Renate Arntz

Chapter 11

Incidence of stroke at young age is increasing, which has been explained by an accompanying increase in the prevalence of traditional vascular risk factors. Especially for this younger age group, long-term information on the years after the stroke is of utmost importance, as these patients usually have a long life ahead. However, reliable long-term information on complications after a stroke at young age is scarce. Therefore we investigated the long-term risk of post-stroke epilepsy and its association with outcome and the long-term risk of vascular disease after a stroke at young age.
The studies described in this thesis are based on the FUTURE study, a prospective cohort study on causes and consequences of patients with a transient ischemic attack (TIA), ischemic stroke or intracerebral haemorrhage (ICH) aged 18-50 years old. All consecutive patients who were admitted to the Radboud University Medical Centre between 1980 and 2010 were included in the study. An extensive follow-up assessment took place between 2010 and 2012 and between 2014 and 2015. The design of the FUTURE study is described in Chapter 2.

Post-stroke epilepsy after a stroke at young age
In part II the occurrence of post-stroke epilepsy after a stroke at young age and its association with outcome is described. Chapter 3 reports the incidence of post-stroke epilepsy. After a maximum follow-up of 30 years, cumulative risk of post-stroke epilepsy was 14% and 7% for recurrent seizures. Patients who had an initial late seizure more often developed recurrent seizures than patients with an initial early seizure. Patients with an ICH or ischemic stroke had a 4 times higher risk of developing seizures than patients with a TIA. In addition a higher National Institutes of Stroke Scale (NIHSS) was independently associated with a higher risk of post-stroke epilepsy.
In chapter 4 we investigated the association of post-stroke epilepsy with functional outcome in young stroke survivors. Ischemic stroke patients with post-stroke epilepsy more often had a poor functional outcome than those without both on modified Rankin Scale (mRS) and Instrumental Activities of Daily Living (IADL) after more than 10 years of follow-up; almost 30% of the patients with post-stroke epilepsy had a poor outcome compared to 10% of the patients without. This effect was independent from for sex, age, stroke severity, follow-up duration and recurrent stroke. For patients with a TIA or ICH there was no such relation. In chapter 5 we investigated the association of post-stroke epilepsy with cognitive performance after a TIA or ischemic stroke. After mean follow-up of 10 years we investigated seven cognitive domains. Patients with post-stroke epilepsy had a worse global cognitive performance than those without after adjustment for age at follow-up, education level, stroke severity and recurrent stroke. Especially the domains processing speed and working memory were more affected. In addition, 46% of the patients with post-stroke epilepsy had a cognitive impairment compared to 25% of the patients without, this difference was independent of previous mentioned confounders. There was no difference in cognitive performance between patients who used anti-epileptic drugs (AEDs) at the moment of cognitive assessment. However patients have stopped and switch AEDs during follow-up which could not be taken into account in our analyses.
Chapter 6 describes the association of post-stroke epilepsy with mortality after a TIA or ischemic stroke at young age. We found that patients with post-stroke epilepsy had a higher cumulative case fatality (death within 30 days after the initial stroke) than patients without (27% and 2% respectively), after adjustment for age, sex and stroke severity. In addition, 20-years cumulative mortality was 57% of patients with post-stroke epilepsy and 33% for those without; this difference was independent of sex, age, history of hypertension, history of diabetes mellitus, TOAST-classifications and recurrent stroke. There was no difference in cause of death between the two groups.

Long-term vascular consequences after a stroke at young age
Part III describes the long-term vascular consequences of a TIA or ischemic stroke at young age. In chapter 7 the very long-term risk of recurrent ischemic events was determined and risk factors associated with the risk of recurrent events were identified. We found that patients with a stroke at young age remain at a substantial risk of developing recurrent vascular events after their initial stroke. After 25 years of follow-up the cumulative risk of any vascular event was 45%; 30% for a recurrent stroke or TIA and 27% for other vascular events. Especially patients with a cardio-embolic stroke or large artery as a cause of their stroke have a very high cumulative risk of vascular events of more than 60% after 25 years. Risk factors independently associated with the risk of recurrent vascular events were poor kidney function, smoking, history of peripheral arterial disease and a history of myocardial infarction. Although the developed prediction model only had a moderate predictive performance, it became clear that traditional vascular risk factors play an important role in the risk of recurrent vascular disease.
In chapter 8 the prevalence of cerebral small vessel disease (SVD) after a stroke at young age was assessed and compared with healthy controls. After mean follow-up of 10 years, 24% of the patients had developed at least one lacune, 13% had developed at least one microbleeds and median white matter hyperintensity (WMH)-volume was 1.5 ML. Patients had an almost 7 times higher risk of developing lacunes, after adjusting for traditional vascular risk factors (age, sex, smoking, diabetes mellitus and hypertension) than healthy controls. Moreover, patients had the same volume of WMHs on average 10-20 years earlier in life compared with healthy controls. Traditional vascular risk factors age, hypertension and smoking at the time of the initial stroke, were independently associated with WMH-volume at follow-up in these patients.

Future perspective
Part IV of this thesis describes the design and rational of the ODYSSEY study (Observational Dutch Symptomatic StrokE study) (chapter 9). This ongoing multicenter cohort study is designed to prospectively determine prognosis after a stroke at young age and get more insight in aetiology of TIA, ischemic stroke and ICH in patients aged 18-49 years old. The aim is to include 1500 patients and patients will be followed every 6 months for at least 3 years. Primary outcome will be all cause mortality and risk of recurrent vascular events. Secondary outcome will be the risk of post-stroke epilepsy and cognitive impairment. In addition well-documented and less well-documented risk factors and potentially acute trigger factors will be investigated. Moreover, the use and (dis)continuation of secondary prevention will be documented. The risk estimates of recurrent vascular events may be used to design future intervention studies on start and withdrawal of secondary prevention in these young patients.

Conclusion
The studies in this thesis show that post-stroke epilepsy after a stroke at young age is a common problem and in addition is associated with a poor outcome in terms of mortality, functional outcome and cognitive performance.
In addition we have shown that patients remain at a lifelong risk of developing recurrent vascular events, especially patients with traditional vascular risk factors. The chronic consequences of a young stroke are also shown by the high proportion of patients who develop SVD compared to control subjects. Future studies should investigate the role of secondary prevention in this specific age group.