Autoimmune Encephalitis Related to Cancer Treatment With Immune Checkpoint Inhibitors: A Systematic Review.

OBJECTIVE: To determine the clinical and laboratory features of immune checkpoint inhibitor (ICPI)-associated autoimmune encephalitis (ICPI-AIE), an increasingly recognized adverse event with ICPI treatment. METHODS: We searched PubMed, The Cochrane Library, and Embase for ICPI-AIE cases from the first description in 2015 until January 2020 using standard bibliographic measures including PRISMA guidelines and preregistration with PROSPERO. RESULTS: Thirty-nine studies met inclusion criteria, resulting in 54 patients with ICPI-AIE (mean age 58.6 years; 43% female). Common cancers included melanoma (30%) and non-small cell lung cancer (30%). Brain metastases were found in 16 patients (30%). The most frequent ICPI was nivolumab (61%). Onset of ICPI-AIE occurred after a median of 3.0 treatment cycles, but very early and late presentations were common. Nonlimbic AIE was roughly twice as frequent as limbic AIE (p < 0.05). The most common laboratory abnormalities included bitemporal fluid-attenuated inversion recovery lesions on MRI, continuous slow waves and diffuse slowing on EEG, and monocytic pleocytosis on CSF analysis. Intraneuronal antibodies were more frequent than neuronal surface antibodies and a significant predictor for lack of improvement after first-line immunotherapy (p < 0.05). CONCLUSIONS: ICPI-AIE consists of a heterogenous group of conditions. Neurologists will likely encounter ICPI-AIE more often in the future, but important unresolved questions include the pathophysiologic mechanisms, the epidemiology, and the best treatment approaches associated with ICPI-AIE.

Iatrogenic cerebral radiation necrosis.

Cerebral radiation necrosis is the most serious late reaction to high doses of ionising radiation to the brain, and its treatment is generally unsatisfactory. We present a patient who developed cerebral radiation necrosis after protracted fluoroscopy during repeated embolisations of an extracranial arteriovenous malformation. Treatment with bevacizumab (a humanised murine monoclonal antibody against vascular endothelial growth factor) was followed by neurological and radiological improvements.

Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism.

This is the first report of presumed sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS) with the prion protein gene c.305C>T mutation (p.P102L) occurring in one family. The father and son were affected with GSS and the mother had a rapidly progressive form of CJD. Diagnosis of genetic, variant, and iatrogenic CJD was ruled out based on the mother's clinical history, genetic tests, and biochemical investigations, all of which supported the diagnosis of sCJD. However, given the low incidence of sCJD and GSS, their co-occurrence in one family is extraordinary and challenging. Thus, a hypothesis for the transmission of infectious prion proteins (PrPSc) via microchimerism was proposed and investigated. DNA from 15 different brain regions and plasma samples of the CJD patient was subjected to PCR and shallow sequencing for detection of a male sex-determining chromosome Y (chr. Y). However, no trace of chr. Y was found. A long CJD incubation period or presumed small concentrations of chr. Y may explain the obtained results. Further studies of CJD and GSS animal models with controlled genetic and proteomic features are needed to determine whether maternal CJD triggered via microchimerism by a GSS fetus might present a new PrPSc transmission route.

Causes of Death Data in the Global Burden of Disease Estimates for Ischemic and Hemorrhagic Stroke.

BACKGROUND: Stroke mortality estimates in the Global Burden of Disease (GBD) study are based on routine mortality statistics and redistribution of ill-defined codes that cannot be a cause of death, the so-called 'garbage codes' (GCs). This study describes the contribution of these codes to stroke mortality estimates. METHODS: All available mortality data were compiled and non-specific cause codes were redistributed based on literature review and statistical methods. Ill-defined codes were redistributed to their specific cause of disease by age, sex, country and year. The reassignment was done based on the International Classification of Diseases and the pathology behind each code by checking multiple causes of death and literature review. RESULTS: Unspecified stroke and primary and secondary hypertension are leading contributing 'GCs' to stroke mortality estimates for hemorrhagic stroke (HS) and ischemic stroke (IS). There were marked differences in the fraction of death assigned to IS and HS for unspecified stroke and hypertension between GBD regions and between age groups. CONCLUSIONS: A large proportion of stroke fatalities are derived from the redistribution of 'unspecified stroke' and 'hypertension' with marked regional differences. Future advancements in stroke certification, data collections and statistical analyses may improve the estimation of the global stroke burden.

Heart rate as a predictor of stroke in high-risk, hypertensive patients with previous stroke or transient ischemic attack.

BACKGROUND: Risk factors for first stroke are well established, but less is known about risk factors for recurrent stroke. In the present analysis, we aimed to assess the effect of heart rate and other possible predictors of stroke in a hypertensive population with previous stroke or transient ischemic attack (TIA). METHODS: The Valsartan Antihypertensive Long-Term Use Evaluation trial was a multicentre, double-masked, randomized controlled, parallel group trial comparing the effects of an angiotensin receptor blocker (valsartan) and a calcium channel blocker (amlodipine) in patients with hypertension and high cardiovascular risk. We used Cox proportional hazard models to investigate the effect of baseline variables on the risk of stroke. Quadratic terms of the continuous variables were entered in the models to test for linearity. RESULTS: Of 15,245 patients included in the trial, 3014 had a previous stroke or TIA at baseline and were included in the present analysis. Stroke recurrence occurred in 239 patients (7.9%) during a median of 4.5 years of follow-up. Resting heart rate (per 10 beats per minute; hazard ratio [HR], 2.78; 95% confidence interval [CI], 1.18-6.58) and diabetes mellitus at baseline (HR, 1.47; 95% CI, 1.03-2.10) were significantly associated with an increased risk of stroke recurrence in the multivariable analysis. CONCLUSIONS: In high-risk, hypertensive patients with previous stroke or TIA, resting heart rate was the strongest predictor of recurrent stroke.

Stroke awareness in Denmark.

BACKGROUND: This is the first study to examine the awareness of major stroke symptoms and stroke risk factors among the general population in Denmark. Early recognition of stroke warning signs and means of reducing stroke occurrence could improve the treatment and prevention of stroke. METHODS: A total of 3,520 subjects were invited to participate in the study, using a web-based, closed questionnaire. The recruitment was stratified by region, age and gender to represent the composition of the general Danish population aged 40+ years. Enrollment was competitive with a predefined target of 800 responses. The subjects were asked to rank the 4 most important acute stroke symptoms, and the 3 most important risk factors for stroke. Multivariable ordinal logistic regression was used for assessing factors associated with awareness of stroke symptoms and major stroke risk factors. RESULTS: From December 12 to December 17, 2008, a total of 811 subjects (mean age: 58 years; SD: 11 years) were included, of which 405 (50%) were women. The 4 most frequently identified stroke symptoms were sudden onset of: speech disturbances (n = 636; 78.4%), facial palsy (n = 450; 55.5%), hemiparesis (n = 435; 53.6%) and visual disturbances (n = 429; 52.9%). The 3 most frequently identified stroke risk factors were: hypertension (n = 586; 72.3%), history of cerebrovascular disease (n = 401; 49.5%) and high concentration of cholesterol (n = 269; 33.2%). Compared with men, women had better knowledge of major stroke symptoms (OR = 1.33; 95% CI: 1.12-1.50) and stroke risk factors (OR = 1.33; 95% CI: 1.10-1.51) in multivariable analyses. CONCLUSIONS: The awareness of major stroke symptoms is insufficient. Whereas hypertension was the most often mentioned stroke risk factor, few subjects recognized tobacco smoking and diabetes mellitus as major risk factors for stroke.

ExStroke Pilot Trial of the effect of repeated instructions to improve physical activity after ischaemic stroke: a multinational randomised controlled clinical trial.

OBJECTIVES: To investigate if repeated verbal instructions about physical activity to patients with ischaemic stroke could increase long term physical activity. DESIGN: Multicentre, multinational, randomised clinical trial with masked outcome assessment. SETTING: Stroke units in Denmark, China, Poland, and Estonia. PARTICIPANTS: 314 patients with ischaemic stroke aged >or=40 years who were able to walk-157 (mean age 69.7 years) randomised to the intervention, 157 (mean age 69.4 years) in the control group. INTERVENTIONS: Patients randomised to the intervention were instructed in a detailed training programme before discharge and at five follow-up visits during 24 months. Control patients had follow-up visits with the same frequency but without instructions in physical activity. MAIN OUTCOME MEASURES: Physical activity assessed with the Physical Activity Scale for the Elderly (PASE) at each visit. Secondary outcomes were clinical events. RESULTS: The estimated mean PASE scores were 69.1 in the intervention group and 64.0 in the control group (difference 5.0 (95% confidence interval -5.8 to 15.9), P=0.36. The intervention had no significant effect on mortality, recurrent stroke, myocardial infarction, or falls and fractures. CONCLUSION: Repeated encouragement and verbal instruction in being physically active did not lead to a significant increase in physical activity measured by the PASE score. More intensive strategies seem to be needed to promote physical activity after ischaemic stroke. TRIAL REGISTRATION: Clinical Trials NCT00132483.

The ExStroke Pilot Trial: rationale, design, and baseline data of a randomized multicenter trial comparing physical training versus usual care after an ischemic stroke.

INTRODUCTION: A high level of physical activity is associated with a decreased risk of first stroke and physical activity modifies recognized stroke risk factors and is recommended for stroke survivors. Available research shows that stroke patients can increase their level of physical performance over a short period. When the intervention period is over, physical performance often declines towards baseline level. Currently, there is no evidence on the association between physical activity and the risk of recurrent stroke. The ExStroke Pilot Trial is a randomized clinical trial with the aim of increasing stroke patients' level of physical activity and secondarily to associate the level of physical activity to the risk of recurrent stroke, myocardial infarction, and all-cause mortality in the two groups. We describe the rationale, design, and baseline data of the ExStroke Pilot Trial. METHODS: Patients with ischemic stroke above 39 years were randomized to intervention or control group. The intervention group will, over a 2-year period, receive information on and verbal instruction to exercise by a physiotherapist or a physician. The control group will receive the department's usual care. Physical activity is assessed in both groups seven times during follow-up using the Physical Activity Scale for the Elderly (PASE) questionnaire, which quantifies the amount of physical activity done in the last seven days prior to interview. The PASE score constitutes the primary outcome measure. The secondary outcome is the time from randomization to recurrent stroke, myocardial infarction, or all-cause mortality. Further outcome measures include: time from randomization to recurrent stroke, myocardial infarction, and vascular death; recurrent stroke; modified Rankin Scale; quality of life; occurrence of falls and fractures. TRIAL STATUS: From 9 centers in 4 countries, 314 patients were included and follow-up is ongoing. Mean age and standard deviation (SD) of the study participants was 68.4 (11.9) years and 56.4% were male. Mean (SD) PASE score was 84.1 (55.9) and median (interquartile range) Scandinavian Stroke Scale score was 54 (51-58).

Level of physical activity in the week preceding an ischemic stroke.

BACKGROUND: Most observational studies investigating physical activity as a risk factor for stroke have concentrated on the years preceding a stroke event. In the present case control study we compared the reported level of physical activity performed during the week preceding an ischemic stroke with that of community controls. Furthermore we calculated the odds ratio for stroke based on the level of physical activity. SUBJECTS AND METHODS: Patients with an ischemic stroke were recruited consecutively from hospitals covering Copenhagen City. Community controls were recruited among participants of the Copenhagen City Heart Study and matched according to age and gender. The level of physical activity was assessed using The Physical Activity Scale for the Elderly (PASE), which quantifies the amount of physical activity done in the last 7 days. RESULTS: A total of 127 cases and 301 control subjects were included in the study. Mean (+/-SD) PASE scores for cases were 76.0 +/- 46.2 and 119.7 +/- 69.4 for controls (p < 0.001). For each 1-point increase in PASE score the odds ratio for ischemic stroke was 0.98 (0.98-0.99), equivalent to an odds ratio of 0.86 (95% CI: 0.82-0.90) for each 10-point increase. CONCLUSION: Stroke patients are less physically active in the week preceding an ischemic stroke when compared to age- and sex-matched controls. Increasing PASE score was inversely, log-linearly and significantly associated with odds ratio for ischemic stroke.

Validity of stroke diagnoses in a National Register of Patients.

BACKGROUND: Many registers containing routine medical information have been developed for research and surveillance purposes. In epidemiological research assessment of endpoints is often conducted via registers. In the present study we validated stroke and transient ischemic attack (TIA) diagnoses in the Danish National Register of Patients (DNRP). METHODS: Subjects from a Danish cohort study, the Copenhagen City Heart Study (n = 19,698), were crosslinked with the DNRP. The following International Classification of Disease 10th revision codes were used to identify possible strokes and TIAs: I60-I69 and G45. Two independent raters reviewed all cases. Positive predictive values of stroke, TIA and stroke subtypes were estimated by dividing the confirmed cases by the total number of cases located in the DNRP. Interrater reliability was tested using kappa statistics. RESULTS: Of 236 possible cerebrovascular events, 1 in 6 stroke diagnoses did not meet study criteria. The majority of events in the DNRP were registered as unspecified stroke (I64), n = 105 (44%), of which two thirds were diagnosed as ischemic stroke events by the raters. Intracerebral hemorrhage and ischemic stroke had a positive predictive value from 74 to 97%, respectively. CONCLUSION: Our results show that the DNRP tends to overestimate the number of cerebrovascular events, while ischemic stroke is underestimated.