American Heart Association


In Quest to Enhance Stroke Recovery, Does Daily Fluoxetine Alone Get Us Closer?

Kate Hayward, PhD, PT

ESO-WSO 2020 Large Clinical Trials Webinar
Presentation: Assessment of fluoxetine in stroke recovery (AFFINITY): A randomised double-blind, placebo-controlled trial
Presenter: Prof. Graeme Hankey

There is much interest in identifying a drug to boost post-stroke recovery. Fluoxetine has received considerable attention since the FLAME trial,1 which demonstrated an improvement in motor recovery (Fugl Meyer Assessment) and functional independence (modified Rankin Scale) in acute stroke patients with moderate to severe hemiparesis.

To address uncertainty that existed concerning the use of fluoxetine,2 a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials were established: EFFECTS (also presented on the ESO-WSO large clinical trials webinar, Sweden), FOCUS (published in 2019,3 United Kingdom), and AFFINITY, which is the focus of this blog post. These international trials collectively aimed to determine whether the routine administration of fluoxetine (20mg daily) for six months after an acute stroke improves patients’ functional outcome.4

Have We EFFECTively Put an End to the Use of SSRIs in Motor Recovery After Acute Stroke?

Abbas Kharal, MD, MPH

ESO-WSO 2020 Large Clinical Trials Webinar
EFFECTS Trial – Efficacy of Fluoxetine: A Randomized Controlled Trial in Stroke
May 13, 2020

Over the past decade, there has been much controversy regarding the potential benefit of selective serotonin reuptake inhibitors (SSRIs) in neuro-recovery and functional independence after stroke. After data from animal stroke studies showed that SSRIs may have potential neuroprotective properties,1 this concept was further analyzed in humans through a Cochrane review2 of 52 studies of a total of 4059 stroke patients, which suggested that SSRIs may improve disability after stroke; however, given the heterogeneity of data, solid conclusions could not be drawn. Furthermore, a randomized controlled clinical trial published in 2011 in Lancet on fluoxetine for motor recovery after acute ischemic stroke (FLAME trial) that enrolled 118 stroke patients showed improved motor recovery after stroke and functional independence (up to 17%) in those treated with fluoxetine versus placebo.3

Pooled evidence from these studies suggested that there was possibly some promising evidence to suggest that the use of SSRIs after acute stroke may lead to neurogenesis, improved motor recovery after stroke and functional independence; however, given the heterogeneity of the data, small sample sizes and methodological limitations, larger well-designed randomized controlled clinical trials were needed to better test this hypothesis in humans.2,4 This led to further development of three large randomized controlled clinical trials, namely FOCUS, EFFECTS ad AFFINITY, which planned to collectively enroll nearly 6000 patients.5,6

Author Interview: Drs. Diogo Haussen, MD, and Yasir Saleem, MD, on “Acute Neurological Deterioration in Large Vessel Occlusions and Mild Symptoms Managed Medically”

Diogo Haussen
Dr. Diogo Haussen
Dr. Yasir Saleem
Dr. Yasir Saleem

A conversation with Diogo Haussen, MD, Assistant Professor of Neurology, Emory School of Medicine/Grady Memorial Hospital, and Yasir Saleem, MD, Assistant Professor of Neurology, Baylor College of Medicine, on the approach to patients with large vessel occlusion (LVO) and mild symptoms.

Interviewed by Jennifer Harris, MD, stroke fellow, Columbia University, and Rachel Forman, MD, stroke fellow, Massachusetts General Hospital.

They will be discussing the article “Acute Neurological Deterioration in Large Vessel Occlusions and Mild Symptoms Managed Medically,” published in the May 2020 issue of Stroke.

Drs. Harris and Forman: Thank you for taking the time to speak with us on this important topic.  

Drs. Haussen and Saleem: Thank you for reaching out. It is a pleasure interacting with you.

Drs. Harris and Forman: As stroke fellows, we run into this scenario from time to time, and it is often a challenging decision that generates good discussion. What was the background for you in wanting to study this specific topic?

Drs. Haussen and Saleem: A common reason for neurological deterioration in patients presenting with mild strokes is the underlying presence of a large vessel occlusion. Importantly, neurological worsening in this setting has been associated with worse clinical outcomes. However, not all individuals with large vessel occlusion and mild presentation end up worsening. We have observed, in our original experience (Haussen DC et al. JNIS 2017 Oct;9(10):917-921), that >40% of patients with LVO medically managed had some degree of neurological deterioration. We wanted to evaluate the potential variables that could potentially predict neurological worsening within patients presenting with minor stroke symptoms and large vessel occlusion.

Drs. Harris and Forman: What is your team’s approach for patients in this category as far as their medical management and ensuring this is optimized (i.e., blood pressure parameters, frequency/duration of neurological monitoring)? Do you include patients with more distal (M3 or PCA) clots in this same category?

Drs. Haussen and Saleem: Although the evidence is lacking, we generally perform a heads-up test in order to stress collaterals and evaluate for acute neurological deterioration in patients with mild presentations. We consider important to optimize the hydration status and to allow the blood pressure to autoregulate. Considering we have observed that patients with large vessel occlusion and mild stroke deteriorate early, it is critical to have patients carefully monitored for the first multiple hours from symptom onset. It is possible that more proximal occlusions (e.g., MCA M1 as compared to MCA M3) may carry a higher risk of deterioration; however, this is anecdotal.

Drs. Harris and Forman: It was interesting to note that there were no clinical or radiological predictors of neurological deterioration on multivariate analysis. From a personal experience, do certain features (either clinically or radiographically) stand out to you where you would be on higher alert in a specific patient?

Drs. Haussen and Saleem: Despite not identifying any predictors, we know that a large proportion of patients deteriorate early. Therefore, all need to be monitored closely. It is relatively clear that rapid improvement may predict subsequent deterioration; therefore, patients that improve and still have an occlusion are at higher risk. Individuals with very high blood pressure levels in order to maintain collaterals could be at risk of failure. In addition to the established factors influencing leptomeningeal collateral strength, large areas of perfusion defect on perfusion imaging, more proximal occlusions, and embolic occlusions (instead of in-situ atherosclerotic thrombosis that generally have better developed collaterals) could be suggested as potential factors influencing the risk of neurological worsening.

Drs. Harris and Forman: In the study, you found that 19.7% of patients had >4 points deterioration on NIHSS and that this occurred pretty rapidly from arrival time (median of 3.6 hours). Did these numbers surprise you, or is it similar to what you have observed in clinical practice?

Drs. Haussen and Saleem: We used a relatively high threshold for defining deterioration, and therefore believe that this number is in line with previous studies and with our experience.

Drs. Harris and Forman: Did the study change your approach to this patient population, and if so, how did it change? Finally, what are the main takeaways you want the readers to have, and what are the next steps with future studies?

Drs. Haussen and Saleem: Significant acute neurological deterioration was observed in a significant proportion of patients (~1/5) with large vessel occlusion and mild symptoms, occurred very early in the hospital course, and impacted functional outcomes. Rescue thrombectomy was associated with improved clinical outcomes and should be considered emergently in patients that worsen during medical management. Considering that we could not identify potential clinical, laboratorial or radiological predictors, it becomes even more evident that controlled studies are needed.

Drs. Harris and Forman: Thank you very much.

Migraine With Aura and Cerebrovascular Disease: The Role of Amyloid Angiopathy

Raffaele Ornello, MD

Koemans EA, Voigt S, Rasing I, van Etten ES, van Zweet EW, van Walderveen MAA, et al. Migraine With Aura as Early Disease Marker in Hereditary Dutch-Type Cerebral Amyloid Angiopathy. Stroke. 2020;51:1094–1099.

Migraine, especially with aura, is associated with monogenic cerebrovascular syndromes such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCLS). Dutch-type cerebral amyloid angiopathy (D-CAA) is a monogenic form of cerebral amyloid angiopathy (CAA). Migraine is common in patients with CAA; however, its characteristics have not been specifically assessed in those patients.

In their retrospective study, the authors assessed the prevalence and characteristics of migraine in 86 in- and outpatients with D-CAA visited in a specialized center over six years (2012-2018); the mean age of patients was 57 years, and 57% were women. The authors found a higher prevalence of migraine (55%) and especially of migraine with aura (all patients with migraine had aura attacks) in their sample compared with what expected in the general population; besides, patients with D-CAA tended to have a late onset of migraine, which is uncommon in migraine. Notably, in two-thirds of patients, migraine was the first symptom of D-CAA, and in more than half of cases, a migraine aura lasting more than 60 minutes signaled an intracerebral hemorrhage.

Small Vessel Disease: Collaterals’ Enemy

Elena Zapata-Arriaza, MD

Lin MP, Brott TG, Liebeskind DS, Meschia JF, Sam K, Gottesman RF. Collateral Recruitment Is Impaired by Cerebral Small Vessel Disease. Stroke. 2020;51:1404–1410.

Small vessel disease (SVD) is clearly related to increased stroke risk and worse functional outcome. However, the effect of mentioned SVD on the vasodilatory capacity of arteriole and microvasculature for collaterals recruitment during an acute stroke scenario is unclear. Lin and colleagues performed a study to asses SVD effect on collaterals development in acute stroke setting.

For this study, consecutive patients with middle cerebral artery or internal carotid artery occlusion presenting within 6 hours after stroke symptom onset who underwent thrombectomy from 2012 to 2017 were included. The primary outcome was poor collateral flow (assessed on baseline computed tomographic angiography). Markers of chronic SVD on brain magnetic resonance imaging were rated for the extent of white matter hyperintensities, enlarged perivascular spaces, chronic lacunar infarctions and cerebral microbleeds using the Standards for Reporting Vascular Changes on Neuroimaging criteria. Severity of SVD was quantified by adding the presence of each SVD feature, with a total possible score of 0 to 4; each SVD type was also evaluated separately.

Functional Stroke Mimics: How Hard Is It to Say This Is Not a Stroke?

Victor J. Del Brutto, MD

Popkirov S, Stone J, Buchan AM. Functional Neurological Disorder: A Common and Treatable Stroke Mimic. Stroke. 2020;51:1629–1635.

Since the work of Jean-Martin Charcot in the 19th century on functional neurological disorders (called “hysteria”), neurologists have developed a variety of examination skills capable of discerning between organic and non-organic causes of neurological symptoms. Functional neurological disorders may manifest as non-epileptic seizures, chronic abnormal movement disorders, and certainly as acute focal neurological deficits prompting the activation of a rapid stroke evaluation aimed to identify candidates for reperfusion therapies. In fact, functional neurological deficits are common stroke mimics frequently presenting as lateralized limb weakness, sensory changes, or speech disturbances.

As stroke neurologists, we rely on clinical scales (i.e., the National Institutes of Health Stroke Scale) and a variety of neuroimaging techniques to make time-sensitive therapeutic decisions. Nevertheless, none of the above are entirely useful to identify functional disorders, thus underscoring the importance of the clinical examination in acute stroke care. In the May issue of Stroke, Popkirov and colleagues bring us a topical review on the diagnosis of functional disorders during the acute evaluation of patients with suspected stroke. Key points of this review include:

– Stereotypical biases based on age, sex, psychiatric comorbidities, or social background are not good predictors of functional disorders at the individual patient level and frequently lead to misdiagnosis. 

– Bedside tests focused on inconsistencies between voluntary and involuntary movements (i.e., Hoover’s sign, hip abductor sign, facial lip pulling) or non-physiological patterns of weakness (i.e., drift without pronation, give-away weakness, inverse pyramidal pattern) have shown to be specific and reliable techniques to identify functional motor weakness (Figure). Generally, sensory signs are less reliable than motor testing.

Figure. Positive clinical signs of functional neurological disorder.
Figure. Positive clinical signs of functional neurological disorder. 

– Speech disorders (i.e., dysarthria, aphasia) in isolation are rare stroke presentations. Functional speech disorders can be recognized by inconsistencies such as aphonia with normal sound production prompted by cough, dysarthria without dysphagia, or non-physiological agrammatism (“baby talk”) rather than the telegraphic speech characteristic of Broca’s aphasia.

Practice Makes Perfect: Article Commentary on “Improving Stroke Care in Times of the COVID-19 Pandemic Through Simulation: Practice your Protocols!”

Muhammad Rizwan Husain, MD, and Muhammad Taimoor Khan, MD

Kurz MW, Ospel JM, Kurz KD, Goyal M. Improving Stroke Care in Times of the COVID-19 Pandemic Through Simulation: Practice Your Protocols! Stroke. 2020.

The COVID-19 pandemic portends a risk to healthcare staff dealing with acute stroke emergencies, and many institutions have developed new protocols to help reduce exposure. On a typical day, acute stroke management progresses through a well-defined algorithm, developed by institutions to provide rapid and timely intravenous thrombolysis and mechanical thrombectomy (MT), with healthcare providers having their own well-defined roles. The COVID-19 pandemic has now required enforcement of strict infection control practices such as use of PPE, methods to minimize exposure to patients and staff during imaging and transport and while providing thrombolytic treatment or MT. However, despite these new well-defined protocols and standards of infection control safety in place, there is still a risk of exposure to healthcare workers, who might not be used to adapting quickly to a new system of management, again risking unwarranted exposure, which further leads to increased anxiety among the front line staff.

In this article, the authors describe how practice simulations catered to help staff adapt to the new standards have helped streamline the process of acute stroke emergencies, reduce staff anxiety and, at the same time, identify potential unknown sources of exposure, as well.

Stroke vs COVID-19: A World Fight

Elena Zapata-Arriaza, MD

Zhao J, Li H, Kung D, Fisher M, Shen Y, Liu R. Impact of the COVID-19 Epidemic on Stroke Care and Potential Solutions. Stroke. 2020.

Since the first COVID-19 case was reported in December 2019 in Wuhan, China, the magnitude of this global pandemic, unimaginable at first, has invaded our daily routine and our professional work, displacing any other pathology to a secondary level. As of Saturday, May 9, 2020 at 1:36 p.m., the global number of infected is 3.94 million people and 275,000 deaths, with a spatial dispersion that increasingly affects more countries. Given its ease of transmission (drops when coughing, speaking, direct contact), we are facing a highly contagious virus capable of saturating the health systems, preventing proper management of time-dependent pathologies such as ischemic stroke. Zhao J et al. aimed to demonstrate COVID-19 impact on stroke care. For this purpose, the authors collected data from the Big Data Observatory Platform for Stroke of China (BOSC), formed by 280 hospitals across China. In addition, they designed a survey to investigate major changes in stroke care during the COVID-19 outbreak.

After performing a retrospective and simple descriptive study, the authors found a drop of 26.7% and 25.3% (p<0.001), respectively, in thrombolysis and thrombectomy cases, in February 2020 as compared to February 2019. In 2020, hospital admissions related to stroke dropped by nearly 40%, due to the reduction in stroke care capacity in the majority of hospitals. In stroke care centers, the majority of them stopped completely or partially their efforts in stroke education for the public, with no difference in the patterns of changes between COVID-19 and non-COVID-19 designated hospitals. Among potential causes of observed changes, the authors found that patients or patients’ families not coming to the hospital was likely the most important factor affecting reduced hospital admission rate, and reduced thrombolysis and thrombectomy cases. Deficiencies in stroke awareness, lack of adequate transportation methods, and the COVID-19 screening process were considered as important factors with a direct impact on stroke care and door-to-needle and door-to-groin times. Finally, the authors offer recommendations to improve stroke care in affected countries.

Stroke Care During World War COVID

Victor J. Del Brutto, MD

Sheth SA, Wu T-C, Sharrief A, Ankrom C, Grotta JC, Fisher, M, et al. Early Lessons From World War COVID: Reinventing Our Stroke Systems of Care. Stroke. 2020.

The past century began with devastating world wars that resulted in immense loss of life and left many countries in ruins and the rest impoverished. These global conflicts not only created negative impacts, but also triggered constructive responses in humanity fueled by the elation for surviving the disaster. The latter resulted in postwar times dominated by the development of society, expansion of economy, and the revolution of technology. This special report published in Stroke draws an analogy between the current global health crisis caused by the COVID-19 pandemic and the damage occasioned by the world wars, and exposes an optimistic point of view regarding the adjustments vascular neurologists have made to take care of stroke patients and how this may influence the way we deliver stroke care in the future.

Endovascular Thrombectomy With or Without Intravenous Alteplase: ESO-WSO Large Clinical Trials Webinar

Parneet Grewal, MD

ESO-WSO 2020 Large Clinical Trials Webinar
Presenter: Dr. Jianmin Liu (China)
Article: Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, et al, for the DIRECT-MT Investigators. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. NEJM. 2020.

The goal of current therapeutic strategies for acute ischemic stroke with large vessel occlusion (LVO) is recanalization of the occlusion before irreversible damage has occurred. In this large multicenter, prospective, randomized, open-label trial with blinded outcome assessment, Dr. Jianmin Liu and his team aimed to answer the question of whether mechanical thrombectomy (MT) alone (thrombectomy alone group) would be non-inferior to combined treatment of IV-tPA and MT (combined group) in patients with LVO.  

This trial included patients ³ 18 years of age who presented to 41 pre-selected academic medical centers in China within 4.5 hours of symptom onset, had National Institutes of Health Stroke Scale (NIHSS) ³ 2 with imaging showing an LVO (intracranial segment of ICA, M1 or proximal M2 only). Any patients who did not meet American Heart Association/American Stroke Association guidelines for alteplase or MT were not included in the trial. The standard dose of tPA at 0.9 mg/kg was used, and the first-line strategy for MT was stent-retriever. Statistically, the trial was designed to provide 80% power (at a two-sided alpha level of 0.05) to determine a non-inferiority margin of 0.8. 656 patients were randomized in 1:1 fashion by a web-based system with 327 patients in the thrombectomy alone group and 329 patients in the combined group. The patient enrollment period was 17 months (February 23, 2018, to July 2, 2019). The baseline characteristics of patients were similar in both the groups with a median age of 69 years, median NIHSS score of 17, and median ASPECTS value of 9. The median duration from stroke onset to randomization was 167 minutes in the thrombectomy alone group and 177 minutes in combined group with time from randomization to groin puncture being 31 minutes and 36 minutes, respectively.