ARTICLE 1: DIAGNOSTIC EVALUATION OF STROKE ETIOLOGY
James F. Meschia, MD, FAAN. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):412–424.
Precise therapies require precise diagnoses. This article provides an evidence-based approach to confirming the diagnosis of ischemic stroke, characterizing comorbidities that provide insights into the pathophysiologic mechanisms of stroke, and identifying targets for treatment to optimize the prevention of recurrent stroke.
Identifying the presence of patent foramen ovale, intermittent atrial fibrillation, and unstable plaque is now routinely included in an increasingly nuanced workup in patients with stroke, even as ongoing trials seek to clarify the best approaches for treating these and other comorbidities. Multicenter trials have demonstrated the therapeutic utility of patent foramen ovale closure in select patients younger than age 60 years. Insertable cardiac monitors detect atrial fibrillation lasting more than 30 seconds in about one in ten patients monitored for 12 months following a stroke. MRI of carotid plaque can detect unstable plaque at risk of being a source of cerebral embolism.
To optimize the prevention of recurrent stroke, it is important to consider pathologies of intracranial and extracranial blood vessels and of cardiac structure and rhythm as well as other inherited or systemic causes of stroke. Some aspects of the stroke workup should be done routinely, while other components will depend on the clinical circumstances and preliminary testing results.
- The stroke workup is the set of diagnostic tests performed to gain insight into modifiable risk factors and stroke mechanism. The stroke workup has fixed and variable components, the latter being contingent on clinical circumstances, initial testing, and therapeutic objectives.
- Recent American Heart Association guidelines on secondary stroke prevention include an algorithm for performing an evidence-based diagnostic evaluation.
- Three or more transient ischemic attacks in a 2-week period in the same arterial distribution suggest an unstable atherosclerotic plaque as a mechanism.
- A stroke evaluation should include examining the patient for preceding strokes or transient ischemic attacks, atherosclerotic risk factors, head or neck trauma or radiation therapy, migraines, and a family history of stroke or dementia.
- Nearly 5% of strokes, most of which are lacunar and infratentorial, have a National Institutes of Health Stroke Scale (NIHSS) score of 0. Although these strokes are usually not treated with thrombolytics, they are nonetheless important to recognize because the stroke recurrence rates for NIHSS 0 and non-0 strokes are very similar.
- Nearly 7% of acute ischemic strokes do not have a focal area of restricted diffusion on initial diffusion-weighted imaging. Patients with posterior circulation stroke are 5 times as likely to have diffusion-weighted imaging–negative stroke as patients with anterior circulation stroke.
- CT angiography in the oblique and axial planes is the imaging modality of choice for identifying carotid webs.
- Long-term cardiac rhythm monitoring detects severalfold more cases of atrial fibrillation than routine inpatient monitoring following a stroke (12.1% versus 1.8%), although the minimum burden of intermittent atrial fibrillation to justify anticoagulation remains uncertain.
- Transesophageal echocardiography may be less sensitive in detecting patent foramen ovale than contrasted transthoracic echocardiography.
- To diagnose embolic stroke of undetermined source, patients should have a stroke workup that includes, at a minimum, brain imaging, ECG, transthoracic echocardiography, cardiac monitoring for at least 24 hours, and imaging of both intracranial and extracranial arteries.
- The yield of testing for genetic stroke syndromes is much higher when patients have a positive family history or a plethora of recurrent strokes and a paucity of conventional risk factors, particularly if the strokes are due to small vessel disease.
- Patients with aseptic cerebral venous thrombosis should be screened for thrombophilia.
- A C-reactive protein level higher than 10 mg/L should raise suspicion for stroke caused by endocarditis.
ARTICLE 2: INTRAVENOUS THROMBOLYSIS FOR ACUTE ISCHEMIC STROKE
James C. Grotta, MD, FAAN. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):425–442.
This article reviews the history of IV thrombolysis, its current indications and implementation, the duality of the “time is brain” versus “tissue clock” approaches, the impact of endovascular thrombectomy on IV thrombolysis, the emergence of tenecteplase, and future research directions.
The growing use of factor Xa inhibitors has increasingly caused patients with stroke to be excluded from treatment with IV thrombolysis. Important geographic, socioeconomic, sex, race, and ethnic disparities have been identified in the implementation of IV thrombolysis and need to be overcome. IV thrombolysis substantially improves outcomes when provided within the first golden hour after stroke onset in patients treated in mobile stroke units, supporting the “time is brain” concept and encouraging the possible value of more widespread implementation of the mobile stroke unit approach. At the same time, other studies have shown that IV thrombolysis can be successful in patients whose “tissue clock” is still ticking up to 9 hours after stroke onset or in patients who awaken with their stroke, as demonstrated by favorable imaging profiles. These considerations, along with the emergence of endovascular thrombectomy, have fostered examination of our care systems, including the “drip and ship” versus direct to comprehensive or endovascular thrombectomy stroke center approaches, as well as the possibility of skipping IV thrombolysis in certain patients treated with endovascular thrombectomy. Data suggesting that tenecteplase is at least noninferior to alteplase, as well as its more convenient dosing, has led to its increased use. Ongoing studies are evaluating newer thrombolytics and adding antithrombotic therapy to IV thrombolysis.
IV thrombolysis remains the most common acute stroke treatment. Advances in acting faster to treat stroke have increased its efficacy, and advances in imaging have expanded its use. However, implementing these advances and overcoming disparities in IV thrombolysis use remain major challenges.
- Extensive clinical trial data and “real world” experience support the efficacy and safety of recombinant tissue plasminogen activator (rtPA) as the primary treatment for acute ischemic stroke.
- An improving deficit or low National Institutes of Health Stroke Scale score does not exclude a patient from receiving rtPA if, after a careful neurologic history and examination, the stroke-related deficit would be disabling if it persisted without treatment.
- While rtPA is approved by the US Food and Drug Administration (FDA) for only up to 3 hours after symptom onset, data and guidelines support its use for up to 4.5 hours after symptom onset.
- The use of factor Xa inhibitors is an increasing cause of exclusion from treatment with IV thrombolysis.
- Use of emergency department telestroke, bringing stroke treatment to the patient’s home via mobile stroke units, improved telecommunication, and other devices will help increase the use of IV thrombolysis.
- There are many disparities in the availability and use of IV thrombolysis, and overcoming them is an important priority for improving stroke outcomes.
- The sooner IV thrombolysis is delivered after symptom onset, the better the outcome; if treatment can be given in the first golden hour via mobile stroke units or by expedited emergency department care, two-thirds of patients will recover with no disability.
- Advanced imaging reveals that the temporal progression of stroke is different in each patient; outcomes with treatment out to 9 hours after symptom onset in imaging-selected patients may result in comparable benefit to earlier treatment.
- Regional systems of care must balance the need to administer IV thrombolysis as soon as possible to those who qualify while also identifying and expediting triage of patients with large vessel occlusion to the nearest endovascular thrombectomy center.
- IV thrombolysis can dissolve 20% to 30% of large vessel occlusion clots and should not be withheld in patients meeting treatment criteria except in rare circumstances.
- Compared with rtPA, tenecteplase is more convenient, delivers the full dose faster, and produces comparable outcomes, but is not yet approved by the FDA for IV thrombolysis.
- Research is ongoing to study the wider implementation of mobile stroke units in speeding up the delivery of IV thrombolysis to patients with stroke.
ARTICLE 3: MECHANICAL THROMBECTOMY FOR ACUTE ISCHEMIC STROKE
Sunil A. Sheth, MD. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):443–461.
Endovascular stroke therapy has greatly improved the ability to treat the deadliest and most disabling form of acute ischemic stroke. This article summarizes some of the recent innovations in this field and discusses likely future developments.
At present, there is robust activity to improve all facets of care for patients with large vessel occlusion stroke, including better prehospital routing, more efficient in-hospital screening, expanding indications for thrombectomy eligibility, innovating novel thrombectomy devices, and improving the effects of recanalization on clinical outcomes. In addition, the integration of endovascular stroke therapy (EVT)—an emergent and frequently off-hours procedure that requires a specialized team of nurses, technologists, and physicians—into acute stroke care has transformed referral patterns, hospital accreditation pathways, and physician practices. The eligibility for the procedure will potentially continue to grow to include patients screened without advanced imaging, larger core infarcts, and more distal occlusions.
In this review, we discuss the current state of EVT and its implications for practice, and present three cases that highlight some of the directions in which the field is moving.
- Endovascular therapy has become the consensus approach for appropriately selected patients and can produce dramatic improvements in clinical outcomes for patients with large vessel occlusion.
- Several endovascular therapy trials published in 2015 established the treatment as clearly beneficial compared to medical management.
- Because neurologists are frequently the frontline evaluators of patients with large vessel occlusion acute ischemic stroke and serve as the gatekeepers for the procedure, they must have a basic understanding of the risks, benefits, and technical aspects of endovascular stroke therapy.
- Despite this growth in endovascular stroke therapy performance, a large proportion of patients receive their acute ischemic stroke care at hospitals not capable of performing endovascular stroke therapy.
- The challenge of how to balance the availability of sufficient daytime neurointerventional elective work with the need for additional physicians to sustainably cover the call burden remains unsolved.
- One of the lingering obstacles to endovascular treatment access remains the absence of a uniformly accepted neurointerventional accreditation system for training and certification.
- The efficacy of endovascular stroke therapy for large vessel occlusion acute ischemic stroke is highly time sensitive and bringing appropriate patients directly to endovascular stroke therapy–performing centers may accelerate treatment times and possibly improve clinical outcomes.
- Given the known adverse effects on clinical outcomes with delays in IV thrombolysis, accurate large vessel occlusion detection in the field to ensure that non–large vessel occlusion patients do not suffer from delays in IV recombinant tissue plasminogen activator (rtPA) is now of heightened importance.
- As clinical experience with endovascular stroke therapy has grown, the need for CTP to screen patients has been called into question.
- Two ongoing randomized clinical trials—MR CLEAN LATE and RESILIENT Extend—are evaluating the efficacy of endovascular stroke therapy in late-window patients without relying on CTP.
- The consensus remains to treat with IV rtPA in all eligible patients, including those with large vessel occlusion acute ischemic stroke for whom endovascular stroke therapy may be needed.
- Two studies, both performed in China, demonstrated superiority of endovascular stroke therapy over medical management alone in patients with basilar artery large vessel occlusion acute ischemic stroke, in both the early time window (<12 hours from last known well in ATTENTION) and late time window (6 to 24 hours from last known well in BAOCHE).
- The natural history for patients with large vessel occlusion acute ischemic stroke presenting in the late treatment window is poor, with over 80% having substantial disability.
- One of the interpretations of the large effect sizes seen in DAWN and DEFUSE 3 is a need to shift from time-based selection paradigms to an imaging-based one.
- Some of the key questions to ask regarding the results of large core trials will be the extent of clinical improvement and the proportion of patients who achieve good quality of life, rather than slightly less but still severe disability.
- Improvement in device technology was likely an important factor in the success of the 2015 thrombectomy trials.
- The goal of endovascular stroke therapy procedures has become achieving complete reperfusion (thrombolysis in cerebral infarction grade 3) with a single pass, termed the first pass effect. This bar has become the new standard by which device performance can be measured.
- Intracranial atherosclerotic disease can lead to large vessel occlusion acute ischemic stroke through several different mechanisms, including artery-to-artery distal embolization, in situ parent vessel occlusion, occlusion of a perforator branch adjacent to the intracranial atherosclerotic disease plaque, or hypoperfusion related to high-grade stenosis.
- Despite the greater than 90% substantial recanalization rates that can be achieved with modern endovascular stroke therapy, about 50% of patients still do not achieve functional independence after treatment.
- While its results will need to be replicated, the CHOICE trial provides one of the first treatment approaches for microvascular dysfunction.
ARTICLE 4: DIAGNOSIS AND MANAGEMENT OF CARDIOEMBOLIC STROKE
Shadi Yaghi, MD, FAHA. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):462–485.
Cardioembolic stroke accounts for nearly 30% of ischemic strokes. Prompt diagnosis of the underlying mechanism may improve secondary prevention strategies. This article reviews recent randomized trials, observational studies, case reports, and guidelines on the diagnosis and treatment of cardioembolic stroke.
Several pathologies can lead to cardioembolic stroke, including atrial fibrillation, aortic arch atheroma, patent foramen ovale, left ventricular dysfunction, and many others. Secondary stroke prevention strategies differ across these heterogeneous mechanisms. In addition to medical treatment advances such as the use of direct oral anticoagulants in patients with atrial fibrillation, surgical treatments such as closure of patent foramen ovale have been shown to reduce the risk of recurrent stroke in select patients. Furthermore, left atrial appendage occlusion is a promising strategy for patients with atrial fibrillation who are candidates for short-term oral anticoagulation therapy but not long-term oral anticoagulation therapy.
A thorough diagnostic evaluation is essential to determine cardioembolic causes of stroke. In addition to risk factor management and lifestyle modifications, identification and targeting of the underlying cardioembolic stroke mechanisms will lead to improved stroke prevention strategies in patients with cardioembolic stroke.
- Direct oral anticoagulants are at least as effective as warfarin in stroke prevention in atrial fibrillation and have lower risk of intracranial hemorrhage.
- There is growing evidence to support left atrial appendage occlusion as an alternative to oral anticoagulation in patients with atrial fibrillation.
- In patients with acute cardioembolic stroke treated with oral anticoagulants, treatment is generally started without bridging with heparin or low-molecular-weight heparin.
- In patients with atrial fibrillation and ischemic stroke despite anticoagulation a full diagnostic evaluation is important to rule out alternative mechanisms such as small vessel disease or large artery atherosclerosis that are not necessarily related to the atrial fibrillation and thus do not signify anticoagulation failure.
- In addition to atrial biomarkers, certain left atrial appendage biomarkers may indicate an increased risk of atrial thromboembolism.
- Patent foramen ovale (PFO) is a congenital septal defect that is present in nearly 25% of the population and is associated with a right-to-left shunt, which is more prominent during Valsalva maneuvers.
- Evidence suggests that transcranial doppler is superior to transthoracic echocardiography in diagnosing a right-to-left cardiac shunt.
- Transesophageal echocardiography provides the best views of the septum and thus is best at visualizing the PFO and associated abnormalities such as atrial septal aneurysm.
- In patients with cryptogenic stroke in the setting of a PFO, medical and in certain cases surgical management are recommended for secondary stroke prevention.
- In the absence of another indication for anticoagulation, antiplatelet therapy may be reasonable for secondary stroke prevention in patients with ischemic stroke in the setting of a PFO.
- Atheromas of the aortic arch, particularly when large or mobile, have been suggested to cause ischemic stroke by artery-to-artery embolism.
- The secondary prevention of ischemic stroke in the setting of aortic arch atherosclerosis consists of risk factor modification, high-intensity statin therapy, and antiplatelet therapy.
- Spontaneous aortic dissections can be seen in patients with Marfan syndrome, familial thoracic aortic aneurysm or dissection, bicuspid aortic valve, Loeys-Dietz aneurysm syndrome, and vascular Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV).
- In patients with systolic heart failure, studies have shown an increased ischemic stroke risk with low left ventricular ejection fraction.
- In patients with ischemic stroke and low ejection fraction, prolonged cardiac rhythm monitoring is important to look for atrial fibrillation which would lead to anticoagulation therapy.
- In the setting of a low ejection fraction and evidence of a left ventricular thrombus with or without ischemic stroke, patients should receive at least 3 months of anticoagulation with warfarin and until repeat cardiac imaging shows resolution of the thrombus.
- Clinical trials are needed to test the safety and efficacy of direct oral anticoagulants when compared to aspirin in patients with left ventricular dysfunction, particularly those with low ejection fraction and with an ischemic stroke.
- There is an increased ischemic stroke risk in patients with an acute myocardial infarction, and this risk is particularly high in the first 12 weeks after myocardial infarction.
- In patients with myocardial infarction and left ventricular thrombus with or without ischemic stroke, anticoagulation treatment should be initiated for at least 3 months pending resolution of the thrombus on follow-up cardiac imaging.
- Valvular pathologies that are associated with increased stroke risk are prosthetic heart valves, rheumatic heart disease, and both infective and noninfective endocarditis.
- In patients with an ischemic stroke in the setting of a bioprosthetic valve, a diagnostic evaluation is needed to exclude valve failure, thrombosis, or infection as an etiology.
- Direct oral anticoagulants are not recommended in patients with mechanical heart valves.
- Ischemic stroke risk in patients with rheumatic mitral disease has been suggested to be linked to atrial fibrillation, particularly since studies demonstrating such associations did not involve cardiac monitoring.
- In patients with marantic endocarditis in the setting of cancer, treatment entails management of the underlying malignancy as well as antithrombotic therapy.
- In patients with ischemic stroke in the setting of Libman-Sacks endocarditis, guidelines suggest anticoagulation with heparin or low-molecular-weight heparin instead of oral anticoagulation if deemed safe, but these suggestions lack high-level supporting evidence.
- Left-sided cardiac tumors such as atrial myxomas and fibroelastomas are very rare causes of ischemic stroke.
- While the optimal stroke prevention strategy for patients with ischemic stroke and left sided cardiac tumors is unknown, in addition to antithrombotic treatment, surgical tumor resection is a reasonable approach.
ARTICLE 5: DIAGNOSIS AND MANAGEMENT OF LARGE ARTERY ATHEROSCLEROSIS
Seemant Chaturvedi, MD, FAAN, FAHA. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):486–500.
Ischemic stroke due to large vessel atherosclerosis is a significant cause of stroke globally. With the aging population, the number of people with atherosclerotic stroke will increase in the coming decades. This article reviews the recent developments in the assessment and treatment of extracranial and intracranial atherosclerotic disease.
More intensive dual antiplatelet therapy can now be recommended for patients with transient ischemic attack or stroke. More stringent blood pressure and lipid control is also advised. The need for carotid revascularization will likely decrease in the coming decades because of advances in multimodal medical therapy; in particular, the role of revascularization for treating asymptomatic carotid stenosis is controversial. Patients with symptomatic intracranial stenosis should receive intensive medical therapy. Interest in high-resolution carotid plaque imaging is growing.
The prevention of stroke due to large vessel atherosclerosis has improved owing to advances in medical therapies. The role of carotid revascularization is unclear for many patient subgroups.
- Clinical trials that compared carotid endarterectomy versus medical therapy for the treatment of patients with carotid stenosis are more than 25 years old and some consider these data to be obsolete.
- In previous trials, several subgroups of symptomatic patients had enhanced benefit from carotid endarterectomy.
- Beyond the periprocedural period, long-term rates of stroke appear similar between patients treated with carotid endarterectomy and carotid artery stenting.
- Timing of revascularization and patient age should be considered in selecting between carotid endarterectomy and carotid artery stenting.
- Transcarotid artery revascularization is an emerging revascularization technique, but randomized studies are lacking.
- It is unclear if carotid revascularization is useful for asymptomatic carotid stenosis.
- For asymptomatic carotid stenosis, men derive greater benefit from revascularization compared with women.
- Microemboli detection using transcranial Doppler can be useful for risk stratification in patients with asymptomatic carotid stenosis.
- There is not an established role for proximal vertebral artery stenosis stenting.
- From a global perspective, intracranial atherosclerosis is a leading cause of stroke.
- Intracranial atherosclerosis needs to be distinguished from recanalized emboli and vasculopathies.
- Intensive medical therapy is essential in the management of patients with intracranial atherosclerosis.
- Intracranial stenosis has a high stroke recurrence rate.
- Stenting is not recommended as a first-line treatment for patients with intracranial atherosclerotic disease.
- Nonstenotic plaques with complex features are potentially linked with otherwise cryptogenic strokes.
ARTICLE 6: DIAGNOSIS AND MANAGEMENT OF CEREBRAL SMALL VESSEL DISEASE
Anjail Sharrief, MD, MPH, FAHA. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):501–518.
Cerebral small vessel disease (CSVD) is a common neurologic condition that contributes to considerable mortality and disability because of its impact on ischemic and hemorrhagic stroke risk and dementia. While attributes of the disease have been recognized for over two centuries, gaps in knowledge remain related to its prevention and management. The purpose of this review is to provide an overview of the current state of knowledge for CSVD.
CSVD can be recognized by well-defined radiographic criteria, but the pathogenic mechanism behind the disease is unclear. Hypertension control remains the best-known strategy for stroke prevention in patients with CSVD, and recent guidelines provide a long-term blood pressure target of less than 130/80 mm Hg for patients with ischemic and hemorrhagic stroke, including those with stroke related to CSVD. Cerebral amyloid angiopathy is the second leading cause of intracerebral hemorrhage and may be increasingly recognized because of newer, more sensitive imaging modalities. Transient focal neurologic episodes is a relatively new term used to describe “amyloid spells.” Guidance on distinguishing these events from seizures and transient ischemic attacks has been published.
CSVD is prevalent and will likely be encountered by all neurologists in clinical practice. It is important for neurologists to be able to recognize CSVD, both radiographically and clinically, and to counsel patients on the prevention of disease progression. Blood pressure control is especially relevant, and strategies are needed to improve blood pressure control for primary and secondary stroke prevention in patients with CSVD.
- Cerebral small vessel disease (CSVD) contributes to significant morbidity and mortality through its impact on stroke risk, cognitive decline, and dementia.
- Several modifiable clinical risk factors are associated with the development of CSVD, including hypertension, obstructive sleep apnea, diabetes mellitus, hyperlipidemia, and tobacco use.
- CSVD is increasingly recognized as a dynamic, whole-brain disorder characterized by endothelial dysfunction and alterations in the function of the neurovascular unit. A better understanding of the underlying mechanisms may help to identify therapeutic targets for treatment.
- There are six radiographic phenotypes of CSVD: (1) recent small subcortical infarct, (2) white matter hyperintensity, (3) lacune of presumed vascular origin, (4) widened perivascular spaces, (5) cerebral microbleed, and (6) brain atrophy.
- Small vessel ischemic (lacunar) stroke is the most commonly encountered acute clinical manifestation of CSVD. It represents 20% to 30% of ischemic stroke cases.
- Hypertension, diabetes mellitus, and tobacco use are important risk factors for small vessel ischemic stroke, and hyperlipidemia may also contribute to risk.
- The American Heart Association/American Stroke Association (AHA/ASA) Guideline for the Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack includes a class 1 (level of evidence B-R) recommendation for target blood pressure less than 130/80 mm Hg for patients with ischemic stroke.
- Given the relationship between uncontrolled blood pressure and recurrent stroke risk, cognitive decline, and dementia after stroke, interventions to improve blood pressure control in all stroke survivors, including those with small vessel stroke, are urgently needed.
- The Boston criteria 2.0 can be used to diagnose cerebral amyloid angiopathy (CAA) based on radiographic features, clinical characteristics, and histopathologic samples when available.
- Radiographic findings in CAA include cortical hemorrhage, cerebral microbleeds, superficial siderosis, convexal subarachnoid hemorrhage, silent infarcts, white matter hyperintensities, and MRI-visible perivascular spaces in the centrum semiovale.
- Episodes of CAA-related intracerebral hemorrhage (ICH) can recur over weeks, months, or years, with a yearly ICH recurrence risk of 7.4% in CAA compared to 1.1% per year in CAA-unrelated ICH.
- Transient focal neurological episodes associated with CAA can present as short (typically less than 30 minutes) disturbances in motor, sensory, language, or visual function which may be difficult to distinguish from transient ischemic attack or seizure.
- Patients who have CAA without ICH may have abnormal cognitive profiles in the absence of self-reported cognitive deficits. The cognitive profile appears to be more similar to that seen with vascular cognitive impairment; that is, impairments in executive function and processing with relatively preserved memory.
- There are no specific management guidelines for reducing ICH recurrence risk in patients with CAA; however, the most recently published AHA/ASA guideline for the management of patients with ICH recommend reducing blood pressure for patients with spontaneous ICH (class 1 recommendation) and suggest a blood pressure target of less than 130/80 mm Hg (class 2a recommendation).
- Migraine is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting often, but not always, in the third decade of life.
- As CADASIL inheritance is autosomal dominant, significant family history also supports the diagnosis, but given the possibility of variable presentation within families and the possibility of sporadic mutation, the absence of family history does not exclude CADASIL as a potential diagnosis.
- Clinical management of CADASIL and cerebral autosomal recessive arteriopathy with subcortical strokes and leukoencephalopathy (CARASIL) involves management of known vascular risk factors, including hypertension and tobacco use, which have been shown to contribute to poorer outcomes in patients with CADASIL.
ARTICLE 7: DIAGNOSIS AND TREATMENT OF CEREBRAL VENOUS THROMBOSIS
Ava L. Liberman, MD. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):519–539.
Cerebral venous thrombosis (CVT), thrombosis of the dural sinus, cerebral veins, or both, is a rare cerebrovascular disease. Although mortality rates after CVT have declined over time, this condition can result in devastating neurologic outcomes. This article reviews the latest literature regarding CVT epidemiology, details new factors associated with the development of CVT, and describes advances in CVT treatment. It also contains a discussion of future directions in the field, including novel diagnostic imaging modalities, and potential strategies to reduce the risks associated with CVT.
The incidence of CVT may be as high as 2 per 100,000 adults per year. It remains a difficult condition to diagnose given its variable clinical manifestations and the necessity of neuroimaging for confirmation. The COVID-19 pandemic has revealed a novel CVT trigger, vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as an association between COVID-19 infection and CVT. Although VITT is a very rare event, timely diagnosis and treatment of CVT due to VITT likely improves patient outcomes. Direct oral anticoagulants are currently being used to treat CVT and emerging data suggest that these agents are as safe and effective as vitamin K antagonists. The role of endovascular therapy to treat CVT, despite a recent clinical trial, remains unproven.
The incidence of CVT has increased, outcomes have improved, and the use of direct oral anticoagulants to treat CVT represents an important advance in the clinical care of these patients. Rates of CVT as a complication of COVID-19 vaccines using adenoviral vectors are very low (<5 per million vaccine doses administered), with the benefits of COVID-19 vaccination far outweighing the risks.
- Unlike arterial strokes, cerebral venous thrombosis (CVT) has a wide spectrum of clinical presentations, tends to affect younger patients with a female predominance, and is often nonapoplectic in onset.
- The latest annual CVT incidence ranges from 1.32 to 2 per 100,000 adults based primarily on data from high-income countries.
- Conditions associated with CVT can be classified as either predisposing (eg, genetic prothrombotic diseases, antiphospholipid syndrome, cancer) or precipitating (eg, oral contraceptives, infections).
- Data from a 2021 study suggest that a rare but demonstrable association between CVT and COVID-19 infection exists, although the underlying mechanisms of this association are uncertain.
- In patients with neurologic symptoms and COVID-19 infection, a high index of suspicion for CVT should be encouraged, and treatment of CVT should be initiated as soon as possible.
- The entity implicated in the rare but potentially devastating cases of CVT and thrombocytopenia following adenovirus-based COVID-19 vaccine administration is now called vaccine-induced immune thrombotic thrombocytopenia (VITT), or thrombosis with thrombocytopenia syndrome.
- In patients with CVT with symptom onset within 4 to 42 days after having received a COVID-19 vaccine using adenoviral vectors, following an algorithmic approach to evaluate and treat VITT is advised.
- Presentations of CVT can be roughly divided into four syndromes: (1) isolated headache or increased intracranial pressure, (2) focal neurologic presentations, (3) subacute encephalopathy, and (4) cavernous sinus syndrome with multiple cranial neuropathies.
- A key feature of focal neurologic deficits due to CVT is that they are frequently progressive in nature in contrast to arterial strokes which tend to be maximal at onset.
- Contrast-enhanced brain MRI provides detailed information about the brain parenchyma and is probably more accurate for diagnosing CVT than non-contrast-enhanced magnetic resonance venography sequences.
- Both the American Heart Association/American Stroke Association (AHA/ASA) and the more recently published European Stroke Organization (ESO) guidelines recommend initiation of parenteral anticoagulation with unfractionated or low-molecular-weight heparin prior to transitioning to oral anticoagulants for CVT treatment.
- The ACTION-CVT study and other retrospective treatment studies are prone to confounding by indication; nevertheless, there do not seem to be major safety issues with the use of direct oral anticoagulants as opposed to vitamin K antagonists in clinical practice.
- As in heparin-induced thrombocytopenia, therapeutic anticoagulation with non-heparin anticoagulants is the primary treatment for VITT with or without CVT.
- Despite the low quality of evidence, the ESO guidelines now strongly recommend using decompressive surgery for patients with acute CVT and parenchymal lesions with impending herniation to prevent death as a randomized controlled trial is unlikely for ethical and feasibility reasons.
- In general, CVT has a favorable outcome with an in-hospital mortality rate ranging from 1% to 4% and from 8% to 10% during long-term follow-up.
ARTICLE 8: CERVICAL ARTERY DISSECTION
Setareh Salehi Omran, MD. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):540–565.
Cervical artery dissection is a common cause of stroke in young adults. This article reviews the pathophysiology, etiology and risk factors, evaluation, management, and outcomes of spontaneous cervical artery dissection.
Cervical artery dissection is believed to be a multifactorial disease, with environmental factors serving as possible triggers in patients who have a genetic predisposition to dissection formation. Cervical artery dissection can cause local symptoms or ischemic events, such as ischemic stroke or transient ischemic attack. Neuroimaging is used to confirm the diagnosis; classic findings include a long tapered arterial stenosis or occlusion, dissecting aneurysm, intimal flap, double lumen, or intramural hematoma. Patients with cervical artery dissection who present with an acute ischemic stroke should be evaluated for IV thrombolysis, endovascular therapy eligibility, or both. Antithrombotic therapy with either anticoagulation or antiplatelet treatment is used to prevent stroke from cervical artery dissection. The risk of recurrent ischemia appears low and is mostly limited to the first two weeks after symptom onset.
Cervical artery dissection is a known cause of ischemic strokes. Current data show no difference between the benefits and risks of anticoagulation versus antiplatelet therapy in the acute phase of symptomatic extracranial cervical artery dissection, thereby supporting the recommendation that clinicians can prescribe either treatment. Further research is warranted to better understand the pathophysiology and long-term outcomes of cervical artery dissection.
- The overall incidence of cervical artery dissection is low at 2.6 to 3.0 per 100,000 people per year.
- Dissections result from the separation of the arterial wall layers causing the formation of a false lumen that allows blood to enter the vessel wall.
- Dissections can cause subintimal or subadventitial hematomas. Subintimal hematomas may lead to intraluminal stenosis or occlusion. Subadventitial hematomas can cause eccentric hematoma growth and aneurysm formation.
- A small portion of cervical artery dissection cases (nearly 2%) have been linked to monogenic connective tissue diseases, such as vascular Ehlers-Danlos syndrome.
- Apart from monogenic disorders, which encompass a small group of cervical artery dissection cases, genetic factors may play a role in a more multifactorial process leading to cervical artery dissection.
- Minor cervical trauma precedes nearly 41% of identified spontaneous cervical artery dissection cases. These minor traumas can be subtle and involve hyperextension, lateroversion, or rotation of the neck.
- Pregnancy and the postpartum period, oral contraceptive use, migraine, recent infection, and vascular risk factors have all been associated with cervical artery dissection.
- Common local signs and symptoms of cervical artery dissection include new-onset headache, neck pain, cranial and cervical neuropathies, Horner syndrome, and pulsatile tinnitus.
- Ischemic strokes from cervical artery dissection are usually due to artery-to-artery embolism of intraluminal thrombus formed at the site of intraluminal stenosis. Less commonly, ischemia may result from hypoperfusion distal to a high-grade intraluminal stenosis or occlusion.
- Subarachnoid hemorrhage may result from intracranial extension of a dissection. Intracranial arteries lack external elastic lamina and have a thinner media, making them more prone to aneurysm formation and subsequent rupture.
- The majority of ischemic events from cervical artery dissection occur within the first 1 to 2 weeks after symptom onset.
- The diagnosis of cervical artery dissection should be suspected in patients with acute onset of local symptoms of headache, neck pain, Horner syndrome, or any combination of the three, particularly if they are associated with an ipsilateral ischemic stroke.
- The most commonly used imaging modalities include CT and CT angiography (CTA), or MRI and magnetic resonance angiography (MRA) of the head and neck.
- MRI in cervical artery dissection may show a pathognomonic crescent sign. The crescent sign is formed by an eccentric rim of hyperintensity, corresponding to intramural hematoma, surrounding a hypointense arterial lumen on axial cross-sectional T1-weighted sequences. The combination of MRA with T1-weighted axial cervical MRI imaging with fat suppression allows for better visualization of intramural hematomas.
- CTA is an efficient tool with high sensitivity and specificity for diagnosing cervical artery dissection. However, image interpretation may be limited due to inaccurate contrast bolus timing or streak artifacts from implants or beam-hardening artifacts.
- Diagnostic cerebral angiography continues to be the gold standard for identifying cervical artery dissection. However, given the high sensitivity and specificity of noninvasive imaging methods, digital subtraction angiography is rarely needed, unless the clinical suspicion for a dissection continues to remain high despite negative noninvasive imaging.
- All patients with acute ischemic stroke from cervical artery dissection should be evaluated to determine eligibility for IV thrombolysis and endovascular therapy.
- Endovascular therapy should be considered in select patients with cervical artery dissection with acute ischemic stroke from a large vessel occlusion. This includes patients with tandem occlusions, although the optimal treatment method is still being explored.
- The most recent American Heart Association (AHA) guidelines recommend either warfarin or aspirin in patients with recent ischemic stroke or transient ischemic attack from extracranial cervical artery dissection.
- The AHA recommends at least 3 months of antithrombotic therapy in patients with recent stroke or transient ischemic attack from cervical artery dissection, but the optimal duration of treatment is unclear.
- Most cases of vessel recanalization after cervical artery dissection occur within the first few months after the initial event (16% at 1 month, 50% at 3 months, and 60% at 6 and 12 months). Initial occlusion reduces the likelihood of complete recanalization, whereas the presence of only local signs and symptoms increases the odds of complete recanalization.
- Repeat neurovascular imaging is typically done 3 to 6 months after symptom onset or diagnosis with the goal of assessing recanalization status of affected arteries and guiding ongoing antithrombotic treatment in cervical artery dissection.
- The rate of recurrent ischemic stroke after cervical artery dissection is low at around 2% to 4% at 3 months and 2.5% at 12 months. The greatest risk of recurrent ischemic stroke is within the first 2 weeks of diagnosis. Dissecting aneurysms do not appear to be associated with an increased risk of recurrent stroke.
- The rate of cervical artery dissection recurrence is uncertain, ranging from 2% to 9.2% within the first 1 to 3 months. The highest risk of cervical artery dissection recurrence is within the first month of the initial dissection.
ARTICLE 9: PEDIATRIC ISCHEMIC STROKE
Christine Fox, MD, MAS. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):566–583.
Pediatric cerebrovascular disease is one of the leading causes of death and disability in children. Survivors of childhood stroke and their families are often left to cope with long-lasting sequelae, such as barriers to school reentry and long-term challenges in attaining independence as adults. Because childhood stroke is rare and providers may not be familiar with the disorder, this article reviews the risk factors, acute management, and sequelae of ischemic stroke in children.
High-quality evidence has resulted in an organized approach to emergent treatment of ischemic stroke in adults, but most front-line providers are less prepared for emergent stroke management in children. The level of evidence for reperfusion therapies in children remains low but is growing. Thrombolysis and thrombectomy are sometimes considered for hyperacute treatment of stroke in children. Readiness for pediatric stroke at regional centers should include an organized approach to pediatric stroke triage and management based on extrapolation from adult stroke trials, expert consensus, and emerging pediatric studies.
This review provides up-to-date information about ischemic stroke risk factors and management in children. Preparation for rapid stroke diagnosis and management in children may improve outcomes.
- Perinatal arterial ischemic stroke occurs in approximately 1 in 3000 live full-term births, which makes the weeks around birth one of the highest-risk time periods for stroke to occur.
- Most children with acute ischemic stroke present with focal neurologic deficits similar to adults with stroke. Unlike adults, children may have a stuttering rather than an abrupt symptom onset and also commonly present with headache or seizure.
- Although a myriad of chronic and acute conditions can predispose a child to have a stroke, many children who present with an initial stroke have no significant medical history and were previously considered to be healthy.
- As evidence grows, guidelines have cautiously moved from recommending against IV thrombolysis or thrombectomy outside of a research study toward a discussion of selecting children who may benefit from IV thrombolysis and endovascular thrombectomy in certain circumstances.
- Although guidelines support consideration of IV thrombolysis or thrombectomy in children in specific circumstances on a case-by-case basis, these treatments are not considered a requirement. Hyperacute treatment decisions should be made in conjunction with neurologists with expertise in the treatment of children with stroke.
- MRI and MR angiography or CT and CT angiography are both reasonable options as initial imaging modalities to evaluate for a suspected childhood stroke, taking timing, circumstances, and available resources into account. In either case, obtaining vascular imaging in addition to brain tissue imaging is crucial to identify a large vessel occlusion or an arteriopathy that influences management.
- Because of the prevalence of arteriopathies in childhood stroke with subsequent cerebrovascular narrowing or loss of normal hemodynamic compensatory mechanisms, in the setting of acute stroke collateral cerebral flow should be supported by initial fluid resuscitation if needed, keeping the head of bed flat, instituting bedrest, and avoiding hypotension.
- Congenital heart disease or acquired heart disease are major risk factors for perinatal or childhood stroke, together accounting for almost one-third of arterial ischemic strokes in children.
- Systematic quality measures that preemptively identify children for closer postprocedural neurologic monitoring after higher-risk cardiac procedures are key to reducing time to stroke detection and increasing opportunities for rapid treatment.
- Cerebral arteriopathy is present in up to half of all children with ischemic stroke and is a risk factor for initial stroke as well as stroke recurrence.
- The acute management of a suspected stroke in children with sickle cell disease differs from other stroke etiologies and should be focused on providing an emergent blood transfusion.
- Assessment of function by a rehabilitation specialist and consideration of inpatient rehabilitation are recommended for children following stroke.
- Children benefit from early recognition of stroke and should be transferred to a hospital that can provide definitive care as soon as safely possible, but systems of care for children with stroke lag behind those for adults.
- Structured and organized health systems that improve the speed of triage, transport, and treatment of children in medical centers with established pediatric stroke guidelines are still lacking in many geographic areas.
ARTICLE 10: MANAGEMENT OF UNRUPTURED INTRACRANIAL ANEURYSMS AND BRAIN ARTERIOVENOUS MALFORMATIONS
Thanh Ngoc Nguyen, MD, FRCPc, FSVIN, FAHA. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):584–604.
Managing a patient with an unruptured brain aneurysm or brain arteriovenous malformation (AVM) can lead to uncertainty about preventive treatment. While the bleeding risks are low, the morbidity or mortality associated with a hemorrhagic event is not insignificant. The objective of this article is to review the natural history of these vascular entities, the risk factors for hemorrhage, preventive treatment options, and the risks of treatment.
Randomized trials to inform preventive treatment strategies for unruptured intracranial aneurysms and brain AVMs are ongoing. Higher angiographic obliteration rates of unruptured intracranial aneurysms have been reported with the flow-diversion technique compared with alternative standard techniques. One randomized trial for unruptured brain AVMs showed a higher rate of morbidity and mortality in patients who underwent interventional treatment compared with observation.
The decision to treat a patient with a brain aneurysm should consider patient factors, the patient’s life expectancy, aneurysm anatomical factors, and treatment risks. Patients with unruptured brain AVMs should be observed in light of recent clinical trial data or enrolled in an ongoing clinical trial.
- An estimated 3% of the population has an unruptured intracranial aneurysm.
- The risk of rupture for an asymptomatic unruptured intracranial aneurysm is estimated at 0.3% to 1% per year.
- The risk of aneurysm rupture increases with aneurysm size, a family history of aneurysm, and prior subarachnoid hemorrhage from another aneurysm.
- An aneurysm that is documented to have growth on serial imaging carries a higher risk of rupture than an aneurysm that has not been documented to grow.
- ISAT (International Subarachnoid Aneurysm Trial) demonstrated better outcomes among patients with ruptured aneurysms who underwent coiling compared to those who underwent surgical clipping.
- Endovascular techniques that are commonly used in the treatment of brain aneurysms include coiling, balloon remodeling, stent-assisted coiling, intrasaccular flow disruption, and flow diversion.
- Higher angiographic obliteration rates of unruptured intracranial aneurysms have been reported with flow diversion compared to alternative standard techniques.
- Ischemic complications related to flow diversion are estimated to occur in up to 9.8% of cases.
- There are no completed randomized trials to inform treatment of unruptured aneurysms, but several are ongoing.
- The decision to treat an intracranial aneurysm is based on the natural history of risk of rupture, patient and aneurysmal anatomical factors, and the risk of repair.
- The risk of an asymptomatic, unruptured brain arteriovenous malformation (AVM) rupture is estimated at 1.3% per year.
- Age and prior AVM hemorrhage are risk factors for future AVM hemorrhage.
- Conservative management, endovascular embolization, radiation, and operative resection are four modalities that can be considered in the treatment of a patient with brain AVM with a multidisciplinary team; the modalities can be performed either in isolation or in combination.
- A randomized trial demonstrated that, overall, patients with unruptured AVMs who were conservatively managed had better outcomes than patients who underwent intervention mostly with endovascular embolization.
ARTICLE 11: STROKE REHABILITATION AND MOTOR RECOVERY
Michael W. O’Dell, MD. Continuum (Minneap Minn). April 2023; 29 (2 Cerebrovascular Disease):605–627.
Up to 50% of the nearly 800,000 patients who experience a new or recurrent stroke each year in the United States fail to achieve full independence afterward. More effective approaches to enhance motor recovery following stroke are needed. This article reviews the rehabilitative principles and strategies that can be used to maximize post-stroke recovery.
Evidence dictates that mobilization should not begin prior to 24 hours following stroke, but detailed guidelines beyond this are lacking. Specific classes of potentially detrimental medications should be avoided in the early days poststroke. Patients with stroke who are unable to return home should be referred for evaluation to an inpatient rehabilitation facility. Research suggests that a substantial increase in both the dose and intensity of upper and lower extremity exercise is beneficial. A clinical trial supports vagus nerve stimulation as an adjunct to occupational therapy for motor recovery in the upper extremity. The data remain somewhat mixed as to whether robotics, transcranial magnetic stimulation, functional electrical stimulation, and transcranial direct current stimulation are better than dose-matched traditional exercise. No current drug therapy has been proven to augment exercise poststroke to enhance motor recovery.
Neurologists will collaborate with rehabilitation professionals for several months following a patient’s stroke. Many questions still remain about the ideal exercise regimen to maximize motor recovery in patients poststroke. The next several years will likely bring a host of new research studies exploring the latest strategies to enhance motor recovery using poststroke exercise.
- Motor recovery is the partial or complete improvement of an individual’s motor symptoms such as weakness, coordination, fine control, or ataxia following a stroke.
- Functional recovery is a partial or complete improvement in an individual’s performance of activities of daily living, instrumental activities of daily living (eg, housekeeping, cooking, washing clothes, paying bills), mobility (eg, transfers, wheelchair use, walking) or communication.
- Although further research is clearly required, the 2018 American Heart Association/American Stroke Association guidelines recommend that specialized acute stroke units “incorporate rehabilitation” into their care and discourage mobilization prior to 24 hours poststroke, but otherwise make only very general recommendations.
- Admission to a skilled nursing facility, without inpatient rehabilitation facility consideration, for the sole purpose of decreasing acute care lengths of stay, maintaining historical referral patterns, or preventing “bleed” outside of a constituent health care system should be viewed as incompatible with best practices.
- In addition to leading the rehabilitation team, the essential task of the attending physiatrist is to ensure that patients at the inpatient rehabilitation facility are medically stable and free of pain and mood or other issues to the degree that they can participate in therapy, remain on the unit, and benefit from the rehabilitation experience.
- Most patients discharged from an inpatient rehabilitation facility to home will continue rehabilitation in an outpatient setting. This could include one to three therapies, two to three times a week from a few weeks to a few months, which likely represents a gross underdosing of therapy.
- If the characteristics and content of exercise constitute the “science of stroke rehabilitation,” equally important must be the “art of rehabilitation” as practiced by an outstanding therapist.
- Significant questions remain surrounding the ideal exercise protocol following stroke, despite numerous large clinical trials over the past 2 decades.
- Given the challenges, expense, and logistics of providing ever greater doses of exercise, identifying strategies to augment the effect of exercise on recovery after stroke is desirable.
- To date no pharmacologic agents in well-designed randomized clinical trials have clearly demonstrated enhanced motor recovery after stroke.
- Despite an underwhelming track record, upper and lower extremity robotics and exoskeletal devices are commonly offered at larger rehabilitation centers.
- Compared to an ankle-foot orthosis, lower extremity functional electrical stimulation may decrease the physiologic cost of gait (based on resting and working heart rate and walking speed) but does not improve gait speed.
- The vagus nerve stimulation group in one trial was about twice as likely to achieve a clinically meaningful gain on the Fugl-Meyer Assessment and 3 times as likely to improve on the Wolf Motor Function Test compared with the control group.
- Defining the optimal nature, characteristics, intensity, and timing of a patient’s participation in task-specific and repetitious exercise to maximize motor recovery constitutes the fundamental challenge in stroke rehabilitation.