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1.
J Control Release ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31765705

RESUMO

Using lipid-based drug delivery systems (LbDDS) is an efficient strategy to enhance the low oral bioavailability of poorly water-soluble drugs. Here the oral absorption of fenofibrate (FF) from LbDDS in rats was investigated in pharmacokinetic, in vitro lipolysis, and SPECT/CT in vivo imaging studies. The investigated formulations were soybean oil solution (SBO), a mixture of soybean oil and monoacyl phosphatidylcholine (MAPC) (SBO-MAPC), self-nanoemulsifying drug delivery systems with and without MAPC (SNEDDS-MAPC and SNEDDS, respectively), and an aqueous suspension (SUSP) as a reference. Oral bioavailability of the LbDDS ranged from 27 to 35%. A two-step in vitro lipolysis model simulating rat gastro-intestinal digestion provided in vitro FF solubilisation data to understand oral absorption. During the in vitro lipolysis, most FF was undissolved for SUSP and distributed into the poorly dispersed oil phase for SBO. For the SNEDDS without MAPC, practically all FF solubilised into the aqueous phase during the dispersion and digestion. Adding MAPC to SBO enhanced the dispersion of the oil phase into the digestion media while adding MAPC to SNEDDS resulted in a distribution of 29% of FF into the oil phase at the beginning of in vitro lipolysis. FF distribution into both oil and aqueous phases explained the higher and prolonged oral absorption of LbDDS containing MAPC. To elucidate the relatively low bioavailability of all formulations, FF and triolein were labeled with 123I and 125I, respectively, to study the biodistribution of drug and lipid excipients in a dual isotope SPECT/CT in vivo imaging study. The concentration of radiolabeled drug as a function of time in the heart correlated to the plasma curves. A significant amount of radiolabeled drug and lipids (i.e., 28-59% and 24-60% of radiolabelled drug and lipids, respectively) was observed in the stomach at 24 h post administration, which can be linked to the low bioavailability of the formulations. The current study for the first time combined in vitro lipolysis and dual isotope in vivo imaging to find the root cause of different fenofibrate absorption profiles from LbDDS and an aqueous suspension.

2.
JAMA Pediatr ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31589251

RESUMO

Importance: Febrile seizures occur in 2% to 5% of children between the ages of 3 months and 5 years. Many affected children experience recurrent febrile seizures. However, little is known about the association between recurrent febrile seizures and subsequent prognosis. Objective: To estimate the risk of recurrent febrile seizures and whether there is an association over long-term follow-up between recurrent febrile seizures and epilepsy, psychiatric disorders, and death in a large, nationwide, population-based cohort in Denmark. Design, Setting, and Participants: This population-based cohort study evaluated data from all singleton children born in Denmark between January 1, 1977, and December 31, 2011, who were identified through the Danish Civil Registration System. Children born in Denmark who were alive and residing in Denmark at age 3 months were included (N = 2 103 232). The study was conducted from September 1, 2017, to June 1, 2019. Exposures: Hospital contacts with children who developed febrile seizures between age 3 months and 5 years. Main Outcomes and Measures: Children diagnosed with epilepsy were identified in the Danish National Patient Register and children diagnosed with psychiatric disorders were identified in the Psychiatric Central Research Register. Competing risk regression and Cox proportional hazards regression were used to estimate the cumulative and relative risk of febrile seizures, recurrent febrile seizures, epilepsy, psychiatric disorders, and death. Results: Of the 2 103 232 children (1 024 049 [48.7%] girls) in the study population, a total of 75 593 children (3.6%) were diagnosed with a first febrile seizure between 1977 and 2016. Febrile seizures were more common in boys (3.9%; 95% CI, 3.9%-4.0%) than in girls (3.3%; 95% CI, 3.2%-3.3%), corresponding to a 21% relative risk difference (hazard ratio, 1.21; 95% CI, 1.19-1.22). However, the risks of recurrent febrile seizures, epilepsy, psychiatric disorders, and death were similar in boys and girls. The risk of (recurrent) febrile seizures increased with the number of febrile seizures: 3.6% at birth, 22.7% (95% CI, 22.4%-23.0%) after the first febrile seizure, 35.6% (95% CI, (34.9%-36.3%) after the second febrile seizure, and 43.5% (95% CI, (42.3%-44.7%) after the third febrile seizure. The risk of epilepsy increased progressively with the number of hospital admissions with febrile seizures. The 30-year cumulative risk of epilepsy was 2.2% (95% CI, (2.1%-2.2%) at birth compared with 15.8% (95% CI, 14.6%-16.9%) after the third febrile seizure, while the corresponding estimates for risk of psychiatric disorders were 17.2% (95% CI, 17.2%-17.3%) at birth and 29.1% (95% CI, 27.2%-31.0%) after the third febrile seizure. Mortality was increased among children with recurrent febrile seizures (1.0%; 95% CI, 0.9%-1.0% at birth vs 1.9%; 95% CI, 1.4%-2.7% after the third febrile seizure), although this risk was associated primarily with children who later developed epilepsy. Conclusions and Relevance: A history of recurrent febrile seizures appears to be associated with a risk of epilepsy and psychiatric disorders, but increased mortality was found only in individuals who later developed epilepsy.

3.
Brain Behav ; 9(11): e01441, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31613060

RESUMO

INTRODUCTION: Factors that influence antidepressant (AD) prescription and use during pregnancy are multiple including, in particular, the balance between the potential risk of untreated depression and the potential risk of AD treatment. Surveillance of temporal trends of AD use might identify areas requiring further research. We studied the use of ADs before, during, and after pregnancy using national data across two decades in Denmark. METHODS: We included 1,232,233 pregnancies leading to live birth in Denmark between 1 January 1997 and 31 December 2016. Information on redemption of AD prescriptions was obtained from the Danish National Prescription Register. RESULTS: We identified 29,504 (2.4%) pregnancies having at least one AD prescription (96,232 AD prescriptions) during pregnancy. The majority redeemed more than one prescription (69.7%) often for a single kind of AD (83.5%), and in 94% of the AD-exposed pregnancies, the estimated duration of treatment was 1 month or longer. Prescription of ADs during pregnancy increased steadily from 0.4% in 1997 to 4.6% in 2011, but decreased thereafter to 3.1% in 2016. The proportion of pregnancies with ADs in 2011 was 6.05-fold higher than that in 1997. The temporal trends in AD prescription in the years before and after pregnancy were similar to the trend during pregnancy. The decreasing use of ADs during pregnancy after 2011 was mainly driven by a decrease in the use of selective serotonin reuptake inhibitors (SSRIs), especially citalopram, the main type of SSRIs used in Denmark. CONCLUSION: Prescription of ADs during pregnancy in Denmark increased steadily from 1997 to 2011 but decreased sharply thereafter. More research is needed to show whether the same trend exists in other populations, like women of reproductive age, men of reproductive age, and old people, and other countries. We also need to find explanation for the decreasing trend in recent years and potential risk for untreated depression.

4.
Ann Neurol ; 86(6): 951-961, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31621936

RESUMO

OBJECTIVE: To examine whether prior suicidal behavior and familial predisposition to psychiatric disorders modify the association between antiepileptic drug use and completed suicide. METHODS: Using the Danish National Prescription Register, we identified all incident users of antiepileptic drugs aged 15 years or older in Denmark between July 1997 and December 2015. We carried out a nested case-control study and defined exposure to antiepileptic drugs at the index date (ie, time of suicide). Conditional logistic regressions were used to estimate mortality rate ratios (MRRs) of suicide in current versus previous users of antiepileptic drugs. We also analyzed suicide risk associated with the 9 most commonly used antiepileptic drugs. RESULTS: We identified 1,759 individuals completing suicide. Current versus previous use of any antiepileptic drug was associated with an increased risk of suicide (MRR = 1.26, 95% confidence interval [CI] = 1.13-1.40). This excess risk was observed in individuals with a history of suicidal behavior (MRR = 1.28, 95% CI = 1.07-1.54) and in those without (MRR = 1.26, 95% CI = 1.11-1.43), and in individuals with a familial predisposition to psychiatric disorders (MRR = 1.48, 95% CI = 1.18-1.87) and in those without (MRR = 1.21, 95% CI = 1.07-1.35). INTERPRETATION: Use of antiepileptic drugs was associated with an increased risk of suicide. The findings do not support that the risk of suicide following treatment with antiepileptic drugs identified in randomized trials is explained by prior suicidality or familial predisposition to psychiatric disorders. The additional risk of suicide associated with use of antiepileptic drugs was generally low and should be balanced against benefits of treatment. ANN NEUROL 2019;86:951-961.

5.
Epilepsia ; 60(10): 2105-2113, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31538347

RESUMO

OBJECTIVE: To assess the feasibility and accuracy of seizure detection based on heart rate variability (HRV) using a wearable electrocardiography (ECG) device. Noninvasive devices for detection of convulsive seizures (generalized tonic-clonic and focal to bilateral tonic-clonic seizures) have been validated in phase 2 and 3 studies. However, detection of nonconvulsive seizures still needs further research, since currently available methods have either low sensitivity or an extremely high false alarm rate (FAR). METHODS: In this phase 2 study, we prospectively recruited patients admitted to long-term video-EEG monitoring (LTM). ECG was recorded using a dedicated wearable device. Seizures were automatically detected using HRV parameters computed off-line, blinded to all other data. We compared the performance of 26 automated algorithms with the seizure time-points marked by experts who reviewed the LTM recording. Patients were classified as responders if >66% of their seizures were detected. RESULTS: We recruited 100 consecutive patients and analyzed 126 seizures (108 nonconvulsive and 18 convulsive) from 43 patients who had seizures during monitoring. The best-performing HRV algorithm combined a measure of sympathetic activity with a measure of how quickly HR changes occurred. The algorithm identified 53.5% of the patients with seizures as responders. Among responders, detection sensitivity was 93.1% (95% CI: 86.6%-99.6%) for all seizures and 90.5% (95% CI: 77.4%-97.3%) for nonconvulsive seizures. FAR was 1.0/24 h (0.11/night). Median seizure detection latency was 30 s. Typically, patients with prominent autonomic nervous system changes were responders: An ictal change of >50 heartbeats per minute predicted who would be responder with a positive predictive value of 87% and a negative predictive value of 90%. SIGNIFICANCE: The automated HRV algorithm, using ECG recorded with a wearable device, has high sensitivity for detecting seizures, including the nonconvulsive ones. FAR was low during the night. This approach is feasible in patients with prominent ictal autonomic changes.

6.
PLoS One ; 14(7): e0219137, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31323024

RESUMO

OBJECTIVE: Traumatic brain injury (TBI) is common and associated with a marked increased risk of developing epilepsy. Animal studies indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the risk of epilepsy after TBI. The aim of this study was to investigate whether use of SSRIs modifies the risk of epilepsy after TBI. METHODS: This was a cohort study of 205,715 persons, who suffered a TBI in Denmark from 1996 to 2013. For each person with TBI, we matched 10 reference persons (N = 2,057,150) who were alive on the day of TBI and who had the same age and gender but had no history of TBI. We used a stratified Cox regression to calculate the relative risk of epilepsy after TBI for persons exposed to TBI, SSRI or both after adjustment for income, civil status, medical and neurological comorbidities, severe mental disease, and substance abuse. RESULTS: The risk of epilepsy was 5.61 times higher for persons who used SSRI at time of TBI (adjusted Hazard Ratio (aHR): 5.61 (95% CI: 4.88; 6.45)), 3.23 times higher for persons who had a TBI but did not use SSRI at time of TBI (aHR: 3.23 (95% CI: 3.12;3.35)), and 1.31 times higher for persons who used SSRI but had no TBI (aHR: 1.31 (95% CI: 1.18; 1.45)) compared to persons unexposed to both TBI and SSRI. CONCLUSIONS: This large population based cohort study showed that people using SSRI at the time of a TBI had higher risk of developing epilepsy compared to people not using SSRI at the time of TBI. The results are in line with those of animal studies and calls for further studies to evaluate whether the association is due to SSRIs or to the underlying disease (e.g. depression or anxiety).

7.
Dan Med J ; 66(8)2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31315793

RESUMO

INTRODUCTION: We studied the use of antiepileptic drugs (AEDs) in women of fertile age and pregnant women in a 16-year-period in Denmark. METHODS: We included all women of fertile age (age 18-44 years) and pregnant women from 2001 to 2016 identified from Danish registers. RESULTS: The median proportion of women of fertile age who took AEDs increased from 10.7‰ (95% confidence interval (CI): 10.5-10.9‰) in 2001 to 27.1‰ (95% CI: 26.8-27.4‰) in 2016. Lamotrigine, levetiracetam, gabapentin and pregabalin have been increasingly used over time and have been the main AEDs used in recent years. The use of valproate in women of fertile age decreased slightly from 2.1‰ (95% CI: 2.0-2.2‰) to 1.9‰ (95% CI: 1.8-2.0‰), which was explained by a decrease in the use after 2014 among women aged 18-24 years. The increased use of AEDs was likely owed to use for other indications than epilepsy. The overall use of AEDs in pregnant women increased from 3.8‰ (95% CI: 3.3-4.3‰) in 2001 to 6.9‰ (95% CI: 6.2-7.6‰) in 2016, and the use of valproate decreased from 0.6‰ (95% CI: 0.4-0.8‰) in 2001 to 0.2‰ (95% CI: 0.1-0.4‰) in 2016. CONCLUSIONS: The overall use of AEDs in women of fertile age and pregnant women has increased in the past 16 years, especially due to an increased use of lamotrigine. However, valproate use in pregnant women and in younger women of fertile age has become less frequent. FUNDING: This study received funding from the Lundbeck Foundation, the Danish Epilepsy Association, the Central Denmark Region and the Novo Nordisk Foundation (NNF16OC0019126). TRIAL REGISTRATION: none.

8.
Epilepsia ; 60(6): 1200-1208, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31077351

RESUMO

OBJECTIVE: To determine the mortality for persons with epilepsy and schizophrenia by absolute and relative measures. METHODS: This is a population-based nationwide cohort study of persons born in Denmark from 1960 to 1987 who were alive and residing in Denmark on their 25th birthday. We identified persons diagnosed with epilepsy and schizophrenia prior to their 25th birthday and followed them to death, emigration, or December 31, 2012, whichever came first. The primary outcome was overall mortality. Data were analyzed using Cox regressions. RESULTS: Persons were followed for 24 167 573 person years; the median was 15 years. The mortality rate ratio was 4.4 (95% confidence interval [CI] = 4.1-4.7) for persons with epilepsy, 6.6 (95% CI = 6.1-7.1) for persons with schizophrenia, and 12.8 (95% CI = 9.1-18.1) for persons with both disorders, compared with persons without these disorders. The estimated cumulative mortality at the age of 50 years was 3.1% (95% CI = 3.0-3.1) for persons without epilepsy and schizophrenia, 10.7% (95% CI = 9.7-11.8) for persons with epilepsy, 17.4% (95% CI = 16.0-18.8) for persons with schizophrenia, and 27.2% (95% CI = 15.7-40.1) for persons with both disorders. SIGNIFICANCE: Persons with epilepsy and schizophrenia have very high mortality; more than one in four persons with both disorders died between the age of 25 and 50 years, indicating that these patients need special clinical attention.

9.
JAMA Netw Open ; 2(1): e186606, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30646190

RESUMO

Importance: Valproate is an antiepileptic drug (AED) used in the treatment of epilepsy and many other neurological and psychiatric disorders. Its use in pregnancy is associated with increased risks of congenital malformations and adverse neurodevelopment in the offspring and may be associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD). Objective: To determine whether prenatal exposure to valproate and other AEDs is associated with an increased risk of ADHD in the offspring. Design, Setting, and Participants: This was a population-based cohort study of all live-born singleton children in Denmark from January 1, 1997, to December 31, 2011 (N = 913 302). Information on prenatal exposure to AEDs, including valproate, was obtained from the Danish National Prescription Registry and all children with ADHD were identified (children with diagnosed ADHD in the Danish Psychiatric Central Research Register or children who redeemed a prescription for ADHD medication). The cohort was followed up from birth until the day of the ADHD diagnosis, death, emigration, or December 31, 2015, whichever came first. Data were analyzed in September 2018. Exposures: Maternal use of valproate and other AEDs in pregnancy. Main Outcomes and Measures: Cox regression estimates of the hazard ratio of ADHD. Estimates were adjusted for potential confounders. Results: The cohort included 913 302 children (mean age at end of study, 10.1 years; median age, 9.4 years; interquartile range, 7.2-12.8 years; 468 708 [51.3%] male). A total of 580 were identified as having been exposed to valproate during pregnancy; of them, 49 (8.4%) had ADHD. Among the 912 722 children who were unexposed to valproate, 29 396 (3.2%) had ADHD. Children with prenatal valproate exposure had a 48% increased risk of ADHD (adjusted hazard ratio, 1.48; 95% CI, 1.09-2.00) compared with children with no valproate exposure. The absolute 15-year risk of ADHD was 4.6% (95% CI, 4.5%-4.6%) in children unexposed to valproate and 11.0% (95% CI, 8.2%-14.2%) in children who were exposed to valproate in pregnancy. No associations were found between other AEDs and ADHD. Conclusions and Relevance: Maternal use of valproate, but not other AEDs, during pregnancy was associated with an increased risk of ADHD in the offspring. These findings have important implications for the counseling of women of childbearing potential using valproate.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Epilepsia/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal , Ácido Valproico/efeitos adversos , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/classificação , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Criança , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Exposição Materna/efeitos adversos , Exposição Materna/estatística & dados numéricos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Sistema de Registros , Medição de Risco
10.
Lancet Child Adolesc Health ; 3(2): 99-108, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30528754

RESUMO

BACKGROUND: Paediatric seizures have been linked to psychiatric disorders in childhood, but there is a paucity of large-scale population-based studies of psychiatric comorbidity in later life. We aimed to examine the relation between childhood seizures and the risk of psychiatric disorders in adolescence and early adulthood. METHODS: We did a register-based cohort study of all individuals born in Denmark in 1978-2002. Using diagnostic information from the Danish National Patient Register, all cohort members were categorised according to occurrence of febrile seizures and epilepsy, before entering the follow-up period on their 10th birthday. Individuals were followed up until onset of mental illness, death, emigration, or the end of the study period on Dec 31, 2012. Cox regression analyses were used to estimate the risk of five predefined groups of psychiatric disorders (substance abuse disorders, schizophrenia, mood disorder, anxiety, and personality disorder), separately and combined. Models were adjusted for relevant confounders. FINDINGS: Between Jan 1, 1978, and Dec 31, 2002, 1 291 679 individuals were born in Denmark and followed up in our population cohort (approximately 15 million person-years). 43 148 individuals had a history of febrile seizures, 10 355 had epilepsy, and 1696 had both these disorders. 83 735 (6%) cohort members were identified with at least one of the psychiatric disorders of interest. The risk of any psychiatric disorder was raised in individuals with a history of febrile seizures (hazard ratio [HR] 1·12, 95% CI 1·08-1·17), epilepsy (1·34, 1·25-1·44), or both disorders (1·50, 1·28-1·75). Excess risk of psychiatric illness associated with childhood seizures was present across a range of different disorders, most notably schizophrenia but also anxiety and mood disorders. Associations did not differ between males and females (p=0·30) but increased with a growing number of admissions for febrile seizures (p<0·0001) and with later onset of childhood epilepsy (p<0·0001). INTERPRETATION: Children with epilepsy and febrile seizures-with and without concomitant epilepsy-are at increased risk of developing a broad range of psychiatric disorders in later life. Clarification of the underlying mechanisms attributable to these associations is needed to identify potential options for prevention. FUNDING: Novo Nordisk Foundation, Danish Epilepsy Association, Central Denmark Region, Lundbeck Foundation, and Stanley Medical Research Institute.

11.
Epilepsia ; 60(2): 275-283, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30577081

RESUMO

OBJECTIVE: The development of epilepsy has been linked to infections of the central nervous system, but recently also to infections and inflammation outside of the central nervous system. Thus we investigated the association between infections and the risk of subsequent epilepsy. METHODS: This was a Danish nationwide population-based cohort study comprising a total of 1 938 555 individuals born between 1982 and 2012. Individuals were followed from birth until December 31, 2012, death, disappearance, emigration, or epilepsy diagnosis, whichever came first (28 512 666 person-years of follow-up). The exposure was hospital contacts for infection and the outcome was a diagnosis of epilepsy as recorded in the Danish National Hospital Register. Hazard ratios were calculated using Cox proportional hazards models adjusted for age, sex, calendar period, Apgar score, gestational age, birth weight, and parental history of epilepsy. RESULTS: A total of 25 825 individuals received an epilepsy diagnosis during the study period, among whom 8235 (32%) had a previous hospital contact for infection. A hospital contact for infection was associated with a 78% increase in the risk of subsequently receiving an epilepsy diagnosis (hazard ratio 1.78, 95% confidence interval [CI] 1.73-1.83) compared with those without infection. The highest risk was observed after central nervous system infections (hazard ratio 4.97, 95% CI 4.42-5.59), but increased risks were identified across all infected organ systems and types of pathogens. The risk of receiving an epilepsy diagnosis was correlated with the temporal proximity of the infection (P < 0.001) and increased with the number of hospital contacts for infection (P < 0.001) and with the severity of infection (P < 0.001). SIGNIFICANCE: The risk of receiving an epilepsy diagnosis was increased after a wide range of infections, suggesting that systemic inflammatory processes may be involved in the development of epilepsy.

14.
Neurology ; 91(18): e1716-e1720, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30258019

RESUMO

OBJECTIVE: To determine the maternal mortality in women with epilepsy. METHODS: This was a matched case-control study of pregnant women in Denmark who were born in Denmark between January 1, 1962, and December 31, 1994, and who were alive on their 18th birthday. We defined maternal mortality as deaths in pregnancy and the first 42 days after termination of pregnancy. Cases were pregnancies in women with a diagnosis of epilepsy before the termination of pregnancy. Data were analyzed with a conditional logistic model. For comparison, we estimated the mortality in women of childbearing age (18-50 years) diagnosed with epilepsy regardless of pregnancy status using a Poisson model. RESULTS: We identified 2,105,084 pregnancies, including 11,976 (0.57%) pregnancies in which the mother was diagnosed with epilepsy. Of the 176 maternal deaths in this cohort, 5 women had a diagnosis of epilepsy. The mortality associated with an epilepsy diagnosis was >5 times higher compared to the mortality in women without this diagnosis (odds ratio 5.57, 95% confidence interval 2.23-13.9, p < 0.001). CONCLUSIONS AND RELEVANCE: Maternal mortality in women with epilepsy in Denmark was lower than what has previously been reported from United States and the United Kingdom. However, the maternal mortality in women with epilepsy was considerably higher compared to women without epilepsy. Further studies should address whether improving epilepsy care in women with epilepsy could reduce the rate of maternal deaths.

15.
Clin Epidemiol ; 10: 809-829, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30038522

RESUMO

Introduction: Detailed knowledge of prediagnostic health care use among patients with primary intracranial tumors is sparse. We aimed to investigate the health care use among adults during the 2 years preceding a diagnosis of a benign or malignant primary intracranial tumor in Denmark. Methods: We conducted a population-based matched cohort study using historical data from Danish nationwide registries, including all patients aged 30-90 years diagnosed with a first-time primary intracranial tumor from January 1, 2009 to December 31, 2014, and with no prior cancer diagnosis (n=5,926). For each patient, ten comparison subjects were identified using density sampling. We analyzed differences in the frequency and timing of health care use within general practice, physiotherapy, radiology, ear -nose -throat, ophthalmology, neurology, and psychiatry. Odds ratios of having multiple contacts were calculated using a conditional logistical regression model. Monthly incidence rate ratios were estimated using a negative binomial regression model. Results: Of all patients, 62% had a benign tumor. Patients with benign tumors were more likely to have multiple consultations with health care providers in the period 2-12 months prior to diagnosis and to have increased rates of consultations 1-24 months prior to diagnosis, depending on health service. Conclusion: Patients diagnosed with a benign or a malignant primary intracranial tumor use the health care services differently. Increased health care use is seen within relatively close proximity to the diagnosis for patients with malignant tumors. However, patients with benign tumors have increased health care use from up to 2 years prior to diagnosis; this suggests a window of opportunity for earlier diagnosis.

16.
Epilepsia ; 59(7): 1334-1343, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29897612

RESUMO

OBJECTIVE: This study aims to examine the association between maternal age, paternal age, and parental age difference at the time of birth and the risk of epilepsy in the offspring. METHODS: We carried out a prospective population-based register study of all singletons born in Denmark between 1981 and 2012. Cox regression was used to estimate hazard ratios (HRs) of epilepsy and their corresponding 95% confidence intervals (CIs), adjusted for relevant confounders. RESULTS: We followed 1 587 897 individuals for a total of ~25 million person-years and identified 21 797 persons with epilepsy during the study period. An excess risk of epilepsy was found in individuals born to mothers younger than 20 years (HR = 1.17, 95% CI = 1.07-1.29) and born to parental couples where paternal age exceeded maternal age by at least 5 years. The risk of epilepsy increased with increasing parental age gap and was highest when the father was ≥15 years older than the mother (adjusted HR = 1.28, 95% CI = 1.16-1.41). In contrast to maternal age, we found that paternal age did not independently contribute to offspring epilepsy risk, once we accounted for the parental age difference (P = .1418). The observed associations with maternal age and parental age gap were invariant to epilepsy subtypes, but were modified by age of epilepsy onset, with the effect being most pronounced in the first 10 years of the child's life. SIGNIFICANCE: Maternal age and parental age gap, but not paternal age, were associated with the offspring's risk of epilepsy. Our results do not support the hypothesis that de novo mutations associated with advanced paternal age increase the risk of epilepsy in the offspring.

17.
Biol Sex Differ ; 9(1): 21, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29866174

RESUMO

BACKGROUND: There is a complex interaction between female and male sex hormones and the risk of epilepsy. Whether prenatal exposure to higher levels of sex hormones affects the development of epilepsy in childhood or later in life is not well known. The sex hormone environment of fetuses may be affected by the sex of the co-twin. We estimated the risk of epilepsy for twins with an opposite-sex (OS) co-twin compared with twins with a same-sex (SS) co-twin. METHODS: From the Danish Twin Registry, we identified OS female twins (n = 11,078), SS female twins (n = 19,186), OS male twins (n = 11,080), and SS male twins (n = 20,207) born between 1977 and 2009. The SS twins include monozygotic twins, dizygotic twins, and twins with unknown zygosity. These children were followed up from day 29 after birth until diagnosis of epilepsy, death, emigration, or end of follow-up (31 December 2011) whichever came first. Information on diagnosis of epilepsy was obtained from the Danish National Patient Registry. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for epilepsy in the OS twins using a Cox proportional hazards regression model compared with the SS twins. To account for the correlation of twins from the same mother when estimating standard errors, we used the cluster option in Stata. RESULTS: We identified 152 OS female twins, 282 SS female twins, 162 OS male twins, and 335 SS male twins diagnosed with epilepsy corresponding to an incidence rate of 9.9 and 9.7 per 10,000 person years for the OS and SS female twins, and 10.6 and 10.9 per 10,000 person years for the OS and SS male twins, respectively. We found a similar risk of epilepsy among the OS and SS female twins [HR = 1.01; 95% CI 0.83-1.24] as well as among the OS and SS male twins [HR = 0.94; 95% CI 0.78-1.14] CONCLUSIONS: In this population-based study of Danish twins, we did not find difference in the risk of epilepsy between twins with an OS co-twin and twins with a SS co-twin. This applied to both female and male twins. The study therefore does not support the hypothesis that subtle hormone difference in fetal life due to co-twin may play a role in the development of epilepsy later in life.

18.
Epilepsy Res ; 144: 25-29, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29751353

RESUMO

PURPOSE: To investigate the change in zonisamide (ZNS) serum concentration and its consequences in pregnant women with epilepsy. METHODS: Six hospitals in Norway and Denmark screened their records for women who had been using ZNS during pregnancy. Absolute serum concentrations as well as concentration/dose (CD)-ratios were compared to non-pregnant values. Descriptive data on seizure control and obstetrical data were also collected. RESULTS: 144 serum concentrations from 23 pregnancies in 15 individual women with epilepsy were included (six on monotherapy). The mean ZNS serum concentration fell to a minimum of 58.6 ±â€¯15.1%, while the C/D-ratio fell to as low as 55.1 ±â€¯15.3% of the non-pregnant-value. The lowest values were seen in gestational months six to nine, and the individual nadir varied considerably (range: 24-81% of the non-pregnant value). Four out of ten previously seizure-free patients experienced breakthrough seizures. Gestational age, weight at birth and head circumference of the newborns were within the reference ranges. CONCLUSIONS: ZNS serum concentrations may fall by over 40% during pregnancy, with large interindividual variability. In some patients, this may lead to worsened seizure control. These findings are in line with reports on other AEDs and suggest that regular therapeutic drug monitoring and dose adjustments may be useful.

19.
Pharmacoepidemiol Drug Saf ; 27(10): 1131-1138, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29664233

RESUMO

PURPOSE: It is not possible to fully assess intention of self-harm and suicidal events using information from administrative databases. We conducted a validation study of intention of suicide attempts/self-harm contacts identified by a commonly applied Danish register-based algorithm (DK-algorithm) based on hospital discharge diagnosis and emergency room contacts. METHODS: Of all 101 530 people identified with an incident suicide attempt/self-harm contact at Danish hospitals between 1995 and 2012 using the DK-algorithm, we selected a random sample of 475 people. We validated the DK-algorithm against medical records applying the definitions and terminology of the Columbia Classification Algorithm of Suicide Assessment of suicidal events, nonsuicidal events, and indeterminate or potentially suicidal events. We calculated positive predictive values (PPVs) of the DK-algorithm to identify suicidal events overall, by gender, age groups, and calendar time. RESULTS: We retrieved medical records for 357 (75%) people. The PPV of the DK-algorithm to identify suicidal events was 51.5% (95% CI: 46.4-56.7) overall, 42.7% (95% CI: 35.2-50.5) in males, and 58.5% (95% CI: 51.6-65.1) in females. The PPV varied further across age groups and calendar time. After excluding cases identified via the DK-algorithm by unspecific codes of intoxications and injury, the PPV improved slightly (56.8% [95% CI: 50.0-63.4]). CONCLUSIONS: The DK-algorithm can reliably identify self-harm with suicidal intention in 52% of the identified cases of suicide attempts/self-harm. The PPVs could be used for quantitative bias analysis and implemented as weights in future studies to estimate the proportion of suicidal events among cases identified via the DK-algorithm.

20.
Lancet Psychiatry ; 5(5): 424-431, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29653873

RESUMO

BACKGROUND: Traumatic brain injury (TBI) has been associated with increased risk of dementia; however, large-scale studies with long follow-up have been scarce. We investigated the association between TBI, including severity and number of TBIs, and the subsequent long-term risk of dementia. METHODS: We did a nationwide population-based observational cohort study in Denmark using information on citizens from national registries. We used the Danish Civil Registration System to establish a population-based cohort consisting of all people born in Denmark who were living in the country on Jan 1, 1995, and who were at least 50 years old at some point during follow-up (between 1999 and 2013). We obtained information on TBIs from the Danish National Patient Register (NPR), and obtained information on dementia by combining data recorded in the NPR, the Danish Psychiatric Central Register, and the Danish National Prescription Registry (DNPR). The long-term risk of dementia after TBI was established using survival analysis. We used three prespecified models for each of the three analyses: different time periods since the TBI, multiple TBIs, and sex. The first model adjusted for sociodemographic factors, the second model added medical and neurological comorbidities, and the third added psychiatric comorbidities. FINDINGS: We used data from a cohort of 2 794 852 people for a total of 27 632 020 person-years (mean 9·89 years per patient) at risk of dementia. 132 093 individuals (4·7%) had at least one TBI during 1977-2013, and 126 734 (4·5%) had incident dementia during 1999-2013. The fully adjusted risk of all-cause dementia in people with a history of TBI was higher (hazard ratio [HR] 1·24, 95% CI 1·21-1·27) than in those without a history of TBI, as was the specific risk of Alzheimer's disease (1·16, 1·12-1·22). The risk of dementia was highest in the first 6 months after TBI (HR 4·06, 3·79-4·34) and also increased with increasing number of events (1·22, 1·19-1·25 with one TBI to 2·83, 2·14-3·75 with five or more TBIs). Furthermore, TBI was associated with a higher risk of dementia (1·29, 1·26-1·33) in people with TBI than in individuals with a non-TBI fracture not involving the skull or spine. The younger a person was when sustaining a TBI, the higher the HRs for dementia when stratified by time since TBI. INTERPRETATION: TBI was associated with an increased risk of dementia both compared with people without a history of TBI and with people with non-TBI trauma. Greater efforts to prevent TBI and identify strategies to ameliorate the risk and impact of subsequent dementia are needed. FUNDING: Lundbeck Foundation.

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