Prevalence of and factors associated with the early prescription of antiseizure medications in adults newly diagnosed with epilepsy in Germany.

BACKGROUND: There is little information on prescription patterns of antiseizure medications (ASMs) during the early management of patients with epilepsy in Germany. Therefore, this study investigated the prevalence of and the factors associated with ASM prescription in patients newly diagnosed with epilepsy in this country. METHODS: Adults diagnosed for the first time with epilepsy in one of 128 neurology practices in Germany between 2005 and 2021 were included (Disease Analyzer database, IQVIA). The prescription of ASMs was assessed within 30 days, six months, and 12 months of the diagnosis. Covariates were demographic factors, epilepsy sub-diagnoses, and co-diagnoses frequently associated with epilepsy. RESULTS: This study included 55,962 participants (mean [SD] age 52.5 [20.0] years; 50.5 % men). The prevalence of ASM prescription ranged from 45.0 % within 30 days to 66.0 % within 12 months of the diagnosis. Men were less likely to receive ASMs within six and 12 months of epilepsy diagnosis than women. In addition, epilepsy sub-diagnoses of symptomatic, complex, or generalized nature were associated with increased odds of ASM prescription compared with epilepsy of unspecified nature. Finally, there was an inverse and significant association between multiple co-diagnoses (e.g., diabetes, mental and behavioral disorders due to use of alcohol, and traumatic brain injury) and ASM prescribing. CONCLUSIONS: A substantial proportion of participants were prescribed ASMs in the year following epilepsy diagnosis, highlighting that the early prescription of ASMs was necessary for these patients. Further research is warranted to corroborate the present findings in other countries and settings.

Sex-related associations between body mass index and the incidence of epilepsy.

BACKGROUND: The aim of this study was to investigate the association between both overweight and underweight and epilepsy in adult individuals using a large German database. METHODS: This retrospective cohort study was based on data from the Disease Analyzer database (IQVIA) and included patients with documented body mass index (BMI) values followed up in one of 832 general practices in Germany between January 2006 and December 2019. The association between BMI categories and the 10-year incidence of epilepsy was studied separately for women and men using Cox regression models adjusted for age and comorbidities. RESULTS: This study included 822,071 patients. The proportions of underweight, normal weight, overweight, and obesity were 1.6%, 33.4%, 36.7%, and 28.3% respectively. Underweight was significantly and positively associated with the incidence of epilepsy (HR = 1.67, 95% CI = 1.31-2.11) compared to normal weight. This association was much stronger in men (HR = 2.57, 95% CI = 1.71-3.88) than in women (HR = 1.48, 95% CI = 1.10-1.98). However, underweight was significantly associated with an increased risk of generalized epilepsy only (HR: 4.38; 95% CI: 1.34-14.35), but no significant associations between weight and the incidence of focal epilepsy was observed. CONCLUSION: In conclusion, a significant and positive association between underweight and generalized and unclassified epilepsy was observed, which was stronger in men than in women. Further studies are needed to confirm these results and find the reasons for this association.

Atrial fibrillation is associated with a subsequent epilepsy diagnosis independent of stroke: A retrospective matched administrative cohort study on 149,632 patients.

Recently there has been a rising interest in the identification and possible prevention of risk factors for epilepsies. In the present study, we investigated the potential association between atrial fibrillation (AF) and epilepsy in a German cohort of ambulatory patients aged ≥18 with an initial diagnosis of atrial fibrillation documented in 1274 general practices in Germany between January 2005 and December 2018. Using the IQVIA Disease Analyzer database, we identified 74,681 ambulatory patients with AF. These were matched 1:1 to patients without AF based on sex, age, index year, yearly consultation frequency, and defined co-diagnoses like stroke. Cox regression models were used to evaluate the association between AF and epilepsy. Within 10 years of the index date, 1.9% of individuals with AF and 1.5% of individuals without AF were diagnosed with epilepsy (log-rank p < 0.001). Atrial fibrillation was significantly associated with an increase in the incidence of epilepsy (Hazard Ratio (HR): 1.51, p < 0.001). The association was significant in all age groups, except in patients >80 years of age (HR: 1.29, p = 0.031). Our study demonstrates that AF is associated with an increased incidence of epilepsy. This finding could help understand the mechanisms of epilepsy in heart disease and to better protect affected individuals in the future.

Epilepsy is associated with an increased incidence of heart failure diagnoses.

OBJECTIVE: Epilepsy is a complex disease with serious consequences for the quality of life and prognosis of those affected. The importance of comorbidities in disease progression and prognosis has gained increasing recognition in recent years. In the present study, we investigated the potential association between epilepsy and heart failure in an outpatient cohort in Germany. METHODS: Using the IQVIA Disease Analyzer database, we identified a total of 9646 patients with late-onset epilepsy and a matched cohort of equal size without late-onset epilepsy who were followed up between 2005 and 2018. Cox regression models were used to evaluate the potential association between epilepsy and heart failure. RESULTS: Within 10 years of the index date, 28.6% of patients with epilepsy and 20.4% of patients without epilepsy had been diagnosed with HF (log-rank p < 0.001). The incidences were 36.3 cases per 1,000 patient years in the epilepsy cohort versus 23.1 cases in the non-epilepsy cohort. In regression analyses, epilepsy was significantly associated with the incidence of HF (Hazard Ratio (HR): 1.56, p < 0.001). The association was somewhat stronger in men (HR: 1.63, p < 0.001) than in women (HR: 1.49, p < 0.001). The HR in the epilepsy group decreased with increasing age. CONCLUSION: Our study provides strong evidence that epilepsy is associated with an increased incidence of heart failure. This finding should help raise awareness of this important comorbidity and could trigger specific cardiovascular screening programs in patients with epilepsy.

Association between gout and epilepsy in adults - a retrospective cohort study with 244,964 primary care outpatients.

BACKGROUND: Recently there has been a rising interest in the identification of possible risk factors for epilepsies. In the present study, we investigated the potential association between gout and epilepsy in an outpatient cohort in Germany. METHODS: Using the IQVIA Disease Analyzer database, we identified 112,482 patients with gout treated in outpatient departments. These were matched 1:1 to non-gout patients based on sex, age, yearly consultation frequency during the follow-up period, and diagnoses associated with an increased epilepsy risk documented prior to or on the index date. Cox regression models were used to evaluate the association between gout and epilepsy. RESULTS: Within 10 years after the index date, epilepsy had been diagnosed in 2.2% of gout and 1.6% of non-gout patients (log-rank p<0.001). In the regression analysis, we observed a significant association between gout and subsequent epilepsy (HR: 1.32; 95% CI: 1.21-1.44). The association was significant in all age groups, but strongest in the youngest age group (18-50) (HR: 1.86; 95% CI: 1.44-1.2.41). CONCLUSION: Our study demonstrates that gout is associated with an increased incidence of epilepsy. This finding could help us to understand the mechanisms of epilepsy and better protect affected individuals in the future.

Association between Antiepileptic Drugs and Incident Parkinson's Disease among Patients Followed in German Primary Care Practices.

BACKGROUND: The aim of this study was to analyze whether prescriptions of antiepileptic drugs (AEDs) are significantly associated with an increased incidence of Parkinson's disease (PD) in the German population. METHODS: This study used data from German primary care practices found in the Disease Analyzer database (IQVIA) and included all patients aged ≥18 years who were diagnosed with PD between January 2010 and December 2021 (index date). The controls were patients without PD matched (1:1) by age, sex, and pre-diagnostic observation time in years. Associations between AED prescriptions (any AED as well as separate evaluations for carbamazepine, lamotrigine, levetiracetam, sodium valproate, gabapentin, and pregabalin) and subsequent diagnosis of PD were examined using a logistic regression model adjusted for epilepsy, restless legs syndrome, and neuropathy diagnoses. RESULTS: We identified 24,950 cases that were matched with 24,950 controls (mean age 75.2 years, 47.3% women). Diagnoses of epilepsy, restless legs syndrome, and neuropathy as well as AED prescription were significantly associated with an increased incidence of PD. In the multivariate analysis, incidence of PD was significantly associated with epilepsy (OR: 1.91; 95% CI: 1.69-2.15), restless legs syndrome (OR: 3.02; 95% CI: 2.73-3.34), and neuropathy (OR: 1.53; 95% CI: 1.44-1.62)), as well as the prescription of any AED (OR: 1.43; 95% CI: 1.33-1.53), sodium valproate (OR: 2.39; 95% CI: 1.84-3.11), gabapentin (OR: 1.36; 95% CI: 1.22-1.52), and pregabalin (OR: 1.28; 95% CI: 1.15-1.41). Conclusion: Prescriptions of AEDs, including sodium valproate, gabapentin, and pregabalin, were associated with an increased risk of subsequent PD, even after adjustment for underlying diagnoses. Further studies are needed to confirm the present results.

The Association between Antibiotic Use and the Incidence of Heart Failure: A Retrospective Case-Control Study of 162,188 Outpatients.

The pathogenesis of heart failure (HF) is multifactorial, and is characterized by structural, cellular, and molecular remodeling processes. Inflammatory signaling pathways may play a particularly understudied role in HF. Recent data suggest a possible impact of antibiotic use on HF risk. Therefore, the aim of this retrospective case-control study was to investigate the association between antibiotic use and the incidence of HF. Data from the Disease Analyzer (IQVIA) database for patients diagnosed with HF and matched non-HF controls from 983 general practices in Germany between 2000 and 2019 were analyzed. A multivariable conditional logistic regression model was performed. Regression models were calculated for all patients, as well as for data stratified for sex and four age groups. A total of 81,094 patients with HF and 81,094 patients without HF were included in the analyses. In the regression analysis, low, but not high, total antibiotic use was significantly associated with a slightly lower HF risk compared with non-antibiotic users (OR: 0.87; 95% CI: 0.85-0.90). A significantly lower HF incidence was observed for sulfonamides and trimethoprim (OR: 0.87, 95% CI: 0.81-0.93) and for macrolides (OR: 0.87, 95% CI: 0.84-0.91). High use of cephalosporins, however, was associated with an increased HF risk (OR: 1.16; 95% CI: 1.11-1.22). In conclusion, this study from a large real-world cohort from Germany provides evidence that the use of different antibiotics may be associated with HF risk in a dose-dependent manner, possibly due to involved inflammatory processes. Overall, this study should provide a basis for future research to offer new therapeutic strategies for HF patients to improve their limited prognosis.

Association Between Angiotensin Receptor Blocker Therapy and Incidence of Epilepsy in Patients With Hypertension.

Importance: Arterial hypertension is associated with an increased incidence of epilepsy. Results from animal studies suggest that angiotensin receptor blocker (ARB) therapy could inhibit epileptic seizures. However, there is a lack of clinical data to support the use of ARB therapy in humans. Objective: To assess whether ARB therapy is associated with a decreased incidence of epilepsy in patients with hypertension. Design, Setting, and Participants: This cohort study obtained data from the Disease Analyzer database (IQVIA) on patients aged 18 years or older who had hypertension and at least 1 antihypertensive drug prescription. Patients were treated at 1274 general practices between January 2010 and December 2020 in Germany. Data were available for 1 553 875 patients who had been prescribed at least 1 antihypertensive drug. Patients diagnosed with epilepsy before or up to 3 months after the index date were excluded. A total of 168 612 patients were included in propensity score matching. Patients treated with 1 of 4 antihypertensive drug classes (ß-blockers, ARBs, angiotensin-converting enzyme inhibitors, and calcium channel blockers [CCBs]) were matched to each other using propensity scores. Main Outcomes and Measures: The main outcome of the study was the incidence of epilepsy associated with ARB therapy compared with other antihypertensive drug classes. Cox regression models were used to study the association between the incidence of epilepsy and ARBs compared with all other antihypertensive drug classes as a group. Results: The study included a total of 168 612 patients, with 42 153 in each antihypertensive drug class. The mean [SD] age of patients was 62.3 [13.5] years, and 21 667 (51.4%) were women. The incidence of epilepsy within 5 years was lowest among patients treated with ARBs (0.27% at 1 year, 0.63% at 3 years, 0.99% at 5 years) and highest among patients receiving ß-blockers and CCBs (0.38% for both ß-blockers and CCBs at 1 year; 0.91% for ß-blockers and 0.93% for CCBs at 3 years; ß-blockers, 1.47%; and CCBs, 1.48% at 5 years). Angiotensin receptor blocker therapy was associated with a significantly decreased incidence of epilepsy (hazard ratio, 0.77; 95% CI, 0.65-0.90) compared with the other drug classes as a group. Conclusions and Relevance: In this cohort study of patients with hypertension, ARB therapy was associated with a significantly decreased incidence of epilepsy. The findings suggest antihypertensive drugs could be used as a novel approach for preventing epilepsy in patients with arterial hypertension.

Infectious mononucleosis is associated with an increased incidence of multiple sclerosis: Results from a cohort study of 32,116 outpatients in Germany.

Background: The pathogenesis of multiple sclerosis (MS) has not yet been fully uncovered. There is increasing evidence that Epstein-Barr-Virus (EBV) infection, which affects over 90% of people during life and causes infectious mononucleosis, leads to an increased incidence of MS, and thus may play a crucial role in the pathophysiology of the disease. Methods: Using the Disease Analyzer database (IQVIA) featuring diagnoses as well as basic medical and demographic data of outpatients from general practices in Germany, we identified a total of 16,058 patients with infectious mononucleosis that were matched to a cohort of equal size without infectious mononucleosis based on patients' age, sex, index year and yearly consultation frequency. Incidence of MS was compared within a 10-year follow-up period. Results: Within 10 years from the index date, the incidence of MS was 22.6 cases per 100,000 person-years among patient with infectious mononucleosis but only 11.9 cases per 100,000 person-years among individuals without infectious mononucleosis. In regression analysis, infectious mononucleosis was significantly associated with the incidence of MS (HR: 1.86, 95% CI: 1.09-3.16). Subgroup analysis revealed the strongest association between infectious mononucleosis and MS in the age group between 14 and 20 years (HR: 3.52, 95% CI: 1.00-12.37) as well as a stronger association in men compared to women. Conclusion: Infectious mononucleosis is associated with an increased incidence of MS especially in younger individuals. Our data support the growing evidence of a decisive involvement of EBV in the currently unknown pathophysiology of MS and should trigger further research efforts to better understand and potentially prevent cases of this disabling disease in future.

Effects of budesonide inhalation on energy expenditure, somatic growth and salivary cortisol levels in preterm infants with chronic lung disease.

BACKGROUND: We hypothesized that the use of inhaled budesonide (BUD) would alter somatic growth by increasing energy expenditure (EE) in premature infants with chronic lung disease (CLD). METHODS: A prospective study was conducted of the effect of BUD on EE, growth and salivary cortisol excretion in infants with CLD who required supplemental oxygen and were treated with inhaled BUD for 4 weeks according the severity of their CLD, or without BUD treatment. Infants were compared with a healthy control group matched for gestational age. EE, anthropometric measures and salivary cortisol levels were examined before, during and after BUD treatment. RESULTS: A total of 30 spontaneously breathing premature infants were enrolled in the study. EE in CLD (BUD) and CLD (no BUD) patients were greater than EE in healthy preterm infants (p < 0.01) at the study time points. Growth did not differ between the groups. Salivary cortisol levels of treated infants were significantly lower when compared with the levels of nontreated infants. CONCLUSION: The administration of inhaled BUD in preterm infants with CLD was associated with an increase in EE, a suppression of endogenous cortisol production and with no effect on duration of supplemental oxygen, but did not compromise their somatic growth.

Induction of chronic renal allograft injury by injection of a monoclonal antibody against a donor MHC Ib molecule in a nude rat model.

BACKGROUND: Chronic allograft injury induced by immunological as well as non-immunological mechanisms is still a major cause of long-term graft loss after renal transplantation. Major histocompatibility complex (MHC) incompatibilities as well as donor-specific alloantibodies are known risk factors, but the interaction of cellular and humoral mechanisms leading to allograft damage remains to be defined. The aim of this study was to analyze the impact of donor-specific post-transplant antibodies against a non-classical MHC Ib antigen apart from T-cell-dependent immune response. Therefore, we utilized a transplant rat model injecting a moAb directed against a donor MHC Ib molecule into athymic nude recipients lacking an immunocompetent T-cell system. METHODS: F344 kidneys were transplanted into LEW.RNU rats. Donor and recipient differ in the RT1.C locus (MHC Ib) but are phenotypically identical for the RT1.A (MHC I) and RT1.B/D (MHC II) loci. A moAb directed against the donors RT1.C(lv1) was injected into recipients with stable graft function. A control group remained untreated after transplantation. The rats were monitored for renal function and grafts were analyzed for morphological changes, infiltrating cells and C4d deposition. RESULTS: Antibody-infused rats developed renal impairment with massive urine albumin excretion. Histological changes consistent with antibody-mediated injury were interstitial fibrosis, tubular atrophy and severe glomerulopathy accompanied by an infiltrate of numerous macrophages. At time of death, grafts were negative for C4d at the peritubular capillaries and arterial endothelium. CONCLUSION: Antibodies directed against a MHC Ib antigen are able to induce allograft injury in T-cell-deficient rats. This model underlines the role of non-classical MHC disparities for long-term allograft survival and demonstrates the long-term results of antibody-induced allograft damage.

Effect of high volume intake of mother's milk with an individualized supplementation of minerals and protein on early growth of preterm infants <28 weeks of gestation.

OBJECTIVE: A prospective study was designed to evaluate the effects of high volume intake of mother's milk fortified (FMM) with an individualized supplementation of minerals and protein on tolerance, short-term somatic growth, serum concentrations of calcium, phosphorus, alkaline phosphatase, and total plasma protein in healthy preterm infants below 28 weeks of gestation. METHODS: Sixty preterm infants were included in the FMM group, for having received >80% or more of the milk volume as their own mother's milk at 3 weeks of postnatal age to 38 weeks of corrected gestational age. This group was compared with 60 preterm infants fed exclusively preterm formula milk (PF). Intended fluid volume of the FMM group was approximately 200 and 150-170 mL/kg/d in the PF group. Mother's milk was supplemented with the goal of a daily protein intake of 3.5-4 g/kg/d. Phosphorus was supplemented from 15.5 to 31 mg per 100mL mother's milk. RESULTS: Both feeding regimes were well tolerated. At the end of the study, nutritional management in both groups resulted in a body weight between the 25th and 50th percentiles of intrauterine growth expectations. Serum values of electrolytes, alkaline phosphatase, plasma protein, blood urea nitrogen, and urinary mineral excretion did not differ significantly between the two groups at study entry as well as at the end of the investigation. CONCLUSIONS: Mother's milk fed at higher volumes with an individualized fortification of minerals and protein provides sufficient nutrients to allow adequate growth of preterm infants <28 weeks of gestation.

Analysis of epileptic seizure count time series by ensemble state space modelling.

We propose an approach for the analysis of epileptic seizure count time series within a state space framework. Time-dependent dosages of several simultaneously administered anticonvulsants are included as external inputs. The method aims at distinguishing which temporal correlations in the data are due to the medications, and which correspond to an unrelated background signal. Through this method it becomes possible to disentagle the effects of the individual anticonvulsants, i.e., to decide which anticonvulsant in a particular patient decreases or rather increases the number of seizures.

Myoclonic astatic epilepsy (Doose syndrome) - a lamotrigine responsive epilepsy?

PURPOSE: Myoclonic astatic epilepsy (MAE, Doose syndrome) is a difficult to treat idiopathic generalized epilepsy of early childhood. MAE frequently shows the course of an epileptic encephalopathy and may result in permanent cognitive impairment. Systematic analyses on clinical effects of different AED combinations are still needed. The purpose of our study was to analyze the therapeutic effect of adjunctive lamotrigine (LTG) in pharmacoresistant MAE patients. PATIENTS AND METHODS: In an exploratory, retrospective study, 10 pharmacoresistant MAE patients were included who had been admitted to the Northern German Epilepsy Center between 07/2007 and 12/2010 and had been treated with LTG. Documentation was performed with the electronic seizure diary Epivista. A total observation period of 32 weeks was defined: 8-week 'pre LTG treatment phase' (before starting with LTG), 16-week 'titration phase' (starting with very low LTG doses), 8-week 'follow-up phase'. Seizure frequency, medication and adverse events were extracted from the electronic diary and evaluated in each particular patient. The individual reduction of seizure frequency per day was defined as primary outcome variable. Additionally, a dose-effect-relationship was analyzed for each patient. RESULTS: Six out of ten patients were seizure free during the follow-up phase. Statistical analysis indicated a significant seizure reduction in seven patients at follow-up compared to the pre LTG treatment phase. Seizure frequency did not significantly decrease in two patients and increased in one patient. A significant relationship between seizure frequency per day and LTG dosage during titration and follow-up phase could be demonstrated in nine patients. Group statistics using the exact Wilcoxon test revealed a significant reduction in seizure frequency (p = 0.049, two-sided). CONCLUSION: Our data provide evidence that adjunctive LTG is an eligible therapeutic option for the treatment of pharmacoresistant MAE and encourage further prospective studies to verify this observation.

An association between infantile haemangiomas and erythropoietin treatment in preterm infants.

BACKGROUND: Infantile haemangiomas are benign vascular neoplasms that occur frequently in premature infants. The authors hypothesised that in addition to gestational age and birth weight, erythropoietin therapy may influence the incidence of these soft tissue tumours in preterm infants. METHODS: 2563 infants born prematurely and admitted to the Division of Neonatology, University of Heidelberg Medical School were investigated in a retrospective analysis. Hospital charts for all infants were reviewed for clinical data. The primary endpoint was the percentage of infants who had received erythropoietin treatment and were diagnosed with a haemangioma. RESULTS: Haemangiomas were diagnosed in 4.3% (n=110) of the 2563 preterm infants. These 110 infants had a median gestational age of 29 weeks (IQR 27-33 weeks) and the female:male ratio was 1.8:1. A higher incidence of haemangiomas (12-15%) was detected in premature infants with a lower gestational age (<31 weeks). Erythropoietin therapy was shown to be an independent risk factor after adjusting for all other known factors and oxygen therapy in multivariable analysis (HR 2.82, 95% CI 1.55 to 5.12). Subgroup analysis revealed that the effect was more pronounced in male than female infants (HR 3.61, 95% CI 1.52 to 8.57). CONCLUSIONS: This retrospective study demonstrates that erythropoietin treatment is associated with an increase in the incidence of these benign vascular tumours after adjusting for all other factors.

Chronic allograft nephropathy in athymic nude rats after adoptive transfer of primed T lymphocytes.

The impact of presensitized T lymphocytes on the development of chronic allograft nephropathy (CAN) was investigated in nude athymic LEW.RNU recipients of F344 renal allografts. The recipients (n = 8) were reconstituted with 5 x 10(7) T lymphocytes primed against donor skin grafts to induce graft rejection. LEW.RNU (n = 8) and euthymic LEW recipients (n = 6) which underwent no further intervention after transplantation served as control groups. Adoptive transfer of primed T cells induced CAN in LEW.RNU rats. Their kidney function decreased progressively. After 90 days a moderate glomerulopathy, tubular atrophy and interstitial fibrosis were observed, vascular changes were only mild or absent. Cellular infiltrates were predominated by CD4+ T cells and ED1+ macrophages. Deposition of tenascin and laminin was enhanced. Grafts of euthymic recipients displayed only mild signs of CAN according to the Banff criteria. These data implicate an important role for the cellular immune response in the development of CAN.

Energy expenditure in neonates with Down syndrome.

Resting energy expenditure was measured in term neonates with Down syndrome during the first week of life and compared with healthy neonates. Infants with Down syndrome expended 14% fewer calories than did healthy infants of the same age.