Unprovoked seizures in children : incidence, neurodevelopmental comorbidities and treatment

Epilepsy is considered to be the neurological disease that gives the largest burden of disease in children. It is a heterogeneous disease with very diverse consequences in the lives of the patient. Comorbidities with other neurological, as well as developmental, and psychiatric, diseases are common. The aim of this thesis was to describe the incidence of epileptic seizures in children and adults, the prevalence of neurodevelopmental comorbidities and cerebral palsy (CP) in children with seizures, and the implication of these comorbidities on the seizure prognosis in children.

The thesis was based on data from the Stockholm Incidence Registry of Epilepsy (SIRE). Medical records of all inhabitants of a designated area in northern Stockholm, seeking medical assistance for an unprovoked seizure between September 1st 2001 and December 31st 2006 were screened. Those who were diagnosed with an epileptic seizure for the first time (index seizure) during that timeframe were included in the Stockholm Incidence Registry of Epilepsy (SIRE). Medical records from before, and up until six months after, the index seizure were assessed regarding seizure type, epilepsy type and aetiology. The comorbidities developmental delay, speech/language and learning difficulties, intellectual disability, CP, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and unspecified psychiatric disorders were given special attention. The medical records of the children in SIRE were also assessed two years after the index seizure for information regarding the neurodevelopmental comorbidities and CP, treatment with antiepileptic drugs (AEDs) and seizure remission. SIRE was also linked to the Swedish Prescribed Drug Registry (SPDR) for the period 2005–2014, where information of the use of AEDs, neuroleptics, antidepressants and medication for ADHD was retrieved.

Study I included all patients (of all ages, 56% men) included in SIRE between Sept 1st 2001 and Aug 31st 2004 (N=1015). The incidence of a first unprovoked seizure was 35/100,000 person years (95% CI: 33.3–37.6). Seizure classification was possible in 72%, with generalized seizure debut only identified among those younger than 50 years old. A presumed aetiology was identified in 28% of the children (0–15 years old), in 37% of those 15 to 69 years, and in 64% of those over 70 years old. Stroke (11%) and brain tumours (9%) were the most common causes (primarily in adults). Neurological deficits from births were identified in 10% of the patients. The methodology of SIRE seemed effective regarding identification of seizure patients. Study II included all children (28 days up to 19 years old, 56% boys) included in SIRE between Sept 1st 2001 and Dec 31st 2006 (n=766). The seizure incidence was 67/100,000 person years overall and highest for those younger than one-year-old (204/100,000). Neurodevelopmental comorbidity or CP was found in 32% of the children, and 11% had more than one of the defined comorbidities. Study III was based on a 2-year follow-up of children included in Study II (n=750 with available records). Neurodevelopmental comorbidity or CP was found in 35% (95% CI:32– 38%) of the children. Remission from seizures month 13 to 24 after the index seizure, or start of treatment with AEDs, was achieved by 69% of all the children, but those with a neurodevelopmental comorbidity or CP still had seizures almost three times as often as those without a comorbidity (OR: 2.87, 95% CI:2.07–3.99). Study IV was also based on the children in Study II, with a few new inclusions due to late access to medical journals (n=769). Eight years after the index seizure, 31% of all the children were still dispensed AEDs, four times more often to children with neurodevelopmental comorbidity or CP compared to those without (OR: 4.0 95% CI: 2.9– 5.6). Neuroleptics, antidepressants and drugs for ADHD were dispensed to between 1-5% of the children in SIRE, this was 2–10 times more often than what was reported in the general population at the time.

In conclusion, neurodevelopmental comorbidities and CP were common among children with epileptic seizures and were present already at the time of onset of seizures. This indicating that these conditions may have a common innate cause, rather than epilepsy per se causing the neurodevelopmental deficiencies. Children with comorbidities were less likely to achieve seizures remission and also more likely to receive treatment with neuroleptics, antidepressants and medication for ADHD. The clinical implication of these findings is that children with a first unprovoked seizure should be assessed for neurodevelopmental comorbidities and CP. This since these diagnoses are more prevalent in this group and deserves attention, and since children with these comorbidities have a worse prognosis and may benefit from more careful monitoring regarding their seizures.

List of scientific papers

I. C. Adelöw, E. Åndell, P. Åmark, T. Andersson, E. Hellebro, A. Ahlbom and T. Tomson. (2009). Newly diagnosed single unprovoked seizures and epilepsy in Stockholm, Sweden: First report from the Stockholm Incidence Registry of Epilepsy (SIRE). Epilepsia. 50(5):1094-1101. Errata: Epilepsia. 52(8):1529.
https://doi.org/10.1111/j.1528-1167.2008.01726.x

II. E. Åndell, T. Tomson, S. Carlsson, E. Hellebro, T. Andersson, C. Adelöw and P. Åmark. (2015). The incidence of unprovoked seizures and occurrence of neurodevelopmental comorbidities in children at the time of their first epileptic seizure and during the subsequent six months. Epilepsy Res. 113:140-150.
https://doi.org/10.1016/j.eplepsyres.2015.04.002

III. E. Åndell, T. Tomson, S. Carlsson, K. Tedroff and P. Åmark. (2018). Neurodevelopmental comorbidities and seizure control 24 months after a first unprovoked seizure in children. Epilepsy Res. 143:33-40.
https://doi.org/10.1016/j.eplepsyres.2018.03.015

IV. E. Åndell, T. Tomson, P. Åmark, N. Pihlström, K. Tedroff, S. Carlsson. Childhood onset seizures: Long-term follow-up of antiepileptic drugs, and drugs for neuropsychiatric use. [Manuscript]