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.

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.

Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial.

BACKGROUND: Tumour necrosis factor (TNF) inhibition and B-cell depletion are highly effective treatments for active rheumatoid arthritis, but so far no randomised controlled trials have directly compared their safety, efficacy, and cost-effectiveness. This study was done to test the hypothesis that using rituximab would be clinically non-inferior and cheaper compared with TNF inhibitor treatment in biological-treatment naive patients with rheumatoid arthritis. METHODS: This open-label, randomised controlled, non-inferiority trial enrolled patients with active, seropositive rheumatoid arthritis and an inadequate response to synthetic disease modifying anti-rheumatic drugs (DMARDs) from 35 rheumatology departments in the UK. Patients were randomly assigned 1:1 to the rituximab or TNF inhibitor groups with minimisation to account for methotrexate intolerance using a web-based randomisation system. Patients were given intravenous rituximab 1 g on days 1 and 15, and after 26 weeks if they responded to treatment but had persistent disease activity (28 joint count disease activity score [DAS28-ESR] >3.2; rituximab group) or a TNF inhibitor-adalimumab (40 mg subcutaneously every other week) or etanercept (50 mg per week subcutaneously) according to the patient's and rheumatologist's choice (TNF inhibitor group). Patients could switch treatment in the case of drug-related toxic effects or absence or loss of response. The primary outcome measure was the change in DAS28-ESR between 0 and 12 months in the per-protocol population of patients who were assigned to treatment and remained in follow-up to 1 year. We assessed safety in all patients who received at least one dose of study drug. We also assessed the cost-effectiveness of each strategy. The non-inferiority margin was specified as 0.6 DAS28-ESR units. This study is registered with ClinicalTrials.gov, number NCT01021735. FINDINGS: Between April 6, 2009, and Nov 11, 2013, 295 patients were randomly assigned and given either rituximab (n=144) or TNF inhibitor (n=151) treatment. After 12 months, the change in DAS28-ESR for patients assigned to rituximab was -2.6 (SD 1.4) and TNF inhibitor was -2.4 (SD 1.5), with a difference within the prespecified non-inferiority margin of -0.19 (95% CI -0.51 to 0.13; p=0.24). The health-related costs associated with the rituximab strategy were lower than the TNF inhibitor strategy (£9,405 vs £11,523 per patient, p<0.0001). 137 (95%) of 144 patients in the rituximab group and 143 (95%) of 151 patients in the TNF inhibitor group had adverse events. 37 serious adverse events occurred in patients receiving rituximab compared with 26 in patients receiving TNF inhibitors, of which 27 were deemed to be possibly, probably, or definitely related to the treatment (15 vs 12, p=0.5462). One patient in each group died during the study. INTERPRETATION: Initial treatment with rituximab is non-inferior to initial TNF inhibitor treatment in patients seropositive for rheumatoid arthritis and naive to treatment with biologicals, and is cost saving over 12 months. FUNDING: Arthritis Research UK, Roche.

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.

Eligibility for clinical trials in primary Sjögren's syndrome: lessons from the UK Primary Sjögren's Syndrome Registry.

OBJECTIVE: To identify numbers of participants in the UK Primary Sjögren's Syndrome Registry (UKPSSR) who would fulfil eligibility criteria for previous/current or potential clinical trials in primary SS (pSS) in order to optimize recruitment. METHODS: We did a retrospective analysis of UKPSSR cohort data of 688 participants who had pSS with evaluable data. RESULTS: In relation to previous/current trials, 75.2% fulfilled eligibility for the Belimumab in Subjects with Primary Sjögren's Syndrome study (Belimumab), 41.4% fulfilled eligibility for the Trial of Remicade in primary Sjögren's syndrome study (Infliximab), 35.4% for the Efficacy of Tocilizumab in Primary Sjögren's Syndrome study (Tocilizumab), 31.6% for the Tolerance and Efficacy of Rituximab in Sjögren's Disease study (Rituximab), 26.9% for the Trial of anti-B-cell therapy in pSS study (Rituximab) and 26.6% for the Efficacy and Safety of Abatacept in Patients With Primary Sjögren's Syndrome study (Abatacept). If recent measures of outcome, such as the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score ⩾5 (measure of patient symptoms) and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ⩾5 (measure of systemic disease activity) are incorporated into a study design, with requirements for an unstimulated salivary flow >0 and anti-Ro positivity, then the pool of eligible participants is reduced to 14.3%. CONCLUSION: The UKPSSR identified a number of options for trial design, including selection on ESSDAI ⩾5, ESSPRI ⩾5 and serological and other parameters.

The Scottish Early Rheumatoid Arthritis (SERA) Study: an inception cohort and biobank.

BACKGROUND: The Scottish Early Rheumatoid Arthritis (SERA) study is an inception cohort of rheumatoid (RA) and undifferentiated arthritis (UA) patients that aims to provide a contemporary description of phenotype and outcome and facilitate discovery of phenotypic and prognostic biomarkers METHODS: Demographic and clinical outcome data are collected from newly diagnosed RA/UA patients every 6 months from around Scotland. Health service utilization data is acquired from Information Services Division, NHS National Services Scotland. Plain radiographs of hands and feet are collected at baseline and 12 months. Additional samples of whole blood, plasma, serum and filtered urine are collected at baseline, 6 and 12 months RESULTS: Results are available for 1073 patients; at baseline, 76 % were classified as RA and 24 % as UA. Median time from onset to first review was 163 days (IQR97-323). Methotrexate was first-line DMARD for 75 % patients. Disease activity, functional ability and health-related quality of life improved significantly between baseline and 24 months, however the proportion in any employment fell (51 to 38 %, p = 0.0005). 24 % patients reported symptoms of anxiety and/or depression at baseline. 35/391 (9 %) patients exhibited rapid radiographic progression after 12 months. The SERA Biobank has accrued 60,612 samples CONCLUSIONS: In routine care, newly diagnosed RA/UA patients experience significant improvements in disease activity, functional ability and health-related quality of life but have high rates of psychiatric symptoms and declining employment rates. The co-existence of a multi-domain description of phenotype and a comprehensive biobank will facilitate multi-platform translational research to identify predictive markers of phenotype and prognosis.

Do the EULAR Sjögren's syndrome outcome measures correlate with health status in primary Sjögren's syndrome?

OBJECTIVE: This study sets out to investigate the relationship between health status [EuroQol five-dimensions questionnaire (EQ-5D)] in primary SS and three of the European League Against Rheumatism (EULAR) SS outcome measures-the disease activity index (ESSDAI), the patient reported index (ESSPRI) and the sicca score. In particular, the goal was to establish whether there is a relationship between the EULAR outcome measures and quality of life. METHODS: Health status was evaluated using a standardized measure developed by the EuroQol Group-the EQ5D. This permits calculation of two measures of health status: time trade-off (TTO) values and the EQ-5D visual analogue scale (VAS) scores. We used Spearman's rank correlation analysis to investigate the strength of association between health status and three EULAR measures of physician- and patient-reported disease activity in 639 patients from the UK primary SS registry (UKPSSR) cohort. RESULTS: This study demonstrates that the EULAR SS disease-specific outcome measures are significantly correlated with health outcome values (P < 0.001). Higher scores on the ESSDAI, EULAR sicca score and ESSPRI are associated with poorer health states-i.e. lower TTO values and lower VAS scores. While all three are significantly correlated with TTO values and EQ-5D VAS scores, the effect is strongest for the ESSPRI. CONCLUSION: This study provides further evidence supporting the use of ESSDAI, EULAR sicca score and ESSPRI measures in the clinic. We also discuss the need for disease-specific measures of health status and their comparison with standardized health outcome measures.

The characterisation and determinants of quality of life in ANCA associated vasculitis.

OBJECTIVES: To contextualise and identify the determinants of poor health related quality of life (QOL) among patients with antineutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV). METHODS: A multicentre AAV case-control study was conducted using two matched groups of population and chronic disease controls. Measures of physical and mental QOL as well as putative bio-psychosocial determinants of QOL impairment were collected. Concurrently, putative clinical QOL determinants were recorded. Conditional logistic regression analyses characterised group differences while multivariable logistic regression identified within-case QOL associations which were further quantified using population attributable risks (PAR). RESULTS: Cases (n=410) experienced similar QOL to chronic disease controls (n=318) (physical QOL: OR 0.7, 95% CI 0.4 to 1.1; mental QOL: OR 1.1, 95% CI 0.8 to 1.6). However, they were substantially more likely to report poor QOL compared to general population controls (n=470) (physical QOL: OR 7.0, 95% CI 4.4 to 11.1; mental QOL: OR 2.5, 95% CI 1.7 to 3.6). A few clinical, but many more bio-psychosocial factors were independently associated with poor QOL. In population terms, fatigue was found to be of principal importance (physical QOL: PAR 24.6%; mental QOL: PAR 47.4%). CONCLUSIONS: AAV patients experienced significant QOL impairment compared to the general population, but similar to those with other chronic diseases whose considerable needs are already recognised. Potentially modifiable clinical determinants have been identified; however bio-psychosocial interventions are likely to provide the greater QOL gains in this patient population.

Health-related utility values of patients with primary Sjögren's syndrome and its predictors.

OBJECTIVES: EuroQoL-5 dimension (EQ-5D) is a standardised preference-based tool for measurement of health-related quality of life and EQ-5D utility values can be converted to quality-adjusted life years (QALYs) to aid cost-utility analysis. This study aimed to evaluate the EQ-5D utility values of 639 patients with primary Sjögren's syndrome (PSS) in the UK. METHODS: Prospective data collected using a standardised pro forma were compared with UK normative data. Relationships between utility values and the clinical and laboratory features of PSS were explored. RESULTS: The proportion of patients with PSS reporting any problem in mobility, self-care, usual activities, pain/discomfort and anxiety/depression were 42.2%, 16.7%, 56.6%, 80.6% and 49.4%, respectively, compared with 5.4%, 1.6%, 7.9%, 30.2% and 15.7% for the UK general population. The median EQ-5D utility value was 0.691 (IQR 0.587-0.796, range -0.239 to 1.000) with a bimodal distribution. Bivariate correlation analysis revealed significant correlations between EQ-5D utility values and many clinical features of PSS, but most strongly with pain, depression and fatigue (R values>0.5). After adjusting for age and sex differences, multiple regression analysis identified pain and depression as the two most important predictors of EQ-5D utility values, accounting for 48% of the variability. Anxiety, fatigue and body mass index were other statistically significant predictors, but they accounted for <5% in variability. CONCLUSIONS: This is the first report on the EQ-5D utility values of patients with PSS. These patients have significantly impaired utility values compared with the UK general population. EQ-5D utility values are significantly related to pain and depression scores in PSS.

Markers for work disability in anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) commonly affects those of working age. Since survival rates have been transformed by immunotherapeutics, the measurement of other outcomes has become increasingly relevant. Work disability is an important outcome for both patient and society that has yet to be fully evaluated in AAV. We aimed to assess employment status in AAV patients and identify putative predictors of their work disability. METHODS: A cross-sectional study was undertaken. AAV cases were recruited according to consecutive clinic attendance. Subjects completed a questionnaire that determined employment status and other psychosocial measures. Clinical factors were concurrently recorded by the attending physician. From the data of those subjects of working age, a multivariable model was developed using forward stepwise logistic regression to identify the independent associations of work disability, defined by those subjects reporting unemployment secondary to ill-health. Results are expressed as odds ratios (ORs) and 95% CIs. RESULTS: Of the 410 participants (84.4% response rate), 149 (36.7%) were employed, 197 (48.6%) retired and 54 (13.3%) unemployed secondary to ill health. Of those of working age, 26.0% were considered work disabled. Fatigue (OR 7.1, 95% CI 1.5, 33.1), depression (OR 4.4, 95% CI 1.8, 10.8), severe disease damage [Vasculitis Damage Index (VDI) > 4 (OR 3.9, 95% CI 1.01, 14.7)] and being overweight (OR 3.4, 95% CI 1.3, 8.9) were independently associated with their unemployment. CONCLUSION: A quarter of working-age AAV subjects reported unemployment as a result of ill health and are characterized by high levels of fatigue, depression, disease damage and being overweight. These potentially modifiable factors may inform future multidisciplinary interventions aimed at alleviating work disability.

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.

Explaining fatigue in ANCA-associated vasculitis.

OBJECTIVES: To identify the determinants of fatigue among patients with ANCA-associated vasculitis (AAV). METHODS: A multicentre cross-sectional study was conducted. Subjects fulfilling the European Medicines Agency criteria for granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) were approached according to consecutive clinic attendance and invited to complete a questionnaire assessing fatigue and putative biopsychosocial determinants of this symptom. Concurrently, potential clinical determinants were recorded. Independent associations of fatigue were identified using forward stepwise logistic regression modelling and their overall impact expressed as population attributable risk (PAR). RESULTS: The majority (74.8%) of participants (n = 410) reported high levels of fatigue that were found to be significantly associated with numerous biopsychosocial and clinical factors. Sleep disturbance [odds ratio (OR) 5.3, 95% CI 2.7, 10.5] and pain (OR 3.8, 95% CI 2.0, 7.3) were the strongest independent associations of fatigue and, on a population level, each was more than twice as important as any other putative determinant (PAR 18.1% and 16.5%, respectively). Female gender (OR 2.1, 95% 1.1, 4.0), elevated CRP (OR 3.7, 95% CI 1.7, 8.1) and the dysfunctional coping strategies of behavioural disengagement (OR 2.4, 95% CI 1.04, 5.6) and denial (OR 2.4, 95% CI 0.9, 6.7) were also independently associated with fatigue. CONCLUSION: The data suggest that AAV-related fatigue is multifactorial in origin. Sleep disturbance and pain were found to be most important, although inflammation, as measured by CRP, was also associated. This study has identified potentially modifiable determinants that will inform future interventions aimed at alleviating fatigue.

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.

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.

Autonomic symptoms are common and are associated with overall symptom burden and disease activity in primary Sjogren's syndrome.

OBJECTIVES: To determine the prevalence of autonomic dysfunction (dysautonomia) among patients with primary Sjögren's syndrome (PSS) and the relationships between dysautonomia and other clinical features of PSS. METHODS: Multicentre, prospective, cross-sectional study of a UK cohort of 317 patients with clinically well-characterised PSS. Symptoms of autonomic dysfunction were assessed using a validated instrument, the Composite Autonomic Symptom Scale (COMPASS). The data were compared with an age- and sex-matched cohort of 317 community controls. The relationships between symptoms of dysautonomia and various clinical features of PSS were analysed using regression analysis. RESULTS: COMPASS scores were significantly higher in patients with PSS than in age- and sex-matched community controls (median (IQR) 35.5 (20.9-46.0) vs 14.8 (4.4-30.2), p<0.0001). Nearly 55% of patients (vs 20% of community controls, p<0.0001) had a COMPASS score >32.5, a cut-off value indicative of autonomic dysfunction. Furthermore, the COMPASS total score correlated independently with EULAR Sjögren's Syndrome Patient Reported Index (a composite measure of the overall burden of symptoms experienced by patients with PSS) (ß=0.38, p<0.001) and disease activity measured using the EULAR Sjögren's Syndrome Disease Activity Index (ß=0.13, p<0.009). CONCLUSIONS: Autonomic symptoms are common among patients with PSS and may contribute to the overall burden of symptoms and link with systemic disease activity.

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.

EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis.

OBJECTIVES: The systemic vasculitides are multiorgan diseases where early diagnosis and treatment can significantly improve outcomes. Robust nomenclature reduces diagnostic delay. However, key aspects of current nomenclature are widely perceived to be out of date, these include disease definitions, classification and diagnostic criteria. Therefore, the aim of the present work was to identify deficiencies and provide contemporary points to consider for the development of future definitions and criteria in systemic vasculitis. METHODS: The expert panel identified areas of concern within existing definitions/criteria. Consequently, a systematic literature review was undertaken looking to address these deficiencies and produce 'points to consider' in accordance with standardised European League Against Rheumatism (EULAR) operating procedures. In the absence of evidence, expert consensus was used. RESULTS: There was unanimous consensus for re-evaluating existing definitions and developing new criteria. A total of 17 points to consider were proposed, covering 6 main areas: biopsy, laboratory testing, diagnostic radiology, nosology, definitions and research agenda. Suggestions to improve and expand current definitions were described including the incorporation of anti-neutrophil cytoplasm antibody and aetiological factors, where known. The importance of biopsy in diagnosis and exclusion of mimics was highlighted, while equally emphasising its problems. Thus, the role of alternative diagnostic tools such as MRI, ultrasound and surrogate markers were also discussed. Finally, structures to develop future criteria were considered. CONCLUSIONS: Limitations in current classification criteria and definitions for vasculitis have been identified and suggestions provided for improvement. Additionally it is proposed that, in combination with the updated evidence, these should form the basis of future attempts to develop and validate revised criteria and definitions of vasculitis.

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.