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• Volume 13, Issue 8
• Clinical course of a 66-year-old man with an acute ischaemic stroke in the setting of a COVID-19 infection
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• http://orcid.org/0000-0002-7441-6952 Saajan Basi 1 , 2 ,
• Mohammad Hamdan 1 and
• Shuja Punekar 1
• 1 Department of Stroke and Acute Medicine , King's Mill Hospital , Sutton-in-Ashfield , UK
• 2 Department of Acute Medicine , University Hospitals of Derby and Burton , Derby , UK
• Correspondence to Dr Saajan Basi; saajan.basi{at}nhs.net

A 66-year-old man was admitted to hospital with a right frontal cerebral infarct producing left-sided weakness and a deterioration in his speech pattern. The cerebral infarct was confirmed with CT imaging. The only evidence of respiratory symptoms on admission was a 2 L oxygen requirement, maintaining oxygen saturations between 88% and 92%. In a matter of hours this patient developed a greater oxygen requirement, alongside reduced levels of consciousness. A positive COVID-19 throat swab, in addition to bilateral pneumonia on chest X-ray and lymphopaenia in his blood tests, confirmed a diagnosis of COVID-19 pneumonia. A proactive decision was made involving the patients’ family, ward and intensive care healthcare staff, to not escalate care above a ward-based ceiling of care. The patient died 5 days following admission under the palliative care provided by the medical team.

• respiratory medicine
• infectious diseases
• global health

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https://doi.org/10.1136/bcr-2020-235920

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SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is a new strain of coronavirus that is thought to have originated in December 2019 in Wuhan, China. In a matter of months, it has erupted from non-existence to perhaps the greatest challenge to healthcare in modern times, grinding most societies globally to a sudden halt. Consequently, the study and research into SARS-CoV-2 is invaluable. Although coronaviruses are common, SARS-CoV-2 appears to be considerably more contagious. The WHO figures into the 2003 SARS-CoV-1 outbreak, from November 2002 to July 2003, indicate a total of 8439 confirmed cases globally. 1 In comparison, during a period of 4 months from December 2019 to July 2020, the number of global cases of COVID-19 reached 10 357 662, increasing exponentially, illustrating how much more contagious SARS-CoV-2 has been. 2

Previous literature has indicated infections, and influenza-like illness have been associated with an overall increase in the odds of stroke development. 3 There appears to be a growing correlation between COVID-19 positive patients presenting to hospital with ischaemic stroke; however, studies investigating this are in progress, with new data emerging daily. This patient report comments on and further characterises the link between COVID-19 pneumonia and the development of ischaemic stroke. At the time of this patients’ admission, there were 95 positive cases from 604 COVID-19 tests conducted in the local community, with a predicted population of 108 000. 4 Only 4 days later, when this patient died, the figure increased to 172 positive cases (81% increase), illustrating the rapid escalation towards the peak of the pandemic, and widespread transmission within the local community ( figure 1 ). As more cases of ischaemic stroke in COVID-19 pneumonia patients arise, the recognition and understanding of its presentation and aetiology can be deciphered. Considering the virulence of SARS-CoV-2 it is crucial as a global healthcare community, we develop this understanding, in order to intervene and reduce significant morbidity and mortality in stroke patients.

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A graph showing the number of patients with COVID-19 in the hospital and in the community over time.

Case presentation

A 66-year-old man presented to the hospital with signs of left-sided weakness. The patient had a background of chronic obstructive pulmonary disease (COPD), atrial fibrillation and had one previous ischaemic stroke, producing left-sided haemiparesis, which had completely resolved. He was a non-smoker and lived in a house. The patient was found slumped over on the sofa at home on 1 April 2020, by a relative at approximately 01:00, having been seen to have no acute medical illness at 22:00. The patients’ relative initially described disorientation and agitation with weakness noted in the left upper limb and dysarthria. At the time of presentation, neither the patient nor his relative identified any history of fever, cough, shortness of breath, loss of taste, smell or any other symptoms; however, the patient did have a prior admission 9 days earlier with shortness of breath.

The vague nature of symptoms, entwined with considerable concern over approaching the hospital, due to the risk of contracting COVID-19, created a delay in the patients’ attendance to the accident and emergency department. His primary survey conducted at 09:20 on 1 April 2020 demonstrated a patent airway, with spontaneous breathing and good perfusion. His Glasgow Coma Scale (GCS) score was 15 (a score of 15 is the highest level of consciousness), his blood glucose was 7.2, and he did not exhibit any signs of trauma. His abbreviated mental test score was 7 out of 10, indicating a degree of altered cognition. An ECG demonstrated atrial fibrillation with a normal heart rate. His admission weight measured 107 kg. At 09:57 the patient required 2 L of nasal cannula oxygen to maintain his oxygen saturations between 88% and 92%. He started to develop agitation associated with an increased respiratory rate at 36 breaths per minute. On auscultation of his chest, he demonstrated widespread coarse crepitation and bilateral wheeze. Throughout he was haemodynamically stable, with a systolic blood pressure between 143 mm Hg and 144 mm Hg and heart rate between 86 beats/min and 95 beats/min. From a neurological standpoint, he had a mild left facial droop, 2/5 power in both lower limbs, 2/5 power in his left upper limb and 5/5 power in his right upper limb. Tone in his left upper limb had increased. This patient was suspected of having COVID-19 pneumonia alongside an ischaemic stroke.

Investigations

A CT of his brain conducted at 11:38 on 1 April 2020 ( figure 2 ) illustrated an ill-defined hypodensity in the right frontal lobe medially, with sulcal effacement and loss of grey-white matter. This was highly likely to represent acute anterior cerebral artery territory infarction. Furthermore an oval low-density area in the right cerebellar hemisphere, that was also suspicious of an acute infarction. These vascular territories did not entirely correlate with his clinical picture, as limb weakness is not as prominent in anterior cerebral artery territory ischaemia. Therefore this left-sided weakness may have been an amalgamation of residual weakness from his previous stroke, in addition to his acute cerebral infarction. An erect AP chest X-ray with portable equipment ( figure 3 ) conducted on the same day demonstrated patchy peripheral consolidation bilaterally, with no evidence of significant pleural effusion. The pattern of lung involvement raised suspicion of COVID-19 infection, which at this stage was thought to have provoked the acute cerebral infarct. Clinically significant blood results from 1 April 2020 demonstrated a raised C-reactive protein (CRP) at 215 mg/L (normal 0–5 mg/L) and lymphopaenia at 0.5×10 9 (normal 1×10 9 to 3×10 9 ). Other routine blood results are provided in table 1 .

CT imaging of this patients’ brain demonstrating a wedge-shaped infarction of the anterior cerebral artery territory.

Chest X-ray demonstrating the bilateral COVID-19 pneumonia of this patient on admission.

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Clinical biochemistry and haematology blood results of the patient

Interestingly the patient, in this case, was clinically assessed in the accident and emergency department on 23 March 2020, 9 days prior to admission, with symptoms of shortness of breath. His blood results from this day showed a CRP of 22 mg/L and a greater lymphopaenia at 0.3×10 9 . He had a chest X-ray ( figure 4 ), which indicated mild radiopacification in the left mid zone. He was initially treated with intravenous co-amoxiclav and ciprofloxacin. The following day he had minimal symptoms (CURB 65 score 1 for being over 65 years). Given improving blood results (declining CRP), he was discharged home with a course of oral amoxicillin and clarithromycin. As national governmental restrictions due to COVID-19 had not been formally announced until 23 March 2020, and inconsistencies regarding personal protective equipment training and usage existed during the earlier stages of this rapidly evolving pandemic, it is possible that this patient contracted COVID-19 within the local community, or during his prior hospital admission. It could be argued that the patient had early COVID-19 signs and symptoms, having presented with shortness of breath, lymphopaenia, and having had subtle infective chest X-ray changes. The patient explained he developed a stagnant productive cough, which began 5 days prior to his attendance to hospital on 23 March 2020. He responded to antibiotics, making a full recovery following 7 days of treatment. This information does not assimilate with the typical features of a COVID-19 infection. A diagnosis of community-acquired pneumonia or infective exacerbation of COPD seem more likely. However, given the high incidence of COVID-19 infections during this patients’ illness, an exposure and early COVID-19 illness, prior to the 23 March 2020, cannot be completely ruled out.

Chest X-ray conducted on prior admission illustrating mild radiopacification in the left mid zone.

On the current admission, this patient was managed with nasal cannula oxygen at 2 L. By the end of the day, this had progressed to a venturi mask, requiring 8 L of oxygen to maintain oxygen saturation. He had also become increasingly drowsy and confused, his GCS declined from 15 to 12. However, the patient was still haemodynamically stable, as he had been in the morning. An arterial blood gas demonstrated a respiratory alkalosis (pH 7.55, pCO 2 3.1, pO 2 6.7 and HCO 3 24.9, lactate 1.8, base excess 0.5). He was commenced on intravenous co-amoxiclav and ciprofloxacin, to treat a potential exacerbation of COPD. This patient had a COVID-19 throat swab on 1 April 2020. Before the result of this swab, an early discussion was held with the intensive care unit staff, who decided at 17:00 on 1 April 2020 that given the patients presentation, rapid deterioration, comorbidities and likely COVID-19 diagnosis he would not be for escalation to the intensive care unit, and if he were to deteriorate further the end of life pathway would be most appropriate. The discussion was reiterated to the patients’ family, who were in agreement with this. Although he had evidence of an ischaemic stroke on CT of his brain, it was agreed by all clinicians that intervention for this was not as much of a priority as providing optimal palliative care, therefore, a minimally invasive method of treatment was advocated by the stroke team. The patient was given 300 mg of aspirin and was not a candidate for fibrinolysis.

Outcome and follow-up

The following day, before the throat swab result, had appeared the patient deteriorated further, requiring 15 L of oxygen through a non-rebreather face mask at 60% FiO 2 to maintain his oxygen saturation, at a maximum of 88% overnight. At this point, he was unresponsive to voice, with a GCS of 5. Although, he was still haemodynamically stable, with a blood pressure of 126/74 mm Hg and a heart rate of 98 beats/min. His respiratory rate was 30 breaths/min. His worsening respiratory condition, combined with his declining level of consciousness made it impossible to clinically assess progression of the neurological deficit generated by his cerebral infarction. Moreover, the patient was declining sharply while receiving the maximal ward-based treatment available. The senior respiratory physician overseeing the patients’ care decided that a palliative approach was in this his best interest, which was agreed on by all parties. The respiratory team completed the ‘recognising dying’ documentation, which signified that priorities of care had shifted from curative treatment to palliative care. Although the palliative team was not formally involved in the care of the patient, the patient received comfort measures without further attempts at supporting oxygenation, or conduction of regular clinical observations. The COVID-19 throat swab confirmed a positive result on 2 April 2020. The patient was treated by the medical team under jurisdiction of the hospital palliative care team. This included the prescribing of anticipatory medications and a syringe driver, which was established on 3 April 2020. His antibiotic treatment, non-essential medication and intravenous fluid treatment were discontinued. His comatose condition persisted throughout the admission. Once the patients’ GCS was 5, it did not improve. The patient was pronounced dead by doctors at 08:40 on 5 April 2020.

SARS-CoV-2 is a type of coronavirus that was first reported to have caused pneumonia-like infection in humans on 3 December 2019. 5 As a group, coronaviruses are a common cause of upper and lower respiratory tract infections (especially in children) and have been researched extensively since they were first characterised in the 1960s. 6 To date, there are seven coronaviruses that are known to cause infection in humans, including SARS-CoV-1, the first known zoonotic coronavirus outbreak in November 2002. 7 Coronavirus infections pass through communities during the winter months, causing small outbreaks in local communities, that do not cause significant mortality or morbidity.

SARS-CoV-2 strain of coronavirus is classed as a zoonotic coronavirus, meaning the virus pathogen is transmitted from non-humans to cause disease in humans. However the rapid spread of SARS-CoV-2 indicates human to human transmission is present. From previous research on the transmission of coronaviruses and that of SARS-CoV-2 it can be inferred that SARS-CoV-2 spreads via respiratory droplets, either from direct inhalation, or indirectly touching surfaces with the virus and exposing the eyes, nose or mouth. 8 Common signs and symptoms of the COVID-19 infection identified in patients include high fevers, severe fatigue, dry cough, acute breathing difficulties, bilateral pneumonia on radiological imaging and lymphopaenia. 9 Most of these features were identified in this case study. The significance of COVID-19 is illustrated by the speed of its global spread and the potential to cause severe clinical presentations, which as of April 2020 can only be treated symptomatically. In Italy, as of mid-March 2020, it was reported that 12% of the entire COVID-19 positive population and 16% of all hospitalised patients had an admission to the intensive care unit. 10

The patient, in this case, illustrates the clinical relevance of understanding COVID-19, as he presented with an ischaemic stroke underlined by minimal respiratory symptoms, which progressed expeditiously, resulting in acute respiratory distress syndrome and subsequent death.

Our case is an example of a new and ever-evolving clinical correlation, between patients who present with a radiological confirmed ischaemic stroke and severe COVID-19 pneumonia. As of April 2020, no comprehensive data of the relationship between ischaemic stroke and COVID-19 has been published, however early retrospective case series from three hospitals in Wuhan, China have indicated that up to 36% of COVID-19 patients had neurological manifestations, including stroke. 11 These studies have not yet undergone peer review, but they tell us a great deal about the relationship between COVID-19 and ischaemic stroke, and have been used to influence the American Heart Associations ‘Temporary Emergency Guidance to US Stroke Centres During the COVID-19 Pandemic’. 12

The relationship between similar coronaviruses and other viruses, such as influenza in the development of ischaemic stroke has previously been researched and provide a basis for further investigation, into the prominence of COVID-19 and its relation to ischaemic stroke. 3 Studies of SARS-CoV-2 indicate its receptor-binding region for entry into the host cell is the same as ACE2, which is present on endothelial cells throughout the body. It may be the case that SARS-CoV-2 alters the conventional ability of ACE2 to protect endothelial function in blood vessels, promoting atherosclerotic plaque displacement by producing an inflammatory response, thus increasing the risk of ischaemic stroke development. 13

Other hypothesised reasons for stroke development in COVID-19 patients are the development of hypercoagulability, as a result of critical illness or new onset of arrhythmias, caused by severe infection. Some case studies in Wuhan described immense inflammatory responses to COVID-19, including elevated acute phase reactants, such as CRP and D-dimer. Raised D-dimers are a non-specific marker of a prothrombotic state and have been associated with greater morbidity and mortality relating to stroke and other neurological features. 14

Arrhythmias such as atrial fibrillation had been identified in 17% of 138 COVID-19 patients, in a study conducted in Wuhan, China. 15 In this report, the patient was known to have atrial fibrillation and was treated with rivaroxaban. The acute inflammatory state COVID-19 is known to produce had the potential to create a prothrombotic environment, culminating in an ischaemic stroke.

Some early case studies produced in Wuhan describe patients in the sixth decade of life that had not been previously noted to have antiphospholipid antibodies, contain the antibodies in blood results. They are antibodies signify antiphospholipid syndrome; a prothrombotic condition. 16 This raises the hypothesis concerning the ability of COVID-19 to evoke the creation of these antibodies and potentiate thrombotic events, such as ischaemic stroke.

No peer-reviewed studies on the effects of COVID-19 and mechanism of stroke are published as of April 2020; therefore, it is difficult to evidence a specific reason as to why COVID-19 patients are developing neurological signs. It is suspected that a mixture of the factors mentioned above influence the development of ischaemic stroke.

If we delve further into this patients’ comorbid state exclusive to COVID-19 infection, it can be argued that this patient was already at a relatively higher risk of stroke development compared with the general population. The fact this patient had previously had an ischaemic stroke illustrates a prior susceptibility. This patient had a known background of hypertension and atrial fibrillation, which as mentioned previously, can influence blood clot or plaque propagation in the development of an acute ischaemic event. 15 Although the patient was prescribed rivaroxaban as an anticoagulant, true consistent compliance to rivaroxaban or other medications such as amlodipine, clopidogrel, candesartan and atorvastatin cannot be confirmed; all of which can contribute to the reduction of influential factors in the development of ischaemic stroke. Furthermore, the fear of contracting COVID-19, in addition to his vague symptoms, unlike his prior ischaemic stroke, which demonstrated dense left-sided haemiparesis, led to a delay in presentation to hospital. This made treatment options like fibrinolysis unachievable, although it can be argued that if he was already infected with COVID-19, he would have still developed life-threatening COVID-19 pneumonia, regardless of whether he underwent fibrinolysis. It is therefore important to consider that if this patient did not contract COVID-19 pneumonia, he still had many risk factors that made him prone to ischaemic stroke formation. Thus, we must consider whether similar patients would suffer from ischaemic stroke, regardless of COVID-19 infection and whether COVID-19 impacts on the severity of the stroke as an entity.

Having said this, the management of these patients is dependent on the likelihood of a positive outcome from the COVID-19 infection. Establishing the ceiling of care is crucial, as it prevents incredibly unwell or unfit patients’ from going through futile treatments, ensuring respect and dignity in death, if this is the likely outcome. It also allows for the provision of limited or intensive resources, such as intensive care beds or endotracheal intubation during the COVID-19 pandemic, to those who are assessed by the multidisciplinary team to benefit the most from their use. The way to establish this ceiling of care is through an early multidisciplinary discussion. In this case, the patient did not convey his wishes regarding his care to the medical team or his family; therefore it was decided among intensive care specialists, respiratory physicians, stroke physicians and the patients’ relatives. The patient was discussed with the intensive care team, who decided that as the patient sustained two acute life-threatening illnesses simultaneously and had rapidly deteriorated, ward-based care with a view to palliate if the further deterioration was in the patients’ best interests. These decisions were not easy to make, especially as it was on the first day of presentation. This decision was made in the context of the patients’ comorbidities, including COPD, the patients’ age, and the availability of intensive care beds during the steep rise in intensive care admissions, in the midst of the COVID-19 pandemic ( figure 1 ). Furthermore, the patients’ rapid and permanent decline in GCS, entwined with the severe stroke on CT imaging of the brain made it more unlikely that significant and permanent recovery could be achieved from mechanical intubation, especially as the damage caused by the stroke could not be significantly reversed. As hospitals manage patients with COVID-19 in many parts of the world, there may be tension between the need to provide higher levels of care for an individual patient and the need to preserve finite resources to maximise the benefits for most patients. This patient presented during a steep rise in intensive care admissions, which may have influenced the early decision not to treat the patient in an intensive care setting. Retrospective studies from Wuhan investigating mortality in patients with multiple organ failure, in the setting of COVID-19, requiring intubation have demonstrated mortality can be up to 61.5%. 17 The mortality risk is even higher in those over 65 years of age with respiratory comorbidities, indicating why this patient was unlikely to survive an admission to the intensive care unit. 18

Regularly updating the patients’ family ensured cooperation, empathy and sympathy. The patients’ stroke was not seen as a priority given the severity of his COVID-19 pneumonia, therefore the least invasive, but most appropriate treatment was provided for his stroke. The British Association of Stroke Physicians advocate this approach and also request the notification to their organisation of COVID-19-related stroke cases, in the UK. 19

Learning points

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) is one of seven known coronaviruses that commonly cause upper and lower respiratory tract infections. It is the cause of the 2019–2020 global coronavirus pandemic.

The significance of COVID-19 is illustrated by the rapid speed of its spread globally and the potential to cause severe clinical presentations, such as ischaemic stroke.

Early retrospective data has indicated that up to 36% of COVID-19 patients had neurological manifestations, including stroke.

Potential mechanisms behind stroke in COVID-19 patients include a plethora of hypercoagulability secondary to critical illness and systemic inflammation, the development of arrhythmia, alteration to the vascular endothelium resulting in atherosclerotic plaque displacement and dehydration.

It is vital that effective, open communication between the multidisciplinary team, patient and patients relatives is conducted early in order to firmly establish the most appropriate ceiling of care for the patient.

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• Wunderink RG
• van Doremalen N ,
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• Wang X-G , et al
• Grasselli G ,
• Pesenti A ,
• Wang M , et al
• American Stroke Assocation, 2020
• Zhang Y-H ,
• Zhang Y-huan ,
• Dong X-F , et al
• Li X , et al
• Hu C , et al
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• Jiang B , et al
• Xu J , et al
• British Association of Stroke Physicians

Contributors SB was involved in the collecting of information for the case, the initial written draft of the case and researching existing data on acute stroke and COVID-19. He also edited drafts of the report. MH was involved in reviewing and editing drafts of the report and contributing new data. SP oversaw the conduction of the project and contributed addition research papers.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent for publication Next of kin consent obtained.

Provenance and peer review Not commissioned; externally peer reviewed.

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Chapter 7:  10 Real Cases on Transient Ischemic Attack and Stroke: Diagnosis, Management, and Follow-Up

Jeirym Miranda; Fareeha S. Alavi; Muhammad Saad

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Case 1: Management of Acute Thrombotic Cerebrovascular Accident Post Recombinant Tissue Plasminogen Activator Therapy

A 59-year-old Hispanic man presented with right upper and lower extremity weakness, associated with facial drop and slurred speech starting 2 hours before the presentation. He denied visual disturbance, headache, chest pain, palpitations, dyspnea, dysphagia, fever, dizziness, loss of consciousness, bowel or urinary incontinence, or trauma. His medical history was significant for uncontrolled type 2 diabetes mellitus, hypertension, hyperlipidemia, and benign prostatic hypertrophy. Social history included cigarette smoking (1 pack per day for 20 years) and alcohol intake of 3 to 4 beers daily. Family history was not significant, and he did not remember his medications. In the emergency department, his vital signs were stable. His physical examination was remarkable for right-sided facial droop, dysarthria, and right-sided hemiplegia. The rest of the examination findings were insignificant. His National Institutes of Health Stroke Scale (NIHSS) score was calculated as 7. Initial CT angiogram of head and neck reported no acute intracranial findings. The neurology team was consulted, and intravenous recombinant tissue plasminogen activator (t-PA) was administered along with high-intensity statin therapy. The patient was admitted to the intensive care unit where his hemodynamics were monitored for 24 hours and later transferred to the telemetry unit. MRI of the head revealed an acute 1.7-cm infarct of the left periventricular white matter and posterior left basal ganglia. How would you manage this case?

This case scenario presents a patient with acute ischemic cerebrovascular accident (CVA) requiring intravenous t-PA. Diagnosis was based on clinical neurologic symptoms and an NIHSS score of 7 and was later confirmed by neuroimaging. He had multiple comorbidities, including hypertension, diabetes, dyslipidemia, and smoking history, which put him at a higher risk for developing cardiovascular disease. Because his symptoms started within 4.5 hours of presentation, he was deemed to be a candidate for thrombolytics. The eligibility time line is estimated either by self-report or last witness of baseline status.

Ischemic strokes are caused by an obstruction of a blood vessel, which irrigates the brain mainly secondary to the development of atherosclerotic changes, leading to cerebral thrombosis and embolism. Diagnosis is made based on presenting symptoms and CT/MRI of the head, and the treatment is focused on cerebral reperfusion based on eligibility criteria and timing of presentation.

Symptoms include alteration of sensorium, numbness, decreased motor strength, facial drop, dysarthria, ataxia, visual disturbance, dizziness, and headache.

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A Case-based Guide to Acute Ischemic Stroke Management

• © 2021
• Ferdinand K. Hui 0 ,
• Alejandro M. Spiotta 1 ,
• Michael J. Alexander 2 ,
• Ricardo A. Hanel 3 ,
• Blaise William Baxter 4

Department of Radiology, Johns Hopkins Hospital, Baltimore, USA

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Department of Neurosurgery, Medical University of South Carolina, Charleston, USA

Department of neurosurgery, cedars-sinai medical center, los angeles, usa, baptist neurological institute, jacksonville, usa, department of radiology, lehigh valley health network, allentown, usa.

• Outlines state-of-the art approaches to interventional management of complex stroke cases
• Includes the latest evidence-based clinical guidelines from ASA and AAN
• Provides a case-based, easy to read, practical approach to enhance learning

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Table of contents (23 chapters)

Front matter, fundamentals and systems, evidence on mechanical thrombectomy in acute ischemic stroke.

• Matias Negrotto, Sami Al Kasab

In Vitro Clot Modeling and Clinical Applications

• Sarah Johnson, Juyu Chueh, Ajit S. Puri, Peter E. McHugh, Rose A. Arslanian, Matthew J. Gounis

Pediatric Acute Ischemic Stroke: Nuances for the Neurointerventionalist

• Matias Negrotto, Ronil V. Chandra, Todd A. Abruzzo

ELVO in Urban Areas: Evolution of Stroke Systems of Care

• Johanna T. Fifi, Jacob Morey

Surviving Large Vessel Occlusions in Uruguay: Current Challenges and Solutions

• Roberto Crosa

Direct to Angiography—An Emerging Paradigm in Large Vessel Occlusion Stroke: Rationale, Feasibility, and Preliminary Results

• Tudor G. Jovin

Thrombectomy Techniques: Stent Retriever – Balloon Guide

• Dennys Reyes, Italo Linfante, Guilherme Dabus

Direct Aspiration Thrombectomy for Acute Stroke: Evolution of Technique and Evidence

• Sami Al Kasab, Alejandro M. Spiotta

The Stentriever-Mediated Aspiration Thrombectomy (SMAT) Technique

• Benjamin Zussman, Ashutosh Jadhav, Tudor G. Jovin

Transradial Approach for Stroke

• Stephanie H. Chen, Robert M. Starke, Dileep R. Yavagal, Eric C. Peterson

Thrombectomy Techniques: Remote Aspiration

• David Dornbos III, Tarek Abuelem, David J. Fiorella, Adam S. Arthur

Endovascular Therapy for Middle Cerebral Artery Occlusions

• Ansaar T. Rai

Thrombectomy for Basilar Occlusion: Approach and Strategy

• Amin Aghaebrahim, Mohamad A. Asfour, John J. Entwistle, Manuel F. Granja, Ricardo A. Hanel

Carotid Terminus Occlusion

• Sami Al Kasab, Eyad Almallouhi, Alejandro M. Spiotta

Thrombectomy for Acute Occlusion in Intermediate-Sized Distal Arteries

• Angelique Sao Mai S. Do, Robin M. Babadjouni, Michael J. Alexander

The Tandem Occlusion

• Charlotte Y. Chung, Liwei Jiang, Ferdinand K. Hui, Blaise William Baxter
• basilar occlusion
• Cervical Stenoses
• Distal Clot
• Cervical Occlusions
• underlying stenosis

About this book

This comprehensive, case-based resource provides the state-of-the-art knowledge that can help readers improve access and optimize delivery of stroke thrombectomy.  Improving access to stroke is of particular importance because patients often misinterpret their symptoms or cannot speak for themselves if they have aphasia.  More importantly, access needs to be organized because stroke therapies are all extremely time-sensitive.  Scalable, choreographed protocols are necessary for emergency medical systems to ‘capture’ stroke patients and automatically transport and triage to time-sensitive treatments.  Many of the chapters in the first section on Fundamentals and Systems provide valuable insight in improving access to stroke care.   Replete with illustrative case studies and emphasizing that treatment approaches to stroke should not be comprised of a one-size-fits-all approach, this illuminating title provides the complete thought, detail, insight and organization that will help readers meet the needs of stroke patients with large vessel occlusions.  12 Strokes: A Case-based Guide to Acute Ischemic Stroke Management examines the primary technical principles that underlie the current thrombectomy approaches.  Instead of continuing the conceptual dichotomy of stent vs. aspiration, many of the chapters look at underlying principles and then discuss ways in which the currently available devices and approaches can best exploit them.  The variety, creativity and detail in many of these chapters will help the reader develop a deeper understanding that might assist their ability to successfully take care of their next patient that ‘doesn’t follow the textbook.’  In addition, the anatomic and pathophysiologic classification of the core Twelve Chapters will help readers organize their thinking and approach.  This knowledge, particularly because it is organized based on common, challenging syndromes, will arm the reader to quickly recognize patterns and deftly adapt their management approaches to the needs of the patient. 

An invaluable contribution to the clinical literature, 12 Strokes:  A Case-based Guide to Acute Ischemic Stroke Management will be of great interest to not only neurosurgeons and neurologists but other specialists, primary care providers, and trainees as well.

“The book is well referenced and reasonably indexed, with a good ratio of illustrations to text. … It is quite quick to read, with the authors’ enthusiasm for the subject carrying the reader. Bar highly technical aspects, it is an accessible source of information on the current state of play in stroke intervention for other interested professionals with some prior knowledge of the subject, such as radiologists reporting stroke imaging, senior radiology and stroke trainees, and neuro-interventional radiographers.” (Jolanta Webb, RAD Magazine, August, 2021)

Editors and Affiliations

Ferdinand K. Hui

Alejandro M. Spiotta

Michael J. Alexander

Ricardo A. Hanel

Blaise William Baxter

About the editors

Alejandro M. Spiotta, MD Professor Neurosurgery and Neuroendovascular Surgery Program Director, Neurosurgery Residency  Director, Neuroendovascular Surgery Medical University of South Carolina Charleston, SC USA

Michael J. Alexander, MD Professor and Vice-Chairman Department of Neurosurgery Director, Neurovascular Center Cedars Sinai Medical Center Los Angeles, CA USA

Ricardo A  Hanel, MD PhD Endowed Chair, Stroke and Cerebrovascular Surgery Director, Baptist Neurological Institute Jacksonville, FL USA

Blaise William Baxter, MD Department of Radiology Lehigh Valley Health Network Allentown, PA USA

Bibliographic Information

Book Title : 12 Strokes

Book Subtitle : A Case-based Guide to Acute Ischemic Stroke Management

Editors : Ferdinand K. Hui, Alejandro M. Spiotta, Michael J. Alexander, Ricardo A. Hanel, Blaise William Baxter

DOI : https://doi.org/10.1007/978-3-030-56857-3

Publisher : Springer Cham

eBook Packages : Biomedical and Life Sciences , Biomedical and Life Sciences (R0)

Copyright Information : Springer Nature Switzerland AG 2021

Hardcover ISBN : 978-3-030-56856-6 Published: 12 January 2021

Softcover ISBN : 978-3-030-56859-7 Published: 12 January 2022

eBook ISBN : 978-3-030-56857-3 Published: 11 January 2021

Edition Number : 1

Number of Pages : XVII, 337

Number of Illustrations : 55 b/w illustrations, 60 illustrations in colour

Topics : Neurosurgery , Neurology , Imaging / Radiology

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Statement of ethics, conflict of interest statement, funding sources, author contributions, ischemic stroke in a 29-year-old patient with covid-19: a case report.

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Christian Avvantaggiato , Loredana Amoruso , Maria Pia Lo Muzio , Maria Assunta Mimmo , Michelina Delli Bergoli , Nicoletta Cinone , Luigi Santoro , Lucia Stuppiello , Antonio Turitto , Chiara Ciritella , Pietro Fiore , Andrea Santamato; Ischemic Stroke in a 29-Year-Old Patient with COVID-19: A Case Report. Case Rep Neurol 2 September 2021; 13 (2): 334–340. https://doi.org/10.1159/000515457

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Increasing evidence reports a greater incidence of stroke among patients with Coronavirus disease 2019 (COVID-19) than the non-COVID-19 population and suggests that SARS-CoV-2 infection represents a risk factor for thromboembolic and acute ischemic stroke. Elderly people have higher risk factors associated with acute ischemic stroke or embolization vascular events, and advanced age is strongly associated with severe COVID-19 and death. We reported, instead, a case of an ischemic stroke in a young woman during her hospitalization for COVID-19-related pneumonia. A 29-year-old woman presented to the emergency department of our institution with progressive respiratory distress associated with a 2-day history of fever, nausea, and vomiting. The patient was transferred to the intensive care unit (ICU) where she underwent a tracheostomy for mechanical ventilation due to her severe clinical condition and her very low arterial partial pressure of oxygen. The nasopharyngeal swab test confirmed SARS-CoV-2 infection. Laboratory tests showed neutrophilic leucocytosis, a prolonged prothrombin time, and elevated D-dimer and fibrinogen levels. After 18 days, during her stay in the ICU after suspension of the medications used for sedation, left hemiplegia was reported. Central facial palsy on the left side, dysarthria, and facial drop were present, with complete paralysis of the ipsilateral upper and lower limbs. Computed tomography (CT) of the head and magnetic resonance imaging of the brain confirmed the presence of lesions in the right hemisphere affecting the territories of the anterior and middle cerebral arteries, consistent with ischemic stroke. Pulmonary and splenic infarcts were also found after CT of the chest. The age of the patient and the absence of serious concomitant cardiovascular diseases place the emphasis on the capacity of SARS-CoV-2 infection to be an independent cerebrovascular risk factor. Increased levels of D-dimer and positivity to β2-glycoprotein antibodies could confirm the theory of endothelial activation and hypercoagulability, but other mechanisms – still under discussion – should not be excluded.

Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus SARS-CoV-2, is characterized by a wide range of symptoms, most of which cause acute respiratory distress syndrome [1, 2], associated with intensive care unit (ICU) admission and high mortality [3]. On March 11, 2020, the large global outbreak of the disease led the World Health Organization (WHO) to declare COVID-19 a pandemic, with 11,874,226 confirmed cases and 545,481 deaths worldwide (July 9, 2020) [4]. In many cases, the clinical manifestations of COVID-19 are characteristic of a mild disease that may, however, worsen to a critical lower respiratory infection [2]. At the onset of the disease, the most frequent symptoms are fever, dry cough, fatigue, and shortness of breath as the infection progresses may appear signs and symptoms of respiratory failure that require ICU admission [5, 6]. Although acute respiratory distress syndrome is the most important cause of ICU admission for COVID-19 patients, several studies have underlined the presence of neurological symptoms such as confusion, dizziness, impaired consciousness, ataxia, seizure, anosmia, ageusia, vision impairment, and stroke [7, 8]. In particular, the state of hypercoagulability in patients affected by COVID-19 favors the formation of small and/or large blood clots in multiple organs, including the brain, potentially leading to cerebrovascular disease (ischemic stroke but also intracranial hemorrhage) [9, 10 ].

We found an interesting case of stroke following a SARS-CoV-2 infection in a young patient. A 29-year-old woman, during her ICU hospitalization for COVID-19-related pneumonia, was diagnosed with ischemic stroke of the right hemisphere, without other cardiac/cerebrovascular risk factors except hypertension. The young age of the patient and the absence of higher cerebrovascular risk factors make the present case very interesting as it can help demonstrate that COVID-19 is an independent risk factor for acute ischemic stroke. In a case series of 214 patients with COVID-19 (mean [SD] age, 52.7 [15.5] years), neurologic symptoms were more common in patients with severe infection who were older than the others [ 11 ]. New-onset CVD was more common in COVID-19 patients who had underlying cerebrovascular risk factors, such as older age (>65 years) [ 12 ], and very few cases of stroke in patients younger than 50 years have been reported [ 12, 13 ]. Our case seems to be the only one younger than 30 years.

On the night between March 19 and 20, 2020, a 29-year-old woman was referred to our hospital “Policlinico Riuniti di Foggia” due to a progressive respiratory distress associated with a 2-day history of fever, nausea, and vomiting. At presentation, the heart rate was 128 bpm, the blood oxygen saturation measured by means of the pulse oximeter was 27%, the respiratory rate was 27 breaths per minute, and the blood pressure was 116/77 mm Hg. The arterial blood gas test showed a pH of 7.52, pO 2 20 mm Hg, and pCO 2 34 mm Hg. The patient was immediately transferred to the ICU where she underwent tracheostomy and endotracheal intubation for mechanical ventilation due to her severe clinical condition and deteriorated pulmonary gas exchange. The diagnosis of COVID-19 was confirmed by PCR on a nasopharyngeal swab.

The family medical history was normal, and the only known pre-existing medical conditions were polycystic ovary syndrome (diagnosed 3 years earlier), conversion disorder, and hypertension (both diagnosed 2 years earlier). Ramipril and nebivolol were prescribed for the high blood pressure treatment, and sertraline was prescribed for the conversion disorder treatment. Drug therapy adherence was inconstant. The patient had no history of diabetes, cardiac pathologies, strokes, transient ischemic attacks, thromboembolic, or other vascular pathologies.

Laboratory tests showed neutrophilic leukocytosis (white blood cell count 14.79 × 10 3 , neutrophil percentage 89.8%, and neutrophil count 13.29 × 10 3 ), a prolonged prothrombin time (15.3 s) with a slightly elevated international normalized ratio (1.38), and elevated D-dimer (6,912 ng/mL) and fibrinogen levels (766 mg/dL). Other findings are shown in Table  1 .

Laboratory test

This pharmacological therapy was set as follows: enoxaparin 6,000 U.I. once a day, piperacillin 4 g/tazobactam 0.5 g twice a day; Kaletra, a combination of lopinavir and ritonavir indicated for human immunodeficiency virus (HIV) infection treatment, 2 tablets twice a day; hydroxychloroquine 200 mg once a day; and furosemide 250 mg, calcium gluconate, and aminophylline 240 mg 3 times a day. No adverse events were reported.

On April 7, 2020, during her stay in the ICU and after suspension of the medications used for sedation, left hemiplegia was reported. The same day, the patient underwent a computed tomography examination of the head, which showed areas of hypodensity in the right hemisphere due to recent cerebral ischemia.

On April 16, 2020, the patient was oriented to time, place, and person. Central facial palsy on the left side, dysarthria, and facial drop were present, with complete paralysis of the ipsilateral upper and lower limbs. The power of all the muscles of the left limbs was grade 0 according to the Medical Research Council (MRC) scale. Deep tendon reflexes were reduced on the left upper limb but hyperactive on the ipsilateral lower limb, with a slight increase in the muscle tonus. The senses of touch, vibration, and pain were reduced on the left side of the face and body.

On the same day, the patient underwent magnetic resonance imaging (MRI) of the brain (Fig.  1 a), showing lesions on the right hemisphere affecting the territories of the anterior and middle cerebral arteries. On May 5, 2020, magnetic resonance angiography showed an early duplication of the sphenoidal segment of the right middle cerebral artery, the branches of which are irregular with rosary bead-like aspects (Fig.  1 d, e); on the same day, the second MRI (Fig.  1 b) confirmed the lesions. Computed tomography of the chest (Fig.  1 c) and abdomen (Fig.  1 f), performed 5 days after the MRI of the brain, showed not only multifocal bilateral ground-glass opacities but also a basal subpleural area of increased density within the left lung (4 × 4 × 3 cm), consistent with a pulmonary infarction. In addition, a vascular lesion, consistent with a splenic infarct, was found in the inferior pole of the spleen. Doppler echocardiography of the hearth showed regular right chambers and left atrium and a slightly hypertrophic left ventricle with normal size and kinetics (ejection fraction: 55%). The age of the patient and the absence of serious concomitant cardiovascular diseases place the emphasis on the capacity of SARS-CoV-2 infection to be an independent cerebrovascular risk factor.

Imaging. a April 16, 2020; MRI of the brain: lesions in the right hemisphere affecting the territories of the anterior and the middle cerebral arteries. b May 5, 2020; MRI of the brain: same lesions in the right hemisphere shown in the previous image. d , e May 5, 2020; MRA showed an early duplication of the sphenoidal segment of the right middle cerebral artery, the branches of which are irregular with rosary bead-like aspect and reduction of blood flow in the middle cerebral artery. c April 20, 2020; CT of the abdomen: vascular lesion, consistent with a splenic infarct, found in the inferior pole of the spleen. f April 20, 2020; CT of the chest: basal subpleural area of increased density within the left lung (4 × 4 × 3 cm), consistent with a pulmonary infarction. MRA, magnetic resonance angiography; CT, computed tomography; MRI, magnetic resonance imaging.

The pandemic outbreak of novel SARS-CoV-2 infection has caused great concern among the services and authorities responsible for public health due to not only the mortality rate but also the danger of filling up hospital capacities in terms of ICU beds and acute non-ICU beds. In this regard, the nonrespiratory complications of COVID-19 should also be taken into great consideration, especially those that threaten patients’ lives and extend hospitalization times. Stroke is one of these complications, since a greater incidence of stroke among patients with COVID-19 than the non-COVID-19 population has been reported, and a preliminary case-control study demonstrated that SARS-CoV-2 infection represents a risk factor for acute ischemic stroke [ 14 ].

We found that the reported case is extremely interesting, since the woman is only 29 years old and considering how stroke in a young patient without other known risk factors is uncommon. Not only elderly people have higher risk factors associated with acute ischemic stroke or embolization vascular events [ 15 ], but it is also true that advanced age is strongly associated with severe COVID-19 and death. The severity of the disease is directly linked to immune dysregulation, cytokine storm, and acute inflammation state, which in turn are more common in patients who present immunosenescence [6].

Inflammation plays an important role in the occurrence of cardiovascular and cerebrovascular diseases since it favors atherosclerosis and affects plaque stability [ 16 ]. The ischemic stroke of the 29-year-old woman does not appear to be imputable to emboli originating a pre-existing atheromatous plaque, both for the age of the patient and for the absence of plaques at the Doppler ultrasound study of the supra-aortic trunks.

Most likely, COVID-19-associated hypercoagulability and endothelial dysfunction are the causes of ischemic stroke, as suggested by other studies and case reports [ 10, 13, 17 ]. Although the mechanisms by which SARS-CoV-2 infection leads to hypercoagulability are still being studied, current knowledge suggests that cross talk between inflammation and thrombosis has a crucial role [ 18 ]. The release of inflammatory cytokines leads to the activation of epithelial cells, monocytes, and macrophages. Direct infection of endothelial cells through the ACE2 receptor also leads to endothelial activation and dysfunction, expression of tissue factor, and platelet activation and increased levels of VWF and FVIII, all of which contribute to thrombin generation and fibrin clot formation [ 17 ]. The 29-year-old patient showed an increased level of D-dimer, which is a degradation product of cross-linked fibrin, indicating a global activation of hemostasis and fibrinolysis and conforming to the hypothesis of COVID-19-associated hypercoagulability. Endothelial activation and hypercoagulability are also confirmed by positivity to β2 glycoprotein antibodies. Anticardiolipin antibody and/or β2 glycoprotein antibody positivity has been reported in a few studies [ 17, 19, 20 ]. In addition, widespread thrombosis in SARS-CoV-2 infection could also be caused by neutrophil extracellular traps (NETs). Neutrophilia [ 21 ] and an elevated neutrophil-lymphocyte ratio [ 22 ] have been reported by numerous studies as predictive of worse disease outcomes, and recently, the contribution of NETs in the pathophysiology of COVID-19 was reported [ 23 ]. Thrombogenic involvement of NETs has been described in various settings of thrombosis, including stroke, myocardial infarction, and deep vein thrombosis [ 24 ]. The high neutrophil count found in our case does not exclude the hypothesis that NETs are involved in the pathogenesis of ischemic stroke.

Ischemic stroke in young patients without pre-existing cerebrovascular risk factors is very unusual. In this regard, our case of an ischemic stroke, reported in a 29-year-old woman, is very interesting. Although it is not possible to determine precisely when the thromboembolic event occurred, our case of stroke during COVID-19-related pneumonia seems to confirm that COVID-19 is an independent risk factor for acute ischemic stroke. The mechanisms by which coronavirus disease leads to stroke are still under study, but it is clear that hypercoagulability and endothelial activation play a key role. Testing for SARS-CoV-2 infection should be considered for patients who develop neurologic symptoms, but it is equally important to monitor COVID-19 patients during their hospitalization to find any neurological sign or symptom in a timely manner. Our case suggests that discovering neurological deficits in sedated patients promptly can be very difficult; for this reason, sedation in mechanically ventilated patients has to be considered only if strictly necessary. Performing serial laboratory testing and waking up the patient as soon as clinical conditions allow are strategies that should be taken into account.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal.

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

No funding was received for the publication of this case report.

All authors agree with the contents of the manuscript and were fully involved in the study and preparation of the manuscript. All authors read and approved the final version of the manuscript. M.A. Mimmo, M.P. Lo Muzio, M. Delli Bergoli, and L. Amoruso collected the data. C. Avvantaggiato wrote the manuscript with support of N. Cinone, L. Santoro, and C. Ciritella. C. Avvantaggiato, A. Turitto, and L. Stuppiello researched and discussed the neurophysiological principles of this study. P. Fiore and A. Santamato supervised the project.

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This case study presents a 68-year old “right-handed” African-American man named Randall Swanson. He has a history of hypertension, hyperlipidemia and a history of smoking one pack per day for the last 20 years. He is prescribed Atenolol for his HTN, and Simvastatin for Hyperlipidemia (but he has a history of not always taking his meds). His father had a history of hypertension and passed away from cancer 10 years ago. His mother has a history of diabetes and is still alive.

Randall was gardening with his wife on a relaxing Sunday afternoon. Out of nowhere, Randall fell to the ground. When his wife rushed to his side and asked how he was doing, he answered with garbled and incoherent speech. It was then that his wife noticed his face was drooping on the right side. His wife immediately called 911 and paramedics arrived within 6 minutes. Upon initial assessment, the paramedics reported that Randall appeared to be experiencing a stroke as he presented with right-sided facial droop and weakness and numbness on the right side of his body. Fortunately, Randall lived nearby a stroke center so he was transported to St. John’s Regional Medical Center within 17 minutes of paramedics arriving to his home.

Initial Managment

Upon arrival to the Emergency Department, the healthcare team was ready to work together to diagnose Randall. He was placed in bed with the HOB elevated to 30 degrees to decrease intracranial pressure and reduce any risks for aspiration. Randall’s wife remained at his side and provided the care team with his brief medical history which as previously mentioned, consists of hypertension, hyperlipidemia and smoking one pack per day for the last 20 years. He had no recent head trauma, never had a stroke, no prior surgeries, and no use of anticoagulation medications.

Physical Assessment

Upon first impression, Nurse Laura recognized that Randall was calm but looked apprehensive. When asked to state his name and date of birth, his speech sounded garbled at times and was very slow, but he could still be understood. He could not recall the month he was born in but he was alert and oriented to person, time, and situation. When asked to state where he was, he could not recall the word hospital. He simply pointed around the room while repeating “here.”

Further assessment revealed that his pupils were equal and reactive to light and that he presented with right-sided facial paralysis. Randall was able to follow commands but when asked to move his extremities, he could not lift his right arm and leg. He also reported that he could not feel the nurse touch his right arm and leg. Nurse Laura gathered the initial vital signs as follows: BP: 176/82, HR: 93, RR: 20, T:99.4, O2: 92% RA and a headache with pain of 3/10.

Doctor’s Orders

The doctor orders were quickly noted and included:

-2L O2 (to keep O2 >93%)

– 500 mL Bolus NS

– VS Q2h for the first 8 hrs.

-Draw labs for: CBC, INR, PT/INR, PTT, and Troponin

-Get an EKG

-Chest X ray

-Glucose check

-Obtain patient weight

-Perform a National Institute of Health Stroke Scale (also known as NIHSS) Q12h for the first 24 hours, then Q24h until he is discharged

-Notify pharmacy of potential t-PA preparation.

Nursing Actions

Nurse Laura started an 18 gauge IV in Randall’s left AC and started him on a bolus of 500 mL of NS. A blood sample was collected and quickly sent to the lab. Nurse Laura called the Emergency Department Tech to obtain a 12 lead EKG.

Pertinent Lab Results for Randall

The physician and the nurse review the labs:

WBC 7.3 x 10^9/L

RBC 4.6 x 10^12/L

Plt 200 x 10^9/L

LDL 179 mg/dL

HDL 43 mg/dL

Troponin <0.01 ng/mL

EKG and Chest X Ray Results

The EKG results and monitor revealed Randall was in normal sinus rhythm; CXR was negative for pulmonary or cardiac pathology

CT Scan and NIHSS Results 

The NIH Stroke Scale was completed and demonstrated that Randall had significant neurological deficits with a score of 13. Within 20 minutes of arrival to the hospital, Randall had a CT-scan completed. Within 40 minutes of arrival to the hospital, the radiologist notified the ED physician that the CT-scan was negative for any active bleeding, ruling our hemorrhagic stroke.

The doctors consulted and diagnosed Randall with a thrombotic ischemic stroke and determined that that plan would include administering t-PA. Since Randall’s CT scan was negative for a bleed and since he met all of the inclusion criteria he was a candidate for t-PA. ( Some of the inclusion criteria includes that the last time the patient is seen normal must be within 3 hours, the CT scan has to be negative for bleeding, the patient must be 18 years or older, the doctor must make the diagnosis of an acute ischemic stroke, and the patient must continue to present with neurological deficits.)

Since the neurologist has recommended IV t-PA, the physicians went into Randall’s room and discussed what they found with him and his wife. Nurse Laura answered and addressed any remaining concerns or questions.

Administration

Randall and his wife decided to proceed with t-PA therapy as ordered, therefore Nurse Laura initiated the hospital’s t-PA protocol. A bolus of 6.73 mg of tPA was administered for 1 minute followed by an infusion of 60.59 mg over the course of 1 hour. ( This was determined by his weight of 74.8 kg).  After the infusion was complete, Randall was transferred to the ICU for close observation. Upon reassessment of the patient, Randall still appeared to be displaying neurological deficits and his right-sided paralysis had not improved. His vital signs were assessed and noted as follows: BP: 149/79 HR: 90 RR: 18 T:98.9 O2: 97% 2L NC Pain: 2/10.

Randall’s wife was crying and he appeared very scared, so Nurse John tried to provide as much emotional support to them as possible. Nurse John paid close attention to Randall’s blood pressure since he could be at risk for hemorrhaging due to the medication. Randall was also continually assessed for any changes in neurological status and allergic reactions to the t-PA. Nurse John made sure that Stroke Core Measures were followed in order to enhance Randall’s outcome.

In the ICU, Randall’s neurological status improved greatly. Nurse Jan noted that while he still garbled speech and right-sided facial droop, he was now able to recall information such as his birthday and he could identify objects when asked. Randall was able to move his right arm and leg off the bed but he reported that he was still experiencing decreased sensation, right-sided weakness and he demonstrated drift in both extremities.

The nurse monitored Randall’s blood pressure and noted that it was higher than normal at 151/83. She realized this was an expected finding for a patient during a stroke but systolic pressure should be maintained at less than 185 to lower the risk of hemorrhage. His vitals remained stable and his NIHSS score decreased to an 8. Labs were drawn and were WNL with the exception of his LDL and HDL levels. His vital signs were noted as follows: BP 151/80 HR 92 RR 18 T 98.8 O2 97% RA Pain 0/10

The Doctor ordered Physical, Speech, and Occupational therapy, as well as a swallow test.

Swallowing Screen

Randall remained NPO since his arrival due to the risks associated with swallowing after a stroke. Nurse Jan performed a swallow test by giving Randall 3 ounces of water. On the first sip, Randall coughed and subsequently did not pass. Nurse Jan kept him NPO until the speech pathologist arrived to further evaluate Randall. Ultimately, the speech  pathologist determined that with due caution, Randall could be put on a dysphagia diet that featured thickened liquids

Physical Therapy & Occupational Therapy

A physical therapist worked with Randall and helped him to carry out passive range of motion exercises. An occupational therapist also worked with Randall to evaluate how well he could perform tasks such as writing, getting dressed and bathing. It was important for these therapy measures to begin as soon as possible to increase the functional outcomes for Randall. Rehabilitation is an ongoing process that begins in the acute setting.

Day 3- third person 

During Day 3, Randall’s last day in the ICU, Nurse Jessica performed his assessment. His vital signs remained stable and WNL as follows: BP: 135/79 HR: 90 RR: 18 T: 98.9 O2: 97% on RA, and Pain 0/10. His NIHSS dramatically decreased to a 2. Randall began showing signs of improved neurological status; he was able to follow commands appropriately and was alert and oriented x 4. The strength  in his right arm and leg markedly improved. he was able to lift both his right arm and leg well and while he still reported feeling a little weakness and sensory loss, the drift in both extremities was absent.

Rehabilitation Therapies

Physical, speech, and occupational therapists continued to work with Randall. He was able to call for assistance and ambulate with a walker to the bathroom and back. He was able to clean his face with a washcloth, dress with minimal assistance, brush his teeth, and more. Randall continued to talk with slurred speech but he was able to enunciate with effort.

On day 4, Randall was transferred to the med-surg floor to continue progression. He continued to work with physical and occupational therapy and was able to perform most of his ADLs with little assistance. Randall could also ambulate 20 feet down the hall with the use of a walker.

Long-Term Rehabilitation and Ongoing Care

On day 5, Randall was discharged to a rehabilitation facility and continued to display daily improvement. The dysphagia that he previously was experiencing resolved and he was discharged home 1.5 weeks later. Luckily for Randall, his wife was there to witness his last known well time and she was able to notify first responders. They arrived quickly and he was able to receive t-PA in a timely manner. With the help of the interdisciplinary team consisting of nurses, therapists, doctors, and other personnel, Randall was put on the path to not only recover from the stroke but also to quickly regain function and quality of life very near to pre-stroke levels. It is now important that Randall continues to follow up with his primary doctor and his neurologist and that he adheres to his medication and physical therapy regimen.

Case Management

During Randall’s stay, Mary the case manager played a crucial role in Randall’s path to recovery. She determined that primary areas of concern included his history of medical noncompliance and unhealthy lifestyle. The case manager consulted with Dietary and requested that they provide Randall with education on a healthy diet regimen. She also provided him with smoking cessation information. Since Randall has been noncompliant with his medications, Mary determined that social services should consult with him to figure out what the reasons were behind his noncompliance. Social Services reported back to Mary that Randall stated that he didn’t really understand why he needed to take the medication. It was apparent that he had not been properly educated. Mary also needed to work with Randall’s insurance to ensure that he could go to the rehab facility as she knew this would greatly impact his ultimate outcome. Lastly, throughout his stay, the case manager provided Randall and his wife with resources on stroke educational materials. With the collaboration of nurses, education on the benefits of smoking cessation, medication adherence, lifestyle modifications, and stroke recognition was reiterated to the couple. After discharge, the case manager also checked up with Randall to make sure that he complied with his follow up appointments with the neurologist and physical and speech therapists,

• What risk factors contributed to Randall’s stroke?
• What types of contraindications could have prevented Randall from receiving t-PA?
• What factors attributed to Randall’s overall favorable outcome?

Nursing Case Studies by and for Student Nurses Copyright © by jaimehannans is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License , except where otherwise noted.

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Ischemic Stroke

Author: Cynthia Leung MD PhD, The Ohio State University College of Medicine.

Editor: Rahul Patwari, MD, Rush University, Chicago, Illinois.

Last Update: November 2019

A 68-year-old female, with a history of hypertension and diabetes mellitus, presented to the ED after acute onset of speech difficulty and right-sided weakness. Her symptoms began 3 hours ago. On physical exam, the patient was found to have severe expressive aphasia, right hemiplegia, and right hemi-sensory loss.

Upon completion of this module, the student will be able to:

• Recognize signs and symptoms of stroke
• Identify clinical features suggestive of common stroke mimics
• Describe the initial management of acute stroke
• Discuss the treatment options for acute ischemic stroke

Introduction

Stroke is the fifth leading cause of death and the leading cause of disability in the US with estimated direct and indirect costs of roughly 70 billion dollars per year. Based on current estimates, the prevalence of stroke is expected to increase by twenty percent by the year 2030. Advancements in the diagnosis and treatment of stroke must continue to compensate for the increasing stroke burden on our society.

Stroke is characterized by the acute onset of neurologic deficit caused by disruption of cerebral blood flow to a localized region of the brain. The reversibility and extent of symptoms in stroke is critically dependent on the duration of this disruption. Therefore, early recognition and treatment is the key to reducing morbidity and mortality associated with stroke. As the first physician to see the patient with acute stroke, the actions of the Emergency Physician can have a profound impact on the outcome of stroke patients.

Acute stroke most commonly results from occlusion of an intracranial artery by thrombosis within the artery, thromboembolism from an extracranial source, or hemorrhage. Eighty seven percent of strokes are ischemic in etiology, with the remainder caused by intracerebral or subarachnoid hemorrhage. This module will focus exclusively on the evaluation and treatment of acute ischemic stroke. The evaluation and treatment of hemorrhagic stroke can be found in the intracranial hemorrhage module.

Patients with stroke may present with a variety of neurologic symptoms including changes in vision, changes in speech, focal numbness or weakness, disequilibrium or alteration in level of consciousness. There are many alternate diagnoses that can mimic the symptoms of stroke.

The differential diagnosis includes:

• Structural brain lesion (tumor, AVM, aneurysm, hemorrhage)
• Infection (cerebral abscess, septic emboli)
• Seizure Disorder and post-seizure neurologic deficit (Todd’s paralysis)
• Peripheral Neuropathy (Bell’s palsy)
• Complicated Migraine
• Toxic-metabolic disorders (Hypoglycemia and Hyponatremia)
• Conversion Disorder

Initial Actions and Primary Survey

The initial actions in the evaluation of a patient with suspected stroke begin with emergent stabilization of the patient. As with any emergent patient, the primary survey includes assessment of the patient’s airway, breathing and circulation. Hypoxemia and hypotension due to stroke or co-morbid conditions may worsen stroke symptoms and lead to death. Therefore, treatment of any critical conditions found on primary survey must be initiated prior to continuing the evaluation. Next, a focused H&P is performed to assess level of neurologic dysfunction, exclude alternate diagnoses, and determine the patient’s eligibility for therapy.

Presentation

The initial diagnosis of acute stroke is based on clinical findings. Part of the challenge in making the diagnosis is that there is no “textbook” presentation of stroke. The signs and symptoms of stroke are highly variable and depend not only on the particular blood vessel occluded, but also the extent of occlusion and amount of circulation provided by collateral vessels. Presentations may vary from multiple profound neurologic deficits in a large vessel occlusion to very subtle isolated deficits when smaller vessels are occluded.

The single most important component of the history is the exact time of onset of symptoms. This is defined as the time when the patient was last known to be symptom-free, commonly referred to as the “last known well”. In cases where the patient’s last known well time is unclear, focused questions should be deployed to help narrow down the time window as much as possible.  For example, if the patient awakens from sleep with symptoms, questioning the patient about waking in the middle of the night to walk to the restroom or kitchen may help to determine a more accurate last known well time. In patients who were awake during symptom onset, asking about specific activities such as phone calls or television shows may help to further focus the timeframe of onset. Friends and family should also be asked to provide collateral information when possible.

The remainder of the history should focus on factors which may help differentiate a stroke mimic from a true stroke. The HPI should include a detailed history of the onset, time course and pattern of symptoms to help distinguish between stroke and alternate diagnoses. Symptoms which achieve maximal intensity within seconds to minutes of onset and simultaneously affect multiple different systems at once are typical of stroke. In contrast, symptoms which progress slowly over time or progress from one area of the body to another are more suggestive of stroke mimic. The past medical history should include assessment of stroke risk factors as well as risk factors for stroke mimics. Stroke risk factors include hypertension, diabetes, hyperlipidemia, tobacco abuse, advanced age, atrial fibrillation or prosthetic heart valve, and prior stroke. In patients receiving thrombolytic therapy, the most common stroke mimics include complicated migraine, seizure and conversion disorder. A past medical history which includes any of these disorders should heighten suspicion of these alternate diagnoses.  

Once the primary survey is complete, a thorough neurologic exam should be performed. This should include assessment of level of consciousness, cranial nerves, strength, sensation, cerebellar function and gait.

Common Stroke Syndromes

Signs and symptoms of stroke should follow a vascular distribution of the brain. Knowledge of the functional areas supplied by each of the major intracranial blood vessels helps to predict signs and symptoms associated with occlusion of that particular vessel.

Image 1. Circle of Willis and the primary cerebral vessels. Labels added. Contect accessed from https://medlineplus.gov/ency/imagepages/18009.htm

Anterior Cerebral Artery (ACA): unilateral weakness and/or sensory loss of contralateral lower extremity greater than upper extremity

Middle Cerebral Artery (MCA): unilateral weakness and/or sensory loss of contralateral face and upper extremity greater than lower extremity with either aphasia (if dominant hemisphere) or neglect (if non-dominant hemisphere)

Posterior Cerebral Artery (PCA): unilateral visual field deficit in both eyes (homonymous hemianopsia).

Vertebrobasilar syndromes have multiple deficits which typically include contralateral weakness and/or sensory loss in combination with ipsilateral cranial nerve palsies. Suspicion for posterior circulation stroke is heightened if the patient exhibits one of these signs or symptoms beginning with “D”: diplopia, dysarthria, dysphagia, droopy face, dysequilibrium, dysmetria, and decreased level of consciousness.   Nausea and vomiting are also frequently associated with brainstem stroke.

Lacunar infarcts are small strokes (measuring less than 1.5 cm) caused by occlusion of one of the deep perforating arteries which supplies the subcortical structures and brainstem. Lacunar infarcts can produce a large variety of clinical deficits depending on their location within the brainstem and have been characterized by more than 70 different clinical syndromes. However, the vast majority of lacunar strokes are described by the 5 most common lacunar syndromes: pure motor hemiparesis, sensorimotor stroke, ataxic hemiparesis, pure sensory stroke, and dysarthria-clumsy hand syndrome.

Diagnostic Testing

Rapid evaluation of patients with suspected stroke is critical because there is a very narrow time window in which stroke patients are eligible for treatment.  A panel of experts convened by the National Institute of Neurological Disorders and Stroke (NINDS) has established several critical events in the identification, evaluation, and treatment of stroke patients in the ED. The most important of these time goals include a door to head CT time less than 25 minutes and a door to drug administration time of less than 60 minutes. 

The diagnosis of stroke is based primarily on clinical presentation. The NIH Stroke Scale (NIHSS) provides a standardized clinical assessment which is generalizable from one physician to another and allows monitoring of the patient’s neurologic deficits over time. The NIHSS can serve as a measure of stroke severity and has been shown to be a predictor of both short and long term outcome of stroke patients. Many Emergency physicians find it convenient to keep an App on their phone to aid in rapidly calculating the NIHSS. There are also a variety of on-line NIHSS calculators available, such as the one found on MDcalc.com

The remainder of the diagnostic workup is focused on excluding alternative diagnoses, assessing for comorbid conditions and determining eligibility for therapy. The diagnostic workup includes:

Brain Imaging

Head CT without contrast should be performed on all patients to exclude intracranial hemorrhage. Unenhanced head CT is often able to identify other structural brain lesions and may detect early signs of stroke. Because radiologic changes associated with stroke are usually not visible on CT for several hours, the most common CT finding in acute ischemic stroke is normal brain. However, multiple subtle findings associated with acute ischemic stroke may be present in the first 3 hours after symptom onset. The earliest finding that may be seen on CT is hyperdensity representing acute thrombus or embolus in a major intracranial vessel. This is most frequently seen in the MCA (“hyperdense MCA sign”, see Image 2) and basilar arteries (“hyperdense basilar artery sign”). Subsequent findings include subtle hypo-attentuation causing obscuration of the nuclei in the basal ganglia and loss of gray/white differentiation in the cortex. Frank hypodensity on CT is indicative of completed stroke and may be a contraindication to thrombolytic therapy.

Image 2. MCA sign on CT head. Case courtesy of A.Prof Frank Gaillard, <a href=" https://radiopaedia.org/ ">Radiopaedia.org</a>.  From the case <a href="https://radiopaedia.org/cases/7150">rID: 7150</a>

At specialized stroke centers, alternative testing such as diffusion weighted MRI (DWI) or CT angiography/CT perfusion studies may also be performed as these modalities are more sensitive for detecting early or evolving infarct and may help determine the most appropriate therapy.

Serum Glucose

Hypoglycemia may cause alteration in level of consciousness and any variety of neurologic symptoms. Point of care blood glucose level must be performed to exclude hypoglycemia prior to initiation of thrombolytic therapy.

EKG should be performed to exclude contemporaneous acute MI or atrial fibrillation as these conditions are frequently associated with thromboembolic stroke.

Additional laboratory studies

CBC, chemistries, PT/INR, aPTT, and cardiac markers are recommended to assess for serious comorbid conditions and aid in selection of therapy.  Treatment should not be delayed for results of these additional studies unless a bleeding disorder is suspected.

The main goal of therapy in acute ischemic stroke is to remove occlusion from the involved vessel and restore blood flow to the affected area of the brain. The AHA/ASA currently recommends two forms of treatment for eligible patients with acute ischemic stroke: intravenous thrombolytic agents and mechanical thrombectomy.

Intravenous Thrombolytic Therapy

Intravenous recombinant Tissue Plasminogen Activator (rtPA) is a fibrinolytic agent that catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Treatment with IV rtPA has been shown to increase the percentage of patients with good functional outcome at 3 months and 1 year after stroke onset.

rtPA has been FDA approved for use in adult patients with symptoms attributable to ischemic stroke up to 3hrs after symptom onset. In addition, the American Heart Association has recommended rtPA for use up to 4.5 hours after symptom onset in a select subgroup of patients. Good functional outcomes are most likely to be achieved if rtPA is administered within 90 minutes of symptom onset. The likelihood of a good outcome decreases with increasing time from onset of symptoms. Therefore, every effort should be made to ensure that there are no delays in administration of thrombolytic therapy to eligible patients.

The major complication of rtPA administration in stroke is symptomatic intracranial hemorrhage. Careful selection of patients with an appropriate risk/benefit ratio is imperative to reduce the risk of symptomatic ICH. Exclusion criteria most commonly reflect factors that may increase likelihood of ICH including uncontrolled severe hypertension, coagulopathies, recent intracranial or spinal surgery, recent head trauma or stroke and history of prior ICH.  The full list of inclusion and exclusion criteria for intravenous rtPA therapy can be found in the most recent version of the AHA Guidelines for the Early Management of Patients with Acute Ischemic Stroke (see references below).

In addition, strict adherence to the NINDS recommended protocol for administration of rtPA is critical to successful treatment in stroke patients. This protocol specifies important aspects of care during and after administration of rtPA. Admission to an ICU or stroke unit, frequent reassessment of the patient’s neurologic status and careful blood pressure monitoring are all vital in the first 24 hours after administration of rtPA. Most importantly, any patient who develops acute severe headache, acute severe hypertension, intractable nausea and vomiting, altered mental status or other evidence of neurologic deterioration during or after rtPA administration should have emergent noncontrast head CT to evaluate for ICH. In addition, rtPA infusion should be discontinued immediately if it has not already been completed.

Mechanical Thrombectomy

Mechanical thrombectomy  is recommended for adult patients with ischemic stroke caused by occlusion of the internal carotid or proximal middle cerebral (M1) arteries and an NIHSS greater than 6, presenting within 6 hours of symptom onset. Thrombectomy is also recommended for a select group of patients presenting up to 16 hours after symptom onset if they have demonstrated perfusion mismatch on MRI or CTP and meet additional eligibility requirements. This recommendation was based on pooled analysis of 5 studies which demonstrated lower degree of disability at 3 months in patients undergoing mechanical thrombectomy compared to those undergoing thrombolytic therapy alone. This effect was most pronounced when the time from symptom onset to thrombectomy was under 2 hours, but persisted up to 7 hours after symptom onset.

Supportive Care

Unfortunately, only a small percentage of stroke patients present to the ED within the time limit to receive specialized therapy. In stroke patients not receiving rtPA or mechanical thrombectomy, the goal of care is to prevent or treat acute complications by providing supportive care. This includes ventilatory support and oxygenation if needed, prevention of hyperthermia, cardiac monitoring, and control of blood pressure and blood glucose.

Goals for Blood Pressure Control

In patients receiving intravenous rtPA, the rate of symptomatic ICH is directly related to increasing blood pressure. Therefore, strict guidelines for blood pressure control must be enforced in these patients to prevent ICH. Blood pressure should be maintained below 180/105 mm Hg in the first 24 hours after receiving thrombolytic therapy.

In contrast, the ideal blood pressure range for acute stroke patients not receiving thrombolytic therapy has not yet been determined. The current recommendations stress the importance of an individualized approach to blood pressure control with avoidance of hypotension or large fluctuations in blood pressure. For patients who do not have other medical conditions requiring aggressive blood pressure control, antihypertensive treatment should not be initiated unless blood pressure exceeds 220/120 mm Hg.

Antiplatelet Therapy

Administration of Aspirin within 48 hours after stroke has been shown to improve outcomes by reducing the rate of early recurrent stroke. In stroke patients not receiving rtPA, oral administration of aspirin within 24 – 48 hours of stroke onset is recommended. The safety of antiplatelet agents in combination with thrombolytic therapy has not been established. Therefore, aspirin should not be administered for at least 24 hours after administration of rtPA

Pearls and Pitfalls

• Use creative questioning to establish time of onset.
• Consider common conditions which may mimic the symptoms of stroke including seizure, complicated migraine, hypoglycemia, and conversion disorder. All adult patients presenting with neurologic deficit attributable to ischemic stroke within 3 hours of symptom onset should be considered for thrombolytic therapy.
• Minimum workup prior to thrombolytic therapy includes focused H&P, CT Head to exclude intracranial hemorrhage and point of care blood glucose level to exclude hypoglycemia.
• Time is brain! Do not delay administration of thrombolytic therapy to eligible patients.
• Adult patients presenting with acute ischemic stroke due to large vessel occlusion within 16 hours of symptom onset should be considered for mechanical thrombectomy.
• Patients that do not receive thrombolytic therapy should receive aspirin within 24 hours of symptom onset.

Case Study Resolution

The patient’s initial NIHSS was 11. Noncontrast CT of the head did not show any evidence of ICH. CT angiography revealed left M1 occlusion. The patient underwent mechanical thrombectomy with marked improvement in symptoms. Repeat NIHSS was 3. The patient was transferred to the neurologic critical care unit for further monitoring.

Guidelines for the Early Management of Patients with Acute Ischemic Stroke. Powers WJ, et al. Stroke 2018 Mar;49(3): e46-e99. PMID:29367334

Heart disease and StrokeStatistics—2018 Update: a report from the American Heart Association.  Benjamin ES, et al. Circulation. 2018 Mar 1;137(12):e67-e493. PMID:29386200

Safety of thrombolysis in stroke mimics: results from a multicenter cohort study. Zinkstok SM, et al. Stroke. 2013 Apr;44(4):1080-4. PMID:23444310

Time to Treatment with Endovascular Thrombectomy and Outcomes from Ischemic Stroke: A Meta-analysis. Saver JL, et al. JAMA 2016; 316(12):1279-1288. PMID:

Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.  Lees KR, et al. Lancet. 2010 May 15;375(9727):1695-1703. PMID:20472172

• Ischemic stroke

Citation, DOI, disclosures and case data

At the time the case was submitted for publication Abdulmajid Bawazeer had no recorded disclosures.

Presentation

Right-sided hemiparesis, aphasia, and mouth deviation.

Patient Data

A large area of hypo-attenuation with loss of gray-white matter differentiation involving the left temporal, parietal, and occipital lobes, and the caudate nucleus. These changes are more evident in the stroke window.

First three annotated images show hyper-attenuation of the left internal carotid artery and left middle cerebral (M1 and M2 segments) artery. This is known as the hyperdense MCA sign.

The fourth annotated image shows loss of differentiation of the gray-white interface in the lateral margin of the left insular cortex. This is known as the loss of the insular ribbon sign.

High diffusion signal involving the entire left caudate nucleus and cortex of left temporal, parietal and occipital lobes.

Hyperintensity along the intraluminal part of the left internal carotid artery and left middle cerebral artery.

Case Discussion

Non-enhanced CT scan is the initial step to rule out intracranial hemorrhage during a 'stroke call', and can demonstrate some clear signs of ischemic stroke.

This case illustrates the classic signs of middle cerebral artery territory infarct, such as the loss of the insular ribbon sign , the hyperdense MCA sign , and loss of gray-white matter differentiation. Adjusting the window and level (e.g. W:40 L:40 or W:8 L:32) is used for optimized visualization of subtle loss of gray-white matter differentiation.

Restriction diffusion on DWI and ADC maps are in-keeping with extensive acute ischemic infarction of left middle cerebral artery territory.

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Ischemic stroke: A case study

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• Published: 12 May 2024

Endovascular treatment in Danon disease: a case report

• Rayco Jiménez-Bolaños 1 ,
• Francisco Hernández-Fernández   ORCID: orcid.org/0000-0001-6681-2683 2 ,
• Jorge García-García 2 ,
• Óscar Ayo-Martín 2 ,
• Laura del Rey Megias 3 ,
• Juan David Molina-Nuevo 4 &
• Tomás Segura 2 , 5  

Journal of Medical Case Reports volume  18 , Article number:  244 ( 2024 ) Cite this article

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Danon disease is a lysosomal storage disorder with X-linked inheritance. The classic triad is severe hypertrophic cardiomyopathy, myopathy, and intellectual disability, with different phenotypes between both genders. Ischemic stroke is an uncommon complication, mostly cardioembolic, related to intraventricular thrombus or atrial fibrillation, among others.

We report the case of a 14-year-old Caucasian male patient with Danon disease who suffered from an acute ischemic stroke due to occlusion in the M1 segment of the middle cerebral artery. He underwent mechanical thrombectomy, resulting in successful revascularization with satisfactory clinical outcome. We objectified the intraventricular thrombus in the absence of arrhythmic events.

To our knowledge, we report the first case of ischemic stroke related to Danon disease treated with endovascular treatment.

Peer Review reports

Danon disease (DD) is a lysosomal storage disorder caused by the mutation of the Lysosomal Associated Membrane Protein 2 ( LAMP-2 ) gene. The exact LAMP-2 protein functions are unknown; however, it seems to play an important role in autophagy [ 1 ]. Its inheritance is X-linked dominant, located in Xq24, with more than 20 mutations described. Severe cardiomyopathy and myopathy are typical features, commonly associated with mental disability. Nevertheless, isolated cardiomyopathy is not infrequent [ 2 ]. Generally, men develop symptoms earlier and more intensely than women [ 3 ]. The prevalence of DD is unknown, but it is estimated at 0.7% of adult patients with hypertrophic cardiomyopathy (HCM) [ 7 ]. To date, approximately 500 cases have been described [ 3 ].

Early morbidity and mortality due to heart failure are known to occur in DD. Furthermore, cardioembolic complications may be relatively common in these patients even with normal systolic function. Indeed, one of the more devastating complications in the natural evolution of patients with DD is the onset of an ischemic stroke secondary to atrial fibrillation (AF) [ 4 ] or intracardiac thrombi, located in the left ventricle [ 3 , 5 ]. Formation of these thrombi is uncommon in non-metabolic HCM except when associated with severe ventricular dysfunction or AF or Wolff-Parkinson-White (WPW) arrhythmias, which may often occur in patients with DD. There is a lack of research on the management of acute stroke in these patients.

We present the first case of a patient with DD who suffered an acute ischemic stroke and treated with mechanical thrombectomy.

Medical history

An 18-month-old Caucasian boy, with no relevant prenatal, medical, or family history, parents not consanguineous, suffered from delayed motor development, hypotonia, and an increase in creatine-kinase and liver enzymes. The patient developed progressive proximal muscle weakness in both upper and lower limbs with bilateral winged scapula. Electromyography revealed a myopathic pattern. During follow-up at 10 years, after identifying a heart murmur, echocardiography revealed severe global left ventricular hypertrophy, mainly at the intraventricular septum (IVS 14–15 mm), with multiple trabeculae and preserved systolic function. The electrocardiogram showed WPW syndrome. The muscle biopsy reported vacuolar myopathy with autophagic characteristics and glycogen accumulation. The genetic test confirmed the presence of a mutation c.973dup;p (leu325profs25) in the LAMP-2 gene. An implantable cardioverter defibrillator was inserted due to atrioventricular block.

Case history

At the age of 14 years, he experienced speech impairment and right limb weakness upon awakening. Physical examination showed aortic systolic murmur and normal vital signs (blood pressure 116/81 mmHg; heart rate 60 beats per minute; temperature 36 °C). Neurological examination revealed moderate dysarthria, right central facial paresis and ipsilateral hemiparesis, right Babinski reflex and left brachial hypesthesia. The National Institute of Health Stroke Scale (NIHSS) score was 9.

Diagnostic investigations and endovascular procedure

A head computed tomography (CT) scan and CT angiogram demonstrated an Alberta Stroke Program Early CT Score (ASPECTS) of 10 and a complete occlusion of the left middle cerebral artery (MCA) bifurcation. A CT-perfusion study showed a large area of long mean transit time (MTT) with complete conservation of cerebral blood volume (CBV) in the left frontal-parietal-temporal territory. According to the local ischemic stroke protocol, the patient met the criteria for mechanical thrombectomy, except for age (less than 18 years) and DD. Therefore, due to excellent prognostic factors (ASPECTS 10 and favorable mismatch), emergent primary endovascular treatment was decided upon after informing the parents. Mechanical thrombectomy was performed using stent retriever with complete flow restoration (TICI 3) in one pass (Fig.  1 A).

A Cerebral angiography during procedure demonstrating a complete occlusion of the left middle cerebral artery bifurcation. B Echocardiogram revealed a hypertrophic cardiomyopathy and an echogenic mass at the left ventricular apex suggestive of intracardiac thrombus

Post-procedure care and etiological evaluation

The patient was admitted to the stroke unit and became asymptomatic 24 hours post-procedure (NIHSS 0). The CT scan evidenced hypo-attenuation of left caudate and lentiform nuclei and anterior limb of internal capsule. An etiological assessment was performed and an echocardiogram revealed worsening of the left ventricular hypertrophy (IVS 30–35 mm) showing an echogenic mass at the left ventricular apex suggestive of intracardiac thrombus (Fig.  1 B), secondary to heart disease previously observed during follow-up. The laboratory findings showed an increased in creatine-kinase (CK 1596 μmol/l) and liver enzymes glutamate pyruvate alanine aminotransferase (GPT 274 U/L), similar to previous values, without other alterations (glucose 106 mg/dL; urea 25 mg/dL; creatinine 0.62 mg/dL; sodium 141 mEq/L; potassium 4 mEq/L; chlorine 103 mEq/L). Urinary sediment analysis and toxin screen were negative. The coagulation test was normal, including international normalized ratio (INR) 1.36. We initiated low-molecular weight heparin (enoxaparin 60 mg/12 hours) for 15 days as bridging therapy despite the determination of a factor VII deficiency. Subsequently, we replaced apixaban 5 mg/12 hours instead of vitamin-K antagonist due to high bleeding risk. On discharge, the patient had completely recovered to his prior neurological state, which included winged scapulae and waddling gait. The patient remained asymptomatic during the 6-month follow-up and the apical thrombus disappeared.

Discussion and conclusions

DD may be a rare cause of ischemic stroke due to a cardioembolic mechanism, even in those with normal systolic function. In selected cases based on the main criteria, endovascular treatment may be an effective therapeutic strategy to prevent disability in patients with large-vessel-occlusion ischemic stroke, but further research is needed to improve upon knowledge.

DD is a rare multisystem disorder characterized by the triad of HCM, skeletal myopathy and intellectual disability. Cardiac involvement typically described is HCM; nevertheless, dilated cardiomyopathy has also been reported, mainly in women [ 2 ]. The X-linked dominant inheritance involves differences in clinical severity between both genders. Women usually develop a milder clinical phenotype, and occasionally only have heart disease, which can be as serious as in men [ 3 ]. Women usually develop a milder clinical phenotype, though with an exclusive cardiac involvement with similar damage.

DD prevalence is unknown. Around 500 cases have been reported worldwide since it was first described first in 1981 [ 3 ]. Many patients develop ischemic stroke, frequently at younger ages and with unfavorable prognosis. No endovascular treatment in acute event has been informed [ 3 ].

In 2008, Spinazzi et al . described three patients (two men and one woman) with severe HCM and AF who suffered from ischemic stroke [ 4 ]. In 2016, Marino et al . described a patient with hemodynamic ischemic stroke following cardiac arrest secondary to WPW [ 6 ]. In 2017, Takeshi et al . described a patient with ischemic stroke secondary to intracardiac thrombus [ 5 ]. Embolic stroke from the heart is common in DD and is associated with left ventricular dysfunction, older age, AF, or congestive heart failure [ 4 ]. Intracardiac thrombus formation is very rare in HCM, unless associated with very severe left ventricular dysfunction, AF, or WPW syndrome. Early identification of embolic source is relevant for prompt initiation of anticoagulation if indicated [ 3 , 5 ]. In our case, we established the cardioembolic source of the ischemic stroke after demonstrating an intraventricular thrombus on echocardiography.

To our knowledge, we present the first case of an acute ischemic stroke in a patient with DD who received mechanical thrombectomy. We performed the most widely used extraction method, that is, the stent retriever, with excellent angiographic and clinical results.

Therefore, it is reasonable to consider endovascular treatment beneficial in these patients. In addition, it is the most efficient therapeutic tool to prevent disability secondary to ischemic stroke. The development of impairment may contraindicate cardiac transplantation, therefore avoiding disability should be of major importance. Nonetheless, further studies are necessary to confirm our results.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Javaad Ahmad for the revision of the English translation.

AMIDA, Asociación de Médicos Investigadores de Albacete, Albacete, Spain.

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Department of Neurology, Complejo Hospitalario Universitario Insular-Materno Infantil de Canarias, Las Palmas, Spain

Rayco Jiménez-Bolaños

Department of Neurology, Complejo Hospitalario Universitario de Albacete, C/Hermanos Falcó 37, 02006, Albacete, Spain

Francisco Hernández-Fernández, Jorge García-García, Óscar Ayo-Martín & Tomás Segura

Pediatric Cardiology, Department of Pediatrics, Complejo Hospitalario Universitario de Albacete, Albacete, Spain

Laura del Rey Megias

Department of Radiology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain

Juan David Molina-Nuevo

Institute for Research in Neurologic Disabilities (IDINE), Medical School, University of Castilla-La-Mancha, Albacete, Spain

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RJB was responsible for the integrity of the study; FHF, RJB, and JGG for study design; RJM, JDMN, and LDR for data collection; TS and OAM for data analysis and interpretation; NA for statistical treatment; RJB and JGG for bibliographic search; RJB and FHF for writing—manuscript; FHF, TS, and JGG for critical revision of the manuscript with intellectually relevant contributions; and FHF, TS, RJB, OAM, JDMN, LDR, and JGG for approval of the final version:.

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Correspondence to Francisco Hernández-Fernández .

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The authors of the research asked all patients to sign an informed consent prior to undergoing the diaphragmatic ultrasonography. The good clinical practice guidelines and the Declaration of Helsinki were followed. Confidentiality of the data obtained was kept and they were only used for the study purposes. Our clinical research was reviewed and approved by the Clinical Research Ethics committee of the University Hospital Complex of Albacete.

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Jiménez-Bolaños, R., Hernández-Fernández, F., García-García, J. et al. Endovascular treatment in Danon disease: a case report. J Med Case Reports 18 , 244 (2024). https://doi.org/10.1186/s13256-024-04555-7

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May 15, 2024

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Study finds severe ischemic strokes are rare in patient population

by Tim Tedeschi, University of Cincinnati

A new University of Cincinnati study provides more insight into how few patients have severe ischemic strokes compared to the total stroke patient population in the region.

UC's Yasmin Aziz, MD, will present a poster on the team's findings during the European Stroke Organisation Conference (ESOC) this week in Basel, Switzerland.

Ischemic strokes, the most common form of strokes, are caused by a lack of blood flow and oxygen to specific parts of the brain. When a stroke patient arrives at the hospital, Aziz explained, they undergo a CT scan that can help doctors assess the severity of the damage the stroke has caused using a 10-point scale.

"Low scores indicate bigger strokes, while higher scores indicate smaller ones," said Aziz, assistant professor in the Department of Neurology and Rehabilitation Medicine in UC's College of Medicine and a neurologist at the UC Gardner Neuroscience Institute. "Much of our early treatment options and long-term prognosis depend on this simple score, as strokes due to blood clots can grow without intervention."

Aziz said this study asked a simple question: How many patients in the region arrive at the hospital with low scores?

Using data from the ongoing Greater Cincinnati/Northern Kentucky Stroke Study, the team found nearly 90% of all patients who arrive at the hospital within 24 hours of symptom onset have minimal ischemic damage on their CT scans, or scores of 9–10 on the scale.

When narrowing down the data to the most severe type of stroke caused by blood clots in the brain, the team found around 14% of these patients have the most severe damage, or scores of 0–2 on the scale.

"Patients with low scores due to large strokes require considerable resources from the health care system in order to facilitate their care," Aziz said. "A lot of research in the last two years has been dedicated to determining if we can treat patients with really low scores. Our results show the rarity of these severe strokes in a real-world population, rather than in a strictly controlled clinical trial setting."

Aziz said she was not surprised by the results, as the data on the occurrence of patients with low scores lined up with prior estimates.

"Thankfully, the majority of strokes are not due to large vessel occlusion, or due to blood clots in vessels supplying large areas of the brain," she said.

A recent series of clinical trials has shown benefit to blood clot removal for patients with severe strokes, and the research community is working to adjust to this paradigm shift , Aziz said. The study's data on how common these strokes occur is part of a larger puzzle to optimize research and patient care for all patients, she said.

This study is one of the first publications to come out of the Assessing Population-based Radiological brain health in Stroke Epidemiology (APRISE) study, an offshoot of the Cincinnati-area stroke study that adds a neuroimaging component to the data collection and research.

"Our team, comprised of internationally renowned experts in stroke epidemiology, radiology and acute stroke treatment, is extremely excited to utilize APRISE to provide the highest quality research to our field," Aziz said. "We are deeply thankful to the community for their participation in this research, which will be shared with experts from all around the world at ESOC. Together, we hope to push the boundaries of treatment for stroke patients."

Aziz will present "Early Ischemic Change at Late Ischemic Stroke Presentation is Uncommon: A Population-Based Study of the Greater Cincinnati Northern Kentucky Stroke Study" May 15 at ESOC.

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• Open access
• Published: 10 May 2024

Effect of plateletcrit and methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on folic acid efficacy in stroke prevention

• Yuncong Shi 1   na1 ,
• Zhengzhipeng Zhang 1   na1 ,
• Binyan Wang 2 ,
• Yu Wang 3 ,
• Xiangyi Kong 4 ,
• Yong Sun 5 ,
• Aimin Li 5 ,
• Yimin Cui 6 ,
• Yan Zhang 7 ,
• Jianping Li 7 ,
• Yong Huo 7 &
• Hui Huang   ORCID: orcid.org/0000-0001-5716-4012 1  

Signal Transduction and Targeted Therapy volume  9 , Article number:  110 ( 2024 ) Cite this article

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• Prognostic markers

Previous studies have shown that low platelet count combined with high plasma total homocysteine (tHcy) increased stroke risk and can be lowered by 73% with folic acid. However, the combined role of other platelet activation parameters and the methylenetetrahydrofolate reductase ( MTHFR ) C677T genotypes on stroke risk and folic acid treatment benefit remain to be examined. This study aimed to investigate if platelet activation parameters and MTHFR genotypes jointly impact folic acid treatment efficacy in first stroke prevention. Data were derived from the China Stroke Primary Prevention Trial. This study includes a total of 11,185 adult hypertensive patients with relevant platelet activation parameters and MTHFR genotype data. When simultaneously considering both platelet activation parameters (plateletcrit, platelet count, mean platelet volume, platelet distribution width) and MTHFR genotypes, patients with both low plateletcrit (Q1) and the TT genotype had the highest stroke incidence rate (5.6%) in the enalapril group. This subgroup significantly benefited from folic acid treatment, with a 66% reduction in first stroke (HR: 0.34; 95% CI: 0.14–0.82; p  = 0.016). Consistently, the subgroup with low plateletcrit (Q1) and the CC/CT genotype also benefited from folic acid treatment (HR: 0.40; 95% CI: 0.23–0.70; p  = 0.001). In Chinese hypertensive adults, low plateletcrit can identify those who may greatly benefit from folic acid treatment, in particular, those with the TT genotype, a subpopulation known to have the highest stroke risk.

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Introduction.

About 50% of cardiovascular and cerebrovascular disease deaths are closely related to hypertension, which is one of the major culprit for death. 1 Stroke is the most common cardiovascular event in hypertensive patients. Hyperhomocysteinemia is regarded as an important risk factor for increased stroke risk. A previous report revealed that folic acid can reduce the 21% stroke risk in Chinese hypertensive patients, mainly through reducing total homocysteine (tHcy). 2 At present, clinical guidelines suggest that folic acid can decrease serum tHcy to a certain extent and reduce the risk of stroke. 3 However, not all hypertensive patients with elevated tHcy will benefit from folic acid supplementation. Methylenetetrahydrofolate reductase ( MTHFR ) is a folic acid metabolism crucial factor. There is a single nucleotide gene polymorphism C677T in the MTHFR coding gene and mutations in this enzyme lead to decreased activity and heat resistance, resulting in increased tHcy levels. 4 Carriers of the MTHFR C677T gene mutation are not sensitive to folic acid treatment due to folate utilization disorder. Huang et al. showed that hypertensive patients with the MTHFR C677T gene mutation caused an increased incidence of stroke due to folic acid metabolism disorder, however they did not benefit from folic acid treatment. 5 The proportion of TT homozygous genotype population in Europe and the United States is about 11.1 to 32.2%. 6 , 7 The distribution of the MTHFR 677 CC, CT and TT genotype in a European population was reported by Spence et al. as 40.4%, 46.6% and 13%, respectively. 8 The prevalence of the Chinese hypertensive MTHFR 677 TT genotype adults is much larger than other countries. In China, there are 300 million people with hypertension and of those, about 17.9 to 25% had MTHFR 677 TT genotype, that is, there are about 53.7 to 75 million hypertensive people with MTHFR 677 TT genotype. 9 , 10 A meta-analysis in the Lancet showed that the MTHFR 677 TT genotype compared with CC homozygotes increased the risk of stroke in Western populations without cardiovascular disease by 26%. 11 Therefore, identifying an effective biomarker among MTHFR 677 TT genotype to guide folic acid treatment is important for reducing first stroke risk.

Previous studies have found that elevated tHcy can increase the production of thrombin by platelets, thereby affecting platelet aggregation and the activity of coagulation factors, accelerating platelet activation, promoting coagulation and inhibiting anticoagulation, thus increasing the risk of stroke. 12 Platelet activation and aggregation promote the platelet vasoactive factors production, resulting in vascular endothelial cell injury and decreased vascular elasticity. 13 It has been reported that platelet activation may be a crucial intermediate link by which hyperhomocysteinemia promotes stroke progression. However, folic acid treatment can reduce platelet activation levels. This suggests that the assessment of folic acid in the treatment of stroke based on platelet activation status may have important value. 14 , 15 Studies have reported that folic acid treatment can increase tetrahydrobiopterin levels, participate in the synthesis of nitric oxide in the body, decrease superoxide anion levels, improve endothelial function, maintain the elasticity and patency of vessels, and thus reduce the risk of thrombosis. 16 Kong et al. 17 found that folic acid treatment reduced the 73% stroke risk in a subgroup with low platelet count (PLT) and high tHcy among Chinese hypertensive adults. 17 Platelet activation parameters may best reflect the folic acid clinical efficacy. Nevertheless, the effect of other platelet activation parameters on the prevention of first stroke risk with folic acid treatment is unclear. A recent study identified plateletcrit (PCT) is a early-warning index for stroke. 18 The rise in blood pressure accelerates platelet aggregation, resulting in enhanced platelet consumption and decreased PCT. 19 , 20 , 21 Platelet volume related activation parameters are a series of simple and easy to measure indicators, which reflect the level of platelet activation through the platelet morphology and structure changes. In vitro studies have shown that the hypertension increases the stress on the blood vessel wall, causing mechanical damage that destroys the integrity of blood vessel endothelial cells and promotes platelet activation. 22 , 23 Increased platelet activation leaded to massive platelet depletion. With time, the hematopoietic function of bone marrow underwent compensatory proliferation and accelerated megakaryocyte to product more small platelets. 19 , 20 , 21 The newly generated platelets had particularly active features in terms of metabolism and enzymes, and their dense particles increase the production of thromboxane A2 and B2, thereby accelerating thrombosis. 24

Folic acid treatment to reduce tHcy level and platelet activation while taking into account MTHFR C677T genotypes polymorphism is an important strategy for prevention and control of stroke in China, and it is also the most economical and effective method to curb the high incidence of stroke. At present, the combined effect and clinical significance of platelet activation parameters and MTHFR C677T genotypes in folic acid treatment for stroke risk prevention remain to be systematically studied. Therefore, this study aimed to identify the subpopulations who could benefit most from folic acid treatment in reducing the first stroke risk through simultaneous consideration of MTHFR C677T genotypes and platelet activation parameters in hypertensive patients.

Supplementary Fig. 1 showed the study flow chart. Since platelet parameters’ baseline measurements were only obtained at the Lianyungang study center of the Chinese Stroke Primary Prevention Study (CSPPT), our analysis was limited to the 15,486 participants from this center. Participants with missing data on platelet parameters or tHcy, or those on antiplatelet drugs at the trial entry were also excluded from the study. There were 11,185 patients in the study, of whom 5602 were treated with enalapril-folic acid and 5583 were only treated with enalapril. The median time of study was 4.2 years, and 385 patients occurred first strokes.

Baseline characteristics of study participants by MTHFR C677T genotype

As shown in Table 1 , participant baseline characteristics are presented according to MTHFR C677T genotype: normal (CC/CT) and mutant (TT). With the exception of blood glucose, tHcy, folic acid, and platelet distribution width (PDW), other baseline characteristics were not significantly different in patients with MTHFR 677 CC/CT and TT genotypes. There were significant differences in PDW in the MTHFR 677 CC/CT genotype group and in creatinine in the MTHFR 677 TT genotype group between the enalapril and enalapril-folic acid treatment groups. All other baseline characteristics were not significantly different between the treatment groups (enalapril and enalapril-folic acid). In addition, when baseline characteristics were presented according to PCT quartiles (PCT Q1–Q4), with the exception of fasting glucose in PCT (Q1), creatinine, mean platelet volume (MPV) and PDW in PCT (Q3), and tHcy in PCT(Q4), there were no significant differences in any other baseline characteristics between the enalapril-folic acid and enalapril groups in each PCT quartile (Supplementary Table 1 ).

First stroke risk in different platelet activation parameters and MTHFR C677T genotype subgroups

Patients with MTHFR 677 CC/CT genotype who received folic acid treatment to prevent stroke occurrence had a better response. However, patients with MTHFR 677 TT genotype who received folic acid treatment to prevent the first stroke risk were less effective (Supplementary Fig. 2 ). Although elevated tHcy is an important risk factor for stroke in populations with MTHFR 677 CC/CT genotypes, our analyses found that tHcy level is not an useful indicator for the benefits of folic acid treatment in MTHFR 677 TT genotype population (Supplementary Table 2 ). Furthermore, we investigated the effect of platelet activation parameters on the prevention of first stroke in patients with MTHFR C677T genotype who received or did not receive folic acid treatment. Figure 1 and Supplementary Fig. 3 show a non-linear relationship between platelet activation parameters and first stroke and ischemic stroke risk stratified by the MTHFR C677T genotype among the two treatment groups. In the enalapril group, the hazard ratios of stroke and ischemic stroke were higher with lower PCT and PLT (Fig. 1 and Supplementary Fig. 3 a, c). In the enalapril folic acid group, the stroke and ischemic stroke risk showed a significant reduction among participants with lower PCT and PLT, especially those with the TT genotype, suggesting that folic acid treatment is more beneficial for patients with lower PCT or PLT and the TT genotype (Fig. 1 and Supplementary Fig. 3 b, d). However, there were no apparent stroke and ischemic stroke risk reduction in relation to decreasing MPV and PDW in either the enalapril group (Fig. 1 and Supplementary Fig. 3 e, g) or the enalapril folic acid group (Fig. 1 and Supplementary Fig. 3 f, h).

Smoothing plots of platelet activation parameters and first stroke risk by MTHFR C677T genotypes among the enalapril group ( a , c , e , g ) and the enalapril-folic acid group ( b , d , f , h ). a , c , e , g Smoothing plots of plateletcrit, platelet count, mean platelet volume, platelet distribution width and first stroke risk stratified by the MTHFR C677T genotypes (CC/CT vs. TT) among the enalapril group. b , d , f , h Smoothing plots of plateletcrit, platelet count, mean platelet volume, platelet distribution width and first stroke risk stratified by the MTHFR C677T genotypes (CC/CT vs. TT) among the enalapril-folic acid group

MTHFR C677T genotypes and PCT on the effect of folic acid treatment in prevention of first stroke

Table 2 and Supplementary Table 3 further quantify the effect of the platelet activation parameters PCT, PLT, MPV, and PDW on folic acid treatment to reduce stroke risk based on MTHFR C677T genotype stratification. In patients with MTHFR 677 TT genotype, folic acid treatment had no significant benefit in preventing the first stroke occurrence (HR: 0.87; 95% CI: 0.61–1.24; p  = 0.442) (Table 2 ). folic acid treatment among patients with the MTHFR 677 TT genotype showed no benefit in reducing the risk of first stroke. However, when further assessed on the basis of PCT quartile stratification, the subgroup with low PCT (Q1) and the MTHFR 677 TT genotype had the highest stroke and ischemic stroke incidence rate (5.6 and 5.1%). With folic acid treatment, the first stroke and ischemic stroke hazard ratio in the highest risk group [low PCT(Q1) and TT genotype] was reduced by 66% (HR: 0.34; 95% CI: 0.14–0.82; p  = 0.016) and 67% (HR: 0.33; 95% CI: 0.13–0.83; p  = 0.019). In the highest risk group, folic acid treatment showed significantly the best effect on decreasing the risk of first stroke (NNT = 27). Tests of interaction between PCT (Q1 vs. Q2–Q4) and MTHFR 677 TT genotype subgroup and folic acid treatment on first stroke ( p  = 0.021) and ischemic stroke ( p  = 0.018) were statistically significant. Furthermore, Table 2 also shows that patients with low PCT (Q1) and normal MTHFR 677 genotype (CC/CT) subgroups receiving folic acid reduced 60% (HR: 0.40; 95% CI: 0.23–0.70; p  = 0.001) and 70% (HR: 0.30; 95% CI: 0.16–0.57; p  < 0.001) stroke and ischemic stroke risk during the trial period, respectively. Tests of interaction effect between the low PCT(Q1) and the MTHFR 677 normal genotype (CC/CT) subgroup and folic acid treatment on first stroke ( p  = 0.023) and ischemic stroke ( p  = 0.005) were statistically significant. However, the risk reduction was not statistically significant for any of the other subgroups. Supplementary Table 3 shows that the PLT quartile was not able to screen out the MTHFR 677 TT genotype subgroup in which folic acid treatment significantly decreased stroke risk. In the low PLT (Q1) and normal MTHFR 677 genotype (CC/CT) subgroups, folic acid treatment decreased in a 59% (HR: 0.41; 95% CI: 0.23–0.72; p  = 0.002) and 65% (HR: 0.35; 95% CI: 0.18–0.66; p  = 0.001) risk of first stroke and ischemic stroke. In contrast, the risk reduction was not statistically significant for any of the other subgroups. Folic acid treatment in the MPV(Q2) and the MTHFR 677 CC/CT genotype subgroup reduced stroke risk by 43% (HR: 0.57; 95% CI: 0.36–0.91; p  = 0.019), but the other subgroups were not significant. Folic acid treatment in the MPV(Q1–2) and the MTHFR 677 CC/CT genotype subgroup reduced ischemic stroke risk by 44% (HR: 0.56; 95% CI: 0.33–0.95; p  = 0.032) and 49% (HR: 0.51; 95% CI: 0.30–0.85; p  = 0.010), but the other subgroups were not significant. In the subgroup with PDW (Q2) and the MTHFR 677 TT genotype, folic acid treatment had a 2.31-fold increased risk of stroke (HR: 2.31; 95% CI: 1.06–5.04; p  = 0.035), while folic acid treatment within the PDW (Q4) and the MTHFR 677 TT genotype subgroup reduced stroke risk by 59% (HR: 0.41; 95% CI: 0.20–0.85; p  = 0.016). Folic acid treatment within the PDW (Q4) and the MTHFR 677 TT genotype subgroup reduced ischemic stroke risk by 53% (HR: 0.47; 95% CI: 0.23–0.98; p  = 0.043). Nevertheless, the other subgroups were not significant. These results suggest that among platelet activation parameters, PCT is the best biomarker for identifying those hypertension patients with the TT genotype who may benefit the most from folic acid treatment.

In this study, for the first time, we evaluated the protective effect of folic acid treatment on stroke by simultaneous consideration of MTHFR C677T genotypes and all platelet activation parameters in hypertensive patients, which has never been reported before. This study revealed two main findings. First, we evaluated the platelet activation parameters PCT, PLT, MPV, and PDW as indicative function of folic acid treatment among the MTHFR C677T genotypes patients. Our analysis showed that PCT may be better for evaluating the effect of folic acid treatment on reducing the risk of first stroke in hypertensive patients with MTHFR C677T genotype, especially those with the TT genotype. Second, we found that among those without folic acid treatment, patients with both low PCT (Q1) and MTHFR 677 TT genotype had the highest stroke incidence rate (5.6%). Low PCT (Q1) and MTHFR 677 TT genotype highest risk subgroup received folic acid treatment which benefited the most. Low PCT (Q1) can also be used to screen the benefit of folic acid treatment to reduce the first stroke risk in patients with MTHFR 677 CC/CT genotypes. Taken together, PCT can be regarded as a significant biomarker to identify those who would greatly benefit from folic acid treatment, especially for MTHFR 677 TT genotype patients, a subgroup known to have the highest stroke risk (Fig. 2 ).

Among the MTHFR 677 TT genotype population, total homocysteine metabolism dysfunction causes vascular endothelial injury, accelerates platelet aggregation and activation, thus leading to a large consumption of platelets and a decrease in plateletcrit, which ultimately promotes thrombosis and stroke. Folic acid treatment can prevent endothelial damage, reduce total homocysteine levels and the first stroke risk in the TT genotype populations. This figure was created with the aid of Biorender ( https://biorender.com/ )

The MTHFR 677 TT genotype frequency in the Chinese populations is higher than that in other populations; the other ethnicities populations’ MTHFR 677 TT genotype frequency is 10 to 12%, but it is as high as 25% in the Chinese hypertensive population. 25 , 26 As an important rate-limiting enzyme in tHcy and folate metabolism, individuals carrying the MTHFR 677 TT genotype have a 70% reduction in activity, which decreases the ability of tHcy to remethylate to methionine, resulting in a disturbance of the folic acid metabolic cycle and folic acid deficiency, as well as hyperhomocysteinemia. 7 These metabolic and physiological changes can greatly increase stroke occurrence. In this study, we found that patients with the MTHFR 677 TT genotype had a higher risk of first stroke compared to patients with the MTHFR 677 CC/CT genotype. In addition, folic acid utilization efficiency was decreased in the MTHFR 677 TT genotype patients. Therefore, it is particularly important to find an effective test for hypertension patients with MTHFR 677 TT genotype to identify those who benefit from folic acid in order to better prevent stroke.

Hyperhomocysteinemia is deemed as a crucial risk factor for stroke. The 2021 American Guidelines for the Secondary Prevention of Stroke state that folic acid treatment can decrease the incidence of stroke. 13 While folic acid contribute to decrease tHcy, its effectiveness, however, may differ depending on the MTHFR C677T genotype. Huo et al. 2 showed that even though tHcy levels in TT genotype hypertensive patients were significantly higher than those in CC/CT genotype hypertensive patients. Although elevated tHcy is an important risk factor for stroke in populations with CC/CT genotypes. Our analysis found that tHcy level did not contribute to additional information in screening the benefits of folic acid treatment in MTHFR 677 TT genotype population. None of the quartiles of tHcy levels showed any response to folic acid treatment within the TT genotype group. The use of simple and universal indicators and methods in clinical treatment to find these more beneficial groups will help popularize precision targeted therapy efficiently. At the same time, it also provides useful enlightenment for deepening the targeted therapy mechanism and biological path scientific exploration.

As the most common cerebrovascular disease, the pathological process of stroke is closely related to thrombosis and platelet activation. Studies have reported that population with activated platelets have a higher risk of stroke, as platelet activation is closely related to the stroke pathophysiological mechanism. 27 , 28 , 29 Endothelial dysfunction and platelet activation are important mediators of thrombosis in atherosclerosis. Hypertension give rise to vascular endothelial injury through shear stress, triggering coagulation and fibrinolysis systems. 30 Activated platelets recruited monocytes to the walls of blood vessels and then evolved into macrophages, promoting the atherosclerosis. 31 When active atherosclerotic plaques rupture, circulating platelets are exposed to subcutaneous collagen, fibronectin, and von Willebrand factor, stimulating platelet activation and eventually thrombosis. 32 Platelet activation is also affected by tHcy. In the case of hyperhomocysteinemia, increased hydrogen sulfide in platelets triggered the arachidonic acid cascade pathway, promoting increased TXA2 production and leading to changes in platelet volume and capacity. 33 Elevated tHcy is associated with increased platelet activity, manifested by increased secretion of soluble CD40L and β-thromboglobulin after microvascular injury. 14 tHcy promotes thrombosis by activating platelets and the clotting pathway. 34 Therefore, the process of platelet activation and thrombosis may partially mediate the effect of hyperhomocysteinemia on stroke progression.

Folic acid can inhibit ERK1/2/NOX4/ROS pathway to reduce peroxide production, enhance antioxidant enzyme activity to attenuate oxidative stress and inflammation, and thus play a protective role on stroke. 35 More importantly, folic acid may alleviate thromboxane A2 release and clotting factor expression by decreasing tHcy, thereby reducing platelet activation and thrombosis, and ultimately preventing stroke. Undas et al. 14 had found that elevation of tHcy may accelerate platelet activation induced by vascular injury, while folic acid treatment can eliminate platelet hyperreactivity. 14 Previous studies have also reported that combining PLT with serum tHcy levels can significantly improve the indicator power of the folic acid on stroke prevention. 17 Based on this evidence, we speculate that platelet activation parameters such as PCT may indirectly reflect endothelial injury and the benefit of folic acid treatment. Hypertensive patients with low PCT may already have endothelial cell damage, resulting in reduced platelet consumption, so this group of population at higher risk of stroke. Folic acid treatment is particularly important.

In this study, we found that PCT was superior to other platelet activation parameters for assessing those who may benefit most from folic acid treatment, especially for patients with the MTHFR 677 TT genotype who are at the highest stroke risk. This finding has the potential to guide the clinical management of patients with the MTHFR C677T genotype, but further prospective studies will be needed to confirm this finding.

This study has the following strengths: first, our study used the largest data from the folic acid intervention in stroke primary prevention trial (CSPPT). This study is strengthened by its large sample size, derived from a high-quality randomized folic acid clinical trial that for the first time incorporated MTHFR C677T genotypes in the randomization. 2 We comprehensively analyzed the prospective association between platelet activation parameters (PCT, PLT, MPV, and PDW) and the first stroke risk in patients with MTHFR C677T genotype, and determined that PCT assessment was the most useful. Second, the study population consisted of Chinese adults with hypertension, with a higher prevalence of TT genotypes compared to Western populations (25% in China compared to 10 to 12% in America). 7 , 9 Third, our study is the first to evaluate folic acid benefit situation on stroke prevention by performing a comprehensive analysis of platelet activation parameters and the MTHFR C677T genotype. Our finding that patients in the subgroup of low PCT and with the TT genotype benefited the most from folic acid treatment. Despite its many advantages, there are still some limitations in this study. First, our current study only analyzed baseline levels of platelet activation parameters. The dynamic changes of platelet activation parameters in patients during follow-up will also need to be monitored in the future. Second, 0.8 mg/day of folic acid was selected for this study, therefore, we were unable to assess whether higher doses of folic acid would benefit more patients with different MTHFR C677T genotypes and tHcy levels. In the end, this is a post hoc study, our study findings might not be generalizable to whole China and could be perceived as hypotheses-generating, further extensive research would be needed.

Conclusions

In this study, we found that low PCT can further help identify who would greatly benefit from folic acid treatment to reduce the first stroke risk, particularly in hypertensive patients with the TT genotype who are at the highest risk of stroke. Therefore, PCT has the potential to be a biomarker for evaluating folic acid efficacy in hypertensive patients with the MTHFR 677 TT genotype.

Materials and methods

All participants in this study were from the China Stroke Primary Prevention Trial (CSPPT) (NCT00794885). Our paper follows the practice of the Journal of the American Heart Association in implementing transparency and openness promotion guidelines. The CSPPT was approved by the Ethics Committee of the Institute of Biomedical Research of Anhui Medical University in Hefei, China. (FWA assurance number FWA00001263). All participants signed a written, informed consent.

In short, CSPPT was a multi-community, randomized, double-blind, controlled trial. The study was conducted at 32 community research centers in Jiangsu and Anhui provinces of China from May 19, 2008 to August 24, 2013. Eligible participants’ inclusion criteria included: (1) Age 45–75 years old; (2) Sitting blood pressure criteria were met at both screening visits and enrollment visits (at least 24 h apart) : seated, resting systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg, or currently receiving antihypertensive medications. The main exclusion criteria included: (1) Previous history of stroke; (2) History of myocardial infarction; (3) Patients with confirmed secondary hypertension; (4) suffering from congenital or acquired organic heart disease; (5) Previous history of heart failure; (6) suffering from serious systemic physical diseases, unable to cooperate with the completion of the interview.

Eligible participants were first stratified by the MTHFR C677T genotype (CC, CT, or TT), and then were randomly assigned in a 1:1 ratio within each genotype group to receive one of two oral treatments daily: one tablet of 10 mg enalapril and 0.8 mg folic acid, or one tablet of 10 mg enalapril. During the trial, concurrent use of other antihypertensive drugs (mainly calcium channel blockers or diuretics) was allowed, but B vitamins were not allowed. Participants were scheduled for follow-up every 3 months.

Laboratory evaluation

Venous blood samples were collected from all participants after fasting for more than 10 h. Laboratory testing was conducted at the National Clinical Research Center for Kidney Diseases laboratory (Nanfang Hospital, Guangzhou, China). 2 BC-3200 hematology analyzer (Mindray Medical, Shenzhen, China) measured a complete baseline blood cell count, including PCT, PLT, mean platelet volume (MPV) and platelet distribution width (PDW). Fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, tHcy, creatinine and MTHFR C677T genotypes were obtained by a fully automated clinical analyzer (Beckman Coulter, Brea, California) and an ABI Prism 7900HT sequence detection system (Life Technologies, Carlsbad, California). Serum folic acid was measured through using a chemiluminescent immunoassay in the commercial laboratory (New Industry, Shenzhen, China).

The primary outcome event of this study was symptomatic stroke (including ischemic stroke, hemorrhagic stroke and stroke with uncertain subtype, but excluding subarachnoid hemorrhage and silent stroke) that occurred for the first time during entry into randomized treatment. 2 The experts of the outcome event adjudication board judge the occurrence of the outcome event. 2

Covariables

The adjusted model in this study mainly adjusts the following variables: age, sex, smoking status, body mass index, baseline systolic and diastolic blood pressure, total cholesterol, triglycerides, and HDL-C, tHcy, glucose, creatinine. These covariates were selected on the basis of the original CSPPT study results, and details on the definitions of each covariable have been previously reported. 2

Statistical analysis

According to MTHFR C677T genotype grouping, continuous variables and categorical variables data in this study, we used mean ± SD and frequency (%) to represent, respectively. Kaplan–Meier curves (log-rank test) were used to evaluate the benefit of first stroke in MTHFR C677T genotype patients receiving folic acid treatment. We used a Cox proportional hazard model of unadjusted and adjusted for correlated variables to estimate the hazard ratio and 95% confidence interval for stroke occurrence in folic acid treatment subgroups defined by the MTHFR C677T genotype combined with tHcy levels or platelet activation parameters, and tested their interactions. A receiver operating curve of platelet activation parameters and stroke risk was plotted for those in the enalapril folic acid group, as well as a restricted cubic spline curve based on a multifactor Cox regression model. p  < 0.05 was considered statistically significant. In this study, R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria) and Empower (X&Y Solutions, Inc. Boston, Massachusetts) were used for data analysis.

Data availability

All data supporting this paper are presented in the text and Supplementary Materials. The original data sets are also available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank the investigators of the China Stroke Primary Prevention Trial and all the study participants who made possible for this study. This work was supported by the National Nature Science Foundation of China (82330021, 82061160372, 82270771), the National Key Research and Development Program (2020YFC2004405), the Shenzhen Key Laboratory of Precision Prevention and Control of Major Chronic Diseases and Metabolic Research (ZDSYS20220606100801004), the Central Military Commission Key Project of Basic Research for Application (BWJ21J003), the Regional Joint Funding Key Project of Guangdong Basic Research and Basic Research for Application (2021B1515120083), the Key Project of Sustainable Development Science and Technology of Shenzhen Science and Technology Innovation Committee (KCXFZ20211020163801002), Shenzhen Science and Technology Program (ZDSYS20220606100801004, SGDX20230116092459009), Shenzhen Medical Research Fund (B2302020), and Shenzhen Key Medical Discipline Construction Fund (SZXK002), the Sun Yat-sen University-Shenzhen TAILORED Medical Ltd. Postgraduate joint training base, the Futian District Public Health Scientific Research Project of Shenzhen (FTWS2022001), Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, the Chinese Association of Integrative Medicine-Shanghai Hutchison Pharmaceuticals Fund (HMPE202202), China Heart House-Chinese Cardiovascular Association HX fund (2022-CCA-HX-090) and the Shenzhen Key Medical Discipline Construction Fund (SZXK002) to H.H. Shenzhen Medical Research Fund (A2302013) to Zhengzhipeng Zhang. The fifth “333” high-level talent training project of Jiangsu Province (BRA2019247). Medical Research Project of Jiangsu Provincial Health Commission in 2020 (ZDA2020018).

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These authors contributed equally: Yuncong Shi, Zhengzhipeng Zhang

Authors and Affiliations

Cardiovascular Department, The Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China

Yuncong Shi, Zhengzhipeng Zhang & Hui Huang

Shenzhen Evergreen Medical Institute, Shenzhen, China

Binyan Wang

Shenzhen Tailored Medical Laboratory, Shenzhen, China

Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

Xiangyi Kong

Department of Neurosurgery, The First Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, China

Yong Sun & Aimin Li

Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China

Department of Cardiology, Peking University First Hospital, Beijing, China

Yan Zhang, Jianping Li & Yong Huo

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Contributions

H.H., Y.C.S. and Z.Z. designed the clinical trial protocol. Y.Z., J.L. and Y.H. finished the investigations, including recruit patients and data collection. B.W., Y.W. and X.K. designed and drawed figures and tables. B.W., Y.S., A.L., Y.C. and Z.Z. accomplished data statistical analysis and re-check. Y.C.S., Z.Z. and B.W. wrote the manuscript. All authors have read and approved the manuscript. All authors contributed to the critical review and final approval of the manuscript. H.H. is guarantor of this work and responsible for data integrity and accuracy of data analysis.

Corresponding author

Correspondence to Hui Huang .

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The authors declare no competing interests.

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Shi, Y., Zhang, Z., Wang, B. et al. Effect of plateletcrit and methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on folic acid efficacy in stroke prevention. Sig Transduct Target Ther 9 , 110 (2024). https://doi.org/10.1038/s41392-024-01817-0

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Received : 30 October 2023

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Accepted : 25 March 2024

Published : 10 May 2024

DOI : https://doi.org/10.1038/s41392-024-01817-0

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UC study: Severe ischemic strokes rare in total patient population

Uc researcher presents findings at european stroke organisation conference.

A new University of Cincinnati study provides more insight into how few patients have severe ischemic strokes compared to the total stroke patient population in the region.

Yasmin Aziz, MD. Photo/University of Cincinnati.

UC’s Yasmin Aziz, MD, will present a poster on the team’s findings during the European Stroke Organisation Conference (ESOC) this week in Basel, Switzerland.

Ischemic strokes, the most common form of strokes, are caused by a lack of blood flow and oxygen to specific parts of the brain. When a stroke patient arrives at the hospital, Aziz explained, they undergo a CT scan that can help doctors assess the severity of the damage the stroke has caused using a 10-point scale.

“Low scores indicate bigger strokes, while higher scores indicate smaller ones,” said Aziz, assistant professor in the Department of Neurology and Rehabilitation Medicine in UC’s College of Medicine and a neurologist at the UC Gardner Neuroscience Institute. “Much of our early treatment options and long-term prognosis depend on this simple score, as strokes due to blood clots can grow without intervention.”

Aziz said this study asked a simple question: How many patients in the region arrive at the hospital with low scores?  

Using data from the ongoing Greater Cincinnati/Northern Kentucky Stroke Study, the team found nearly 90% of all patients who arrive at the hospital within 24 hours of symptom onset have minimal ischemic damage on their CT scans, or scores of 9-10 on the scale.

When narrowing down the data to the most severe type of stroke caused by blood clots in the brain, the team found around 14% of these patients have the most severe damage, or scores of 0-2 on the scale.

Our results show the rarity of these severe strokes in a real-world population, rather than in a strictly controlled clinical trial setting.

Yasmin Aziz, MD

“Patients with low scores due to large strokes require considerable resources from the health care system in order to facilitate their care,” Aziz said. “A lot of research in the last two years has been dedicated to determining if we can treat patients with really low scores. Our results show the rarity of these severe strokes in a real-world population, rather than in a strictly controlled clinical trial setting.”

Aziz said she was not surprised by the results, as the data on the occurrence of patients with low scores lined up with prior estimates.

“Thankfully, the majority of strokes are not due to large vessel occlusion, or due to blood clots in vessels supplying large areas of the brain,” she said.

A recent series of clinical trials has shown benefit to blood clot removal for patients with severe strokes, and the research community is working to adjust to this paradigm shift, Aziz said. The study’s data on how common these strokes occur is part of a larger puzzle to optimize research and patient care for all patients, she said.

This study is one of the first publications to come out of the Assessing Population-based Radiological brain health in Stroke Epidemiology (APRISE) study, an offshoot of the Cincinnati-area stroke study that adds a neuroimaging component to the data collection and research.

“Our team, comprised of internationally renowned experts in stroke epidemiology, radiology and acute stroke treatment, is extremely excited to utilize APRISE to provide the highest quality research to our field,” Aziz said. “We are deeply thankful to the community for their participation in this research, which will be shared with experts from all around the world at ESOC. Together, we hope to push the boundaries of treatment for stroke patients.” 

Impact Lives Here

The University of Cincinnati is leading public urban universities into a new era of innovation and impact. Our faculty, staff and students are saving lives, changing outcomes and bending the future in our city's direction.  Next Lives Here.

Aziz will present “Early Ischemic Change at Late Ischemic Stroke Presentation is Uncommon: A Population-Based Study of the Greater Cincinnati Northern Kentucky Stroke Study” May 15 at ESOC. 

Other UC involvement at ESOC includes:

• Joseph Broderick, MD, presenting “Optimal blood pressure control for secondary stroke prevention” May 16.
• Pooja Khatri, MD, presenting “Adjunct thrombolytic therapies preventing reocclusion” May 17.

Featured photo at top of illustration of brain with stroke symptoms. Photo/PeterSchreiber.media/iStock.

• Faculty Staff
• College of Medicine
• UC Gardner Neuroscience Institute
• Academic Health Center
• Neurology & Rehabilitation Medicine

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ORIGINAL RESEARCH article

Comparison of two automated ct perfusion software packages in patients with ischemic stroke presenting within 24 h of onset.

• 1 Department of Neurology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
• 2 Artificial Intelligence Research Center, JLK Inc., Seoul, Republic of Korea
• 3 Department of Radiology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
• 4 Department of Neurology, Seongnam Citizens Medical Center, Seongnam, Republic of Korea

Background: We compared the ischemic core and hypoperfused tissue volumes estimated by RAPID and JLK-CTP, a newly developed automated computed tomography perfusion (CTP) analysis package. We also assessed agreement between ischemic core volumes by two software packages against early follow-up infarct volumes on diffusion-weighted images (DWI).

Methods: This retrospective study analyzed 327 patients admitted to a single stroke center in Korea from January 2021 to May 2023, who underwent CTP scans within 24 h of onset. The concordance correlation coefficient ( ρ ) and Bland–Altman plots were utilized to compare the volumes of ischemic core and hypoperfused tissue volumes between the software packages. Agreement with early (within 3 h from CTP) follow-up infarct volumes on diffusion-weighted imaging ( n  = 217) was also evaluated.

Results: The mean age was 70.7 ± 13.0 and 137 (41.9%) were female. Ischemic core volumes by JLK-CTP and RAPID at the threshold of relative cerebral blood flow (rCBF) < 30% showed excellent agreement ( ρ  = 0.958 [95% CI, 0.949 to 0.966]). Excellent agreement was also observed for time to a maximum of the residue function ( T max ) > 6 s between JLK-CTP and RAPID ( ρ  = 0.835 [95% CI, 0.806 to 0.863]). Although early follow-up infarct volume showed substantial agreement in both packages (JLK-CTP, ρ  = 0.751 and RAPID, ρ  = 0.632), ischemic core volumes at the threshold of rCBF <30% tended to overestimate ischemic core volumes.

Conclusion: JLK-CTP and RAPID demonstrated remarkable concordance in estimating the volumes of the ischemic core and hypoperfused area based on CTP within 24 h from onset.

Introduction

In the rapidly evolving field of neuroimaging, the analysis of computed tomography perfusion (CTP) scans has become a cornerstone in the diagnosis and management of acute ischemic stroke ( Abdalkader et al., 2023 ). CTP scans have played a major role in expanding the time window for endovascular treatment (EVT) in patients with ischemic stroke ( Albers et al., 2018 ; Jovin et al., 2018 ). Using perfusion scans, clinical trials that compare EVT with medical treatment for patients with anterior circulation large vessel occlusion beyond 6 h have shown the clinical benefit of EVT in the extended time window ( Albers et al., 2018 ; Jovin et al., 2018 ). Furthermore, our group has demonstrated that even beyond 24 h, selected individuals identified through perfusion imaging can benefit from EVT ( Kim et al., 2020 ). In this context, it is of the utmost importance to precisely quantify the perfusion parameters to make an informed decision for acute ischemic stroke patients ( Sarraj et al., 2020 ).

To streamline the analysis of perfusion and minimize variations among different observers, various commercial CTP software solutions have been introduced ( Lim et al., 2023 ). These solutions automatically identify the ischemic core and penumbral regions. Nonetheless, there has been considerable inconsistency in the parameters of CTP and the quantitative benchmarks set for delineating the ischemic core and penumbra ( Yedavalli et al., 2023 ). Gradually, relative CBF (rCBF) has emerged as the preferred metric for determining the ischemic core ( Ballout et al., 2023 ). A threshold for the time to peak of the residue function ( T max ) exceeding 6 s has been identified as a reliable predictor for tissues at risk of infarction if there is no reperfusion ( Fainardi et al., 2022 ). However, the extent to which different software solutions can be used interchangeably, especially in terms of their clinical significance for planning treatment and estimating prognosis, remains uncertain. Previous research has indicated significant discrepancies in the calculated volumes of the ischemic core across different software, leading to inconsistent predictions of final infarct volume after EVT ( Koopman et al., 2019 ; Yedavalli et al., 2023 ).

Previous research has shown that the epidemiology of stroke, encompassing its frequency, contributing factors, and death rates, differs markedly across ethnic groups ( Venketasubramanian et al., 2017 ; Kim et al., 2018 ; Kang et al., 2024 ). For example, in comparison to North Americans and Europeans, the incidence of intracranial arterial disease is comparatively higher among Asians and Black individuals ( Kim et al., 2018 ). One may postulate that ischemic core thresholds derived from studies on Caucasian populations may lead to an overestimation of ischemic core volumes in Asian patients due to the pre-stroke development of leptomeningeal collaterals after chronic intracranial stenosis ( Sacco et al., 1995 ; Qiao et al., 2017 ). Additionally, disparities in ischemic core volume may be influenced by various comorbidities, such as hypertension and diabetes, as well as delays in both seeking and receiving timely stroke treatment.

In this study, we compared the volumes of ischemic core and hypoperfused tissue volumes estimated by RAPID (iSchemaView Inc., Menlo Park, CA) and JLK-CTP (JLK Inc., Seoul, Korea). In addition, we aimed to evaluate the agreement of patient selection eligible for EVT between the two packages.

Materials and methods

Study design and study population.

In this retrospective study using prospectively collected data, we included patients who were admitted to Seoul National University Bundang Hospital between January 2021 and May 2023 and underwent CTP scans within 24 h of symptom onset. We excluded patients with (1) severe motion artifacts on CTP or poor contrast bolus arrival and (2) failed automated perfusion calculation by RAPID. A subset of patients, who had available follow-up diffusion-weighted images (DWI) taken within 3 h of the CTP, was used to compare the baseline ischemic core volumes predicted by the CTP with the early follow-up infarct volumes. The study protocol was approved by the institutional review board of Seoul National University Bundang hospital [IRB# B-1710-429-102], and patients or their legal representatives provided a written informed consent.

Clinical data collection

Using a standardized protocol ( Kim et al., 2015 ), we prospectively collected demographic data, prior medication history, and the presence of vascular risk factors including hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, atrial fibrillation, and smoking history. Stroke subtypes were determined by an experienced vascular neurologist, using a validated MRI-based classification system built on the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria ( Ko et al., 2014 ).

Imaging and image reconstruction

All CTP scans were performed using a 256-Slice CT scanner (Brilliance iCT 256, Philips Healthcare, Best, the Netherlands). The imaging parameters for CTP scans were as follows: 80 kVp, 150 mAs, Beam collimation 6 × 1.25 mm, rotation time 0.45 s. In the arterial phase scan, 30 cycles were captured every 2 s, resulting in a total duration of 60 s. Following a delay of 9 s, the delayed phase scan acquires 2 cycles at intervals of 10 s, amounting to a total duration of 20 s. A total of 50 mL of iodinated contrast agent (Iomeprol 400; Bracco Imaging, Milan, Italy) followed by 30 mL of saline flush was administered intravenously at a rate of 5 mL/s. The image matrix was 512 × 512 and the images were reconstructed with the slice thickness of 10 mm and the increment of 10 mm covering 8 cm in z -axis ( Biesbroek et al., 2013 ).

Automated software analyzing CTP

JLK-CTP is a fully automated CTP software package to visualize and quantify ischemic core and hypoperfused tissue, which relies on a block-circulant singular value decomposition method ( Kudo et al., 2010 ). We compared the volumes of ischemic core and hypoperfused tissue volumes estimated by RAPID and JLK-CTP, both of which are automated CTP analysis packages using a delay-insensitive algorithm. A default setting of rCBF <30% was used for defining the ischemic core. For assessing of hypoperfused tissue volume, we used the default setting of both packages ( T max  > 6 s). Both software packages carry out automated registration, segmentation, and motion correction, employing a delay-insensitive method, and conducting post-processing ( Figure 1 ). The RAPID software package has been routinely used for CTP in our hospital setting. Restored CTP source images were analyzed with the research version of JLK-CTP within the hospital for this study.

Figure 1 . A representative case employing JLK-CTP and RAPID. (A) Color map produced by RAPID, indicating an ischemic core volume (rCBF < 30%) of 10 mL and total hypoperfused tissue ( T max  > 6 s) of 168 mL. (B) Color map generated by JLK-CTP, showing an ischemic core volume (rCBF < 30%) of 8.8 mL and total hypoperfused tissue ( T max  > 6 s) of 159.1 mL. (C) Early follow-up DWI taken 110 min after CTP, following endovascular treatment with TICI 2a, reveals patchy areas of abnormally restricted diffusion in territories of the right middle cerebral artery (Top). RAPID DWI, based on the threshold of the apparent diffusion coefficient, estimated a total infarct volume of 3 mL (Middle). JLK-DWI, utilizing a deep learning algorithm, estimated a total infarct volume of 14.61 mL (Bottom). CTP, computed tomography perfusion; rCBF, relative cerebral blood flow; T max , time to maximum of the residue function; DWI, diffusion-weighted image.

Early follow-up infarct volume measurement

We collected DWI (3.0 Tesla, Ingenia CX, Phillips Medical Systems [ n  = 192] or MAGNETOM Vida, Siemens Healthcare system [ n  = 27]) taken within 3 h of the CTP scans. Areas of infarction were automatically segmented using a validated deep learning algorithm (JLK-DWI, JLK Inc., Seoul, Korea) ( Ryu et al., 2023 ). Automatically segmented infarct areas underwent visual inspection by a stroke neurologist (W-SR) and were manually corrected as necessary.

Statistical analysis

Data were presented as mean ± standard deviation, median (interquartile range [IQR]), and number (percentage), as appropriate. To compare the volumes of ischemic core and hypoperfused tissue using two software packages, we utilized the concordance correlation coefficient ( ρ ) with 95% confidence intervals (CIs) and further investigated the data using reduced major axis regression ( Lin, 1989 ). The magnitude of agreement was classified as follows: values from 0.0 to 0.2 indicating poor agreement; 0.21 to 0.40 indicating fair agreement; 0.41 to 0.60 indicating moderate agreement; 0.61 to 0.80 indicating substantial agreement; and 0.81 to 1.0 indicating excellent agreement. Additionally, Bland–Altman plots were used to assess the agreement of ischemic core volumes and hypoperfused areas as determined by the two packages. For the comparison between follow-up infarct volumes and ischemic core volumes analyzed by the two packages, both concordance correlation coefficients and Bland–Altman plots were employed. In the subgroup analysis, concordance correlation coefficients and Bland–Altman plots were utilized after stratifying patients by EVT and early infarct volume, arbitrarily divided at 20 mL. The agreement between ischemic core volume and follow-up infarct volume, categorized according to the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) clinical trial’s criteria ( Jovin et al., 2018 ), was assessed using Cohen’s kappa. A two-tailed p value of <0.05 was considered statistically significant. All statistical analyses were performed using STATA (version 16.0, StataCorp LP, College Station, TX).

Baseline characteristics of the study population

During the study period, a total of 2,544 patients were diagnosed with ischemic stroke, and 657 patients underwent a CTP scan. We excluded 315 patients who received CTP more than 24 h after their last known well and 15 patients who had severe motion artifacts or whose automated perfusion calculations failed using RAPID. Among the 327 patients included in the analysis, the mean age was 70.7 (SD 13.0), and 41.9% were women ( Table 1 ). The median of the initial National Institute of Health stroke scale score was 9 (IQR, 4 to 17). The most common stroke etiology was identified as cardioembolism. Of the 205 (62.7%) patients who received revascularization therapy, 83 (25.3%) underwent intravenous thrombolysis alone, 59 (18.0%) underwent EVT alone, and 63 (19.3%) received combined therapy. The median interval between the time last known well to CTP scan was 192 min (IQR, 101 to 395 min). The median interval between CTP and DWI was 41 min (IQR, 27 to 100 min).

Table 1 . Baseline characteristics.

Concordance correlation analysis of the volumes of ischemic core and hypoperfused tissue by RAPID vs. JLK-CTP

The mean difference between ischemic core volumes calculated by RAPID and JLK-CTP was −0.54 mL (95% CI, −1.72 to 0.64 mL; p  = 0.85). There was excellent agreement in between JLK-CTP and RAPID ( ρ  = 0.958 [95% CI, 0.949 to 0.966]; Figure 2A ). In the Bland–Altman plot, the limits of agreement were −20.74 and 21.83 mL ( Figure 2B ). We observed excellent agreement between JLK-CTP and RAPID ( ρ  = 0.942 [95% CI, 0.916 to 0.960]) with the mean difference of −0.94 mL (95% CI, −4.90 to 3.00 mL), when we restricted the analysis to patients whose ischemic core volume was not zero by both JLK-CTP and RAPID (n = 90; Supplementary Figure S1 ).

Figure 2 . Comparison of ischemic core volumes and hypoperfused tissue volumes by JLK-CTP and RAPID. (A) Scatter plot illustrating ischemic core volumes as determined by JLK-CTP and RAPID, with the slope and intercept of the reduced major axis being 1.097 and −2.067, respectively. (B) Bland–Altman plot for the analysis of agreement in ischemic core volumes. (C) Scatter plot illustrating hypoperfused tissue volumes as determined by JLK-CTP and RAPID, with the slope and intercept of the reduced major axis being 1.337 and −8.350, respectively. (D) Bland–Altman plot for the analysis of agreement in hypoperfused tissue volumes. The green dotted line represents the line of perfect concordance, while the blue line denotes the reduced major axis. For (B,D) , the blue solid line and the red dotted lines represent the mean difference and the limits of agreement between JLK-CTP and RAPID, respectively.

The mean difference between hypoperfused tissue volumes calculated by JLK-CTP and RAPID was 13.31 mL (95% CI, 8.22 to 18.39; p  = 0.06). There was excellent agreement between JLK-CTP and RAPID ( ρ  = 0.855 [95% CI, 0.828 to 0.877]; Figure 2C ). In the Bland–Altman plot, the limits of agreement were −78.22 and 104.83 mL ( Figure 2D ). When the analysis was confined to patients receiving EVT (n = 122), there was excellent agreement in ischemic core volumes and substantial agreement in hypoperfused tissue volumes between JLK-CTP and RAPID ( Supplementary Figure S2 ).

Comparison of ischemic core volumes calculated by software tools and follow-up infarct volumes on diffusion-weighted images

In patients with available early follow-up DWI (n = 218), there was substantial agreement between follow-up infarct volumes and ischemic core volumes as determined by JLK-CTP ( ρ  = 0.753 [95% CI, 0.699 to 0.800]; Figure 3A ) and RAPID ( ρ  = 0.736 [95% CI, 0.685 to 0.780]; Figure 3C ) at the default rCBF threshold of <30%. The limits of agreement for the volumes of the ischemic core and the follow-up infarct volume were comparable between the two packages ( Figures 3B , D ). Nevertheless, at the default rCBF threshold of <30%, both packages tended to overestimate infarct core volumes, as indicated by the slope of the reduced major axis being under one. Furthermore, in patients with visible infarcts on the follow-up DWI (n = 187), the ischemic core volume determined by RAPID was zero in 123 (65.8%) cases, whereas it was zero in 104 (55.6%; p  = 0.04) cases as determined by JLK-CTP (see Table 2 ).

Figure 3 . Comparison of early follow-up infarct volume on diffusion-weighted image and ischemic core volumes by JLK-CTP and RAPID. (A) Scatter plot illustrating follow-up infarct volumes and ischemic core volumes as determined by JLK-CTP, with a concordance correlation coefficient of 0.753, and the slope and intercept of the reduced major axis being 0.706 and −0.598, respectively. (B) Bland–Altman plot for the analysis of agreement in between follow-up infarct volumes and ischemic core volumes by JLK-CTP. (C) Scatter plot illustrating follow-up infarct volumes and ischemic core volumes as determined by RAPID, with a concordance correlation coefficient of 0.736, and the slope and intercept of the reduced major axis being 0.633 and 0.804, respectively. (D) Bland–Altman plot for the analysis of agreement in between follow-up infarct volumes and ischemic core volumes by RAPID. The green dotted line represents the line of perfect concordance, while the blue line denotes the reduced major axis. For (B,D) , the blue solid line and the red dotted lines represent the mean difference and the limits of agreement between follow-up infarct volume and ischemic core volumes calculated by JLK-CTP (B) and RAPID (D) .

Table 2 . Comparison of ischemic core volumes by JLK-CTP and RAPID versus early follow-up infarct volume stratifying by the DAWN trial ( n  = 218).

When dividing patients by early follow-up infarct volume (<20 mL [n = 193] vs. ≥20 mL [n = 24]), in patients with follow-up infarct volume < 20 mL, both packages exhibited similarly poor agreement with early follow-up infarct volume ( ρ  = 0.196 for JLK-CTP and ρ  = 0.181 for RAPID, respectively; Supplementary Figure S3 ). In patients whose early follow-up infarct volume was ≥20 mL, both JLK-CTP ( ρ  = 0.497; 95% CI, 0.213 to 0.704) and RAPID demonstrated fair agreement ( ρ  = 0.438; 95% CI, 0.182 to 0.639). Setting the rCBF threshold to <26% improved the correlation between early follow-up infarct volume and ischemic core volumes determined by JLK-CTP, as shown by both the concordance correlation coefficient and Bland–Altman analysis ( Supplementary Figure S4 ).

Mismatch volume analysis and application of clinical trial’s criteria

The median mismatch volumes determined by JLK-CTP and RAPID were 23.26 (IQR 0 to 85.33) and 23 (0 to 101), respectively, and there was substantial agreement between the mismatch volumes determined by JLK-CTP and RAPID ( ρ  = 0.774; 95% CI 0.735 to 0.808; Figure 4A ). The mean difference in mismatch volume between the two software tools was 13.85 mL (95% CI, 8.80 to 18.90 mL; p  = 0.01; Figure 4B ).

Figure 4 . Comparison of mismatch volumes by JLK-CTP and RAPID. (A) Scatter plot depicting mismatch volumes as measured by JLK-CTP and RAPID, with a slope of 1.425 and an intercept of −6,783 on the reduced major axis. The green dotted line represents the line of perfect concordance, the blue line denotes the reduced major axis. (B) Bland–Altman plot illustrating the agreement in mismatch volumes between JLK-CTP and RAPID. The blue line represents the mean difference, and the red dotted lines denote the limits of agreement.

When considering early infarct volume as a standard reference and categorizing ischemic core volumes by JLK-CTP and RAPID according to the DAWN trial’s criteria, similar Cohen’s kappa values were observed for JLK-CTP (0.55) and RAPID (0.51). However, in the medium-sized ischemic core volume groups (20–30 mL and 30–50 mL), the ischemic core volumes determined by both JLK-CTP and RAPID exhibited poor agreement with the categorization by early infarct volumes.

We observed a comparable estimation of the ischemic core and hypoperfused area volume between RAPID and JLK-CTP, a newly developed CTP analysis package utilizing a delay-insensitive algorithm, based on 327 ischemic stroke patients who had CTP scans within 24 h from their last known well. Furthermore, both JLK-CTP and RAPID demonstrated a comparable correlation of ischemic core volumes with early DWI infarct volumes. Additionally, we observed that the default threshold of rCBF <30% tends to overestimate ischemic core volumes in comparison with early follow-up infarct volumes on DWI.

We observed an excellent agreement between ischemic core volumes calculated by RAPID and JLK-CTP. This correlation remained high even after excluding patients with ischemic core volumes of zero as determined by either JLK-CTP or RAPID. Additionally, hypoperfused tissue volumes identified using the default settings of both software tools also demonstrated substantial agreement. Consequently, mismatch volumes calculated by both software tools exhibited a substantial agreement. When the image criteria from the DAWN trial was applied ( Jovin et al., 2018 ), ischemic core volumes calculated by the two packages showed overall good agreement with early follow-up infarct volumes. However, for medium-sized ischemic core volumes (20–30 mL and 30–50 mL), the estimated parameters differed substantially compared with early infarct volumes on DWI. These findings suggest that ischemic core volume in CTP scans, analyzed by automated software packages, should be interpreted with caution in patients with medium-sized ischemic core volumes.

DWI is the method of choice when it comes to assessing ischemic core ( van Everdingen et al., 1998 ). Our results showed that automated CTP analysis packages have a tendency to overestimate ischemic core volume, consistent with previous studies ( Boned et al., 2017 ; Garcia-Tornel et al., 2021 ; Sarraj et al., 2022 ). Compared to JLK-CTP, RAPID was more likely to estimate the ischemic core as zero even when the ischemic core exceeded 20 mL. The discrepancy may result from differences in preprocessing images to correct patient motion and post-processing to reduce noise in both rCBF and T max maps. Moreover, our results contrast with a prior study demonstrating that CTP analysis packages tend to underestimate follow-up infarct volume on various imaging modalities such as DWI, fluid-attenuated inversion recovery image, and non-contrast CT ( Pisani et al., 2023 ). This discrepancy may result from different study populations: consecutive patients presenting at the hospital within 24 h of onset versus patients undergoing mechanical thrombectomy. In addition, shorter time intervals from the last known well to CTP scans (median 168 vs. 402 min) and from CTP to follow-up images (median 0.7 vs. 18.7 h) in our study may have led to smaller follow-up infarct volumes on DWI, subsequently leading to the overestimation of ischemic core volume in CTP scans by software tools. Given that DWI is the gold standard for measuring ischemic core and CTP scans are screening tools to select patients who may benefit from intervention, a more stringent rCBF threshold may be required to accurately estimate infarct core, as shown in our analysis employing an rCBF threshold of 26%, which in turn ultimately provides opportunities for more patients with ischemic stroke to regain functional independence.

The interpretation of our findings must be contextualized within the inherent limitations of this research. Conducted as a retrospective analysis at a single stroke center, our study’s observational nature is susceptible to the influence of unmeasured confounding variables. The software utilized for analysis reflects the versions available at the time of the study, acknowledging that subsequent updates and modifications could affect the applicability of our results. Moreover, the management of patients included in this study was guided by the outcomes from the RAPID software, introducing a potential source of bias. Furthermore, we utilized follow-up infarct volumes that were automatically segmented by validated software. This approach may limit comparing our results with prior studies that utilized a threshold for apparent diffusion coefficients of 620 × 10 −6 mm 2 /s.

In conclusion, the perfusion parameters from the JLK-CTP and RAPID were documented to be substantially consistent. In addition, ischemic core volumes calculated by JLK-CTP and RAPID at the default rCBF threshold of <30% also showed excellent agreement with early follow-up infarct volumes on DWI. However, CTP parameters should be interpreted with caution when making recanalization treatment decisions.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving humans were approved by Seoul National University Bundang hospital [IRB# B-1710-429-102]. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

N-HK: Conceptualization, Data curation, Investigation, Resources, Validation, Writing – original draft, Writing – review & editing. SH: Writing – original draft, Writing – review & editing. G-HP: Data curation, Formal analysis, Writing – original draft. J-HP: Data curation, Formal analysis, Writing – original draft. DK: Funding acquisition, Investigation, Software, Writing – original draft. LS: Conceptualization, Data curation, Writing – original draft. M-SK: Data curation, Methodology, Writing – original draft. SB: Supervision, Validation, Writing – review & editing. CJ: Supervision, Validation, Writing – review & editing. W-SR: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing. BK: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Multiministry Grant for Medical Device Development (KMDF_PR_20200901_0098).

Conflict of interest

SH, G-HP, J-HP, DK, and W-SR were employed by Artificial Intelligence Research Center, JLK Inc.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnins.2024.1398889/full#supplementary-material

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Keywords: computed tomography perfusion (CTP), automated CTP analysis software, ischemic stroke, ischemic core, hypoperfused tissue

Citation: Kim N-H, Ha SY, Park G-H, Park J-H, Kim D, Sunwoo L, Kye M-S, Baik SH, Jung C, Ryu W-S and Kim BJ (2024) Comparison of two automated CT perfusion software packages in patients with ischemic stroke presenting within 24 h of onset. Front. Neurosci . 18:1398889. doi: 10.3389/fnins.2024.1398889

Received: 11 March 2024; Accepted: 03 May 2024; Published: 15 May 2024.

Reviewed by:

Copyright © 2024 Kim, Ha, Park, Park, Kim, Sunwoo, Kye, Baik, Jung, Ryu and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Wi-Sun Ryu, [email protected] ; Beom Joon Kim, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Timing and Outcomes of Percutaneous Endoscopic Gastrostomy After Ischemic Stroke

Shoma bommena.

a Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Banner University Medical Center, Phoenix, AZ, USA

Pooja Rangan

Joyce lee-iannotti.

b Department of Neurology, University of Arizona College of Medicine-Phoenix, Banner University Medical Center, Phoenix, AZ, USA

Wahid Wassef

Rakesh nanda.

c Division of Gastroenterology, University of Arizona College of Medicine-Phoenix, Phoenix VA Health Care System, Phoenix, AZ, USA

Associated Data

Any inquiries regarding supporting data availability of this study should be directed to the corresponding author.

Guidelines recommend using percutaneous endoscopic gastrostomy (PEG) for dysphagia after 2 weeks of stroke onset. We aimed to study the impact of PEG timing on outcomes in patients with ischemic stroke.

In this retrospective study of patients with ischemic stroke and PEG between 2014 and 2019, early PEG was defined as PEG tube placed within 14 days of stroke and late PEG after 14 days. Outcomes of 30-day mortality, PEG-related complications, and functional swallow recovery were compared between early and late PEG. Logistic regression model assessed factors associated with PEG timing.

The median time of PEG tube placement after stroke was 10.9 days. Of the 161 included patients, 60.9% had early PEG, and its associated patient factors were nursing facility discharge (adjusted odds ratio (OR): 3.4, confidence interval (CI): 1.48 - 7.82) and infection (OR: 0.32, CI: 0.139 - 0.178). Late PEG had 3.27 times greater odds of swallowing recovery, but mortality and complications were not significantly different between early and late PEG.

Conclusions

Skilled nursing facility disposition and lack of infection were predictors of early PEG, constituting the majority of PEG placed for ischemic stroke-related dysphagia. Although better odds of swallowing recovery were seen with late PEG, likely implicating better patient selection, overall, the timing of PEG tube placement did not impact short-term mortality and complications.

Introduction

The reported long-term outcomes in patients who receive percutaneous endoscopic gastrostomy (PEG) for stroke-related dysphagia are poor [ 1 , 2 ], with 2-year mortality as high as 65% and only 14% alive with the regained ability to eat after 2 years of hospitalization. Furthermore, PEG during the index stroke admission is also an independent predictor of 30- and 60-day hospital readmissions [ 1 , 3 ]. Hence, in patients with dysphagia due to acute stroke, careful patient selection is essential for PEG tube placement, which is, after all, an invasive procedure that is not risk-free [ 4 , 5 ].

The incidence of dysphagia after acute stroke is greater than 60% [ 6 ]. Typically, a nasogastric tube (NGT) or nasoduodenal tube is used initially to administer medications and nutrition, and a PEG is placed later in those with prolonged dysphagia [ 7 ]. Regarding timing, the American Stroke Association (ASA) and American Heart Association (AHA) guidelines suggest NGT feeding until 2 - 4 weeks after stroke onset and consider PEG afterward [ 8 ]. However, in practice, the PEG tube placement rates in acute ischemic strokes vary widely across US hospitals, and most PEG tube placement happens earlier than the recommended guidelines [ 9 - 11 ]. However, there is a knowledge gap on the factors associated with early vs. late PEG tube placement timing relative to stroke onset and its impact on patient outcomes. The significance of the patient selection criterion is particularly relevant in the widely prevailing heterogeneity in the timing of PEG tube placement in patients with ischemic stroke [ 12 ].

We aimed to assess the impact of the timing of PEG tube placement relative to stroke onset on outcomes in patients with dysphagia from an acute ischemic stroke. The primary outcome was 30-day mortality. Secondary outcomes were PEG-related complications and functional swallowing recovery. We also aimed to assess factors associated with the timing of PEG tube placement in patients with acute ischemic stroke.

Materials and Methods

We conducted a retrospective single-center cohort study of all adult patients admitted for an acute ischemic stroke who received a PEG between 2014 and 2019. The study population was limited to ischemic strokes without including hemorrhagic stroke, as the neurological outcomes of hemorrhagic stroke are very different compared to ischemic stroke [ 13 ]. Inclusion criteria were patients with acute ischemic stroke with a PEG placed for dysphagia during the same hospital admission. In our study, early PEG was defined as PEG placed within 14 days of ischemic stroke onset, and late PEG was defined as PEG placed at or 14 days after the ischemic stroke. We used 14 days from stroke onset to classify the timing of PEG, based on the ASA guidelines that recommend choosing NGT for 2 - 3 weeks after stroke. Additionally, this definition was used in a previous study that evaluated the trends of PEG tube timing in stroke patients [ 3 , 8 ]. We compared outcomes between the patients who received early and late PEG. The primary outcome of our study was 30-day mortality. Secondary outcomes included PEG-related complications and functional swallowing recovery. The complications related to PEG included minor (tube dislodgement, PEG wound leakage, and wound infection) and major complications (peritonitis, gastric peroration, and significant bleeding). Functional swallowing recovery was defined as the ability to independently consume a pre-stroke oral diet and have PEG removed at follow-up visits. Partial recovery was defined as oral intake along with supplemental PEG tube feeding.

International Classification of Disease, Ninth Revision, and Clinical Modification (ICD-9-CM) codes of 434.xx and International Classification of Disease, Tenth Revision, and Clinical Modification (ICD-10-CM) codes of I63.xx were used to identify all cases of ischemic stroke in the study period. In addition, the PEG procedure during the hospital stay was identified by the procedure order (PEG tube placement, AN plc G tube Perc) and the ICD-10-CM of Z 93.1. In addition, medical records were reviewed, and the presence of ischemic stroke was verified based on documentation in the clinical progress notes and findings on diffusion-weighted imaging (DWI) on the brain magnetic resonance imaging (MRI). Among the confirmed patients with ischemic stroke, only those PEG placed due to dysphagia after the index stroke in the same admission were included ( Fig. 1 ), and the rest were excluded.

Distribution of the cohort.

Patient demographics, comorbidities, stroke-related vascular risk factors, and characteristics were abstracted from medical records. For comorbidity assessment, we utilized the Charlson Comorbidity Index (CCI), an index associated with outcomes and mortality in patients with ischemic stroke [ 14 ]. Based on diabetes mellitus, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, malignancies, peripheral vascular disease, and dementia, the CCI score was calculated to categorize them into three groups: mild (CCI score 1 - 2), moderate (CCI score 3 - 4), and severe (CCI score > 5). In addition, mechanical ventilation, tracheostomy status, and infections, including sepsis, pneumonia, urinary tract infections, and complications after PEG tube placement, were collected. The mean follow-up period of our study was 5.4 months. The study was conducted in accordance with the approval of the institutional review board in compliance with all the applicable institutional ethical guidelines for the care, welfare and use of animals.

Data analysis

The data were analyzed to estimate 30-day mortality (primary outcome), PEG-related complications, and functional swallow recovery after PEG removal (secondary outcomes). Data were described using descriptive statistics, and non-parametric methods were employed when data were not normally distributed. Continuous data were compared between groups with two-group t -tests or Wilcoxon rank-sum (Mann-Whitney) test as appropriate. The Chi-square test compared categorical data. Logistic regression was used to study the effect of PEG timing on dichotomous outcomes of 30-day mortality, PEG-related complications, and swallowing recovery. Clinical factors associated with early compared to late PEG tube placement were identified by univariable analysis with an alpha of 0.2 cut-offs, followed by multivariable logistic regression analysis. A backward stepwise selection method was implemented for variable selection, and statistical significance was defined as an alpha of 0.05, with two-sided alternative hypotheses. Data were analyzed using STATA ® Version 17 (StataCorp, College Station, TX).

Distribution and demographics

A total of 6,418 ischemic stroke patients were identified based on ICD codes ( Fig. 1 ). Of these, 268 (4.2%) were identified as having PEG. Of the 268 patients, 70 were excluded after chart review as they did not have an ischemic stroke. Of the 198 patients with confirmed ischemic stroke and PEG, 37 were excluded as they had PEG placed before the ischemic stroke for dysphagia unrelated to the stroke. The final cohort comprised 161 patients with ischemic stroke and gastrostomy tubes placed after the index stroke.

The incidence of gastrostomy tubes in patients with ischemic stroke was 2.54%. Overall, the median time of PEG tube placement after ischemic stroke was 10.9 days (interquartile range (IQR): 7.6 - 17.9). Of them, 60.9% (n = 98) had an early PEG with a median duration of 8.4 days (IQR: 6.2 - 11.8) ( Fig. 2 ). The clinical characteristics of the cohort and a comparison between the two groups of early and late PEG are shown in Table 1 . The two groups had no significant difference in patient demographics, clinical features, comorbidities, and stroke severity based on National Institute of Health Stroke Scale (NIHSS) scores (16 vs. 17; P = 0.968). However, early PEG was associated with a significantly shorter length of stay (mean 15.8 vs. 20.11; P = 0.029).

Distribution of median time from stroke to PEG in early vs. late PEG. PEG: percutaneous endoscopic gastrostomy.

CCI: Charlson Comorbidity Index; IQR: interquartile range; PEG: percutaneous endoscopic gastrostomy; SD: standard deviaton; NIHSS: National Institute of Health Stroke Scale.

The association of the timing of PEG with primary and secondary outcomes

The overall 30-day mortality of the cohort was 6.8% (n = 11). The 30-day mortality was not significantly different between early and late PEG (7.14% vs. 6.35%, P = 0.558) ( Table 2 ). The functional swallow recovery rate in the cohort was 26.7% (n = 43), and it was significantly higher in the late PEG compared to early PEG at a mean follow-up of 5.4 months (36.51% vs. 20.41%, respectively; P = 0.024). In the multiple logistic regression model, those patients with late PEG had 3.27 times greater odds of swallowing recovery and PEG removal after adjusting for covariates, including age, gender, race comorbidities, and stroke severity (adjusted OR: 3.27; 95% CI: 1.22 - 8.74; P = 0.02). A low NIHSS score was the other factor that predicted swallowing recovery with PEG removal in this model ( Table 3 ).

PEG: percutaneous endoscopic gastrostomy.

Dash (-) indicates that the variable was included in the multivariable model but was not statistically significant. CCI: Charles Comorbidity Index; CI: confidence interval; NIHSS: National Institute of Health Stroke Scale; PEG: percutaneous endoscopic gastrostomy.

There were no significant differences in overall PEG-associated complications between late PEG and early PEG (3.2% vs. 9.2%; P = 0.204). Our study had two major PEG-related complications (1.24%): one case of PEG malposition in the transverse colon and one case of gastric wall necrosis at the gastrostomy tube site that required partial gastric resection. The minor PEG-related complications included four dislodged gastrostomies, one G-tube leakage, one G-tube clog, and one G-tube malposition, most requiring PEG tube replacement. In addition, 75.8% of patients in the cohort were on uninterrupted antiplatelet (100 aspirin + 9 dual antiplatelet therapy with aspirin and clopidogrel) or anticoagulation therapy (n = 13 including intravenous heparin drip held 6 h prior to procedure; enoxaparin and apixaban with morning of procedure dose held). No direct PEG procedure-related gastrointestinal bleeding was observed in our cohort.

Patient factors associated with the timing of PEG tube placement

In order to evaluate the factors associated with the timing of PEG relative to stroke onset, we performed a univariate followed by multivariable regression analysis ( Table 4 ). After adjusting for age, sex, comorbidities, intubation, tracheostomy status, and length of stay, those discharged to a skilled nursing facility after an ischemic stroke had 3.4 times higher odds of receiving an early PEG tube placement (adjusted odds ratio (OR): 3.4, confidence interval (CI): 1.48 - 7.82, P = 0.004) than those discharged to home or acute rehabilitation. In addition, those with infection during the ischemic stroke-related hospital stay (including sepsis from any cause, pneumonia, and urinary tract infection) had lower odds of having an early PEG (adjusted OR: 0.32, CI: 0.139 - 0.178, P = 0.007).

Dash (-) indicates that the variable was included in the multivariable model but was not statistically significant. CCI: Charles Comorbidity Index; CI: confidence interval; NIHSS: National Institute of Health Stroke Scale; PEG: percutaneous endoscopic gastrostomy; SNF: skilled nursing facility.

The incidence of PEG tube placement for dysphagia after an acute ischemic stroke was 2.54% in our cohort. The majority (60.9%, n = 63) had an early PEG within 2 weeks of acute ischemic stroke. Disposition to a skilled nursing facility from the stroke hospital admission was associated with 3.4 times higher odds of receiving an early PEG. In addition, sepsis and infection during the stroke hospital admission were associated with 0.32 times lower odds of early PEG. Although late PEG had higher odds of functional swallowing recovery and PEG removal at follow-up, we did not find significant differences in the 30-day mortality and PEG-related complications between early and late PEG groups. Our results suggest that patients who received PEG after 14 days were adequately prepared for PEG construction

A PEG tube was placed at a median of 10.9 days after the stroke. The distribution of early vs. late PEG in our study is aligned with the previously reported discrepancy between guidelines and practice trends in PEG tube placement across the USA. However, our late PEG rate of 39% is higher than that reported in previous studies. For example, a state inpatient database study on PEG after an acute stroke had a 14% prevalence of late PEG [ 9 ], and another study utilized National Inpatient Sample (NIS) data to study PEG timing in patients with ischemic stroke, where greater than 50% PEG happened within a week of admission [ 10 ]. Differences in dysphagia assessments of speech pathologists [ 15 ], physicians overestimating PEG benefits, and lack of awareness of late PEG benefits among providers are some of the speculated factors associated with varied PEG practices of nationwide hospitals after stroke [ 10 , 11 , 16 ].

In our study, discharge to a skilled nursing facility was associated with early PEG tube placement. Previous studies have speculated that policies of skilled nursing homes and their preferences for accepting PEG due to potential NGT dislodgement might contribute to early PEG tube placement [ 17 ]. Consistent with this association are findings of a nationwide survey study of speech pathologists that system pressures for early discharge influenced 35% of their recommendations for PEG tube placement [ 15 ]. Whether the disposition to skilled nursing influenced the decision for early PEG tube placement within 2 weeks of acute stroke and whether this practice, to facilitate early discharge to a skilled nursing facility, might over-select patients for the PEG procedure remains to be investigated further. Incorporating a multidisciplinary approach with the palliative care team while focusing on patient care goals in PEG tube placement, using a nasal bridle in patients who temporarily need NGT to recover swallowing or wish not to get a PEG due to their poor prognosis, and improving education among providers and the nursing homes are some of the proposed solutions [ 18 , 19 ]. The validated objective tools such as the validated Sheffield Gastrostomy Scoring System (SGSS) and predictive swallowing score to predict swallowing recovery in those with dysphagia from ischemic strokes are important clinical tools that can help clinicians and family members in identifying those who would benefit from a feeding tube [ 20 - 22 ]. In addition, in our study, we found that those with infections including pneumonia, urinary tract infections, and sepsis during the stroke hospitalization had lower odds of receiving an early PEG, likely reflecting that these patients were sicker from non-stroke-related issues that delayed the PEG tube placement decision. In comparision, a previous study that looked at factors associated with PEG timing found older age and large stroke volume to be associated with early PEG, placed within a week of stroke [ 10 ].

Although the 30-day mortality rate between early and late PEG in our study was not significantly different, the findings of more significant swallowing recovery followed by PEG removal support the guideline recommendations of PEG timing in stroke. In order to manage dysphagia after stroke in the first 2 - 3 weeks, the guidelines recommend placing an NGT [ 8 ], which helps appropriate patient selection for PEG in stroke by limiting its use to those with persistent dysphagia. A possible explanation for our findings of greater odds of swallowing recovery in the late PEG group may be attributed to better patient selection based on the independent association of swallowing recovery with NIHSS score. In addition, the effect of intense speech therapy services that this group had more access to, as those with late PEG were frequently discharged to an acute rehabilitation facility, might have played a role. Finally, dependency on PEG caused by its early placement might negatively impact swallowing recovery. Similar to our study, the authors of the FOOD randomized controlled trial found that more patients in the early PEG group remained PEG dependent at follow-up, in contrast with the NGT group, in which only 30% of patients randomized to NGT feeding ended up receiving PEG later [ 23 ]. With no difference in the two groups, the rate of post-PEG complications was 6.8%, which is similar to the reported rate in the literature [ 4 ]. Interestingly, our cohort did not have any direct PEG-related bleeding complications, despite 75.8% of patients being on peri-procedural antiplatelet or anticoagulation therapy. This is consistent with findings of recent studies, including a meta-analysis of 12 studies that included 8,471 patients, where antiplatelet therapy did not increase the risk of bleeding after PEG [ 24 ].

Here we review the literature on the outcomes of PEG after an ischemic stroke based on the timing of its placement. The PEG vs. NGT arm trial of multicenter randomized controlled FOOD trial studied the effect of the route of the enteral tube and timing on outcomes and found that early PEG in a week of stroke was associated with an increased borderline significance of the absolute risk of death [ 23 ]. A recent large observational study of patients that included both ischemic stroke and intracerebral hemorrhage found that gastrostomy and jejunostomy tubes placed within week 1 of stroke had significantly greater 30-day mortality than those placed after 5 weeks. However, a severe disability with a modified Rankin Scale (MRS) of 4 - 5 at discharge was also noted in these late tube placement survivors. Unlike our study, patients who died after early PEG more commonly had dementia, advanced age, and greater stroke severity [ 25 ]. Another observational study of 154 patients did not show any difference in 30-day mortality similar to our results, although the authors considered early PEG as those placed within 7 days of stroke [ 26 ]. On the contrary, a systemic review that evaluated the effectiveness and safety of PEG as opposed to NGT in adults with dysphagia, not limited to stroke, found that PEG had lower chances of intervention failure. There was no significant difference in mortality between the two groups. The evidence, however, was of low quality [ 27 ].

Our study has several limitations. First, it is a retrospective study. Second, there might be residual confounding even after matching factors such as stroke severity, medical comorbidities, and age that could have affected our study results. Third, we acknowledge a loss to follow up with both groups in evaluating and comparing swallowing recovery between early and late PEG. However, this was non-differential as the baseline characteristics between the two groups were not statistically different. Lastly, we could not capture and adjust for the mRS in all the patients. Despite these weaknesses, we believe our study findings are significant in the context of varied PEG practices and will aid provider in decision-making on the placement of PEG in acute ischemic stroke.

In conclusion, consistent with current PEG practice patterns in the USA, most PEG tubes were placed within 2 weeks of stroke. Disposition to a skilled nursing facility and lack of infection during hospitalization were significant predictors of early PEG tube placement. Despite greater odds of swallowing recovery with less PEG dependency at follow-up in the late PEG group, no differences in 30-day mortality and post-PEG complications were seen between early and late PEG groups. Our results suggest that patients who received a late PEG after 14 days were adequately prepared for PEG construction. In the current era of widely varied PEG timing practices across the USA, with the potential influence of the health care system, education on the timing of PEG among providers and facilities might standardize the management of acute stroke-related dysphagia.

Acknowledgments

None to declare.

Financial Disclosure

Conflict of interest, informed consent.

Given the retrospective nature of the study, informed consent was waived.

Author Contributions

Shoma Bommena: conceptualization; investigation; methodology; validation; visualization; writing - initial draft and revisions. Pooja Rangan: methodology; statistical analysis. Joyce Lee-Iannotti: methodology; review and editing. Wahid Wassef: methodology; review and editing. Rakesh Nanda: conceptualization, methodology; review, and editing.

Data Availability

Abbreviations.