Friday, September 2, 2016

Comorbidity and childhood epilepsy

Aaberg KM, Bakken IJ, Lossius MI, Lund Søraas C, Håberg SE, Stoltenberg C,
Surén P, Chin R. Comorbidity and Childhood Epilepsy: A Nationwide Registry Study.
Pediatrics. 2016 Aug 1. pii: e20160921. [Epub ahead of print]

Children with epilepsy are at increased risk of other disorders and difficulties, preceding, cooccurring with, or after the diagnosis of epilepsy. Risk estimates vary, few studies are population-based, and few provide comprehensive assessments of comorbidities. We used nationwide registry data to describe frequencies of medical, neurologic, developmental, and psychiatric conditions occurring before and after children are diagnosed with childhood epilepsy.
Data were obtained from the Norwegian Patient Registry, which is an administrative database recording International Classification of Diseases, 10th Revision diagnoses from all government-funded specialist health services in Norway (outpatient consultations and hospitalizations). We included data from the years 2008 through 2013 for all children born in Norway between 1996 and 2013 (0-17 years of age at the end of follow-up). Children with epilepsy were compared with the general child population, adjusting for sex and age. We also compared children with complicated epilepsies (ie, epilepsies with additional neurologic and/or developmental disorders) to children with uncomplicated epilepsies.
The study population included 1 125 161 children. There were 6635 (0.6%) children with epilepsy. Nearly 80% of children with epilepsy had ≥1 comorbid disorder. All types of disorders were more frequent in children with epilepsy, with additional medical disorders recorded in 55%, neurologic disorders in 41%, and developmental/psychiatric disorders in 43%. Children with complicated epilepsies had the highest overall levels of comorbidity, but the risk of medical and psychiatric comorbidities was also substantial among children with uncomplicated epilepsies.
The overall frequency of comorbid disease is high in children with epilepsy, including children with presumably uncomplicated epilepsies.

From the article

Comorbid disorders may share causes or risk factors with epilepsy, or even be the actual cause of epilepsy. They may also be consequences of seizures, epileptic activity, or antiepileptic treatment…

Most studies of comorbidity in childhood epilepsy have focused on neurocognitive, behavioral, social, and psychiatric disorders or difficulties. Knowledge about other medical comorbidities is limited, and only a couple of studies have investigated this in children specifically.  Most studies of medical comorbidities have included only adults or subjects of all ages and primarily reported findings in adults. Some studies have focused on specific diagnoses rather than an extensive range.35–38 For all categories of comorbid conditions, the prevalence estimates vary widely depending on the study design, methodology, and population under study. Only a few studies of children with epilepsy (CWE) have been able to compare with the general child population
Our aim was to capture and categorize all comorbid conditions that were chronic or long-lasting and likely to have a significant effect on overall health and quality of life. Transient conditions (eg, infectious episodes) and conditions unlikely to occur in children (eg, varices) were excluded. 

Comorbid conditions were divided into 3 main categories–medical, neurologic, and developmental/psychiatric–and further subdivided into disease categories based on the ICD-10. The study was not designed to investigate causal relations, and some categories contain comorbid diagnoses that are potential causes of epilepsy, such as brain neoplasms and malformations, metabolic disorders, and chromosomal abnormalities…

All medical conditions were more frequent in CWE than in the general child population (Table 1). The most frequent, both in CWE and the general child population, were gastrointestinal disorders (most commonly constipation and gastroesophageal reflux), which were recorded in 19.1% of CWE versus 5.4% in the general child population. Other frequent disease categories in CWE were congenital malformations outside of the central nervous system (18.2%), musculoskeletal disorders (15.3%), chronic lower respiratory disorders (mainly asthma) (10.3%), and malnutrition and/or eating difficulties (10.1%). The largest relative increases in CWE (the highest ORs) were observed for visual impairments (OR = 30.6), chromosomal abnormalities (OR = 19.6), malnutrition and/or eating difficulties (OR = 16.1), sleep disorders (OR = 13.0), immune disorders (OR = 8.6), nutritional deficiencies (OR = 7.4), and metabolic disorders (OR = 7.3).

For neurologic disorders, the most frequent in CWE were cerebral palsy (13.9%), headache conditions (6.6%), and congenital neurologic malformations (6.5%). Both the absolute and the relative increases were large, with ORs >25 for all types of neurologic disorders except headache conditions.

Developmental and/or psychiatric disorders were registered in 42.9% of CWE overall, compared with 6.6% in the general population. The relative increase in CWE was particularly large for developmental disorders, with intellectual disability in 17.0% (OR = 41.0), disorders of psychological development in 21.3% (OR = 11.6), and unspecified developmental delay (ICD-10 code R62) in 7.5% (OR = 8.2). Of the disorders of psychological development, autism accounted for 7.8% (OR = 10.7). Attention-deficit/hyperactivity disorder (ADHD) was the most common psychiatric diagnosis in CWE, occurring in 12.1% (OR = 5.4). There were few cases of comorbid anxiety or depression in CWE, probably because emotional disturbances in children are mostly coded under the ICD-10 section for childhood behavioral and emotional disorders (F90–98). A total of 10.5% of CWE had diagnoses from this section (OR = 3.6).

Of the 6635 CWE, 3883 (58.5%) were defined as CWE+ and 2752 (41.5%) as CWE–. In general, all medical and psychiatric conditions were more frequent in CWE+ than in CWE– and more frequent in CWE– than in the general child population…

The increase in risk of disorders originating in the brain (ie, neurologic, developmental, and psychiatric conditions) is well known in CWE. Our findings for those conditions are in line with previous studies. Some of the comorbid neurologic, chromosomal, and metabolic disorders are likely to represent causes of epilepsy. The high proportions of medical disorders were a more surprising finding. Some of the specific medical diagnoses, such as asthma, have been investigated in other studies, and found to be increased in CWE. However, few previous studies have assessed a broad range of medical disorders in CWE, so we will focus on this in the remainder of the discussion.

Gastrointestinal disorders were the most frequent type of comorbid disorders. These were mostly treatable conditions, such as constipation and gastrointestinal reflux, occurring among younger CWE. More alarming were the high proportions of malnutrition and eating difficulties, which were found  in 1 out of 6 CWE overall, and increased in both CWE+ and CWE–. Nutritional deficiencies were also considerably more frequent in CWE relative to the general child population…

Sleep disorders were registered in 2.9% of CWE, which is 13 times more often than in the general child population…

The strengths of our study are the assessment of a broad range of comorbid disorders and the size and completeness of the data set. The large numbers allowed us to assess the risk of both rare and common disorders, and the inclusion of the whole child population largely eliminated selection bias, making our findings generalizable to other developed countries as well.

A limitation is the lack of validity data for the epilepsy diagnoses, as well as the other recorded diagnoses…

On the other hand, the relative differences between CWE and the general child population may be somewhat inflated because CWE are in regular contact with specialist health services. This regular contact increases the chance of diagnosing any type of comorbid disorder, a type of ascertainment bias often referred to as Berkson’s bias.80 CWE are also likely to undergo thorough investigations of potential causes of epilepsy, which also increase the chances of discovering comorbid disorders. In general, our data are likely to be most accurate for conditions that are serious enough to warrant specialist treatment and follow-up, both in CWE and the general population, whereas less severe conditions and difficulties, such as headache conditions and sleep disorders, are more likely to be captured in CWE than in the general child population.

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