Lucille D.A. Dorresteijn

Increased Risk of Stroke and Transient Ischemic Attack in 5-Year Survivors of Hodgkin Lymphoma

BACKGROUND Information on clinically verified stroke and transient ischemic attack (TIA) following Hodgkin lymphoma is scarce. We quantified the long-term risk of cerebrovascular disease associated with the use of radiotherapy and chemotherapy in survivors of Hodgkin lymphoma and explored potential pathogenic mechanisms. METHODS We performed a retrospective cohort study among 2201 five-year survivors of Hodgkin lymphoma treated before age 51 between 1965 and 1995. We compared incidence rates of clinically verified stroke and TIA with those in the general population. We used multivariable Cox regression techniques to study treatment-related factors and other risk factors. All statistical tests were two-sided. RESULTS After a median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 strokes, 31 TIAs, and 10 with both TIA and stroke; median age = 52 years). Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolisms (24%). The standardized incidence ratio for stroke was 2.2 (95% confidence interval [CI] = 1.7 to 2.8), and for TIA, it was 3.1 (95% CI = 2.2 to 4.2). The risks remained elevated, compared with those in the general population, after prolonged follow-up. The cumulative incidence of ischemic stroke or TIA 30 years after Hodgkin lymphoma treatment was 7% (95% CI = 5% to 8%). Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (hazard ratio = 2.5, 95% CI = 1.1 to 5.6 vs without radiotherapy). Treatment with chemotherapy was not associated with an increased risk. Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. CONCLUSIONS Patients treated for Hodgkin lymphoma experience a substantially increased risk of stroke and TIA, associated with radiation to the neck and mediastinum. Physicians should consider appropriate risk-reducing strategies.

Long-term Mortality After Stroke Among Adults Aged 18 to 50 Years

IMPORTANCE Long-term data on mortality after first-ever stroke in adults aged 18 through 50 years are scarce and usually restricted to ischemic stroke. Moreover, expected mortality not related to first-ever stroke is not taken in account. OBJECTIVES To investigate long-term mortality and cause of death after acute stroke in adults aged 18 through 50 years and to compare this with nationwide age- and sex-matched mortality rates. DESIGN, SETTING, AND PARTICIPANTS The Follow -Up of Transient Ischemic Attack and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study, a prospective cohort study of prognosis after transient ischemic attack (TIA), ischemic stroke, or hemorrhagic stroke in adults aged 18 through 50 years admitted to Radboud University Nijmegen Medical Centre, the Netherlands, between January 1, 1980, and November 1, 2010. The survival status of 959 consecutive patients with a first-ever TIA (n = 262), ischemic stroke (n = 606), or intracerebral hemorrhage (n = 91) was assessed as of November 1, 2012. Mean follow-up duration was 11.1 (SD, 8.7) years (median, 8.3 [interquartile range, 4.0-17.4]). Observed mortality was compared with the expected mortality, derived from mortality rates in the general population with similar age, sex, and calendar-year characteristics. MAIN OUTCOME MEASURES Cumulative 20-year mortality among 30-day survivors of stroke. RESULTS At the end of follow-up, 192 patients (20.0%) had died. Among 30-day survivors, cumulative 20-year risk of death was 24.9% (95% CI, 16.0%-33.7%) for TIA, 26.8% (95% CI, 21.9%-31.8%) for ischemic stroke, and 13.7% (95% CI, 3.6%-23.9%) for intracerebral hemorrhage. Observed mortality was increased compared with expected mortality (standardized mortality ratio [SMR], 2.6 [95% CI, 1.8-3.7] for TIA, 3.9 [95% CI, 3.2-4.7] for ischemic stroke, and 3.9 [95% CI, 1.9-7.2 for intracerebral hemorrhage, respectively). For ischemic stroke, cumulative 20-year mortality among 30-day survivors was higher in men than in women (33.7% [95% CI, 26.1%-41.3%] vs 19.8% [95% CI, 13.8%-25.9%]). The SMR was 4.3 (95% CI, 3.2-5.6) for women and 3.6 (95% CI, 2.8-4.6) for men. For all etiologic subtypes of ischemic stroke, observed mortality exceeded expected mortality. CONCLUSIONS AND RELEVANCE Among adults aged 18 through 50 years, 20-year mortality following acute stroke was relatively high compared with expected mortality. These findings may warrant further research evaluating secondary prevention strategies in these patients.

Long-term risk of recurrent vascular events after young stroke: The FUTURE study

Long‐term data on recurrent vascular events after young stroke are limited. Our objective was to examine the long‐term risk of recurrent vascular events after young stroke.

Long-Term Cognitive Impairment After First-Ever Ischemic Stroke in Young Adults

Background and Purpose— Up to 14% of all ischemic strokes occur in young adults (<50 years). Poststroke cognitive performance is a decisive determinant of their quality of life. However, virtually no studies report on cognition after young stroke, especially not on the long term. This long-term perspective is important because young patients have a long life expectancy during which they start forming a family, have an active social life, and make decisive career moves. We aimed to evaluate the long-term cognitive outcome. Methods— All consecutive patients between January 1, 1980, and November 1, 2010, with a first-ever young ischemic stroke were recruited for cognitive assessment, using a matched stroke-free population as a reference. Composite Z scores for 7 cognitive domains were calculated and the ANCOVA model was used (Bonferroni correction). A below average performance was defined as >1.0 SD below the age-adjusted mean of the controls and cognitive impairment as >1.5 SD. Results— Two hundred seventy-seven patients and 146 matched controls completed cognitive assessment (mean follow-up, 11.0 years, SD, 8.2; age, 50.9 years, SD, 10.3). Long-term cognitive outcome after an ischemic stroke was worse in most cognitive domains compared with a nonstroke population. Up to 50% of the patients had a below average performance or cognitive impairment. Deficits in processing speed, working memory, and attention were most common. Conclusions— Even 11 years after ischemic stroke in young adults, a substantial proportion of patients must cope with permanent cognitive deficits. These results have implications for information given to patients and rehabilitation services.

Post-stroke epilepsy in young adults: a long-term follow-up study.

Background Little is known about the incidence and risk of seizures after stroke in young adults. Especially in the young seizures might dramatically influence prognosis and quality of life. We therefore investigated the long-term incidence and risk of post-stroke epilepsy in young adults with a transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH). Methods and Findings We performed a prospective cohort study among 697 consecutive patients with a first-ever TIA, IS or ICH, aged 18–50 years, admitted to our hospital between 1-1-1980 till 1-11-2010. The occurrence of epilepsy was assessed by standardized questionnaires and verified by a neurologist. Cumulative risks were estimated with Kaplan-Meier analysis. Cox proportional hazard models were used to calculate relative risks. After mean follow-up of 9.1 years (SD 8.2), 79 (11.3%) patients developed post-stroke epilepsy and 39 patients (5.6%) developed epilepsy with recurrent seizures. Patients with an initial late seizure more often developed recurrent seizures than patients with an initial early seizure. Cumulative risk of epilepsy was 31%, 16% and 5% for patients with an ICH, IS and TIA respectively (Logrank test ICH and IS versus TIA p<0.001). Cumulative risk of epilepsy with recurrent seizures was 23%, 8% and 4% respectively (Logrank ICH versus IS p = 0.05, ICH versus TIA p<0.001, IS versus TIA p = 0.01). In addition a high NIHSS was a significant predictor of both epilepsy and epilepsy with recurrent seizures (HR 1.07, 95% CI 1.03–1.11 and 1.08, 95% CI 1.02–1.14). Conclusions Post-stroke epilepsy is much more common than previously thought. Especially patients with an ICH and a high NIHSS are at high risk. This calls upon the question whether a subgroup could be identified which benefits from the use of prophylactic antiepileptic medication. Future studies should be executed to investigate risk factors and the effect of post-stroke epilepsy on quality of life.

Screening Hodgkin lymphoma survivors for radiotherapy induced cardiovascular disease

Long term prognosis of Hodgkin lymphoma (HL) survivors is affected by late toxicity of radiotherapy and chemotherapy. Cardiovascular complications of radiotherapy have been shown to have a great impact on the long term survival. The aim of this review is to summarize the available data on different screening modalities for cardiovascular disease and to suggest a screening program. Patients older than 45 years at HL diagnosis should be screened for coronary artery disease (CAD) starting 5 years after mediastinal radiotherapy; they are at increased risk of pre-existent atherosclerosis which can be accelerated by radiotherapy. Screening for CAD should start 10 years after radiotherapy in younger patients. The best screening modality for CAD is subject of discussion, based on the latest studies we suggest screening by Coronary artery calcium score measurements or CT-angiography. Valvular disorders should be looked for by echocardiography starting 10 years after radiotherapy. Electrocardiograms should be performed at each cardiovascular screening moment in order to detect arrhythmias or conduction abnormalities. We suggest repeating these screening tests every 5 years or at onset of cardiovascular complaints; patients should be extensively instructed about signs and symptoms of cardiovascular disease. Furthermore traditional risk factors for cardiovascular disease should be carefully monitored and treated. We suggest determining a cardiovascular risk profile at diagnosis of HL in patients older than 45 years. In case of a high risk, treating HL without RT should be considered.

Decreased Risk of Stroke Among 10-Year Survivors of Breast Cancer

PURPOSE To assess treatment-specific risk of cerebrovascular events in early breast cancer (BC) patients, accounting for cerebrovascular risk factors. PATIENTS AND METHODS We studied the incidence of cerebrovascular accidents (CVA; stroke and transient ischemic attack [TIA]) in 10-year survivors of early BC (n = 4,414) treated from 1970 to 1986. Follow-up was 96% complete until January 2000. Treatment-specific incidence of CVA was evaluated by standardized incidence ratios (SIRs) based on comparison with general population rates and by Cox proportional hazards regression. RESULTS After a median follow-up of 18 years, 164 strokes and 109 TIAs were observed, resulting in decreased SIRs of 0.8 (95% CI, 0.6 to 0.9) for stroke and 0.8 (95% CI, 0.7 to 1.0) for TIA. Significantly increased risk of stroke was found in women who had received hormonal treatment (HT; tamoxifen) and in women who had hypertension or hypercholesterolemia, with hazard ratios (HRs) of 1.9, 2.1, and 1.6, respectively. Patients irradiated on the supraclavicular area and/or internal mammary chain (IMC) did not experience a higher risk of stroke (HR = 1.0; 95% CI, 0.7 to 1.6) or TIA (HR = 1.4; 95% CI, 0.9 to 2.5) compared with patients who did not receive radiotherapy or who were irradiated on fields other than the supraclavicular area or IMC. CONCLUSION Long-term survivors of BC experience no increased risk of cerebrovascular events compared with the general population. HT is associated with an increased risk of stroke. Radiation fields including the carotid artery do not seem to increase the risk of stroke compared with other fields.

Epilepsy after TIA or stroke in young patients impairs long-term functional outcome The FUTURE Study

Objective: To determine the influence of poststroke epilepsy on long-term functional outcome in young stroke survivors. Methods: This study is a prospective cohort study among 537 stroke survivors with a first-ever TIA, ischemic stroke, or intracerebral hemorrhagic (ICH) stroke, aged 18 to 50 years. After a mean follow-up of 9.8 years (SD 8.4), we performed a follow-up assessment that included an evaluation for poststroke epilepsy and functional outcome. Odds ratios for poor outcome on the modified Rankin Scale (mRS) (score >2) and Instrumental Activities of Daily Living (IADL) (score <8) were calculated using logistic regression analysis. Results: Forty patients (12.7%) with ischemic stroke, 4 patients (2.2%) with TIA, and 10 patients (25.6%) with ICH developed poststroke epilepsy. Ischemic stroke patients with epilepsy more often had a poor functional outcome than those without, both on the mRS and IADL (mRS score >2: 27.5% vs 9.8%, p = 0.001; IADL <8: 27.8% vs 12.6%, p = 0.02). Epilepsy was not related to functional outcome in patients with TIA and ICH. Multiple regression analysis revealed that epilepsy was an independent predictor of poor functional outcome after ischemic stroke assessed by mRS (mRS score >2: odds ratio 3.38, 95% confidence interval 1.33–8.60). In contrast, there was no such relation for IADL. Conclusions: Epilepsy after stroke in young patients is a common problem that negatively affects functional outcome, even more than 10 years after ischemic stroke.

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.

Progressive muscle atrophy and weakness after treatment by mantle field radiotherapy in Hodgkin lymphoma survivors.

PURPOSE To describe the damage to the muscles and propose a pathophysiologic mechanism for muscle atrophy and weakness after mantle field radiotherapy in Hodgkin lymphoma (HL) survivors. METHODS AND MATERIALS We examined 12 patients treated by mantle field radiotherapy between 1969 and 1998. Besides evaluation of their symptoms, the following tests were performed: dynamometry; ultrasound of the sternocleidomastoid, biceps, and antebrachial flexor muscles; and needle electromyography of the neck, deltoid, and ultrasonographically affected arm muscles. RESULTS Ten patients (83%) experienced neck complaints, mostly pain and muscle weakness. On clinical examination, neck flexors were more often affected than neck extensors. On ultrasound, the sternocleidomastoid was severely atrophic in 8 patients, but abnormal echo intensity was seen in only 3 patients. Electromyography of the neck muscles showed mostly myogenic changes, whereas the deltoid, biceps, and antebrachial flexor muscles seemed to have mostly neurogenic damage. CONCLUSIONS Many patients previously treated by mantle field radiotherapy develop severe atrophy and weakness of the neck muscles. Neck muscles within the radiation field show mostly myogenic damage, and muscles outside the mantle field show mostly neurogenic damage. The discrepancy between echo intensity and atrophy suggests that muscle damage is most likely caused by an extrinsic factor such as progressive microvascular fibrosis. This is also presumed to cause damage to nerves within the radiated field, resulting in neurogenic damage of the deltoid and arm muscles.