Associations between Antiepileptic Use and Hypogammaglobulinaemia: Findings from a Population-Based Case-Control Study Using Data Linkage.

BACKGROUND AND OBJECTIVES: Increased mortality in epilepsy due to infections (other than pneumonia) has been demonstrated. Small case series of people on antiepileptic drugs (AEDs) have described hypogammaglobulinaemia, which may predispose to infections. It is unclear whether hypogammaglobulinaemia is more frequent in people on AEDs, what AEDs it is associated with, or what clinical impact it has. In this population-based study, we aimed to determine whether AEDs were associated with hypogammaglobulinaemia, which AEDs were associated, and whether the associations may be causal. METHODS: We conducted an unmatched case-control study using data linkage of routinely collected biochemistry, prescribing, and morbidity datasets in North-East Scotland from 2009-2021. Cases were participants with immunoglobulin levels less than the reference range. Controls were those with normal/high immunoglobulin levels. Logistic regression was used to investigate associations between AED exposure and any hypogammaglobulinaemia, adjusting for age, sex, and comorbidity. We also analysed low IgA, IgM, and IgG separately. We analysed "any AED" exposure and common individual drugs separately. Cumulative exposure data were used to determine whether an exposure-response relationship was present. RESULTS: 18,666 cases and 127,157 controls were identified. Use of any AED was associated with increased risk of hypogammaglobulinaemia (adjusted odds ratio [aOR] 1.20 [95% CI: 1.15-1.25]). Phenytoin use was strongly associated with low IgA (aOR 5.90 [95% CI: 3.04, 10.43]). Carbamazepine and lamotrigine were also associated with low IgA. Apart from topiramate, which was associated with a non-significant decrease in odds of hypogammaglobulinaemia, there was a consistent increase in odds of hypogammaglobulinaemia across most AEDs studied. Panhypogammaglobulinaemia was associated with any AED use, carbamazepine, lamotrigine, gabapentin, and multiple AED use. There was evidence of an exposure-response relationship between any AED use and any hypogammaglobulinaemia, low IgA, and low IgG. Carbamazepine and probably lamotrigine also had an exposure-response relationship with any hypogammaglobulinaemia. DISCUSSION: AEDs may increase hypogammaglobulinaemia risk. Specific classes of immunoglobulins are differentially affected, and the exposure-response analysis suggests this may be causal. Further work should investigate the clinical impact of these findings. Clinicians should check immunoglobulin levels if unusual or recurrent infections occur in patients treated with AEDs.

Oral antibiotic use and early-onset colorectal cancer: findings from a case-control study using a national clinical database.

BACKGROUND: Antibiotic-induced gut dysbiosis has been associated with colorectal cancer (CRC) in older adults. This study will investigate whether an association exists between antibiotic usage and early-onset colorectal cancer (CRC), and also evaluate this in later-onset CRC for comparison. METHODS: A case-control study was conducted using primary care data from 1999-2011. Analysis were conducted separately in early-onset CRC cases (diagnosed < 50 years) and later-onset cases (diagnosed ≥ 50 years). Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CI) for the associations between antibiotic exposure and CRC by tumour location, adjusting for comorbidities. RESULTS: Seven thousands nine hundred and three CRC cases (445 aged <50 years) and 30,418 controls were identified. Antibiotic consumption was associated with colon cancer in both age-groups, particularly in the early-onset CRC cohort (<50 years: adjusted Odds Ratio (ORadj) 1.49 (95% CI 1.07, 2.07), p = 0·018; ≥50 years (ORadj (95% CI) 1.09 (1.01, 1.18), p = 0·029). Antibiotics were not associated with rectal cancer (<50 years: ORadj (95% CI) 1.17 (0.75, 1.84), p = 0.493; ≥50 years: ORadj (95% CI) 1.07 (0.96, 1.19), p = 0.238). CONCLUSION: Our findings suggest antibiotics may have a role in colon tumour formation across all age-groups.

Young-onset colorectal cancer in the North East of Scotland: survival, clinico-pathological features and genetics.

BACKGROUND: Colorectal cancer (CRC) in patients aged under 55 years is on the rise, constituting approximately 10% of cases. Our aim was to determine the survival and clinico-pathological details of young-onset CRC (yCRC), as well as audit the referral rate to genetic services and thus establish the incidence of inherited cancer syndromes. METHODS: A retrospective case note review was conducted for patients aged under 55 years who were diagnosed with CRC between 2005 and 2015 in the North East of Scotland. Cases were identified by pathology records and data was obtained from patient notes. Analysis was performed using SPSS version 25 (IBM, New York, USA) to produce Kaplan-Meier survival estimates, descriptive statistics and markers predictive for genetic referral. RESULTS: Data from 345 patients (age range 22-54 years) were identified. The one year, five year and overall survival rates were found to be 89, 63 and 55%, respectively. Most patients (61%) presented with advanced disease. Of 201 patients that met criteria for genetic referral, only 93 (46%) were referred to genetic services. Microsatellite instability (MSI) was identified in 14% of those referred. CONCLUSION: Survival in yCRC was found to be better than that in later onset disease, despite higher rates of advanced disease. Patients were under-referred to genetic services, where a significant proportion were found to be MSI positive and investigated for Lynch syndrome.

Progressive multifocal leukoencephalopathy associated with carbamazepine-induced immune dysfunction and recovery after carbamazepine cessation.

A patient with epilepsy on carbamazepine developed a rapidly progressive cerebellar syndrome. Serial MRI showed progressive posterior fossa T2/fluid attenuated inversion recovery hyperintensity with gadolinium enhancement. Standard cerebrospinal fluid (CSF) analysis was normal. Detection of John Cunningham virus DNA in the CSF confirmed progressive multifocal leukoencephalopathy (PML). The only evidence of immune disfunction was hypogammaglobulinaemia and longstanding lymphopenia. After cessation of carbamazepine, the lymphocyte count and immunoglobulin levels returned to normal and the PML resolved, with good clinical recovery. No specific treatments for PML were given. We hypothesise that PML in this case was due to carbamazepine-induced prolonged mild immunosuppression with reconstitution of the immune system after carbamazepine cessation, resulting in recovery from PML. Effects of anticonvulsants on immune function and infection risk may contribute to epilepsy-related morbidity and mortality. Further investigation is needed to determine the frequency of immune dysfunction and infections in patients treated with anticonvulsants such as carbamazepine and whether interventions could reduce infection risk.

Calcaneal broadband ultrasound attenuation predicts physical capability: EPIC-Norfolk prospective population-based study.

BACKGROUND: Calcaneal ultrasound (broadband ultrasound attenuation - BUA), a marker of bone strength, may predict future physical capability and thus provide a strategy to identify individuals at risk of age-related deterioration of health. This study aims to determine if BUA can predict future physical capability among middle-aged and older adults. METHODS: Summary performance scores (SPS), an objective quantification of physical capability, were devised using participants' measures of standing balance, gait speed and timed chair rises. Associations between BUA and SPS, measured at least six years apart, were investigated using univariable and multivariate sex-specific linear and logistic regression, adjusting for confounders. RESULTS: 5893 participants were included. In men and women, for every five points lower BUA, there was a 0.2-point decrease in SPS. In women, BUA less than one standard deviation below the mean was associated with low physical capability (defined as SPS 3-6); fully adjusted odds ratio (OR) (95 % confidence interval (CI)) 1.35 (1.01-1.84). No association existed among men; OR (95 % CI) 0.84 (0.59-1.19). Significant risk factors for low physical capability in men with baseline low BUA were: older age [OR 5.77]; high BMI [OR 2.85]; lower social class [OR 1.59]; low physical activity [OR 1.64]. Risk factors among women were: older age [OR 5.54]; high BMI [OR 2.08]; lower education [OR 1.42], low physical activity [OR 1.27]; steroid use [OR 2.05]; and stroke [OR 2.74]. CONCLUSION: BUA may predict future physical capability in older adults. With further validation, BUA could stratify individuals at risk of deterioration in physical health.

Self-reported physical functional health predicts future bone mineral density in EPIC-Norfolk cohort.

Using a large population sample from the UK, we found that self-reported physical functional health may be used to predict future bone mineral density especially in women. It may be a useful and inexpensive way to identify individuals before further decline in bone mineral density and the risk of fracture. PURPOSE: Self-reported physical functional health may predict bone mineral density (BMD) and thus provide a method to identify people at risk of low BMD. In this study, the association between the 36-item short-form questionnaire (SF-36) physical component summary (PCS) score and future BMD in participants aged 40-79 years enrolled in the European Prospective Investigation of Cancer-Norfolk study was investigated. METHODS: Associations between a participant's SF-36 PCS score, measured 18 months after baseline health check, and broadband ultrasound attenuation (BUA-a measure of BMD), measured 2-5 years after baseline, were examined using sex-specific linear and logistic regression analyses adjusting for age, BMI, medical co-morbidities, lifestyle and socioeconomic factors. RESULTS: Data from 10,203 participants, mean (standard deviation (SD)) age 61.5 (8.9) years (57.4% women), were analysed from 1993 to 2000. For every five points lower PCS score in men and women, there was approximately a 0.5 dB/MHz lower mean BUA. In women, a PCS score of less than one standard deviation (1SD) below the sex-specific mean was associated with having a low BUA (< 1SD below sex-specific mean) and very low BUA (< 2.5SD below the sex specific mean); odds ratio (OR) (95% confidence interval) 1.53 (1.24, 1.88) and 8.28 (2.67, 25.69), respectively. The relationship was lesser so in men; corresponding OR (95% CI) were 1.34 (0.91, 1.98) and 2.57 (0.72, 9.20), respectively. CONCLUSIONS: Self-reported physical functioning predicts BMD in an apparently healthy population, particularly in women. This could potentially provide an inexpensive, simple screening tool to identify individuals at risk of osteoporosis.

Clinical frailty scale as a point of care prognostic indicator of mortality in COVID-19: a systematic review and meta-analysis.

BACKGROUND: COVID-19 has resulted in the largest pandemic experienced since 1918, accounting for over 2 million deaths globally. Frail and older people are at the highest risk of mortality. The main objective of the present research was to quantify the impact of clinical frailty scale (CFS) by increasing severity of frailty and to identify other personal prognostic factors associated with increased mortality from COVID-19. METHODS: This study offers a contemporary systematic review and meta-analysis to analyse the stratified mortality risk by increasing CFS sub-categories (1-3, 4-5 and 6-9). Databases searched included EMBASE, MEDLINE, CAB Abstracts, PsychInfo, and Web of Science with end-search restriction the 18th December 2020. Publications identified via MedRevix were followed up on the 23rd March 2021 in peer-reviewed database search, and citations were updated as published. Prospective and retrospective cohort studies which reported the association between CFS and COVID-19 mortality were included. Thirty-four studies were eligible for systematic review and seventeen for meta-analysis, with 81-87% (I2) heterogeneity. FINDINGS: All studies [N: 34] included patients from a hospital setting, comprising a total of 18,042 patients with mean age 72.8 (Min: 56; Max: 86). The CFS 4-5 patient group had significantly increased mortality when compared to patients with CFS 1-3 [(RE) OR 1.95 (1.32 (95% CI), 2.87 (95% CI)); I2 81%; p = 0.0008]. Furthermore, CFS 6-9 patient group displayed an even more noticeable mortality increase when compared to patients with CFS 1-3 [(RE) OR 3.09 (2.03, 4.71); I2 87%; p<0.0001]. Generic inverse variance analysis of adjusted hazard ratio among included studies highlighted that CFS (p = 0.0001), male gender (p = 0.0009), National Early Warning Score (p = 0.0001), Ischaemic Heart Disease (IHD) (p = 0.07), Hypertension (HT) (p<0.0001), and Chronic Kidney Disease (CKD) (p = 0.0009) were associated with increased COVID-19 mortality. INTERPRETATION: Our findings suggest a differential stratification of CFS scores in the context of COVID-19 infection, in which CFS 1-3 patients may be considered at lower risk, CFS 4-5 at moderate risk, and CFS 6-9 at high risk of mortality regardless of age. Overall, our study not only aims to alert clinicians of the value of CFS scores, but also highlight the multiple dimensions to consider such as age, gender and co-morbidities, even among moderately frail patients in relation to COVID-19 mortality. FUNDING: None.

First delirium episode in Parkinson's disease and parkinsonism: incidence, predictors, and outcomes.

To define the incidence, predictors and prognosis of the first hospital delirium episode in Parkinson's disease (PD) and atypical parkinsonism (AP), we identified the first hospital episode of delirium after diagnosis in the Parkinsonism Incidence in North-East Scotland (PINE) study, a prospective community-based incidence cohort of parkinsonism, using chart-based criteria to define delirium. Of 296 patients (189=PD, 107=AP [dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, vascular parkinsonism]), 152 developed delirium (PD = 98, AP = 54). Incidence of first hospital delirium episode per 100 person years was 8.1 (95% confidence interval [CI] 6.6-9.9) in PD and 18.5 (95% CI 13.9-24.7) in AP. Independent predictors of delirium were atypical parkinsonism (Hazard ratio [HR] vs PD = 2.83 [95% CI 1.60-5.03], age in PD but not in AP (HR for 10-year increase 2.29 [95% CI 1.74-3.02]), baseline MMSE (HR = 0.94 [95% CI 0.89-0.99]), APOE ε4 in PD (HR 2.16 [95% CI 1.15-4.08]), and MAPT H1/H1 in PD (HR 2.08 [95% CI 1.08-4.00]). Hazards of dementia and death after delirium vs before delirium were increased (dementia: HR = 6.93 [95% CI 4.18-11.48] in parkinsonism; death: HR = 3.76 [95% CI 2.65-5.35] in PD, 1.59 [95% CI 1.04-2.42] in AP). Delirium is a common non-motor feature of PD and AP and is associated with increased hazards of dementia and mortality. Whether interventions for early identification and treatment improve outcomes requires investigation.