case study of a stroke patient

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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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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 review, case discussion, clinical symptoms.

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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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Inpatient Stroke Case Studies

Inpatient e/m case studies.

Case study of a stroke patient at varying visit levels to better understand code selection for inpatient encounters under the revised guidelines for 2024.

67-year-old Female with Stroke

Total time* for Inpatient E/M in 2023

Refer to the following tables for correct code selection when billing based on time for inpatient E/M Services:

*Total time includes non face-to-face time on the date of service

Day 1: Critical Care (99291)

A 67-year-old woman with hypertension and diabetes presents to the emergency department with abrupt onset of left hemiparesis 45 minutes ago.

Pre-evaluation : Discussed presentation and vital signs with ED provider (3 mins).

Face-to-face evaluation : Performed medically appropriate history and exam. She has a dense left hemiparesis and an NIH Stroke Scale score of 8. Thrombolysis safety criteria reviewed (7 mins).

Post-evaluation : Non-contrast head CT, CTA of head and neck, and lab results reviewed in the ED. Case discussed with ED provider and thrombolysis recommended. Consultation documented in the ED (25 mins).

Total time : 35 minutes.

Critical Care Coding

According to the 2024 CPT code set, a provider may bill for critical care when the following requirements are met:

• A critical condition: one that acutely impairs a vital organ system with a high probability of imminent or life-threatening deterioration. This includes, for example, central nervous system failure.
• Direct delivery of critical care: high complexity decision-making to assess, manipulate, and support vital systems to treat organ system failure or prevent further life-threatening deterioration.
• At least 30 minutes of time spent solely in the care of the patient. It does not need to be continuous, and it includes both time at the bedside and time spent on the same floor or unit engaged in work directly related to the patient’s care (e.g., documenting critical care, reviewing test results, discussing care with other providers, obtaining history, or discussing treatments or treatment limitations with surrogates when the patient lacks the capacity to do so).

Specific critical care credentials are not required to bill critical care. Critical care is usually provided in a critical care area such as an intensive care unit or emergency department, but this is not always the case (for example, critical care provided to a deteriorating patient in a non-critical care unit).

Other examples of critical care might include:

• Evaluating a patient with status epilepticus and prescribing anti-epileptic drugs or sedative infusions,
• Evaluating a patient with acute respiratory failure from neuromuscular disease and prescribing plasmapheresis,
• Evaluating a patient with coma after cardiac arrest and discussing prognosis, treatment, and goals of care with surrogates (documenting the patient’s lack of capacity to participate)

Critical care, 30-74 minutes CPT 99291 is justified based on the above documentation, although E&M codes (e.g., 99223) associated with fewer wRVUs and lower reimbursement could be used as well.

Day 2: Subsequent Hospital Inpatient Care

Pre-rounds : Reviewed vitals, labs, and studies (LDL, Hemoglobin A1c, EKG, TTE). Review and document independent interpretation of MRI (8 mins).

On Rounds : Performed medically appropriate history and exam. The patient’s symptoms and findings improved somewhat overnight. Patient counseled about stroke evaluation and secondary prevention (10 mins).

Post-rounds : Order atorvastatin, order diabetes consult for management of diabetes. Document discussion with case management possible need for acute inpatient rehabilitation. Documentation completed (10 mins).

Total time : 28 minutes

In this situation, billing according to MDM would be associated with higher reimbursement.

Day 3: Discharge Day Management (By Primary Service)

Pre-rounds : Reviewed vitals, daily CBC and BMP, nursing notes and PT/OT notes (5 mins).

On Rounds : Performed medically appropriate history and exam. The patient reports continued slight improvement in symptoms and requests counseling on how complementary and alternative medicine might help manage her chronic conditions (15 mins).

Post-rounds : Prescribe antiplatelet agent, antidiabetic medications, and antihypertensives. Prepare discharge paperwork and document discharge summary (15 mins).

Total time : 35 minutes

Discharge Day Management Coding (Inpatient or Observation)

Discharge CPTs are selected based on total (face-to-face and non-face-to-face) time, not MDM:

• 99238: 30 minutes or less
• 99239: 31 minutes or more

Discharge CPTs would be used by the primary attending service (e.g., a Neurohospitalist service). Consulting services would continue to choose Subsequent Day codes based on time or MDM.

Discharge Day Management, 31 minutes or more   CPT 99239  

Disclaimer: The billing and coding information provided by the American Academy of Neurology and its affiliates (collectively, “Academy”) are assessments of clinical information provided as an educational service. The information (1) is not clinical advice; (2) does not account for how private payers cover and reimburse procedures or services*; (3) is not continually updated and may not reflect the most current clinical information (new clinical information may emerge between the time information is developed and when it is published or read); and (4) is not a substitute for the independent professional judgment of the treating provider, who is responsible for correctly coding procedures and services.

Using this information is voluntary. The Academy is providing the information on an “as is” basis and makes no warranty, expressed or implied, regarding the information. The Academy specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. The Academy assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.

*The Academy recommends always checking private payer policies before rendering procedures or services

Case Presentation

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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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

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Stroke case study

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Stroke is the leading cause of disability in the United States. As advanced practice nurses, we anticipate caring for those impacted by strokes in many healthcare settings including emergency rooms, acute care, rehab settings, extended care facilities, and in primary care. Early diagnosis and treatment are imperative in the treatment of a stroke in order to minimize permanent deficits so it is important for advanced practice nurses to be proficient in recognizing clinical manifestations of a stroke. There are also many modifiable risk factors for strokes so advanced practice nurses need to be able to educate patients and families on potential lifestyle changes that can decrease stroke risk.

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No difference in 6-month functional outcome between early and late decompressive craniectomies following acute ischaemic stroke in a national neurosurgical centre: a single-centre retrospective case-cohort study

Affiliations.

• 1 Department of Anaesthetics and Intensive Care Medicine, Beaumont Hospital, Dublin, Ireland.
• 2 Department of Neuroradiology, Beaumont Hospital, Dublin, Ireland.
• 3 Department of Neurosurgery, Beaumont Hospital, Dublin, Ireland.
• 4 Department of Geriatric and Stroke Medicine, Beaumont Hospital, Dublin, Ireland.
• 5 Department of Anaesthetics and Intensive Care Medicine, Beaumont Hospital, Dublin, Ireland. [email protected].
• PMID: 39251524
• DOI: 10.1007/s11845-024-03801-7

Background: Decompressive craniectomies (DCs) are recommended for the treatment of raised intracranial pressure after acute ischaemic stroke. Some studies have demonstrated improved outcomes with early decompressive craniectomy (< 48 h from onset) in patients with malignant cerebral oedema following middle cerebral artery infarction. Limited data is available on suboccipital decompressive craniectomy after cerebellar infarction.

Aims: Our primary objective was to determine whether the timing of DCs influenced functional outcomes at 6 months. Our secondary objectives were to analyse whether age, gender, the territory of stroke, or preceding thrombectomy impacts functional outcome post-DC.

Methods: We conducted a retrospective study of patients admitted between January 2014 and December 2020 who had DCs post-acute ischaemic stroke. Data was collected from ICU electronic records, individual patient charts, and the stroke database.

Results: Twenty-six patients had early DC (19 anterior/7 posterior) and 21 patients had late DC (17 anterior/4 posterior). There was no difference in the modified Rankin Scale (mRS) score of the two groups at 90 (p = 0.318) and 180 (p = 0.333) days post early vs late DC. Overall outcomes were poor, with 5 out of 46 patients (10.9%) having a mRS score ≤ 3 at 6 months. There was no difference in mRS scores between the patients who had hemicraniectomies for anterior circulation stroke (n = 35) and suboccipital DC for posterior circulation stroke (n = 11) (p = 0.594).

Conclusion: In this single-centre retrospective study, we found no significant difference in functional outcomes between patients who had early or late DC after ischaemic stroke.

Keywords: Acute ischaemic stroke; Decompressive craniectomies; Modified Rankin scale.

© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.

PubMed Disclaimer

• Powers WJ, Rabinstein AA, Ackerson T et al (2018) 2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 49(3):e46–e110. https://doi.org/10.1161/str.0000000000000158 - DOI - PubMed
• Hofmeijer J, Kappelle LJ, Algra A et al (2009) Surgical decompression for space-occupying cerebral infarction (the hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial [HAMLET]): a multicentre, open, randomised trial. Lancet Neurol 8(4):326–333. https://doi.org/10.1016/s1474-4422(09)70047-x - DOI - PubMed
• Vahedi K, Hofmeijer J, Juettler E et al (2007) Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 6(3):215–222. https://doi.org/10.1016/s1474-4422(07)70036-4 - DOI - PubMed
• Nouh A, Remke J, Ruland S (2014) Ischemic posterior circulation stroke: a review of anatomy, clinical presentations, diagnosis, and current management. Front Neurol 5:30. https://doi.org/10.3389/fneur.2014.00030 - DOI - PubMed - PMC
• Ayling OGS, Alotaibi NM, Wang JZ et al (2018) Suboccipital decompressive craniectomy for cerebellar infarction: a systematic review and meta-analysis. World Neurosurg 110:450-459.e5. https://doi.org/10.1016/j.wneu.2017.10.144 - DOI - PubMed

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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.

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This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

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.

• Cannine M , et al
• Wunderink RG
• van Doremalen N ,
• Bushmaker T ,
• Morris DH , et al
• 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
• Zhang S , et al
• 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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Stroke in young adults, stroke types and risk factors: a case control study

Priscilla namaganda.

1 Kiruddu National Referral Hospital, P.O. Box 6553, Kampala, Uganda

Jane Nakibuuka

2 Mulago National Referral Hospital, Mulago Hospital Complex, P.O. Box 7272, Kampala, Uganda

Mark Kaddumukasa

3 Department of Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda

Elly Katabira

4 Infectious Diseases Institute, Makerere University, Kampala, Uganda

Associated Data

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

Stroke is the second leading cause of death above the age of 60 years, and the fifth leading cause in people aged 15 to 59 years old as reported by the World Health Organization global burden of diseases. Stroke in the young is particularly tragic because of the potential to create long-term disability, burden on the victims, their families, and the community at large. Despite this, there is limited data on stroke in young adults, and its risk factors in Uganda. Therefore, we determined the frequency and risk factors for stroke among young adults at Mulago hospital.

A case control study was conducted among patients presenting consecutively to the general medical wards with stroke during the study period September 2015 to March 2016. A brain Computerized Tomography scan was performed to confirm stroke and classify the stroke subtype. Controls were patients that presented to the surgical outpatient clinic with minor surgical conditions, matched for age and sex. Social demographic, clinical and laboratory characteristics were assessed for both cases and controls. Descriptive statistics including frequencies, percentages, means, and standard deviation were used to describe the social demographics of case and controls as well as the stroke types for cases. To determine risk factors for stroke, a conditional logistic regression, which accounts for matching (e.g., age and sex), was applied. Odds ratio (with 95% confidence interval) was used as a measure for associations.

Among 51 patients with stroke, 39(76.5%) had ischemic stroke and 12(23.5%) had hemorrhagic stroke. The mean age was 36.8 years (SD 7.4) for stroke patients (cases) and 36.8 years (SD 6.9) for controls. Female patients predominated in both groups 56.9% in cases and 52.9% in controls. Risk factors noted were HIV infection, OR 3.57 (95% CI 1.16–10.96), elevated waist to hip ratio, OR 11.59(95% CI 1.98–68.24) and sickle cell disease, OR 4.68 (95% CI 1.11–19.70). This study found a protective effect of oral contraceptive use for stroke OR 0.27 95% CI 0.08–0.87. There was no association between stroke and hypertension, diabetes, and hyperlipidemia.

Among young adults with stroke, ischemic stroke predominated over hemorrhagic stroke. Risk factors for stroke were HIV infection, elevated waist to hip ratio and sickle cell disease.

Stroke is the second leading cause of death above the age of 60 years, and the fifth leading cause in people aged 15 to 59 years old as reported by the World Health Organization (WHO) global burden of diseases [ 1 ]. The severity of stroke in the young is relatively low in developed countries ranging from 2 -7% in Italy and USA respectively [ 2 , 3 ]. In Africa, on the other hand the prevalence of stroke among young adults is 12.9% in Nigeria [ 4 ], 31% in South Africa [ 5 ], 28.9% in Morocco [ 6 ]. The incidence of ischemic stroke in the young has been increasing globally over the last 2–3 decades. From the Danish National Patient Register, the incidence rates of first‐time hospitalizations for ischemic stroke and transient ischemic attack (TIA) in young adults have increased substantially since the mid 1990s while the incidences of hospitalizations for intracerebral hemorrhage and subarachnoid hemorrhage remained stable during the study period [ 7 ].

In Uganda, literature on stroke in young adults is limited however results of a study done among acute stroke patients admitted to the national referral hospital (Mulago hospital) showed a 30-day mortality of 43.8%. Out of 133 patients, 32 patients (25%) were less than 51 years old. Out of the 56 patients that died, 13 patients (23%) were less than 51 years [ 8 ].

Rapid western cultural adaption (sedentary lifestyle, deleterious health behavior like consumption of tobacco and alcohol and high fat/cholesterol diet) and Human immunodeficiency syndrome/ Acquired immunodeficiency syndrome (HIV/AIDS) that is highly prevalent in Africa has accelerated risk factors and increased the burden of stroke [ 9 ].

Most literature indicates that the traditional risk factors i.e., hypertension, diabetes mellitus and dyslipidemia are still the commonest risk factors with hypertension having the highest frequency. Other risk factors common to the young include smoking, excessive alcohol intake, illicit drug use, oral contraceptive use and migraine [ 10 ].

Although stroke is predominantly a disease of the middle age and the elderly, its occurrence in younger age groups is not rare. Stroke in young adults seems to be increasing and is particularly tragic because of the potential to create long-term disability, burden on the victims, their families, and the community at large such as Uganda. Despite the huge socioeconomic impact of stroke in this age group, there is a scarcity of data regarding stroke in young adults in sub-Saharan Africa including Uganda. Effective stroke prevention strategies in the young require comprehensive information on risk factors and possible causes. Although case reports and etiologic investigations of possible causes of stroke in the young have been identified especially in developed countries, there is limited data on risk factors in Africa Uganda inclusive. Information obtained from this study will fill the knowledge gap in this area of stroke in the young which will inform institutional strategies on prevention and management of stroke in this age group. This study, therefore, seeks to determine the frequency of stroke types and risk factors for this population.

The aims of the study were:

• To determine the frequency of stroke types among young adults on the general medical wards in Mulago hospital between September 2015 and March 2016.
• To determine the risk factors for stroke (i.e., ischemic, and hemorrhagic stroke) among young adults on the general medical wards in Mulago hospital between September and March 2016.

This was a case control study. Cases were defined as patients with a confirmed diagnosis of stroke by brain computerized tomography (CT) scan that met the inclusion criteria. Controls were defined as patients with minor surgical conditions that met the inclusion criteria. The study was carried out in Mulago hospital which is the national referral hospital in Uganda as well as the teaching hospital of Makerere University College of health sciences. It has a bed capacity of 1500 beds and has both inpatient wards, outpatient departments both for medical and surgical specialties. It has a radiological department with CT scan and highly trained personnel and a well-equipped laboratory. Cases were recruited consecutively from the medical wards specifically on the neurology ward of Mulago hospital. Patients on the neurology ward are managed by physicians that have had additional training in the management of neurological conditions.

Controls were recruited from general surgical outpatient departments from Mulago hospital. They were matched for age and sex. Eligible patients were patients aged 15–45 years, confirmed diagnosis of stroke on brain CT scan and with a written informed consent or assent for patients less than 18 years. These included patients with intracranial hemorrhages and ischemic stroke, none had subarachnoid hemorrhage. Patients were excluded if they were unconscious and with no valid surrogate (next of kin) and HIV positive with opportunistic infections. Patients eligible as control were, patient aged 15–45 years, minor surgical condition, written informed consent or assent for patients less than 18 years. Patients with features of stroke secondary to non-vascular causes like trauma, tumors were excluded as controls. For controls, we chose patients with minor surgical conditions because we wanted controls to be hospital patients but with non-medical conditions that could confound our findings. Such conditions included lacerations, hernias, lipomas, ingrown toenails, circumcision.

Based on the catchment area of Mulago, patients with minor surgical conditions are likely to have similar social economic status and come from similar neighborhoods as would health controls living in the catchment areas as patients with stroke.

The best alternative would have been healthy controls from the neighborhoods of the patients with stroke, but this would have been resource consuming.

The sample size was calculated assuming a prevalence of 62.2% of hypertension among the stroke patients as was indicated in a similar study among the young Thai adults in Bangkok, Thailand (Bandasak et al., 2011) [ 11 ]. We also assumed that the risk for stroke is higher among the hypertensive with an OR of 3. With this sample size, we were powered to detect associations with other risk factors like smoking (OR 2.6) [ 12 ], diabetes (OR 13.2 for black men and 22.1 for black women) [ 13 ].

With these assumptions, a sample size of 51 cases and 51 controls was found sufficient with 80% power and 0.05 level of significance.

Sampling procedure

All young patients admitted on the general medical wards suspected of having stroke were screened and brain CT scan done. Once a diagnosis of stroke was confirmed on CT scan, participants who consented to participate in the study were recruited consecutively, a standardized questionnaire administered by the research team for those patients able to communicate. For patients not able to communicate, consent and information were obtained through the care givers. Controls were selected from the general surgical outpatient clinic using consecutive sampling method. This was done after we had obtained all the cases. These were matched for age and sex until the sample size was accrued.

Information was collected on:

• Social demographic characteristics i.e., age, sex, level of education, occupation, religion, history of smoking and alcohol consumption, history of illicit drug use, history of oral contraceptive use.

Physical measurements for the weight and hip were taken using a stretchable tape measure. Waist measurements were taken at the narrowest point-umbilicus and hip measurements at the widest point- buttocks. A waist to hip ratio was obtained and recorded on the questionnaire.

• Blood was drawn for laboratory tests; high density lipoprotein, low density lipoprotein (HDL/LDL), fasting blood sugar, full blood count, Hb electrophoresis, prothrombin time/ international normalization ratio (PT/INR), HIV serology, Treponema pallidum hemagglutination (TPHA).

The general surgical outpatient clinic runs every Tuesday, and Thursday in Old Mulago hospital Participants were identified at the surgical outpatient clinic. Those matching the age and sex of the cases were recruited, written consent/assent obtained, and questionnaire was administered by the PI. The procedure as explained above was followed for the controls.

Data collection

A pre-tested and standardized questionnaire was used as a data collection tool. The principal investigator administered the questionnaire to the participants in data collection. Data on socio demographics and past medical history was collected.

Results from imaging and laboratory investigations were also recorded into the questionnaire.

Data collected was double entered into the computer using EPI-DATA (version 3.1) software to minimize data entry errors. Data was then backed up and archived in both soft and hard copy to avoid losses. Confidentiality was ensured using code numbers instead of patients’ names. Questionnaires were stored in a lockable cabinet for safety.

Data analysis

Data was analyzed using STATA Version 12 (StataCorp. 2011.  Stata Statistical Software: Release 12 . College Station, TX: StataCorp LP). Descriptive statistics were used to describe characteristics of the study participants and the stroke subtypes which included frequencies, percentages, means and standard deviation. To determine factors associated with stroke, a conditional logistic regression, which accounts for matching (e.g., age and sex), was applied. Odds ratio (with 95% confidence interval) was used as a measure for associations. Factors with p -values < 0.2 at a bi-variable analysis were entered into a multiple conditional logistic regression to obtain the adjusted estimates. Factors whose 95% confidence interval for the odds ratio that excludes a 1 or whose p -value < 0.05, were considered statistically significant at the adjusted level. Post-hoc power calculation was performed for the adjusted analysis to check if there was enough power to detect a difference between cases and controls.

Quality control

To ensure quality of results several measures were undertaken, these included:

• The questionnaires were pre-tested and standardized before study commenced.
• The research team administered the structured, pre- coded and pre-tested questionnaire to enrolled participants on a face-to-face basis and brain CT scans were done by competent and well-trained radiology technicians and interpretation done by a specialist radiologist at the Radiology Department of Mulago hospital.
• The questionnaires were checked for completeness at the end of every interview. The two files were compared, and any discordance corrected against data recorded with the questionnaire. The data were then backed up.

Ethical consideration

Written informed consent/ assent was obtained from all participants or their parent/guardian or legal authorized representative to participate in the study. Ethical approval was obtained from Makerere University, school of medicine research and ethics committee (SOMREC) (reference number #REC REF 2015–105).

Confidentiality was ensured using code numbers instead of patients’ names. Questionnaires were stored in a lockable cabinet for safety.

Profile of the study

Enrollment of study participants was carried out between September 2015 to March 2016 in Mulago hospital. The patient flow diagram for cases and controls is as shown in Fig.  1 .

Patient flow diagram

Social demographic characteristics of the study population

A total of 51 cases aged 18 to 45 years and the same number of hospital control matched for age and sex were identified. The mean age of cases was 36.8 years (standard deviation (SD) 7.4) and the control was 36.8 years (SD 6.9). Females predominated in both groups with 56.9% in cases and 52.9% in controls. There was no significant difference in other baseline characteristics between cases and controls except in oral contraceptive use, waist to hip ratio, HIV status and sickle cell disease. Details of the social demographic characteristics are shown in Table ​ Table1 1 .

Social Demographic characteristics of study participants

Clinical characteristics of the study participants

The mean fasting blood sugar was 6.6 (SD 3.9) for cases and 5.3 (SD 0.7) for controls. This was statistically significant with a p value of 0.015. Waist to hip ratio was also statistically significant with a p value of 0.007. Cases with an elevated wait to hip ratio were 14 (27.5%) and controls were 3 (5.9%). Table ​ Table2 2 shows the baseline clinical characteristics of the study participants.

Laboratory characteristics of the study participants

HIV serology and Hb electrophoresis were statistically significant with a p value of 0.076 and 0.023 respectively. 18 patients (35.3%) were reactive for HIV among cases and controls 10 (19.6%). 12 patients (23.5%) had abnormal Hb electrophoresis among cases controls 3 (5.9%). Table ​ Table3 3 shows the laboratory characteristics of the study participants.

Stroke types

Stroke types by social demographic characteristics of cases.

Among 62 patients, who had brain CT scan done, 11 patients had non stroke pathologies (4 had brain abscesses, 7 patients had ring enhancing lesions suggestive of toxoplasmosis). Among 51 patients with stroke confirmed on CT scan, the frequency of ischemic stroke was 76.5% and hemorrhagic stroke was 23.5%.

Most participants with ischemic or hemorrhagic stroke were in the age group 36–45 years. Females predominated in both ischemic and hemorrhagic stroke. Details of the social demographic characteristics by stroke types are shown in Table ​ Table4 4 .

Social demographic characteristics by stroke types

Clinical and laboratory characteristics by stroke types

Majority of patients with hemorrhagic stroke were hypertensive (91.7%) compared to only 25.6% among patients with ischemic stroke. Details of the clinical and laboratory characteristics of the study participants by stroke subtypes are shown in Table ​ Table5 5 .

Shows the clinical and laboratory characteristics by stroke types

Risk factors for stroke at univariate analysis

Social demographic characteristics at univariate analysis

Oral contraceptive use showed a significant difference with an unadjusted OR of 0.27 (95% CI 0.08–0.87) case subjects 23.3% and control subjects 56.5%. Belonging to other religion (seventh day advent, Pentecostal) was statistically significant with a p value of 0.009, OR 0.17. These findings are detailed in Table ​ Table6 6 below.

a Obtained accounting for matching by age and sex using a conditional logistic regression

b No comparison made because matching was done using these variables (age and sex)

c Accounting for matching was done only for age because contraceptive use applies only to female gender

Clinical characteristics at univariate analysis

There was a significant difference in waist to hip ratio between cases (27.5%) and controls (5.9%), with unadjusted OR 6.85 (CI 1.70–27.62). HIV serology with an unadjusted OR of 2.64 (95% CI 1.03–6.82). Hb electrophoresis with an unadjusted OR of 4.31 (95% CI- 1.15–16.17). Fasting blood sugar with an unadjusted OR of 1.64 (95% CI 1.02–2.62). Details of the above findings are shown in Table ​ Table7 7 below.

Clinical characteristics of study participants at univariate analysis

b Obtained by adding a 1 on each cell count (due to zero cell count)

c High (male: > 0.95, female > 0.85); Normal (male: < 0.95, female < 0.85)

Risk factors for stroke at multivariate analysis

At multivariate analysis, HIV serology (OR 3.72, 95% CI 1.16–10.96), waist to hip ratio (OR 11.26 95% CI 1.98–68.24) and sickle cell disease OR 4.78 95% CI 1.11–19.70) were independent risk factors for stroke in young adults. Table ​ Table8 8 shows risk factors at multivariate analysis. None of the patients with HIV met the definition of AIDS as defined by the occurrence of any of the more than 20 life-threatening cancers or “opportunistic infections”, by WHO.

a High (male: > 0.95, female > 0.85); Normal (male: < 0.95, female < 0.85)

b Obtained accounting for matching by age and sex using a conditional logistic regression

Variables with p value < 0.2 included in multivariant analysis include fasting blood sugar, hypertension, family of diabetes mellitus, waist to hip ratio, leucocyte count, HIV serology, sickle cell disease and oral contraceptive use

This case–control study showed that the frequency of ischemic stroke was higher than that of hemorrhagic stroke in young Ugandan population. We showed that positive HIV serology, elevated waist to hip ratio and sickle cell disease were independent risk factors for stroke in this population.

This is consistent with several studies that have been done and found ischemic stroke to be more prevalent than hemorrhagic stroke. Studies done in Africa, in Libya reported 77% ischemic stroke and 23% hemorrhagic stroke (these included both intracerebral and subarachnoid hemorrhagic stroke) [ 14 ], in Morocco, 87.3% ischemic stroke and 12.7% hemorrhagic (study did not specify on the subtypes of hemorrhagic stroke) [ 6 ]. In a study from Bosnia and Herzegovina, Subarachnoid hemorrhage was more frequent in young adults compared with older patients (> 45 years of age) (22% vs. 3.5%), intracerebral hemorrhage (ICH) was similar in both groups (16.9% vs. 15.8%), but ischemic stroke (IS) was predominant stroke type in the older group (61% vs. 74%) [ 15 ]. On the other hand, studies focusing on all young stroke patients and including also subarachnoid hemorrhages have found much higher proportion of hemorrhagic strokes in younger vs. older individuals. Population-based studies have reported as low as 57% prevalence for ischemic stroke in those aged > 45, as reported by a recent narrative review [ 16 ]. This difference in occurrence of stroke subtypes could be due to the low prevalence of hypertension in this population in our setting given that hypertension has been reported to be the commonest risk factor for hemorrhagic stroke.

Most previous studies of HIV and stroke have been retrospective, but the prospective studies in Africa and East Africa have reported the importance of HIV as a risk factor for stroke [ 17 ]. A recently published study done in Malawi, with defined cases and population controls and 99% ascertainment of HIV status, reported HIV infection as an independent risk factor for stroke. This study further found that patients who had started standard HIV treatment in the previous six months had a higher risk of stroke (OR 15.6 95% CI 4.21–46.6). This was probably due to an immune reconstitution inflammatory syndrome (IRIS) like process [ 18 ]. A variety of mechanisms have been implicated in the association of HIV and stroke, these include HIV associated vasculopathy, vasculitis which causes abnormality of the intracranial or extracranial cerebral blood vessels and neoplastic involvement. Indirectly through cardioembolic, coagulopathy in association with protein C and protein S deficiency. Some infections are well established causes of stroke, such as Mycobacterium tuberculosi s , syphilis, and varicella zoster virus through increased susceptibility to acquisition or reactivation of these infections [ 19 , 20 ]. Combined antiretroviral therapy (cART) might unmask occult opportunistic infections that subsequently cause a stroke. This possibility should be considered in all patients who have had an acute stroke or have worsening of stroke symptoms after initiation of cART [ 21 ].

An elevated waist to hip ratio (WHR) was associated with 12 times increased risk of stroke among young adults in Mulago hospital compared to individuals with a normal waist to hip ratio. Abdominal obesity (measured as waist–hip ratio) is associated with an increased risk of myocardial infarction, stroke, and premature death [ 22 ]. This agrees with a few studies that have assessed the association of stroke with waist to hip ratio. Aaron et al. 1990, assessed the relation between body fat distribution, and the 2-year incidences of hypertension and stroke in a cohort of 41,837 women aged 55–69 years. Women who developed stroke were 2.1 (95% CI 1.5–2.9) times more likely to have an elevated ratio than those who did not [ 23 ]. Md Habib et al. 2011 assessed high waist to hip ratio as a risk factor for ischemic stroke for overall stroke and he found 64% of the ischemic stroke patient had abnormal WHR in Bangladesh [ 24 ]. Abdominal obesity measured with WHR was an independent risk factor for cryptogenic ischemic stroke (CIS) in young adults after rigorous adjustment for concomitant risk factors in the Revealing the Etiology, Triggers, and Outcome (SECRETO; NCT01934725) study, a prospective case–control study that included patients aged 18–49 years with a first ever CIS at 19 European university centers [ 25 ].

Sickle cell disease was also associated with increased risk of stroke among young adults in Mulago hospital. This agrees with several studies that have associated sickle cell disease with stroke. Ohene et al. 1998 assessed cerebrovascular accidents (CVA) in sickle cell disease, found the highest rates of prevalence of 4.01% and incidence of 0.61 per 100 patient-years. The incidence of hemorrhagic stroke was highest among patients aged 20 to 29 years [ 26 ].

In our study, the unadjusted OR for oral contraceptive use was 0.26 95% CI 0.08–0.87 with a p value of 0.028. This observation at the unadjusted level is significant but could be due to another variable which is a confounder to OC use such as higher socioeconomic status and better control of other possible risk factors.

In our study, we found no association between hypertension and stroke in young adults though it’s an independent risk factor for stroke in the older population. This finding is different from the multinational interstroke study which attributed most strokes among young adults in low- and middle-income countries to hypertension. In that study, only one fifth of the patients were from wealthier African countries where hypertension, diabetes and hypercholesterolemia are likely to occur with higher prevalence than in Mulago hospital [ 27 ]. Other studies have also reported the role of hypertension as a risk factor for stroke in young adults, low physical activity and hypertension were the most important risk factors, accounting for 59.7% and 27.1% of all strokes, respectively among a German nationwide case–control study based on patients enrolled in the SIFAP1 study (Stroke in Young Fabry Patients) 2007 to 2010 and controls from the population-based GEDA study (German Health Update) 2009 to 2010 [ 28 ]. A study that used population-based controls for hospitalized young patients with ischemic stroke demonstrated that independent risk factors for stroke were atrial fibrillation (OR 10.43; cardiovascular disease (OR, 8.01; type 1 diabetes mellitus (OR, 6.72; type 2 diabetes mellitus (OR, 2.31, low high‐density lipoprotein cholesterol (OR, 1.81; current smoking status (OR, 1.81; hypertension (OR, 1.43, and a family history of stroke (OR, 1.37) [ 29 ].

This finding could be explained by the high prevalence of hypertension in the general peri urban Ugandan population among young adults as reported by Kayima et al. 2015. He found a prevalence of 15% (95% CI 14.2 – 19.6%) % for young adults aged 18–44 years [ 30 ].

The study was conducted at Mulago hospital which is a national referral hospital in Uganda situated in central Uganda. Mulago hospital received patients both referred patients from all over Uganda and those from its catchment area. This is generally representative of the whole Ugandan population.

Uganda has a young population and with an HIV prevalence comparable to most countries in Sub-Saharan Africa, so the findings of this study are generalizable to other Sub-Saharan African populations.

Ischemic stroke is more prevalent than hemorrhagic stroke among young adults in Mulago hospital. Independent risk factors for stroke among young adults in Mulago hospital were HIV infection, elevated waist to hip ratio and sickle cell disease. Oral contraceptive use was found to be protective of stroke among young adults in Mulago hospital. There was no significant association between stroke among young adults and hypertension, diabetes, hyperlipidemia, smoking, alcohol use and illicit use.

Study limitations

• The sample size was too small to detect all but the strongest associations with common exposures. When designing the study, we based on hypertension as a significant driver for strokes in this population based on other studies done to calculate the sample size, however based on our findings, hypertension was not a big driver of stroke in this population. Secondly the nature of stroke type associated with hypertension is hemorrhagic which were less common in this study. This was an unexpected finding and needs more evaluation.
• Consecutive sampling methods has selection bias in which a variable that is associated with the outcome under investigation may occur more frequently or less in those sampled in this period as compared to the general population.
• The use of a combined ischemic stroke and intracerebral hemorrhage group may have obscured relationships specific to one group, i.e., the risk factors for stroke were not stratified for type of stroke.
• The best alternative for controls would have been healthy controls from the neighborhoods of the patients with stroke, but this would have been resource consuming hence the choice of hospital controls with different medical conditions from cases.

Acknowledgements

We acknowledge the patients of Mulago hospital who gave us consent to obtain this information.

Authors’ contributions

PN– conception, design of work, acquisition, analysis, interpretation of data, drafted and substantively revised the manuscript, JN– analysis, interpretation of data, drafted and substantively revised the manuscript, MK – analysis, interpretation of data, drafted and substantively revised the manuscript, EK– design of work, acquisition, analysis, interpretation of data, drafted and substantively revised the manuscript. All authors read and approved the final manuscript.

This study was funded with funds from the MEPI-Neurology program under Makerere University. The funding project had no role in the design of the study and collection, analysis, and interpretation of data and no role in writing the manuscript.

Availability of data and materials

Declarations.

Written informed consent/ assent was obtained from all participants or their parent/guardian or legal authorized representative to participate in the study. Ethical approval was obtained from Makerere University, school of medicine research and ethics committee (SOMREC) (reference number #REC REF 2015–105). All methods and procedures were carried out in accordance with relevant guidelines and regulations.

Not applicable.

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

• Systematic Review
• Open access
• Published: 18 September 2024

Systematic review and meta-analysis of stroke and thromboembolism risk in atrial fibrillation with preserved vs. reduced ejection fraction heart failure

• Meijuan Zhang 1 &
• Jie Zhou 1  

BMC Cardiovascular Disorders volume  24 , Article number:  495 ( 2024 ) Cite this article

Metrics details

Stroke and thromboembolism (TE) are significant complications in patients with atrial fibrillation (AF) and heart failure (HF). The impact of ejection fraction status on these risks remains unclear. This study aims to compare the risk of stroke and TE in patients with AF and HF with preserved (HFpEF) or reduced (HFrEF) ejection fraction.

Literature search of PubMed, Embase, and Scopus databases was done for studies in adult (20 years or more) population of AF patients. Included studies had reported on the incidences of stroke and/or TE in patients with AF and associated HF with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Cohort (prospective and retrospective), case-control studies, and studies that were based on secondary analysis of data from a trial were eligible for inclusion. Methodological quality was assessed using the Newcastle Ottawa Scale (NOS). Pooled hazard ratio (HR) with 95% confidence intervals (CI) were reported. Exploratory analysis was conducted based on the different cut-offs used to define HFrEF and HFpEF.

Twenty studies were analyzed. In the overall analysis, HFrEF in AF patients was associated with a significantly reduced risk of stroke and systemic TE (HR 0.88, 95% CI: 0.81, 0.96; n  = 20, I2 = 86.6%), compared to HFpEF. However, most studies showed comparable risk of stroke among the two groups of patients except for two studies that had documented significantly reduced risk. Upon doing the sensitivity analysis by excluding these two studies, we found similar risk among the two group of subjects and with no heterogeneity (HR 1.01, 95% CI: 0.99, 1.03; n  = 18, I2 = 0.0%). Exploratory analysis also showed that the risk of stroke and systemic thromboembolism was similar between those with HFpEF and HFrEF.

The findings suggest that there is no significantly different risk of stroke and systemic thromboembolism in cases of AF with associated HFpEF or HFrEF. The finding does not support integration of left ventricular ejection fraction into stroke risk assessments.

Peer Review reports

Introduction

Atrial fibrillation (AF) is connected to a higher incidence of stroke and systemic thromboembolism (TE) [ 1 , 2 ]. This risk is particularly significant if accompanied by heart failure (HF) [ 3 , 4 ], which is recognized as a risk factor for stroke and systemic TE [ 5 , 6 ]. Echocardiographic parameters allow to stratify HF into two distinct categories based on left ventricular ejection fraction (LVEF): HF with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively) [ 7 , 8 ]. HFrEF is characterized by impaired pumping capability of the heart, which exacerbates blood stasis, and increases the risk of thrombus formation [ 9 ]. HFpEF is defined as HF despite preserved LVEF(≥ 50%), with elevated natriuretic peptides, and impaired blood flow dynamics [ 10 ]. Given the increasing prevalence of AF and HF and their intricate relationship, it becomes imperative to understand nuanced aspects of their association with the risk of stroke and TE [ 11 ].

A prior systematic review that was published in 2015 and included seven studies, investigated cardiovascular outcomes among patients with AF and HFrEF, as opposed to HFpEF [ 12 ], and revealed that HFrEF correlated with a marked increase in all-cause mortality (Risk ratio, RR 1.24; N  = 10). However, there were no differences in the rates of stroke. During the following half-decade, additional studies have been conducted on this particular aspect, but no recent comprehensive updated meta-analysis attempted to summarize most current data.

This meta-analysis aims to bridge this gap by systematically reviewing and quantitatively synthesizing the available literature to compare the risk of stroke and thromboembolism in AF patients with HFpEF or HFrEF.

Materials and methods

Study protocol.

The protocol of the review was preregistered in PROSPERO ( https://www.crd.york.ac.uk/prospero/ ) under the registration number (CRD42024505106). The meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 13 ].

Literature search

Electronic searched were done in PubMed, Embase, and Scopus databases to identify relevant studies, published until 31st December 2023 using a combination of key terms: (Atrial fibrillation OR atrial flutter OR tachycardia) AND (heart failure OR cardiac failure OR cardiac disease) AND (preserved ejection fraction OR reduced ejection fraction OR ejection fraction OR cardiac output) AND (complications OR thromboembolism OR stroke OR cerebrovascular accident). Manual search of reference lists and review articles was also conducted.

We understand that including “atrial flutter” as a keyword was not strictly necessary. We decided to incorporate it to broaden our search and increase the number of potential studies identified. Our goal was to ensure a comprehensive review and reduce the risk of overlooking important studies that could contribute valuable data. Additionally, while not a primary reason, some studies might include results for combined cohorts of atrial fibrillation and atrial flutter patients, and we thought that this keyword may help us identify such studies as well.

Eligibility criteria

This meta-analysis included studies that involved adult populations (aged 20 years or more) diagnosed with AF and concurrent HF where ejection fraction data (preserved or reduced) was documented. We included cohort studies (both prospective and retrospective), case-control studies, and studies that were based on secondary analysis of trial records. The primary outcomes of interest were risk of stroke and systemic thromboembolism in AF patients with associated HF, with a specific focus on the stratification of outcomes by ejection fraction status (HFpEF or HFrEF). Peer-reviewed English-language articles published until 31st December 2023 were considered. We excluded studies involving paediatric patients or patients without a clear diagnosis of AF and/or HR. Review articles, editorials, letters, commentaries, and studies lacking original data, such as case reports, were also excluded. Additionally, non-peer-reviewed sources, such as conference posters, as well as studies with unclear reporting of outcomes or insufficient data were excluded.

Selection of studies for inclusion

Data deduplication was done for the studies identified through the preliminary literature search. Two study authors comprehensively screened titles and abstracts of remaining studies. Full texts of studies that met the initial criteria underwent a detailed evaluation to determine eligibility for inclusion. All discrepancies or disagreements were resolved by discussions.

Quality assessment of the studies

The Newcastle-Ottawa Scale (NOS) was employed for the standardized quality assessment of the selected studies [ 14 ]. The assessment is made based on study groups selection, intergroup comparability, and ascertainment of outcomes, with a maximum achievable value of 9. Higher scores indicate better quality [ 14 ].

Data extraction

Relevant data were extracted and included study authors, publication year, study location, design, subject characteristics, duration of follow-up, type of AF in the included patients, cut-off for ejection fraction used to define HFpEF and HFrEF, sample size, and key findings. Any disagreements were resolved by discussions.

Statistical analysis

Pooled effect sizes were reported as hazard ratios (HR) with 95% confidence intervals (CI). For all the statistical comparisons, HFpEF served as the reference. Subgroup analyses were conducted according to study design, type of AF, duration of follow up and sample size. The random-effects model was employed for all analysis to account for differences in participant characteristics and methodological variations among the included studies. The Cochrane I 2  > 40% indicated significant heterogeneity [ 15 ]. Publication bias was assessed by funnel plot and Egger’s test [ 16 ]. A P  < 0.05 on Egger’s test indicated presence of publication bias and this was supported by visual inspection of funnel plot. All analysis were conducted using STATA software version 15.0. We evaluated the certainty of the evidence using the standard GRADE approach and GRADE Pro software [ 17 ].

Literature search across databases identified 1714 studies. After deduplication, 1226 distinct studies remained. After subsequent evaluation of titles and abstracts, full texts of 51 relevant articles were screened, and additional 31 studies were eliminated. Finally, a total of 20 studies were included (Fig.  1 ) [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].

Process of selecting studies for inclusion

As summarized in Table  1 , there were eight studies with a retrospective and seven studies with a prospective cohort design. Remaining five studies were based on secondary analysis of data collected as part of randomized clinical trial. Most studies were conducted in the USA ( n  = 7). Three studies were conducted in the Republic of Korea and one study each in Russia, Poland, Japan, Sweden, Canada, and France. Four studies were multicenter. In almost all studies, HFpEF correlated with older age and higher proportion of female gender, compared to HFrEF patients. There were differences in the cut-off values used for defining reduced or preserved ejection fraction (EF) among the included studies. Majority of the studies defined HFrEF as EF < 50% and HFpEF as ≥ 50% ( N  = 8) followed by 7 studies that defined HFrEF as EF < 40% and HFpEF as ≥ 50%. This highlights a grey zone for EF between 40 and 50% that should be addressed. Only 11 studies reported on the type of AF. Out of them, eight had predominantly patients with permanent or persistent AF, two had patients with paroxysmal AF and in one study, the equal proportion of patients had either permanent/persistent or paroxysmal AF. We also reported available data from the included studies on CHA2DS2-VASc or CHADS2 score as well as NT-ProBNP or BNP level (Table  1 ). The data suggests that those with reduced ejection fraction had comparatively lower CHA2DS2-VASc/CHADS2 score and higher NT-ProBNP/ BNP level compared to those with preserved ejection fraction.

Most studies had a follow up period of more than one year ( n  = 15). The follow up period in these studies ranged from 15 months to 5 years. The included studies contributed to a total of 1,73,876 subjects. The mean NOS quality score of the studies was 7.5. There were 10 studies with a score of 8 and 10 studies with a score of 7 (Supplementary Tables 1 and 2 ). Overall, quality assessment results indicate that the included studies were of acceptable methodological quality.

Risk of stroke and systemic thromboembolism

HFrEF patients had lower risk of stroke and systemic thromboembolism (HR 0.88, 95% CI: 0.81, 0.96; n  = 20, I2 = 86.6%) compared to AF patients with HFpEF (Fig.  2 ), with no obvious publication bias (Egger’s p-value = 0.120) (Supplementary Fig.  1 ). However, most studies showed comparable risk of stroke among HFrEF and HFpEF patients except for the publication from Uhm et al. and Chung et al. Upon doing the sensitivity analysis by excluding these two studies, we found similar risk among the two group of subjects and with no heterogeneity (HR 1.01, 95% CI: 0.99, 1.03; n  = 18, I2 = 0.0%) (Egger’s p-value = 0.341) (Supplementary Fig.  2 ).

Risk of stroke and systemic thromboembolism among subjects with atrial fibrillation and associated reduced ejection fraction (HFrEF), compared to patients with preserved ejection fraction (HFpEF)

Subgroup analysis showed that the reduced risk of stroke and thromboembolism in HFrEF was only evident in prospective cohort studies (HR 0.74, 95% CI: 0.58, 0.94; n  = 7, I2 = 95.4%), studies with longer follow up (> 1 year) (HR 0.86, 95% CI: 0.77, 0.95; n  = 15, I2 = 90.0%) and studies with larger sample size (≥ 500) (HR 0.85, 95% CI: 0.76, 0.96; n  = 17, I2 = 88.3%) (Table  2 , Supplementary Figs.  3 – 9 ). No statistically significant association could be found on analysis based on the type of AF i.e., persistent or permanent AF (HR 0.86, 95% CI: 0.69, 1.07; n  = 8, I2 = 86.1%) and paroxysmal AF (HR 0.66, 95% CI: 0.25, 1.77; n  = 2, I2 = 98.3%) (Table  2 , Supplementary Figs.  10 and 11 ).

However, when the two studies i.e., Uhm et al. and Chung et al., were excluded from the subgroup analysis, the risk of stroke and thromboembolism was comparable in the two group of subjects (HFrEF and HFpEF) with low to negligible heterogeneity, irrespective of the study design, duration of follow up and sample size (Supplementary Figs.  12 – 14 ). We also conducted an exploratory analysis based on the cut-off used to define reduced and preserved ejection fraction. There were three sets of studies that we identified: first, where EF ≥ 50% indicated HFpEF and EF < 40% indicated HFrEF; second, where EF ≥ 50% indicated HFpEF and EF < 50% indicated HFrEF; and third, where EF ≥ 40% indicated HFpEF and EF < 40% indicated HFrEF. The findings within each of these three strata show that the risk of stroke and systemic thromboembolism is similar between those with HFpEF and HFrEF (Supplementary Fig.  15 ). The overall quality of evidence was judged to be “Low” according to the GRADE assessment criteria (Supplementary Fig.  16 ).

Our overall analysis shows that AF patients with HFrEF may have a lower risk of stroke and systemic thromboembolism than AF patients with HFpEF. However, substantial heterogeneity could affect this interpretation. The sensitivity analysis, after excluding the studies by Uhm et al. and Chung et al., clearly showed a similar risk of stroke and systemic thromboembolism between the two groups, with low heterogeneity. Subgroup analyses, after excluding these two studies, showed comparable risks of stroke and thromboembolism in the HFrEF and HFpEF groups, regardless of study design, duration of follow-up, and sample size. Our findings are consistent with and support those of a previous review that included data from seven studies ( n  = 33,773 subjects) and found a comparable risk of stroke in the HFrEF and HFpEF groups [ 12 ].

If we examine the overall findings, the significantly reduced risk of stroke and thromboembolism observed in those with HFrEF, might be attributed to distinct aspects of the underlying pathophysiology. We may speculate that left ventricular (LV) diastolic dysfunction, as seen in HFpEF, contributes to a higher risk, compared to LV systolic dysfunction found in HFrEF [ 38 , 39 ]. Left atrium (LA) to left ventricle (LV) blood flow is delayed in patients with LV diastolic dysfunction, leading to blood stasis in the LA, and subsequent increase in the risk of thromboembolism and stroke [ 40 ]. However, this reason may not be sufficient, as HFrEF is also associated with some degree of diastolic dysfunction [ 41 ]. Previous study reported higher rates of hypertension and high warfarin usage rate in patients with HFpEF, which might also partly contribute to the risk [ 42 ]. Another possible explanation could be the increased age of patients and a higher proportion of female patients with HFpEF in the included studies. The “congestive heart failure, hypertension, age, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age, sex category” (CHA 2 DS 2 -VASc) score serves as a valuable tool for assessing the risk of stroke associated with AF [ 43 ]. It incorporates various clinical risk factors, including age (higher points for older age) and sex (female sex contributing to a higher score). Patients with HFpEF, therefore, may have increased CHA2DS2-VASc score, and, subsequently, higher risk of stroke and thromboembolism. This brings an interesting perspective: there may actually be no significant difference in the risk of stroke and systemic thromboembolism between the two groups. The adjusting covariates differed between the studies included in this meta-analysis. Patients with AF and HFpEF were older and had a higher prevalence of comorbidities, which, if properly adjusted for in the analysis, could have led to a comparable risk. Additionally, there were differences in the definitions of HFrEF and HFpEF among the included studies. Considering these limitations, the reduced risk of stroke in HFrEF patients might not be significant and could be overstated. The sensitivity analysis (after exclusion of Uhm et al. and Chung et al.) also supports the view that there may be no significant risk difference between the two groups. The low quality of evidence, as judged by the GRADE assessment, strongly supports the need for more studies with robust methodology to provide conclusive evidence.

There were some limitations of our review. We found significant heterogeneity in the reported outcomes which could be due to some differences in the definitions of HFpEF and HFrEF, baseline characteristics of the patients, as well as differences in the methodology (study design and follow up period). The included studies were observational in design and therefore, despite efforts to control for confounding variables, there remains a possibility that some of the important confounders may not have been accounted for. This will ultimately influence the robustness of observed associations. The often-limited longitudinal data in many of the included studies may impact the ability to capture the dynamic nature of HF and AF progression. Additionally, the impact of changing treatment modalities over time on the risk of stroke was not assessed in this review. We were also not able to provide mechanistic insights into the risk of stroke.

Conclusion and implications for clinical practice

In conclusion, the “low” quality evidence from this meta-analysis does not provide convincing evidence that there is significantly different risk of stroke and systemic thromboembolism in cases of AF with associated HFpEF or HFrEF. The finding does not support integration of left ventricular ejection fraction into stroke risk assessments.

Nursing staff may potentially play a crucial role in preventing risk of stroke and systemic thromboembolism in patients with HF and AF. They could be instrumental in educating patients about the importance of adherence to anticoagulation therapy and regularly monitoring their health. Nursing professionals could be involved in assessing medication effectiveness, managing potential complications, and collaborating with healthcare teams for necessary treatment adjustments. They can also contribute to risk stratification, developing individualized care plans based on patient characteristics, and ensuring effective communication within multidisciplinary care teams. Considering limitations of our study, further research would need to focus on the underlying mechanisms contributing to the thromboembolic risk.

Data availability

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

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Zhang, M., Zhou, J. Systematic review and meta-analysis of stroke and thromboembolism risk in atrial fibrillation with preserved vs. reduced ejection fraction heart failure. BMC Cardiovasc Disord 24 , 495 (2024). https://doi.org/10.1186/s12872-024-04133-1

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New drug in preclinical studies indicates a potential therapy for stroke patients

A new study from case western reserve university and university of cincinnati shows promise that a new drug may help repair damage caused by strokes. .

Currently, there are no U.S. Federal Drug Administration-approved drugs to repair the damage caused by a stroke.

But a new preclinical study by researchers at Case Western Reserve University and the University of Cincinnati (in the journal  Cell Reports ) found a drug called NVG-291-R allows nervous system repair and significant functional recovery in an animal model of severe ischemic stroke. 

Jerry Silver, co-author of the study and professor of neurosciences at CWRU’s School of Medicine, said the study showed the drug repaired damage through at least two avenues: creating new neuronal connections and enhancing migration of newly born neurons derived from neuronal stem cells to the site of the damage. 

“NVG-291-R’s ability to enhance plasticity was demonstrated by using staining techniques that clearly showed an increase in axonal sprouting to the damaged part of the brain,” Silver said. “This enhanced plasticity is an excellent validation of the same powerful mechanisms that we and other researchers were able to demonstrate using NVG-291-R in spinal cord injury.”  

Additional studies will be needed to research if NVG-291-R effectively repairs damage caused by hemorrhagic strokes in both animal models and human patients.

NervGen Pharma Corp. holds the exclusive worldwide rights to NVG-291, and the drug is being tested in a clinical trial in healthy human subjects. NervGen plans to initiate patient safety and efficacy trials in spinal cord injury, Alzheimer’s disease and multiple sclerosis in 2022 and 2023.

Agnes (Yu) Luo, associate professor in the Department of Molecular Genetics and Biochemistry in UC’s College of Medicine, was the study’s senior author.

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Role of interatrial block in modulating cryptogenic stroke risk in patients with patent foramen ovale: a retrospective study

• Yanxing Zhang 1 ,
• Yangbo Xing 2 ,
• Xiatian Liu 3 ,
• Huayong Jin 4 ,
• Yuxin Zhang 5 ,
• Chengyi Li 6 &
• Buyun Xu 2  

BMC Neurology volume  24 , Article number:  345 ( 2024 ) Cite this article

Metrics details

The patent foramen ovale (PFO) and interatrial block (IAB) are associated with cryptogenic stroke (CS). However, the role of the interaction between PFO and IAB in CS remains unclear.

This case–control study enrolled 256 patients with CS and 156 individuals without a history of stroke or transient ischemic attack. IAB was defined as P wave duration > 120 ms. PFO was evaluated by contrast transesophageal echocardiography, and classified as no-PFO, low-risk PFO and high-risk PFO. Multiplicative and additive interaction analysis were used to assess the interaction between PFO and IAB in CS.

Multiplicative interaction analysis unveiled a significant interaction between IAB and low-risk PFO in CS (OR for interaction = 3.653, 95% CI, 1.115–12.506; P  = 0.037). Additive interaction analysis indicated that 68.4% (95% CI, 0.333–1.050; P  < 0.001) of the increased risk of CS related to low-risk PFO was attributed to the interaction with IAB. The results were robust in multivariate analysis. However, but no significant multiplicative or additive interaction was observed between IAB and high-risk PFO. When stratified by IAB, high-risk PFO was associated with CS in both patients with IAB (OR, 4.186; 95% CI, 1.617–10.839; P  = 0.003) and without IAB (OR, 3.476; 95% CI, 1.790–6.750; P  < 0.001). However, low-risk PFO was only associated with CS in patients with IAB (OR, 2.684; 95% CI, 1.007–7.149; P  = 0.048) but not in those without IAB (OR, 0.753; 95% CI, 0.343–1.651; P  = 0.479).

The interaction between IAB and PFO might play an important role in CS, particularly in cases with low-risk PFO.

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Introduction

Stroke is a significant contributor to global mortality and disability, of which 70% can be attributed to ischemic stroke (IS). It is essential to understand the mechanisms underlying IS for its secondary prevention. However, the etiology is undetermined in approximately 25% of IS cases, which are categorized as cryptogenic stroke (CS) [ 1 ].

Recently, the role of the patent foramen ovale (PFO) in IS has gained significant attention. PFO-related strokes account for 5% of all stroke cases and up to 10% in younger patients [ 1 ]. Randomized controlled trials have demonstrated the efficacy of PFO closure in preventing CS, reinforcing the significant role of the PFO in stroke etiology [ 1 ]. Paradoxical embolism is deemed the primary mechanism by which PFO contributes to IS [ 2 ], whereas other mechanisms, such as in situ thrombus formation [ 3 ], atrial arrhythmias, and reduced left atrial function, may also play a role in PFO-associated stroke [ 4 ]. In addition to PFO, interatrial block (IAB) is supposedly associated with IS [ 5 ]. IAB not only correlates with atrial fibrillation (AF) [ 5 ], but also increases the risk of IS in patients without AF, potentially due to left atrial blood stasis induced by IAB [ 5 , 6 ].

However, limited studies have focused on the relationship between the PFO and IAB and the role of their interactions on IS risk. The present study aimed to investigate the association between PFO and IAB and elucidate the impact of the interaction between PFO and IAB on CS risk.

Materials and methods

This case–control study was conducted in compliance with the ethical standards of the corresponding institution and the Declaration of Helsinki. The ethics review boards of Shaoxing People’s Hospital approved this study, and the requirement for informed consent was waived owing to the retrospective nature of this study. The analysis was reported in accordance with the STROBE guidelines.

Study population

For the cryptogenic stroke group (CS group), we consecutively enrolled patients with CS aged between 18 and 75 years, who underwent contrast transesophageal echocardiography (cTEE) at the Shaoxing People's Hospital from January 2021 to December 2023. The diagnosis of CS was adjudicated by cardiologists and neurologists based on previously published criteria [ 7 ]. All stroke cases were confirmed by brain magnetic resonance imaging and neurologic examination. The following tests were performed in all patients: transthoracic echocardiography and TEE; extracranial artery ultrasound or computed tomography angiography; laboratory tests; 12-lead electrocardiography; and 24-h Holter electrocardiographic monitoring. Patients with incomplete evaluations were not considered to have CS.

The control group comprised consecutive patients without a history of stroke/ transient ischemic attack (TIA) who underwent cTEE at the Shaoxing People's Hospital during the same period.

The exclusion criteria were as follows: 1) atrial fibrillation/flutter or sustained atrial tachycardia(> 30 s); 2) atrial premature beats within a 24-h period exceeding 10,000; 3) without electrocardiography results within 1 year before IS or cTEE;4) valvular heart disease, congenital heart disease other than PFO, or cardiomyopathy; 5) heart failure stages C to D [ 8 ]; 6) left atrial anteroposterior diameter greater than 45 mm; 7) a history of stroke or TIA; 8) systemic inflammatory diseases, coagulation dysfunction or malignancies; 9) PFO-related diseases other than IS, such as migraines and decompression sickness; and 10) missing key information or other conditions deemed unsuitable for inclusion by investigators.

Electrocardiography and echocardiography measurements

The last patients' ECGs within 1 year before IS or cTEE were obtained electronically. P-wave durations were measured using the MUSE v9 Cardiology Information System (GE HealthCare, UK). IAB was defined as a prolonged P-wave duration (≥ 120 ms) in the inferior leads [ 6 ]. The ECGs were analyzed by an independent experienced electrocardiologist blinded to the patients’ information.

All c-TEE examinations were performed according to local clinical protocols published previously [ 9 ]. A Philips EPIQ 7C real-time three-dimensional color cardiac ultrasound system (Philips Ultrasound, Bothell, Washington, United States) equipped with a transesophageal three-dimensional matrix probe X8-2t (frequency, 2–8 MHz) was utilized for the examinations. The contrast agent used was an agitated saline solution, administered via the antecubital vein. Images of each chamber section were observed both at rest and after a Valsalva maneuver, capturing at least 20 cardiac cycles. PFO was confirmed when the channel was visibly open and microbubbles traversed from the right to the left atrium within three cardiac cycles subsequent to right atrium opacification. All images were stored in a database and assessed by an experienced sonographer blinded to. the patients’ information.

The following characteristics of PFO were evaluated: the grading of right-to-left shunt flow (RLS), PFO size, atrial septal aneurysm (ASA) and hypermobile septum. All characteristics were evaluated at rest, except for RLS, which was evaluated both at rest and after the Valsalva maneuver.

The PFO with a right-to-left shunt (PFO-RLS) typically manifests within the initial 3–6 cardiac cycles following right atrium opacification. PFO-RLS was graded as follows: grade 0, the absence of microbubbles; grade 1, the presence of 1–10 microbubbles; grade 2, the presence of 11–30 microbubbles; and grade 3, the occurrence of > 30 microbubbles or near-complete opacification of the left atrium. The PFO height was measured as the maximum separation between the septum primum and septum secundum in the end-systolic frame, and a large-size PFO was defined as a PFO with a height exceeding 2 mm. ASA was characterized by > 10 mm septal excursion from the midline into the right or left atrium, or > 15 mm total excursion between both atria. Additionally, a moving and floppy septum, defined as > 5 mm septal excursion in every heartbeat, was categorized as a hypermobile interatrial septum [ 10 ].

The PFO with at least one of the following characteristics was defined as a high-risk PFO: PFO-RLS grade > 2 at rest or after the Valsalva maneuver, a large-size PFO, ASA or a hypermobile septum. Otherwise, the PFO was defined as low-risk PFO [ 4 , 7 ].

Data collection

The patients’ medical history was retrieved from medical records. To avoid the impact of IS on laboratory test results, the laboratory tests performed after the acute stage (1–2 weeks) of IS were abstracted for analysis. In the control group, the laboratory tests were conducted within 1 week before or after the cTEE procedure.

Statistical analyses

The Kolmogorov–Smirnov test was utilized to evaluate the normal distribution of continuous variables. Normally distributed data are presented as mean ± standard deviation and were compared using the Student’s t-test. Skewed data are expressed as median (lower quartile-upper quartile) and were compared using the Mann–Whitney test. Categorical variables are presented as counts and were compared using the Fisher’s exact test or Pearson’s chi-squared test, as appropriate.

The association between CS and potential risk factors was estimated by odds ratios (ORs) with 95% confidence intervals (CIs) calculated by logistic regression. Multiplicative and additive methods were used to investigate the role of interaction between IAB and PFO in CS development. Multiplicative interaction was assessed by introducing an interaction term into the logistic regression models. Additive methods were used to calculate the following parameters: 1) the attributable proportion (AP); 2) the relative excess risk due to interaction (RERI); and 3) the synergy index (SI) [ 11 ]. Moreover, subgroup analyses were conducted to evaluate the roles of IAB and PFO in CS development.

All data analyses were performed using R version 4.2.0. The “InteractionR” package was utilized for conducting interaction analyses. Statistical significance was determined at a 2-sided p -value ≤ 0.05.

Characteristics of study population

During the study, 304 patients with CS and 329 individuals without stroke/TIA underwent cTEE and ECG. We excluded 221 participants based on the exclusion criteria. Finally, 412 participants were included in the analysis. Figure  1 illustrates the participant selection process. Of the participants, 256 had CS (CS group) and the remaining 156 were classified as the control group. Participants in the CS group were older (56.7 ± 9.7 vs. 53.7 ± 13.0 years, P  = 0.014) and predominantly comprised men (68.0% vs. 54.5%, P  = 0.006), drinker (37.5% vs. 25.0%, P  = 0.009) and smokers (29.7% vs. 20.5%, P  = 0.040). Moreover, the incidences of hypertension (60.5% vs. 35.9%, P  < 0.001) and diabetes (21.1% vs. 7.7%, P  < 0.001) were significantly higher in the CS group. Additionally, patients in the CS group exhibited lower high-density lipoprotein (HDL) levels, larger left atrial dimensions, longer P-wave durations, and a higher IAB incidence. Regarding PFO, high-risk PFO incidence was higher in the CS group (34.8% vs. 13.5%, P  < 0.001), whereas there was no significant difference in low-risk PFO incidence between the groups (14.8% vs. 15.4%, P  = 0.849). Among patients with PFO, the PFO size was larger in the CS group (2.59 ± 1.37 vs. 1.99 ± 0.85 mm, P  = 0.001), while the RLS grade and incidence of ASA and hypermobile septa were comparable between the groups. Table 1 summarizes the characteristics of the participants. Table 2 presents the morphometric and functional characteristics of the PFO.

Patients’ selection process. AF, atrial fibrillation; AFL, atrial flutter; AT, atrial tachycardia; cTEE, contrast transesophageal echocardiography; PAC, premature atrial complex; TIA, transit ischemic attack

Risk of cryptogenic strokes and interaction of IAB and PFO

In the univariate analysis, conventional risk factors, such as age, sex, alcohol, smoking, hypertension, diabetes, D-dimer levels, high density lipoprotein levels and left atrial size, showed associations with CS. In addition, IAB (OR, 1.961; 95% CI, 1.293–2.973; P  = 0.002) and high-risk PFO (OR, 3.647; 95% CI, 2.127–6.251; P  < 0.001) were also associated with CS, whereas low-risk PFO (OR, 1.362; 95% CI, 0.770–2.410; P  = 0.288) displayed no association. Regarding to PFO characteristics, PFO size was the only factor associated with CS. Tables S1-2 show the results of the univariate analysis. After adjustment for potential confounders, the association between IAB, high-risk PFO, and CS remained significant (Table  3 ).

Before evaluating the interaction, the relationship between PFO and IAB was investigated. The incidence of IAB was comparable among participants with low-risk PFO, high-risk PFO, and those without PFO (31/62 vs. 45/110 vs. 97/240, P  = 0.381). Among participants with PFO, no association was detected between IAB and PFO characteristics (Table S3).

Multiplicative interaction analysis unveiled a significant interaction between IAB and low-risk PFO (OR for interaction = 3.653, 95% CI, 1.115–12.506; P  = 0.037), while no significant multiplicative interaction was observed between IAB and high-risk PFO (OR for interaction = 1.204, 95% CI, 0.378–3.841; P  = 0.753). Regarding additive interaction analysis, a significant AP of 0.684 (95%CI, 0.333–1.050; P  < 0.001) was observed for IAB and low-risk PFO upon using no-IAB/no-PFO as the comparator. Correspondingly, the RERI ( P  = 0.073) and SI ( P  = 0.079) tended to be significant. However, no significant AP, RERI and SI were detected for IAB and high-risk PFO (Table  4 ). The results of the interaction analysis remained robust after adjusting for potential confounders, as depicted in Table  4 . In the subgroup analysis, IAB conferred an increased risk of CS in patients with low-risk PFO (OR, 5.769; 95% CI, 1.843–18.064; P  = 0.003) and tended to increase CS risk in patients without PFO (OR, 1.619; 95% CI, 0.960–2.732; P  = 0.071). However, no significant association between IAB and CS was detected in patients with high-risk PFO (OR, 1.950; 95% CI, 0.693–5.491; P  = 0.206). When stratified by IAB, high-risk PFO was associated with CS in both patients with IAB (OR, 4.186; 95% CI, 1.617–10.839; P  = 0.003) and without IAB (OR, 3.476; 95% CI, 1.790–6.750; P  < 0.001). However, low-risk PFO was only associated with CS in patients with IAB (OR, 2.684; 95% CI, 1.007–7.149; P  = 0.048) but not in those without IAB (OR, 0.753; 95% CI, 0.343–1.651; P  = 0.479).

The present study found a significant interaction between IAB and low-risk PFO pertaining to CS risk. The results of the multiplicative interaction analysis and subgroup analysis indicated that isolated low-risk PFO was not associated with CS; however, when combined with IAB, low-risk PFO increased the risk of CS. The additive interaction results suggested that nearly 70% of the increased risk of CS associated with low-risk PFO was attributed to the interaction with IAB. Nevertheless, no significant multiplicative interaction between high-risk PFO and IAB was observed. Correspondingly, IAB was significantly associated with CS in patients with low-risk PFO, but not in those with high-risk PFO and without PFO.

PFO has been considered as an important risk factor for CS [ 1 ]. The prevalence of PFO is approximately 25% in the general population. Not all PFOs lead to stroke. Identifying high-risk PFOs is a crucial aspect of secondary prevention for patients with CS and may even serve as an important strategy for primary prevention. Currently, the diagnosis of PFO-associated strokes is primarily determined by clinical characteristics and the high-risk features of the PFO. In addition to clinical characteristics and the features of the PFO, the present study suggested that IAB was a neglected but important factor modifying the risk of PFO in CS and should be considered in clinical practice. There are several potential mechanisms underlying the interactions between PFO and IAB.

First, IAB may increase PFO-RLS, thereby raising the risk of paradoxical embolism associated with PFO. Although the mechanisms behind PFO-associated strokes are not fully understood, paradoxical embolism is considered a major contributing factor. PFO-RLS forms the basis of paradoxical embolism and stands as the most significant risk factor for PFO-associated strokes [ 1 ]. Factors leading to an increase in PFO-RLS, such as ASA, prominent Chiari network, and Eustachian valve, may increase CS risk [ 10 ]. Previously, researchers have focused primarily on the morphological factors of PFO that may lead to an increase in PFO-RLS. However, the impact of abnormal atrial electrical activity on PFO-RLS remains unclear. Normal atrial electrical activity originates from the sinoatrial node, and travels through the Bachmann bundle, interatrial septum, and coronary sinus to activate the left atrium. Therefore, the right atrium contracts earlier than the left atrium. When the right atrium contracts before the left, its pressure exceeds that of the left atrium, leading to PFO-RLS. Therefore, when IAB further delays the contraction of the left atrium, the risk of paradoxical embolism increases. A previous study reported that atrial mechanical dyssynchrony, a consequence of IAB, increased PFO-RLS [ 12 ]. Second, PFO may exacerbate the left atrial blood stasis caused by IAB. IAB itself is a risk factor for CS. The mechanisms underlying CS caused by IAB may be associated with left atrial blood stasis [ 5 ]. PFO-RLS may exert a significant effect on left atrial hemodynamics. A recent study reported that PFO-RLS may reduce stroke in the patients with AF by increasing left atrial appendage emptying velocity [ 13 ]. However, in a computational fluid dynamics study, PFO-RLS contributed to increased blood stasis in the left atrium [ 14 ]. Third, IAB may be associated with the risk of in situ thrombus formation in PFO. In addition to the paradoxical embolism, the PFO may also lead to in situ thrombus formation [ 3 ]. IAB may be associated with increased interatrial septal fat, a local marker of endothelial dysfunction and myocardial fibrosis [ 15 , 16 ]. Therefore, IAB may be associated with the risk of in situ thrombus formation in PFO.Furthermore, IAB may also be associated with other risk factors of PFO-associated stroke, such as a hypermobile septum and left atrial enlargement [ 17 , 18 ]. Overall, in theory, a complex interaction may exist between the IAB and PFO in the causation of CS. Future studies are warranted to explore the potential mechanisms underlying the interaction between PFO and IAB.

In the present case–control study, we demonstrated a significant interaction between IAB and PFO in the development of CS. Similar to previous studies, the present study did not observe a significant association between low-risk PFO and CS [ 1 ]. However, low-risk PFO increased the risk of CS approximately thrice in patients with IAB. This finding holds crucial clinical significance. Currently, the diagnosis of PFO-associated stroke is primarily based on clinical features and PFO morphology. In patients with low-risk PFO, the probability of PFO-associated stroke is usually considered low. However, based on our findings, we should not neglect the significance of low-risk PFO in patients with IAB. With regard to high-risk PFO, similar to previous studies, we confirmed the significant association between high-risk PFO and CS. However, it was interesting that no significant interaction between IAB and high-risk PFO was detected. It was speculated that the strong association between high-risk PFO and CS might overshadow the role of interaction between high-risk PFO and IAB negligible. For example, the large RLS of high-risk RLS would dilute the impact of IAB on PFO-RLS, as mentioned above. To further explore the mechanism underlying the interaction between IAB and PFO, we assessed the correlation between IAB and the high-risk features of PFO, including PFO-RLS, ASA, and hypermobile septum, but no significant association was detected. While we did not demonstrate that IAB increases the PFO-RLS, it may still extend the duration of PFO-RLS. Whether this may increase the probability of paradoxical embolism requires further investigation. Furthermore, these results suggest that the interaction between IAB and PFO may be independent of PFO-RLS.

This study had several limitations. First, as a single-center study, the findings should be interpreted with caution and require further validation through multi-center studies. Second, the retrospective design introduces significant bias, particularly selection bias, since the study included only patients who underwent cTEE at our center, potentially resulting in a higher incidence of PFO compared to the general population. However, due to the low incidence of CS, conducting a prospective cohort study would be challenging. Despite these limitations, the primary aim of this study was to investigate the interaction between PFO and IAB. We demonstrated that IAB is not associated with PFO or its characteristics, minimizing the impact of selection bias on the assessment of the interaction. Additionally, subgroup analyses further validated the interaction between PFO and IAB. Lastly, we did not provide evidence for the mechanism underlying PFO and IAB interaction, thus warranting further investigation.

In summary, our study highlights the significant interaction between interatrial block (IAB) and patent foramen ovale (PFO) in cryptogenic strokes, mainly in those with low-risk PFO. These findings enhance our understanding of the mechanisms underlying CS and provide valuable insights into preventive measures.

Availability of data and materials

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Atrial fibrillation

Attributable proportion

Atrial septal aneurysm

Contrast transesophageal echocardiography

Confidence intervals

Cryptogenic stroke

Interatrial block

Ischemic stroke

Patent foramen ovale

Right-to-left shunt flow

Relative excess risk due to interaction

Synergy index

Transient ischemic attack

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Acknowledgements

This work was supported by the Health Commission of Zhejiang Province, China (grant number: 2024KY481), and the Health Commission of Shaoxing, China (grant number: 2022KY031).

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Ye Du & Yanxing Zhang

Department of Cardiology, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), 568 # Zhongxing North Road, Shaoxing, Zhejiang Province, 312000, China

Yangbo Xing & Buyun Xu

Department of Ultrasound, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, China

Xiatian Liu

Department of Electrocardiogram, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, 312000, China

Huayong Jin

Zhejiang University School of Medicine, Hangzhou, 310000, China

Yuxin Zhang

Shaoxing University School of Medicine, Shaoxing, 312000, China

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Conception and design: Ye Du, Buyun Xu, Yanxing Zhang, Yangbo Xing; administrative support: Buyun Xu; provision of study materials or patients: Ye Du, Yanxing Zhang, Yangbo Xing, Xiatian Liu, Huayong Jin; collection and assembly of data: Ye Du, Yanxing Zhang, Yuxin Zhang, Chengyi Li; data analysis and interpretation: Ye Du, Buyun Xu; manuscript writing: all authors; and final approval of the manuscript: all authors. 

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Du, Y., Zhang, Y., Xing, Y. et al. Role of interatrial block in modulating cryptogenic stroke risk in patients with patent foramen ovale: a retrospective study. BMC Neurol 24 , 345 (2024). https://doi.org/10.1186/s12883-024-03829-3

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Single-branched stent-graft with on-table fenestration for the management of zone 2 landing TEVAR with an isolated left vertebral artery: a pilot study

• Xiang Kong 1 ,
• Jiquan Yu 1 ,
• Peng Ruan 1 &
• Jianjun Ge 1  

Journal of Cardiothoracic Surgery volume  19 , Article number:  528 ( 2024 ) Cite this article

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It is challenging to simultaneously conduct total endovascular repair and reconstruct the left subclavian artery (LSA) and isolated left vertebral artery (ILVA) in patients who had an ILVA and required zone 2 anchoring. This pilot study reported the initial application experience of thoracic endovascular aortic repair (TEVAR) with a proximal zone 2 landing for aortic arch reconstruction in patients with ILVA.

This study was a retrospective consecutive single-center case series analysis, which involved four patients with ILVA who required zone 2 anchoring and received TEVAR combined with a single-branched stent graft and concomitant on-table fenestration between March 2021 and December 2022.

The postoperative follow-up period was 6–27 months, and no postoperative deaths or other primary complications occurred. There were no signs of a stroke or spinal cord ischemia, as well as no chest or back pain. The postoperative computed tomography angiography showed unobstructed ILVA and LSA, no stent stenosis and displacement, and no signs of endoleak.

The outcome suggested that this technique might be a feasible, safe, and alternative treatment for such patients. Further studies with larger samples and longer follow-up periods are needed to confirm our findings.

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The isolated left vertebral artery (ILVA) originates from the aortic arch and is usually located between the left common carotid artery (LCCA) and the left subclavian artery (LSA). It is the second most common congenital anomaly of the aortic arch with an incidence of 1.7 to 4.3% [ 1 ]. It is often required to cover LSA and ILVA and establish an adequate proximal landing zone when this aberration is found during thoracic endovascular aortic repair (TEVAR) of aortic arch pathologies. Open revascularization techniques like carotid-subclavian bypass are commonly employed for the treatment of patients with LSA coverage, especially for non-ILVA cases. Improper management of ILVA may result in brain ischemia or infarction [ 2 ]. However, due to the limited data obtained from case reports, the optimal treatment for aortic arch diseases combined with ILVA remains unclear. This study reported the treatment effect of TEVAR in patients with ILVA who underwent zone 2 anchoring with a single-branched stent graft and concomitant on-table fenestration.

It was a retrospective single-center case series study. All patients with aortic arch pathologies who underwent TEVAR between March 2021 and December 2022 were retrospectively evaluated ( n  = 159). Patients without ILVA ( n  = 152), patients with ILVA and who received on-table single big fenestration ( n  = 1), and those following ILVA translocation and LCCA-LSA bypass ( n  = 1) were excluded from the analysis. Finally, patients following on-table fenestration with the branched stent graft comprised the study cohort ( n  = 4; Fig.  1 ). The Institutional Ethics Committee approved the study (IRB number, 2023-RE-123). Participants were not required to provide informed consent due to the retrospective nature of this study. All patients underwent preoperative computed tomography angiography (CTA) of the aortic arteries. Endosize software (Therenva SAS, Rennes, France) was used to evaluate vertebral artery dominance, ILVA diameter, aortic arch type and pathology, the distance between ILVA and LSA, location of the primary entry tear, maximum aortic diameter, and true or false lumen. The aortic reconstruction was completed with CTA in a central-line protocol mode.

Flow diagram for the enrollment of patients treated by TEVAR with a proximal zone 2 landing Note TEVAR, thoracic endovascular aortic repair; ILVA, isolated left vertebral artery

This study used the Castor stent (MicroPort Endovascular, Shanghai, China) as a novel unibody single-branched stent with on-table fenestration for endovascular repair of the aortic arch (Fig.  2 ). Acute type B aortic dissection (AD) patients were treated with medications to control their blood pressure and heart rate. Surgery was performed at least one week after the onset of acute AD when the clinical condition was stable. All procedures were performed in a conventional supine position under general anesthesia and were given 1.5 g of intravenous cefuroxime sodium 30 min before surgery to prevent surgical infection. The systemic heparin was administered at 100 IU/kg after the percutaneous arterial puncture. The stent was 5 to 10% oversized the maximum diameter of the true lumen in zone 2 (Fig.  3 ). The proximal part of the Castor stent was released out of its outer sheath at the operating table. An on-table fenestration was made to preserve the ILVA. The location and size of the fenestration were determined based on the preoperative aortic CTA measurement. The coating part of the stent was excised with a surgical blade for on-table fenestration (Fig.  4 ). The Castor stent was inserted into the delivery system and should avoid being distorted and shortened.

Schematic diagram of surgery. Castor stent as a novel unibody single-branched stent with on-table fenestration for endovascular repair of the aortic arch. Note BT, brachiocephalic trunk; LCCA, left common carotid artery; LSA, left subclavian artery; ILVA, isolated left vertebral artery; TL, true lumen; FL, false lumen

ILVA originating from the aortic arch by preoperative CTA. (A) Transverse plane; (B) Coronal plane; (C) 3D reconstruction model. Note BT, brachiocephalic trunk; LCCA, left common carotid artery; LSA, left subclavian artery; ILVA, isolated left vertebral artery; TL, true lumen; FL, false lumen

On-table fenestration of the Castor stent graft. A Castor branched stent graft; B The outer sheath was released; C The proximal part of the Castor stent was released out of its soft sheath; C An on-table fenestration was made to preserve the ILVA. Note ILVA, isolated left vertebral artery

The detailed operation of the Castor stent was described earlier [ 3 ]. The right femoral artery (RFA) was exposed through a right inguinal incision. The left femoral artery (LFA) and left brachial artery (LBA) were punctured to insert the 6 F sheath. A contrast catheter was inserted into the ascending aorta through the RFA. The diagnosis was confirmed by angiography and preoperative imaging data. The access at LBA and RFA was established to ensure the successful insertion of the catheter in the true lumen of the aorta. A 0.035-inch super-stiff guidewire (Amplatz, Olympus, USA) was inserted into the ascending aorta via the RFA. The main body of the Castor stent was introduced through the super stiff guidewire, and its branch section was introduced into LSA through the access at LBA and RFA. A contrast catheter was placed into the ascending aorta through the sheath in the LFA to confirm that the proximal end of the main body of the Castor stent was located at the posterior edge of the LCCA ostium and that the branch section was pulled into the LSA. The medication treatment was used to maintain the patient’s systolic blood pressure at around 90 mmHg for the deployment of the main body. The main body and the branch section were released successively (Fig.  5 ). The angiography catheter was sent to the ascending aorta again. After the angiography confirmed a satisfactory position of the stent, the delivery system, guide wires, and catheters were withdrawn, and the puncture sheath was removed. The incisions at RFA and right groin were sutured. Hemostasis was achieved by pressing the LFA and LBA puncture sites. After surgery, the patients was treated with 100 mg of aspirin once a day for one year. The aortic CTA was performed six, 12, and 24 months postoperatively. All patients underwent physical examination one month after surgery and were followed up until June 2023.

Successful reconstruction of LSA and LVA confirmed by intraoperative angiography and postoperative CTA. A Intraoperative angiography demonstrated type B aortic dissection and the origin of ILVA from the aortic arch between LCCA and LSA before stent-graft insertion; B Intraoperative angiography revealed that the branch section of the Castor stent was pulled into the LSA; C Intraoperative angiography revealed complete coverage of the primary tear of the aortic dissection without endoleak and normal flow of ILVA and LSA after the Castor stent release; D 3D-CTA showed the patency of ILVA and LSA and the favorable revascularization of aorta arch without endoleak at the three-month follow-up. Note LCCA, left common carotid artery; LSA, left subclavian artery; ILVA, isolated left vertebral artery; TL, true lumen; FL, false lumen; 3D-CTA, 3-dimensional computed tomographic angiography

Between March 2021 and December 2022, four patients in our center, including three cases of acute aortic dissection and one of aortic aneurysm, underwent ILVA and LSA reconstruction using a single-branched stent graft with the on-table fenestration technique. Their preoperative data are shown in Table  1 . The mean age of the patients was 62.8 ± 15.3 years (range, 48–76 years). The total time for creating the on-table fenestration (unsheathing and re-sheathing of the thoracic endograft) was about 20 to 30 min. The mean operation time was 118 ± 21.3 min (range, 91–141 min). The technical success rate (defined as ILVA patency) was 100%. The mean postoperative length of hospital stay was 9.8 ± 5.7 days (range, 3–14 days). Intraoperative angiography confirmed complete isolation of the primary entry tear and ILVA and LSA patency. The postoperative follow-up period was 6–27 months, with an average of 15.8 ± 9.9 months. No postoperative deaths or other primary complications occurred. Besides, there were no stroke or spinal cord ischemia symptoms and no further chest and back pain. One postoperative patient refused to undergo CTA due to renal insufficiency. The postoperative CTA of other patients showed patent ILVA and LSA, false lumen thrombosis, no stent stenosis or displacement, and no signs of endoleak (Fig.  4 ).

It is difficult to reconstruct LSA and ILVA while performing TEVAR in patients with ILVA requiring zone 2 anchoring. Normal vertebral arteries can form the basilar arteries and supply blood to the cerebellum and brainstem. The prevalence of a complete Willis circle is 42% in the Western population and 27% in Chinese people [ 4 , 5 ]. ILVA is not associated with any clinical symptoms; however, it may increase the risk of spinal cord injury (SCI) and cerebral infarction after aortic arch surgery. It remains controversial to cover ILVA during TEVAR, and there are no clear guidelines and few relevant reports. If there exists insufficient vascular connection at the Willis circle, covering ILVA may reduce the brain stem or cerebellar perfusion and increase the risk of neurological deficits. Emerging evidence has suggested that a potential reduction in the brain stem or cerebellar perfusion due to VA occlusion could contribute to nerve injury [ 6 , 7 ].

Previous studies have compared the early and late outcomes of conventional open surgery and hybrid surgery (ILVA translocation and LCCA-LSA bypass) for aortic lesions with ILVA and concluded a favorable effect in both methods [ 8 , 9 ]. Nevertheless, elderly or high-risk patients might not tolerate median sternotomy and its fatal complications. In contrast, hybrid surgery was less invasive than open surgery and showed mild to moderate complications, including bleeding from the wound, wound infection, bypass obstruction, and local nerve damage. Therefore, total endovascular repair during this procedure might reduce the risk of brain disease, early mortality, and length of hospital stay. Recent guidelines suggested that LSA revascularization should be performed during zone 2 TEVAR with an insufficient anchoring zone in non-emergency patients [ 10 ]. The branched stent technique was superior to other methods for LSA reconstruction because it did not cause type Ia (common in chimney technique) and III leakage (common in fenestration technique). The incidence of stent restenosis was high due to the small diameter of ILVA. Therefore, ILVA endograft should be avoided as much as possible. The simultaneous reconstruction of LSA and ILVA using single or double on-table fenestration was a feasible technique for the endovascular repair of ILVA. The cerebral ischemia might occur during traditional on-table fenestration of arch lesions due to misalignment of the fenestration. One prior study found that two patients with dizziness had a partial misalignment of the fenestration to the origin of the ILVA and insufficient blood perfusion of the cerebellum [ 11 ]. We successfully applied a novel “Castor” single branched-stent graft with on-table fenestration to optimize the process of endovascular ILVA reconstruction and reduce the risk of cerebral ischemia. In addition to the successful reconstruction of the blood flow of LSA, the anchoring and positioning effects of the branch section could help quickly and accurately determine the fenestration site and avoid the possibility of poor alignment during fenestration. All ILVA patients were confirmed to have accurate alignment by the results of immediate imaging after stent implantation and postoperative CTA, and there were no postoperative brain complications.

Limitations

The study had certain limitations. This was a single-center, retrospective observational study with limited samples and relatively shorter follow-up periods. In addition, this study lacked a control group.

In summary, our study with limited samples suggested that the unibody single-branched stent graft combined with on-table fenestration was a safe, feasible therapeutic for patients with ILVA who required zone 2 anchoring. Nevertheless, our finding needed to be confirmed by further studies with larger samples and longer follow-up times.

Data availability

All generated or analyzed data, as well as the materials used during this study were included in this article.

Abbreviations

Left Subclavian Artery

Isolated Left Vertebral Artery

Thoracic Endovascular Aortic Repair

Left Common Carotid Artery

Computed Tomography Angiography

Aortic Dissection (AD)

Right Femoral Artery

Left Femoral Artery

Left Brachial Artery

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Xiang Kong designed the work and wrote the main manuscript. Jiquan Yu, and Peng Ruan collected and analyzed the patients’ data. Xiang Kong and Jianjun Ge revised the final manuscript. All authors read and approved the final manuscript.

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The present study was approved by the institutional review board of The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, USTC. (IRB number, 2023-RE-123). Participants were not required to provide informed consent due to the retrospective nature of this study.

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Kong, X., Yu, J., Ruan, P. et al. Single-branched stent-graft with on-table fenestration for the management of zone 2 landing TEVAR with an isolated left vertebral artery: a pilot study. J Cardiothorac Surg 19 , 528 (2024). https://doi.org/10.1186/s13019-024-03024-y

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Received : 23 July 2023

Accepted : 30 August 2024

Published : 13 September 2024

DOI : https://doi.org/10.1186/s13019-024-03024-y

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• Thoracic endovascular aortic repair (TEVAR)
• Isolated left vertebral artery (ILVA)
• Branched stent graft
• On-table fenestration

Journal of Cardiothoracic Surgery

ISSN: 1749-8090

• General enquiries: [email protected]