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
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.
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.
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 (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.
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.
– 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.
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.
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.
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.
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.
Diabetes
mellitus (DM) affects about 422 million people and is one of the leading causes
of death worldwide (World Health Organization). More importantly, the burden of
type 2 diabetes (T2D) has been rising relentlessly in all countries in the past
three decades. However, it is estimated that a significant percentage of cases
of T2D remain undiagnosed. DM is one of the major modifiable risk factors for
stroke. In addition, it has been associated with adverse outcomes after stroke,
including higher mortality, poorer neurological and functional outcomes, longer
hospital stay, higher readmission rates, and stroke recurrence. Another
outcome, the post-stroke cognitive function, and its relationship with DM, are
being evaluated in the STROKOG collaboration study.
Lo
et al. for the STROKOG collaboration present a meta-analysis of individual
participant data (IPD) derived from seven international post-stroke cohorts
with the aim to investigate the relationship between T2M and prediabetes with
cognitive impairment after stroke.
Mohammad Anadani, MD*
Elizabeth M. Aradine, DO
Rohan Arora, MD
Bahar M. Beaver, MD*
Anusha Boyanpally, MD
Alan C. Cameron, MB ChB, BSc (Hons), MRCP*
Pamela Cheng, DO
Kat Dakay, DO*
Danielle de Sa Boasquevisque, MD*
Reyes de Torres Chacon, MD
Victor J. Del Brutto, MD*
Rachel Forman, MD
Alejandro Fuerte, MD*
Parneet Grewal, MD
Deepak Gulati, MD*
Jennifer Harris, MD
Mausaminben Hathidara, MD
Kathryn S. Hayward, PhD, PT
Yan Hou, MD, PhD
Muhammad Rizwan Husain, MD
Richard Jackson, MD*
Wayneho Kam, MD
Gurmeen Kaur, MBBS*
Muhammad Taimoor Khan, MD
Abbas Kharal, MD, MPH*
Grace Y. Kuo, MD, MS, BA
Stephanie Lyden, MD, BS
Piyush Ojha, MBBS, MD, DM
Adeola Olowu, MD
Lin Kooi Ong, PhD*
Raffaele Ornello, MD*
Matthew Maximillian Padrick, MD, BA
Lina Palaiodimou, MD*
Robert W. Regenhardt, MD, PhD*
Shashank Shekhar, MD, MS*
Kristina Shkirkova, BSc
Ravinder-Jeet Singh, MBBS, DM*
Burton J. Tabaac, MD*
Melissa Trotman-Lucas, PhD
Tamaya Van Criekinge, PT
Elena Zapata-Arriaza, MD*
Charlotte Zerna, MD, MSc
*Senior Blogger
Have We EFFECTively Put an End to the Use of SSRIs in Motor Recovery After Acute Stroke?
Author Interview: Drs. Diogo Haussen, MD, and Yasir Saleem, MD, on “Acute Neurological Deterioration in Large Vessel Occlusions and Mild Symptoms Managed Medically”
Migraine With Aura and Cerebrovascular Disease: The Role of Amyloid Angiopathy
Small Vessel Disease: Collaterals’ Enemy
Functional Stroke Mimics: How Hard Is It to Say This Is Not a Stroke?
