Clinical evaluation of a dedicated next generation sequencing panel for routine glioma diagnostics.

Since 2013 next-generation sequencing (NGS) targeting genes mutated in diffuse gliomas is part of routine diagnostics in our institute. In the present report, we evaluate the use of this custom tailored NGS platform on 434 samples. The NGS panel assesses mutations in ATRX, CIC, EGFR, FUBP1, NOTCH1, PTEN; H3F3A, IDH1/2, PIK3CA, and BRAF, amplifications in EGFR or MDM2 and copy number alterations (CNA) of chromosome 1p, 7, 10 and 19q. TERT promoter mutations were assessed separately when indicated. Of the 433 samples of individual tumors with NGS data available, 176 cases were diagnosed as grade 2 or 3 glioma (40.6) and in 201 patients a glioblastoma (46.4%). Of the remaining 56 patients, 22 had inconclusive histology. In 378 cases (87.1%) a diagnosis solely based on glioma-targeted NGS could be established and resulted in a different diagnosis in ~ 1/4 of the cases. In 17 out of 22 cases without a conclusive histological diagnosis NGS resulted in a molecular diagnosis.The current study on a large cohort of patients confirms the diagnostic strength of the platform we developed, with a clear separation of glioma subgroups with different outcomes. It demonstrates the diagnostic value and the efficiency of glioma-targeted NGS for routine glioma diagnostics allowing with a single assay a glioma diagnosis in the large majority of cases. It allows in one run the molecular assessments required for the WHO classification of diffuse gliomas, including the recent recommendations to assess copy number alterations of chromosome 7 and 10, and of the TERT promoter region in IDHwt lower grade glioma.

Increased Risk of Pregnancy Complications After Stroke: The FUTURE Study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation).

BACKGROUND AND PURPOSE: The study goal was to investigate the prevalence of pregnancy complications and pregnancy loss in women before, during, and after young ischemic stroke/transient ischemic attack. METHODS: In the FUTURE study (Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation), a prospective young stroke study, we assessed the occurrence of pregnancy, miscarriages, and pregnancy complications in 223 women aged 18 to 50 years with a first-ever ischemic stroke/transient ischemic attack. Pregnancy complications (gestational hypertension, diabetes mellitus, preeclampsia, and hemolysis, elevated liver enzymes, low platelet count syndrome) were assessed before, during, and after stroke using standardized questionnaires. Primary outcome was occurrence of pregnancy complications and the rate of pregnancy loss compared with the Dutch population. Secondary outcome was the risk of recurrent vascular events after stroke, stratified by a history of hypertensive disorder in pregnancy. RESULTS: Data were available for 213 patients. Mean age at event was 39.6 years (SD=7.8) and mean follow-up 9.5 years (SD=8.5). Miscarriages occurred in 35.2% and fetal death in 6.2% versus 13.5% and 0.9% in the Dutch population, respectively (P<0.05). In nulliparous women after stroke (n=22), in comparison with Dutch population, there was a high prevalence of hypertensive disorders in pregnancy (33.3 versus 12.2%; P<0.05), hemolysis, elevated liver enzymes, low platelet count syndrome (9.5 versus 0.5%; P<0.05), and early preterm delivery <32 weeks (9.0 versus 1.4%; P<0.05). In primi/multiparous women (n=141) after stroke, 29 events occurred (20-year cumulative risk 35.2%; 95% confidence interval, 21.3-49.0), none during subsequent pregnancies, and a history of a hypertensive disorder in pregnancy did not modify this risk (log-rank P=0.62). CONCLUSIONS: When compared with the general population, women with young stroke show higher rates of pregnancy loss throughout their lives. Also, after stroke, nulliparous women more frequently experienced serious pregnancy complications.

Prothrombotic factors do not increase the risk of recurrent ischemic events after cryptogenic stroke at young age: the FUTURE study.

BACKGROUND: The role of hypercoagulable states and preceding infections in the etiology of young stroke and their role in developing recurrent ischemic events remains unclear. Our aim is to determine the prevalence of these conditions in patients with cryptogenic stroke at young age and to assess the long-term risk of recurrent ischemic events in patients with and without a hypercoagulable state or a recent pre-stroke infection with Borrelia or Syphilis. PATIENTS AND METHODS: We prospectively included patients with a first-ever transient ischemic attack or ischemic stroke, aged 18-50, admitted to our hospital between 1995 and 2010. A retrospective analysis was conducted of prothrombotic factors and preceding infections. Outcome was recurrent ischemic events. RESULTS: Prevalence of prothrombotic factors did not significantly differ between patients with a cryptogenic stroke and with an identified cause (24/120 (20.0%) and 32/174 (18.4%) respectively). In patients with a cryptogenic stroke the long-term risk [mean follow-up of 8.9 years (SD 4.6)] of any recurrent ischemic event or recurrent cerebral ischemia did not significantly differ between patients with and without a hypercoagulable state or a recent infection. In patients with a cryptogenic stroke 15-years cumulative risk of any recurrent ischemic event was 24 and 23% in patients with and without any prothrombotic factor respectively. CONCLUSIONS: The prevalence of prothrombotic factors and preceding infections did not significantly differ between stroke patients with a cryptogenic versus an identified cause of stroke and neither is significantly associated with an increased risk of recurrent ischemic events after cryptogenic stroke.

Risk factors and mechanisms of stroke in young adults: The FUTURE study.

Incidence of ischemic stroke and transient ischemic attack in young adults is rising. However, etiology remains unknown in 30-40% of these patients when current classification systems designed for the elderly are used. Our aim was to identify risk factors according to a pediatric approach, which might lead to both better identification of risk factors and provide a stepping stone for the understanding of disease mechanism, particularly in patients currently classified as "unknown etiology". Risk factors of 656 young stroke patients (aged 18-50) of the FUTURE study were categorized according to the "International Pediatric Stroke Study" (IPSS), with stratification on gender, age and stroke of "unknown etiology". Categorization of risk factors into ≥1 IPSS category was possible in 94% of young stroke patients. Chronic systemic conditions were more present in patients aged <35 compared to patients ≥35 (32.6% vs. 15.6%, p < 0.05). Among 226 patients classified as "stroke of unknown etiology" using TOAST, we found risk factors in 199 patients (88%) with the IPSS approach. We identified multiple risk factors linked to other mechanisms of stroke in the young than in the elderly . This can be a valuable starting point to develop an etiologic classification system specifically designed for young stroke patients.

Kidney Dysfunction Increases Mortality and Incident Events after Young Stroke: The FUTURE Study.

BACKGROUND: In about 30% of young stroke patients, no cause can be identified. In elderly patients, kidney dysfunction has been suggested as a contributing risk factor for mortality as well as stroke. There are hypotheses that novel non-traditional risk factors, like chronic inflammation and oxidative stress, are involved in chronic kidney disease, affecting the cerebral microvasculature that would in turn lead to stroke. Our objective is to investigate the influence of kidney dysfunction on long-term mortality and incident vascular events after stroke in young adults aged 18 through 50 and if this relationship would be independent of other cardiovascular risk factors. METHODS: We prospectively included 460 young stroke patients with an ischemic stroke or transient ischemic attack admitted to our department between January 1, 1980 and November 1, 2010. Follow-up was done between 2014 and 2015. Estimated glomerular filtration rate (eGFR) was calculated from baseline creatinine levels and was divided in 3 subgroups: eGFR <60, 60-120 and >120 ml/min/1.73 m2. Cox proportional hazard models were used to determine the effect of kidney dysfunction on mortality and incident vascular events, adjusting for cardiovascular risk factors. RESULTS: An eGFR <60 (HR 4.6; 95% CI 2.6-8.2) was associated with an increased risk of death and an increased risk of incident stroke (HR 4.1; 95% CI 1.9-9.0) independent of cardiovascular risk factors, but it was not associated with other vascular events. The point estimate for the 15-year cumulative mortality was 70% (95% CI 46-94) for patients with a low eGFR, 24% (95% CI 18-30) for patients with a normal eGFR and 30% (95% CI 12-48) for patients with a high eGFR. The point estimate for the 15-year cumulative risk of incident stroke was 45% (95% CI 16-74) for patients with a low eGFR, 13% (95% CI 9-17) for patients with a normal eGFR and 8% (95% CI 0-18) for patients with a high eGFR. CONCLUSIONS: Kidney dysfunction is related to long-term mortality and stroke recurrence, but not to incident cardiovascular disease, on average 11 years after young stroke. This warrants a more intensive follow-up of young stroke patients with signs of kidney dysfunction in the early phase. In addition, the clear association between kidney dysfunction and incident stroke seen in our young stroke population might be a first step in the recognition of kidney dysfunction as a new risk factor for the development of stroke at young age. Also, it can lead to new insights in the etiological differences between cardiovascular and cerebrovascular disease.

Women have a poorer very long-term functional outcome after stroke among adults aged 18-50 years: the FUTURE study.

Due to their young age young stroke survivors have to cope with a dramatic impact on their life for the decades to come. We investigated the sex-specific very long-term functional outcome after transient ischemic attack (TIA) and ischemic stroke (IS) in adults aged 18-50 years. This study is part of a cohort study among 619 first-ever young ischemic stroke patients, admitted to our department between January 1, 1980 and November 1, 2010. Functional outcome was assessed during follow-up in 2009-2011 and in 2014-2015 with the modified Rankin Scale (mRS) and instrumental Activities of Daily Living scale (iADL). Risk factors for a poor functional outcome (mRS > 2 and iADL < 8) were calculated by logistic regression analysis. After a mean follow-up of 13.9 (SD 8.2) years, 24.5 % of TIA patients and 44.7 % of IS patients had a poor functional outcome (mRS > 2). When assessing the survivors, 15.2 % of TIA patients and 22.9 % of IS patients had a poor outcome as assessed by iADL. The strongest baseline predictors of poor outcome were female sex (OR 2.7, 95 % CI 1.5-5.0) and baseline NIHSS (OR 1.1, 95 % CI 1.1-1.2 per point increase). In conclusion, 14 years after an ischemic cerebrovascular event in young adults, one out of five IS survivors and one out of ten TIA survivors is still dependent in daily life, with a two to threefold higher risk of a poor outcome in women. This includes a period of life, during which important decisions regarding work and family life have to be made.

The very long-term risk and predictors of recurrent ischaemic events after a stroke at a young age: The FUTURE study.

INTRODUCTION: Patients who suffer a stroke at a young age, remain at a substantial risk of developing recurrent vascular events and information on very long-term prognosis and its risk factors is indispensable. Our aim is to investigate this very long-term risk and associated risk factors up to 35 years after stroke. PATIENTS AND METHODS: Prospective cohort study among 656 patients with a first-ever ischaemic stroke or transient ischaemic stroke (TIA), aged 18-50, who visited our hospital (1980-2010). Outcomes assessed at follow-up (2014-2015) included TIA or ischaemic stroke and other arterial events, whichever occurred first. Kaplan-Meier analysis quantified cumulative risks. A prediction model was constructed to assess risk factors independently associated with any ischaemic event using Cox proportional hazard analyses followed by bootstrap validation procedure to avoid overestimation. RESULTS: Mean follow-up was 12.4 (SD 8.2) years (8105 person-years). Twenty-five years cumulative risk was 45.4% (95%CI: 39.4-51.5) for any ischaemic event, 30.1% (95%CI: 24.8-35.4) for cerebral ischaemia and 27.0% (95%CI: 21.1-33.0) for other arterial events. Risk factors retained in the prediction model were smoking (HR 1.35, 95%CI: 1.04-1.74), poor kidney function (HR 2.10, 95%CI: 1.32-3.35), history of peripheral arterial disease (HR 2.10, 95%CI: 1.08-3.76) and cardiac disease (HR 1.84, 95%CI: 1.06-3.18) (C-statistic 0.59 (95%CI: 0.55-0.64)). DISCUSSION AND CONCLUSION: Young stroke patients remain at a substantial risk for recurrent events; almost 1 of 2 develops a recurrent ischaemic event and 1 of 3 develops a recurrent stroke or TIA during 25 years of follow-up. Risk factors independently associated with recurrent events were poor kidney function, smoking, history of peripheral arterial disease and cardiac disease.

Cognitive performance and poor long-term functional outcome after young stroke.

OBJECTIVE: To investigate the influence of cognitive performance on long-term functional outcome after ischemic stroke (IS) in young adults aged 18 through 50 years (young IS). METHODS: This study is part of a prospective cohort study among 277 stroke survivors with a young IS admitted to our department between January 1, 1980, and November 1, 2010. Functional outcome was assessed during follow-up between 2009 and 2012 with the modified Rankin Scale (mRS) and Instrumental Activities of Daily Living scale (IADL). Extensive neuropsychological investigation was performed. Logistic regression was used to calculate odds ratios (ORs) for a poor functional outcome (mRS >2 or IADL <8) for the 7 cognitive domains adjudicated for confounders. Cognitive function (continuous) as well as cognitive impairment (dichotomous) were studied. RESULTS: Only decline in working memory (OR 0.3, 95% confidence interval [CI] 0.1-0.6) was associated with poor functional outcome on the mRS. Except for decline in processing speed (OR 0.5, 95% CI 0.3-0.8) and working memory (OR 0.4, 95% CI 0.2-0.7), no relation was found with poor functional outcome on IADL. Impairment in none of the individual cognitive domains was related to long-term functional outcome, although impairment in global cognitive function was related to a poor functional outcome on the IADL (OR 4.8, 95% CI 1.7-14.0). CONCLUSIONS: On average, 11 years after young IS there was no clear relationship between long-term cognitive deficits and long-term functional outcome or IADL, stressing the need for further prospective studies with further development of sensitive measures of functional prognosis.

Quality of Life after Young Ischemic Stroke of Mild Severity Is Mainly Influenced by Psychological Factors.

BACKGROUND: Long-term prognosis in terms of quality of life (QoL) in young stroke patients is of importance because they usually have a long life expectancy and extensive daily life demands. We aimed at determining which medical and psychological factors influence the QoL in young stroke patients (<50 years), after long-term follow-up. METHODS: Young ischemic stroke patients admitted to the St. Elisabeth Hospital and the TweeSteden Hospital, Tilburg, the Netherlands, between 2000 and 2010 were included. One hundred seventy patients and 61 controls filled out the following questionnaires: (1) the Hospital Anxiety and Depression Scale, (2) the Fatigue Assessment Scale, and (3) the shortened World Health Organization Quality of Life scale. Using linear multiple regression analysis, we assessed the factors influencing QoL. RESULTS: QoL did not differ significantly between patients (median modified Rankin Scale score at follow-up, 0) and controls after a mean follow-up of 4.5 (standard deviation, 2.8) years. The presence of excessive fatigue was associated with lower scores on all domains of the QoL (P ≤ .003), but not for general health domain (P = .010). Similarly, depression was associated with worse QoL on the physical (P = .004) and psychological (P = .001) domains and anxiety with lower scores on the psychological (P < .001) QoL domain. No relationship was found between stroke-specific factors and QoL. CONCLUSIONS: Fatigue and to a lesser extent depression and anxiety affect the QoL in young adults after ischemic stroke of mild severity. Therefore, young stroke patients should be informed about, screened, and, if possible, treated for fatigue, depression, and anxiety.

Long-term cognitive outcome of ischaemic stroke in young adults.

BACKGROUND: Long-term prognosis in terms of cognition in young stroke patients is very important because these patients usually still have a long life expectancy and rather extensive daily life demands. However, little is known on cognitive deficits in these patients. We aimed to evaluate cognitive function in young stroke patients (<50 years) after long-term follow-up. METHODS: Young adults with first-ever ischaemic stroke admitted to St. Elisabeth Hospital or the TweeSteden Hospital, Tilburg, the Netherlands, between January 2000 and December 2010 were included. Patients with severe aphasia or pre-existent cognitive impairment were excluded. Cognitive functioning was assessed using a neuropsychological examination focussing on the following cognitive domains: visual perception, visual and verbal memory, mental speed, and executive functioning. Raw scores were compared to the scores of 61 controls using a multivariate analysis of variance with adjustment for education level. RESULTS: The 96 participants (median age at index event 43.0 years; 45.8% male) performed worse than controls on the Stroop Color-Word Test Part 1 (p < 0.001) and on the Symbol-Digit Substitution Task (p < 0.001), both assessing mental speed. Patients had significantly lower scores on the learning slope of the Word Pair test (p = 0.002) assessing verbal memory. Patients performed better on the Rey-Osterrieth Complex Figure than controls (p < 0.001). CONCLUSIONS: In young patients with ischaemic stroke, mental slowness is present even up to 10 years after stroke. When counselling these patients, doctors should actively try to assess the presence of cognitive deficits, also after a long period of follow-up.

Poor long-term functional outcome after stroke among adults aged 18 to 50 years: Follow-Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study.

BACKGROUND AND PURPOSE: Stroke in young adults has a dramatic effect on life; therefore, we investigated the long-term functional outcome after transient ischemic attack, ischemic stroke, or intracerebral hemorrhage in adults aged 18 to 50 years. METHODS: We studied 722 young patients with first-ever stroke admitted between January 1, 1980, and November 1, 2010. Functional outcome was assessed by stroke subtype with the modified Rankin Scale and Instrumental Activities of Daily Living scale. RESULTS: After a mean follow-up of 9.1 (SD, 8.2) years, 32.0% of all patients had a poor functional outcome (modified Rankin Scale, >2); for ischemic stroke, this was 36.5%, for intracerebral hemorrhage 49.3%, and for transient ischemic attack 16.8%. At follow-up, 10.8% of transient ischemic attack, 14.6% of ischemic stroke, and 18.2% of intracerebral hemorrhage patients had a poor outcome as assessed by Instrumental Activities of Daily Living (<8). CONCLUSIONS: Ten years after ischemic stroke or intracerebral hemorrhage in young adults, 1 of 8 survivors is still dependent in daily life.

Observational Dutch Young Symptomatic StrokE studY (ODYSSEY): study rationale and protocol of a multicentre prospective cohort study.

BACKGROUND: The proportion of strokes occurring in younger adults has been rising over the past decade. Due to the far longer life expectancy in the young, stroke in this group has an even larger socio-economic impact. However, information on etiology and prognosis remains scarce. METHODS/DESIGN: ODYSSEY is a multicentre prospective cohort study on the prognosis and risk factors of patients with a first-ever TIA, ischemic stroke or intracerebral hemorrhage aged 18 to 49 years. Our aim is to include 1500 patients. 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. Patients will complete structured questionnaires on outcome measures and risk factors. Both well-documented and less well-documented risk factors and potentially acute trigger factors will be investigated. Patients will be followed every 6 months for at least 3 years. In addition, an extensive neuropsychological assessment will be administered both at baseline and 1 year after the stroke/TIA. Furthermore we will include 250 stroke-free controls, who will complete baseline assessment and one neuropsychological assessment. DISCUSSION: ODYSSEY is designed to prospectively determine prognosis after a young stroke and get more insight into etiology of patients with a TIA, ischemic stroke and intracerebral hemorrhage in patients aged 18 to 49 years old in a large sample size.

[A man with decreased consciousness, weeks after head trauma]. / Een man met bewustzijnsdaling, weken na schedeltrauma.

A 76-year-old man had decreased consciousness, 6 weeks after head trauma. Cerebral CT-scan revealed bilateral subdural haematomas with old and recent components.