continuous scale. The 2 symptom types are predicted by different variables. A large number of factors remain to be explored that may impact symptom sensitivity in primary Sjögren's syndrome, and the proposed method could be used to identify relatively sensitive and stoical patients for future studies.

Physical activity but not sedentary activity is reduced in primary Sjögren's syndrome.

The aim of the study was to evaluate the levels of physical activity in individuals with primary Sjögren's syndrome (PSS) and its relationship to the clinical features of PSS. To this cross-sectional study, self-reported levels of physical activity from 273 PSS patients were measured using the International Physical Activity Questionnaire-short form (IPAQ-SF) and were compared with healthy controls matched for age, sex and body mass index. Fatigue and other clinical aspects of PSS including disease status, dryness, daytime sleepiness, dysautonomia, anxiety and depression were assessed using validated tools. Individuals with PSS had significantly reduced levels of physical activity [median (interquartile range, IQR) 1572 (594-3158) versus 3708 (1732-8255) metabolic equivalent of task (MET) × min/week, p < 0.001], but similar levels of sedentary activity [median (IQR) min 300 (135-375) versus 343 (223-433) (MET) × min/week, p = 0.532] compared to healthy individuals. Differences in physical activity between PSS and controls increased at moderate [median (IQR) 0 (0-480) versus 1560 (570-3900) MET × min/week, p < 0.001] and vigorous intensities [median (IQR) 0 (0-480) versus 480 (0-1920) MET × min/week, p < 0.001]. Correlation analysis revealed a significant association between physical activity and fatigue, orthostatic intolerance, depressive symptoms and quality of life. Sedentary activity did not correlate with fatigue. Stepwise linear regression analysis identified symptoms of depression and daytime sleepiness as independent predictors of levels of physical activity. Physical activity is reduced in people with PSS and is associated with symptoms of depression and daytime sleepiness. Sedentary activity is not increased in PSS. Clinical care teams should explore the clinical utility of targeting low levels of physical activity in PSS.