lacunar stroke case study

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• Volume 92, Issue 8
• Lacunar stroke: mechanisms and therapeutic implications
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• http://orcid.org/0000-0003-0031-1004 Shadi Yaghi 1 ,
• http://orcid.org/0000-0003-2998-8481 Eytan Raz 2 ,
• Dixon Yang 2 , 3 ,
• Shawna Cutting 1 ,
• Brian Mac Grory 4 ,
• Mitchell SV Elkind 5 ,
• http://orcid.org/0000-0001-8178-8597 Adam de Havenon 6
• 1 Department of Neurology , Brown University Warren Alpert Medical School , Providence , Rhode Island , USA
• 2 Department of Radiology , NYU Langone Health , New York , New York , USA
• 3 Department of Neurology , NYU Langone health , New York , New York , USA
• 4 Department of Neurology , Duke Medicine , Durham , North Carolina , USA
• 5 Department of Neurology , Columbia University Medical Center , New York , New York , USA
• 6 Department of Neurology , University of Utah Hospital , Salt Lake City , Utah , USA
• Correspondence to Dr Shadi Yaghi, Department of Neurology, Brown University Warren Alpert Medical School, Providence, RI 02903, USA; shadiyaghi{at}yahoo.com

Lacunar stroke is a marker of cerebral small vessel disease and accounts for up to 25% of ischaemic stroke. In this narrative review, we provide an overview of potential lacunar stroke mechanisms and discuss therapeutic implications based on the underlying mechanism. For this paper, we reviewed the literature from important studies (randomised trials, exploratory comparative studies and case series) on lacunar stroke patients with a focus on more recent studies highlighting mechanisms and stroke prevention strategies in patients with lacunar stroke. These studies suggest that lacunar stroke is a heterogeneous disease with various mechanisms, including most commonly lipohyalinosis and less commonly atheromatous disease and cardioembolism, highlighting the importance of a careful review of brain and neurovascular imaging, a cardiac and systemic evaluation. A better understanding of pathomechanisms of neurological deterioration may lead to investigating the utility of novel treatment strategies and optimisation of short-term antithrombotic treatment strategies to reduce the risk of neurological deterioration and prevent long-term disability in patients with lacunar stroke.

https://doi.org/10.1136/jnnp-2021-326308

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Introduction

Lacunar stroke is a marker of cerebral small vessel disease 1 and accounts for up to 25% of ischaemic stroke. The word lacunar comes from Latin for ‘lacuna’ meaning hole, and it is used to describe a small focus of encephalomalacia containing CSF, which is the end result of liquefactive necrosis. Lacunar stroke is defined as a subcortical infarct measuring less than 20 mm in diameter, caused by occlusion of a perforator of an intracranial artery. 1 In this narrative review, we aim to provide an overview of potential lacunar stroke mechanisms and diagnostic approaches, and discuss therapeutic implications targeting the underlying mechanism.

The incidence of lacunar stroke varies based on the population studied from 25 to 50 per 100 000 people, 2 3 comprising 15%–25% of ischaemic stroke. 2–4 These numbers, however, have been declining over time, likely due to better control of vascular risk factors such as hypertension. 5

Lacunar stroke shares risk factors with other stroke subtypes, namely hypertension, diabetes, advanced age, cigarette smoking and hyperlipidaemia. 6 7 While studies have shown that the overall prevalence of these risk factors is similar between lacunar stroke and other stroke subtypes, 8 some studies suggest that smoking, hypertension and diabetes are particularly important risk factors for lacunar stroke 3 7 and that these risk factors may be more prevalent in patients with lacunar stroke. 9 Among these risk factors, hypertension is most common in patients with lacunar stroke (68%), followed by diabetes (30%). 3 7 9 These studies were performed when the control of risk factors, particularly hypertension, was less aggressive and more recent studies suggest that risk factors for lacunar stroke may be similar to those of other subtypes. 10

In addition to conventional risk factors, rare genetic conditions, such as Cerebral Autosomal Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) can cause lacunar stroke. 11 These typically have other accompanying manifestations, including a positive family history, and the diagnosis is made by clinical suspicion and confirmed by genetic testing ( table 1 ). 11

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Overview of genetic conditions associated with lacunar stroke

Potential mechanisms

There are several potential mechanisms described for the pathogenesis of lacunar stroke. 12 These include lipohyalinosis, atherosclerotic disease and cardiac embolism, which will be discussed separately below.

Lipohyalinosis

Lipohyalinosis is defined as concentric hyaline thickening of the cerebral small vessels leading to occlusion of the small penetrating arteries 13 and is one of the first and most common lacunar stroke mechanisms described and pathologically proven to cause lacunar stroke. 14 Lipohyalinosis is thought to originate from hypertension-related hypertrophy and fibrinoid degeneration of the vessel walls as well as subintimal foam cells obliterating the lumen of small penetrating arteries, leading to small subcortical infarcts. In a case series published by Fisher of 114 lacunar strokes, all but three had direct or indirect evidence of uncontrolled hypertension. 14 Previous studies suggested that lipohyalinosis typically causes infarcts 3–7 mm in size on brain imaging and that if the infarct is larger than 7 mm, other mechanisms should be explored. 15

In addition to lipohyalinosis, some studies hypothesised that endothelial dysfunction and impaired autoregulation as well as extravasation of blood products into the vessel wall resulting in perivascular oedema and damage to the neurovascular unit and surrounding brain tissue may be a contributing factor to the development of lacunar infarcts. 13 This is hypothesised to lead to lacunar stroke and white matter disease. 16 This mechanism has not been pathologically proven and recently data suggests that endothelial dysfunction may be reactive and less likely to be involved in the pathogenesis of the disease itself. 17

Atherosclerotic disease

There are several potential atherosclerotic mechanisms that could lead to lacunar stroke. The most important mechanism that has been pathologically proven is branch atheromatous disease. 18 Atherosclerotic plaques of the parent artery could involve the ostium of perforating branches leading to occlusion and infarction of distal parenchyma. This mechanism has been widely described in patients with luminal narrowing of the parent artery, in which case the lacunar stroke is classified as related to intracranial atherosclerosis as opposed to small vessel disease. On the other hand, certain atherosclerotic plaques may cause perforator disease without significant luminal stenosis. This has been described particularly in patients with pontine lacunar stroke in the setting of branch atheromatous disease of the basilar artery. 19

Other atherosclerotic mechanisms that have been described include embolism from a proximal intracranial or extracranial artery 20 as well as aortic arch disease. 21 These associations, however, do not prove a causal relationship with lacunar stroke because atherosclerosis and lacunar stroke share common risk factors.

Cardioembolism

There is experimental evidence from animal models that small emboli can enter penetrating arteries and cause lacunar stroke. 22 In humans, there is evidence to suggest that cardioembolic mechanisms are unlikely to cause small subcortical infarcts. For instance, one study showed that atrial fibrillation (AF) patients with lacunar stroke are more likely to have increased white matter disease severity and evidence of chronic lacunar stroke than those with cardioembolic-appearing infarcts, suggesting that even in the presence of AF, intrinsic lipohyalinosis is a more likely aetiology. 23 Furthermore, studies have shown that subcortical infarcts are less likely to occur in the setting of a patent foramen ovale. 24 Therefore, current evidence suggests that lacunar stroke is a very rare manifestation of cardioembolism.

Diagnostic approach

Brain imaging and non-invasive intracranial vascular imaging.

Infarct location on brain imaging could help determine the mechanism in lacunar stroke. For instance, one study showed that a lacunar stroke involving the paramedian thalamus could be related to a distant cardioaortic embolic source 25 but more studies are needed to confirm this finding. Obtaining a brain MRI may be particularly helpful not only to confirm the diagnosis but also to help determine the aetiology. For instance, the presence of deep cerebral microbleeds, prior subcortical lacunar infarcts or subcortical white matter disease are better appreciated on brain MRI and may suggest an intrinsic small vessel microangiopathy as opposed to a distant atheroembolic or cardioaortic source. On the other hand, acute infarcts in more than one vascular territory may suggest a proximal cardioarotic source. Future studies are needed to determine the cost-effectiveness of obtaining routine brain MRI versus CT in patients with lacunar stroke.

Furthermore, preliminary data suggests that increased pulsatility index, a marker of arterial stiffness, in the basal ganglia on 7T MRI was more common in patients with lacunar stroke and deep intracerebral haemorrhage than controls indicating the need for further studies to determine whether increased pulsatility index could unravel the underlying mechanism in patients with lacunar stroke. 26 A major limitation of this approach is that 7T MRI is not used in routine clinical care and thus the clinical utility of this remains limited.

Vessel imaging

Non-invasive intracranial vessel imaging may also help determine the aetiology of a lacunar infarct. For instance, irregularity or stenosis on intracranial MRA or CTA in the main artery at the site where the perforating branch supplying the infarct originates may suggest an underlying atherosclerotic mechanism and ischaemic lesion patterns may differ between atherosclerotic and non-atherosclerotic mechanisms ( figure 1 ). 27 In one study, 40% of patients with small striatocapsular infarcts were found to have stenosis of the middle cerebral artery. 28

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Brainstem lacunar infarct from basilar atherosclerosis. diffusion weighted imaging sequence (A), sagittal T1 (B) and MPR from TOF MRA (C). Notice the acute infarct involving the typical territory (black arrows on B) of a paramedian basilar perforator which arise from the mid basilar artery; atherosclerosis of the basilar artery with mild stenosis is well evident on the MRA, asymmetrical to the left side (white arrows on C). MPR, multiplanar reconstruction; MRA, Magnetic Resonance Angiography

Vessel wall imaging (VWI) is a promising MRI sequence that can be added to the standard MRI of the brain and uses signal suppression from the tissues surrounding the intracranial arterial wall, namely the blood and CSF. Atherosclerotic plaques typically are associated with eccentric non-uniform arterial wall thickening, usually T2 hyperintense and enhancing in the setting of recent stroke. 29 VWI may help with the differentiation between the two aetiologies described above—lipohyalinosis and perforator origin atherosclerosis ( figure 2 ). 30 Other VWI studies have focused on analysis of the plaque location compared with the lacunar stroke, confirming that MCA atherosclerotic plaques with a lacunar stroke have more involvement of the superior wall, 31 but this finding needs confirmation in larger studies.

Middle-aged patient with history of hypertension and hyperlipidaemia presented with left arm weakness and facial droop. MRI in panel A revealed a small lacunar appearing stroke (white arrow) in the right internal capsule. Two days later, she developed more severe left-sided weakness and a repeat MRI in panel B showed extension of the prior stroke and a second stroke in a more distal location in the right parietal lobe. The second stroke instigated a thorough workup, including CTA of the head and neck, transthoracic echocardiogram with bubble study, hypercoagulable panel and extended rhythm monitoring, which all failed to reveal the cause of the patient’s strokes. A vessel wall MRI revealed an inflamed atherosclerotic plaque adjacent to the origin of the lenticulostriate perforators responsible for the initial stroke, shown in C on T2-weighted SPACE with DANTE black blood prepulacunar strokee, which enhanced avidly after gadolinium administration, shown in D on T1-weighted SPACE with DANTE black blood prepulacunar strokee. This plaque was determined to be the cause of the patient’s strokes and after being placed on aggressive medical management with DAPT, there was no stroke recurrence. DAPT, dual antiplatelet therapy.

Currently, using vascular imaging and VWI to determine an atherosclerotic mechanism in patients with lacunar stroke may not necessarily lead to a change in secondary stroke prevention strategies. This, however, may change if future studies show a benefit from targeted treatment strategies such as anti-inflammatory agents as well as novel lipid-lowering agents for secondary stroke prevention in patients with cerebrovascular atherosclerosis.

Cardiac evaluation

The utility of cardiac evaluation in patients with lacunar stroke is a subject of interest. This includes echocardiography and outpatient cardiac monitoring to evaluate for paroxysmal occult AF. A recent study challenged the yield of transthoracic echocardiography (TTE) in patients with lacunar stroke. 32 One study showed that an aortic arch atheroma detected on transesophageal echocardiographic (TEE) is more likely to occur in patients with lacunar stroke compared with controls but this finding has not been validated. In addition, detecting an aortic atheroma rarely leads to a change in clinical management because stroke prevention strategies are essentially similar in patients with small vessel disease and complex aortic arch atheromas. 21

In addition, a recent meta-analysis showed that AF detection, with at least 7 days of cardiac monitoring, was significantly higher in patients with cryptogenic stroke versus lacunar stroke subtype (9.2% vs 2.4%, p=0.02). 33 The 2.4% AF detection rate in patients with lacunar stroke in this study may not be trivial and requires more study. The ‘Rate of Atrial Fibrillation Through 12 Months in Patients With Recent Ischaemic Stroke of Presumed Known Origin’ (Stroke-AF) trial showed increased AF detection at 12 months with insertable cardiac monitor versus standard of care in patients with lacunar stroke (HR 13.83 95% CI 1.80 to 111.11, p<0.001) with a 12.6% AF detection at 1 year ( NCT02700945 ). It remains unclear, however, whether anticoagulation therapy in those who were found to have brief subclinical AF has a secondary prevention benefit.

In conclusion, although the yield of echocardiography and cardiac monitoring in patients with lacunar stroke is low, some patients with a suspected distant embolic source based on neuroimaging (such as lack of other signs of small vessel disease) or younger patients without vascular risk factors may benefit from a cardiac diagnostic evaluation including TTE and possibly TEE as well as outpatient cardiac rhythm monitoring in certain patients to determine a potential cardiac mechanism. Ongoing trials will shed light on the utility of extended cardiac monitoring in patients with lacunar stroke.

Genetic testing

While not common, certain genetic conditions such as Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and Collagen Type IV Alpha 2 Chain (COL4A2) may cause lacunar stroke. These conditions should be considered in patients with a lacunar infarct with minimal or no risk factors and the presence of other manifestations of these conditions as well as a positive family history, particularly if there is evidence of other markers of intrinsic small vessel disease. 34 In addition, a thoughtful approach that weighs the cost versus benefit of diagnosing such conditions particularly if treatment is available or for prognosis and family planning purposes, is crucial before these tests are ordered. Furthermore, a recent international pooled analysis of patients with MRI confirmed lacunar stroke identified 12 genetic loci that may be implicated in the pathogenesis of lacunar stroke and may represent future therapeutic targets. 35

Looking beyond the brain

A comprehensive diagnostic evaluation is important to look for evidence of small vessel disease in other organs such as the kidneys, heart, and retina. For instance, one study showed that patients with cerebral small vessel disease were more likely to have changes in the retinal vasculature, suggesting that pathologic changes in the retinal arteries parallel changes in the small cerebral arteries, even in normotensive patients. 36 In addition, recent evidence suggest that small vessel disease is a multisystem disorder that may the culprit in ‘cardiac syndrome X’ or ‘microangina’ as well as chronic kidney disease and ischaemic nephropathy. 37 This concept is further supported by genetic cerebral small vessel disease disorders such as CADASIL which also affects other organs such as the skin and heart. 37 These data underscore the importance of a comprehensive multisystem evaluation in patients with lacunar stroke which may not only help determine the likely stroke mechanism but also lead to changes in management of other organs such as referral to an ophthalmologist in patients with evidence of retinopathy.

Neurological deterioration

Studies suggested that 23%–41% of patients with lacunar stroke exhibit neurological deterioration after symptom onset. 38–40 The definition of neurological deterioration and the inclusion/exclusion criteria varied across these studies thus the rate may be on the higher end with less conservative definitions and lower end with more conservative definitions. Studies have shown that patients with lacunar stroke who exhibit neurological deterioration have increased odds of poor functional outcome at follow-up. 38–41 Identifying potential mechanisms for neurological deterioration may guide strategies to prevent and treat neurological deterioration in lacunar stroke.

Plausible mechanisms

Mechanisms hypothesised to be in the pathogenesis of neurological deterioration after lacunar stroke include branch atheromatous disease, altered haemodynamics, disruption of neurovascular unit resulting in oedema, excitotoxicity and inflammation.

There are data to suggest that branch atheromatous disease is associated with increased risk of neurological deterioration in patients with lacunar stroke. In several studies, the odds of early neurological deterioration in patients with small subcortical infarcts was increased with the presence of branch atheromatous disease. 42 On the other hand, markers of small vessel disease such as cerebral microbleeds and white matter disease severity were not associated with the risk of neurological deterioration. 43 The proposed mechanism is that the atherosclerotic plaque extends to involve more penetrating arteries causing the infarct to expand. As such, patients with branch atheromatous disease have larger infarcts compared with those without branch atheromatous disease. 44

Haemodynamic failure is another proposed mechanism of neurological deterioration in patients with lacunar stroke. In one study, patients with lacunar stroke who exhibited neurological deterioration were found to have lower cerebral blood flow and increased mean transit time in the region of interest. 45 At least 20% of patients with lacunar stroke have an ischaemic penumbra on perfusion weighted imaging, 46 47 which is also associated with neurological deterioration. 47 It remains unclear however whether this association is related to the perfusion abnormality or whether larger initial infarcts are associated with more readily detected penumbra and with greater likelihood of deterioration. The theory of impaired perfusion is further supported by evidence showing that impaired cerebrovascular reactivity is more common in lacunar stroke patients who exhibit neurological deterioration. 48

Other mechanisms hypothesised to be implicated in the pathogenesis in neurological deterioration are oedema, excitotoxicity, and inflammation. It has been hypothesised that oedema caused by the disruption of the blood brain barrier can lead to compression of small perforators near the ischaemic lesion causing infarct extension and neurological deterioration. 49 Another study showed increased serum concentration of glutamate and decreased serum concentration of Gamma aminobutyric acid in patients with lacunar stroke who exhibited neurological deterioration, suggesting that excitotoxicity may be another mechanism of neurological deterioration. 50 Neurological deterioration may also occur in the setting of systemic inflammation and thrombosis. This is supported by studies showing higher levels of inflammatory biomarkers 41 51 and cytokines 52 in those who exhibit neurological deterioration.

Therefore, the exact pathogenesis of neurological deterioration in patients with lacunar stroke remains poorly understood highlighting the need of large observational studies using advanced imaging modalities such as perfusion, VWI, cerebrovascular reactivity in addition to measurement of serum markers of excitotoxicity and inflammation to better understand these mechanisms. A better understanding of the pathogenesis of neurological deterioration may lead to investigating therapeutic strategies to treat and prevent neurological deterioration.

Secondary prevention

Pharmacological interventions.

Pharmacological interventions 53–61 including use of antithrombotic agents, blood pressure (BP) lowering agents, statin therapy, glycaemic agents, as well treatment of insulin resistance for secondary prevention in patients with lacunar stroke are summarised in table 2 . Interest is given to the promising role of cilastozol which is a phosphodiesterase III inhibitor that induces mild antiplatelet effects, BP reduction and reduction in triglycerides for stroke prevention after lacunar stroke.

Summary of pharmacological secondary prevention strategies in patients with lacunar stroke

Key to long-term prevention of recurrent lacunar stroke is sustained control of risk factors, namely hypertension, physical inactivity, tobacco use, diabetes and hyperlipidaemia. Physical activity plays an important supporting role in secondary stroke prevention, as increased physical activity decreases BP, promotes lower HbA1C (when part of a structured programme), reduces insulin resistance, improves the lipid profile and may reduce stroke risk itself, among other positive effects on chronic disease. 62 Current recommendations for adults are 150 min of moderate intensity aerobic physical activity weekly. 63 Because low rates of exercise participation are common in stroke survivors, targeted inquiries into reasons for decreased activity and patient-specific recommendations may better address this missed opportunity. Furthermore, smoking is a risk factor for lacunar stroke and thus smoking cessation is an important intervention in reducing the risk of recurrent stroke and cardiovascular events. 63 64

Future directions: preventing neurological deterioration and targeting the underlying mechanism

Prevention and treatment of neurological deterioration.

For patients with stuttering lacunar stroke, there may be a role for early dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. 65 In a recently published retrospective study of 458 patients with lacunar stroke, 130 (28%) of patients had stuttering symptoms that met the definition of early neurologic deterioration. DAPT treatment reduced stuttering symptoms from 77% of patients receiving antiplatelet monotherapy to only 21% of patients receiving DAPT. 40 Specifically in patients with lacunar stroke and evidence of branch atheromatous disease, a multicentre observational study showed that when compared with aspirin monotherapy, aspirin plus cilostizol within 12 hours from onset was associated lower likelihood of clinical progression. 66 This study, however, is open label and non-randomised and results should be interpreted with caution given the potential for bias. The LACunar Intervention Trial-1 (LACI-1) trial of 57 patients with lacunar stroke in the UK showed that the combination of cilostazol and isosorbide mononitrate was safe and well tolerated. 67 The ongoing LACI-2 is testing the feasibility of conducting a large phase 3 trial to investigate the safety and efficacy of cilostazol and/or isosorbide mononitrate in patients with lacunar stroke. 68 Other small studies have looked at the use of intravenous glycoprotein IIb/IIIa inhibitors to prevent deterioration in stuttering lacunar stroke, with promising preliminary results. 69 70 Nonetheless, additional data is needed to support their use, considering that DAPT with a loading dose has a potential benefit and lower cost.

Two retrospective studies in Korea reported a benefit for induced hypertension with phenylephrine in patients with stuttering lacunar stroke. 71 72 The sample size in these studies was small and conclusions cannot be drawn apart from the preliminary safety of mild induced hypertension. Nonetheless, there is biological plausibility to the concept that inducing hypertension could be beneficial in stuttering lacunar stroke, as it may maximise perfusion of the penumbral region. In the IMAGES study, which randomised 2589 patients to either an intravenous magnesium or placebo within 12 hours of stroke onset, a subgroup analysis of patients with lacunar stroke showed that although the overall IMAGES study was neutral, in 765 patients with lacunar stroke there was benefit for magnesium. 73 The OR for favourable outcome (modified Rankin Scale 0–1 at 90 days) in lacunar stroke patients who received magnesium was 0.70 (95% CI 0.53 to 0.92) and the interaction term between lacunar stroke and magnesium therapy was significant (p=0.005). While subgroup analyses of a clinical trial should be interpreted with caution, the results may warrant additional study given the potentially neuroprotective effects of magnesium on cerebral white matter. 74

Targeted treatments for lacunar stroke in the setting of substenotic atherosclerosis

Studies have shown that in patients with cardiovascular atherosclerotic disease, optimising antithrombotic therapy with the use of low dose rivaroxaban was associated with a reduced risk of major cardiovascular events. 75 The benefit of this treatment in patients with symptomatic stenosing intracranial atherosclerosis or non-stenosing branch atheromatous disease remains uncertain. This was also the case with anti-inflammatory drugs such as low dose colchicine 76 and canakinumab 77 and lipid lowering agents such as proprotein convertase subtilisin/kexin type 9-inhibitors. 78 In addition, the ‘Treat Stroke to Target’ trial showed that in patients with an ischaemic stroke or TIA and evidence of atherosclerosis, a target low-density lipoprotein cholesterol <70 mg/dL had a lower risk of subsequent cardiovascular events compared toa target range of 90–110 mg/dL. 79 These could be investigated in future trials aiming to reduce the risk of recurrence in patients with lacunar stroke whose mechanism is thought to be related to substenotic atherosclerosis.

Lacunar stroke and risk factors for cardioembolism

In patients whose lacunar stroke occurs in the setting of known paroxysmal or permanent AF, anticoagulation is recommended for secondary stroke prevention. Several randomised trials have shown that DOACs are non-inferior to warfarin at prevention of thrombotic events, with lower risk of intracranial haemorrhage. 80 This may be particularly important in patients with lacunar stroke and concomitant microbleeds whose risk of intracerebral haemorrhage may be particularly increased. In such patients with biomarkers of haemorrhagic risk such as high microbleed burden or severe white matter disease, studies investigating the safety and efficacy of left atrial appendage occlusion compared with DOACs are needed.

While lacunar strokes are unlikely to be related to a distant embolic source, in young patients who have a lacunar stroke and a PFO in the absence of AF and risk factors for cerebral small vessel disease, 81 PFO closure may be reasonable ( figure 3 ).

Diffusion-weighted imaging sequence showing a lacunar infarct in a young patient without risk factors who presented with acute onset right sided weakness. Diagnostic evaluation including telemtery, vascular imaging, hypercoagylable labs and echocardiography revelled a patent formen ovale (PFO) with a bidirectional shunt. His Risk of Paradoxical Embolism (ROPE) score was nine suggesting that the PFO is the likely culprit.

Lacunar stroke is a common and heterogeneous disease that necessitates a nuanced approach to diagnosis and treatment. Control of secondary stroke risk factors, principle among them hypertension, is a critical element in lowering the risk of recurrent lacunar stroke. Primary prevention of lacunar stroke has not been studied, but ongoing studies in patients with asymptomatic brain lesions will provide much needed data regarding the safety and efficacy of aggressive medical management to prevent stroke, of which lacunar stroke is the main symptomatic subtype.

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Contributors SY: manuscript preparation, revision, concept and design ER and AdH: manuscript preparation, revision and imaging acquisition. DY, BMG and SC: manuscript preparation and revision. MSVE: manuscript revision.

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.

Provenance and peer review Not commissioned; externally peer reviewed.

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Advances in Understanding the Pathophysiology of Lacunar Stroke : A Review

• 1 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
• 2 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
• 3 Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
• Comment & Response The Importance of Blood Pressure Gradients in the Brain : Cerebral Small Vessel Disease J. David Spence, MD JAMA Neurology

Importance   Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although smaller in size, they create large problems, leaving many patients with intellectual and physical disabilities. Because there are limitations in understanding the underlying pathophysiology of LS, the development of novel therapies has been slow.

Observations   When the term lacune was described in the 1800s, its underlying pathophysiological basis was obscure. In the 1960s, C. Miller Fisher, MD, performed autopsy studies that showed that vessels supplying lacunes displayed segmental arteriolar disorganization, characterized by vessel enlargement, hemorrhage, and fibrinoid deposition. For these pathologic changes, he coined the term lipohyalinosis . Since that time, few attempts have been made to reconcile this pathologic description with modern mechanisms of cerebral small vessel disease (CSVD). During the past 6 years, progress has been made in understanding the clinical mechanisms, imaging characteristics, and genetic basis of LS.

Conclusions and Relevance   Questions persist regarding the order of events related to the initiation and progression of CSVD, how LS is related to other sequelae of CSVD, and whether LS is part of a systemic disease process. The relative roles of aging, oxidative stress, mechanical stress, genetic predisposition, and other vascular risk factors should be further studied, especially in the era of widespread antihypertensive use. Although understanding of endothelial dysfunction has increased, future work on the role of media and adventitial dysfunction should be explored. Recent advances in mapping the brain vasculome may generate new hypotheses. The investigation of new therapeutic targets, aimed at reversing CSVD processes and promoting neural repair after LS, depends upon further understanding these basic mechanisms.

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Regenhardt RW , Das AS , Lo EH , Caplan LR. Advances in Understanding the Pathophysiology of Lacunar Stroke : A Review . JAMA Neurol. 2018;75(10):1273–1281. doi:10.1001/jamaneurol.2018.1073

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Case Study – Lacunar Strokes

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This case study is part of an educational case series, that was commissioned from members of the WSO Education Committee by former WSA Lead Commissioning Editor Professor Peter Sandercock. The aim of the series is to present cases with a useful clinical message relating to common clinical problems. Cases highlight issues in diagnosis, management, organization of care, etc.

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Don’t miss the webinar organized by the @WorldStrokeEd🧠 focusing on #stroke and #IA with our @TRUSTroke_EU Project coordinator @carlosmictusvh as a distinguished speaker🎙️ #webinaralert

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Cerebral and extracerebral vasoreactivity in symptomatic lacunar stroke patients: a case-control study

Affiliation.

• 1 INSERM U-698 and Paris-Diderot University, Department of Neurology and Stroke Center, Bichat University Hospital, Paris, France.
• PMID: 22336034
• DOI: 10.1111/j.1747-4949.2011.00755.x

Background: Whether cerebral artery endothelial dysfunction is a key factor of symptomatic lacunar stroke and cerebral small vessel disease remains unclear.

Methods: Cerebral and extracerebral vasoreactivity were measured in 81 patients with recent symptomatic lacunar stroke and in 81 control subjects matched for main vascular risk factors. Cerebral vasoreactivity and carotid endothelial-dependent vasodilation were measured after five-minutes of carbon dioxide-induced hypercapnia. Brachial endothelial-dependent vasodilation was assessed after hyperemia induced by deflating a cuff around the forearm previously inflated to 200 mmHg for four-minutes. Carotid and brachial endothelial-independent vasodilation were measured five-minutes after administration of sublingual nitroglycerin 300 μg. Brain magnetic resonance imaging were analyzed in lacunar stroke patients.

Results: One-month after stroke onset, patients had more severely impaired cerebral vasoreactivitys than matched controls (mean ± standard deviation, 14·4 ± 12·1% vs. 19·4 ± 17·4%; P = 0·049). Severe alterations of both carotid and brachial endothelial-dependent and at a lesser degree of carotid and brachial endothelial-independent vasodilation were observed in both groups. After adjustment for confounders, subjects with a cerebral vasoreactivity value in the two lower tertiles (≤19·6%) were more likely to have had a symptomatic lacunar stroke (adjusted odds ratio, 3·78; 95% confidence interval, 1·42 to 10·08; P = 0·008). Only alteration of brachial endothelial-independent vasodilation correlated with parenchymal abnormalities, namely microbleeds and leukoaraiosis.

Conclusions: While abnormalities in extracerebral vasoreactivity seem related to vascular risk factors, the severity of endothelial dysfunction in cerebral arteries may be determinant in the occurrence of symptomatic lacunar stroke in patients with small vessel disease.

Keywords: Doppler; diabetes mellitus; endothelium; hypertension; lacunar infarcts.

© 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.

Publication types

• Research Support, Non-U.S. Gov't
• Brachial Artery / physiopathology*
• Case-Control Studies
• Cerebral Arteries / physiopathology*
• Cerebrovascular Circulation / physiology
• Endothelium, Vascular / physiopathology
• Middle Aged
• Stroke, Lacunar / physiopathology*
• Vasodilation

Vascular Endothelial Growth Factor and Ischemic Stroke Risk: A Mendelian Randomization Study

• ORIGINAL RESEARCH
• Open access
• Published: 15 April 2024

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• Xiao Zhang 1 , 2 , 3   na1 ,
• Xinzhi Hu 4   na1 ,
• Shiyuan Fang 4 , 5   na1 ,
• Jiayao Li 1 , 3 ,
• Zhichao Liu 2 ,
• Weidun Xie 6 ,
• Ran Xu 1 , 3 ,
• Adam A. Dmytriw 7 ,
• Kun Yang 8 ,
• Yan Ma 1 , 3 ,
• Liqun Jiao 1 , 3 , 9 &
• Tao Wang 1 , 3  

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Introduction

Previous studies have reported controversial relationships between circulating vascular endothelial growth factors (VEGF) and ischemic stroke (IS). This study aims to demonstrate the causal effect between VEGF and IS using Mendelian randomization (MR).

Summary statistics data from two large-scale genome-wide association studies (GWAS) for 16,112 patients with measured VEGF levels and 40,585 patients with IS were downloaded from public databases and included in this study. A published calculator was adopted for MR power calculation. The primary outcome was any ischemic stroke, and the secondary outcomes were large-artery stroke, cardioembolic stroke, and small-vessel stroke. We used the inverse variance-weighted (IVW) method for primary analysis, supplemented by MR-Egger regression and the weighted median method.

Nine SNPs were included to represent serum VEGF levels. The IVW method revealed no strong causal association between VEGF and any ischemic stroke (odds ratio [OR] 1.01, 95% CI 0.99–1.04, p  = 0.39), cardioembolic stroke (OR 1.04, 95% CI 0.97–1.12, p  = 0.28), large-artery stroke (OR 1.02, 95% CI 0.95–1.09, p  = 0.62), and small-vessel stroke (OR 0.98, 95% CI 0.91–1.04, p  = 0.46). These findings remained robust in sensitivity analyses. MR-Egger regression suggested no horizontal pleiotropy.

Conclusions

This Mendelian randomization study found no relationship between genetically predisposed serum VEGF levels and risks of IS or its subtypes.

Avoid common mistakes on your manuscript.

Vascular endothelial growth factors (VEGF) promote angiogenesis and nurture neurons [ 1 , 2 ]. VEGF have been implicated in multiple stroke-related pathophysiological pathways, including atherosclerosis, promoting collateral circulation, and increasing vascular permeability [ 2 ]. Stroke is the second leading cause of death and loss of disability-adjusted life years worldwide [ 3 ]. Serum VEGF level is considered as a potential biomarker of stroke [ 4 ], because high VEGF levels are often observed concurrently with ischemic attacks. However, the causal relationship between VEGF and ischemic stroke (IS) has never been fully understood. VEGFA is known as the most effective factor to promote neovascularization [ 5 ] and therefore a high-level VEGFA expression within atherosclerotic plaques is believed to lead to plaque revascularization and eventually cause large-artery strokes. Compared to VEGFA, other subtypes of VEGF have received far less research attention. VEGFB is noted as a “survival” factor rather than a potent angiogenic factor, because it protects brain microvasculature stability in injured regions, rather than producing unstable neovascularization [ 6 ]. Observational studies from clinical practice have been giving controversial results in the past few years, and an important cause was the mixed measurement of VEGF. Most studies used the enzyme-linked immunosorbent assay (ELISA) technique to detect circulating VEGF; however, different designs of the primary antibodies would bind different epitopes of VEGF, thus generating mixed results [ 4 ]. Furthermore, a recent Mendelian randomization study aimed to explore whether high serum VEGF levels cause ischemic heart disease, and reported negative results [ 7 ]. In summary, whether high serum VEGF levels would cause ischemic stroke remains unknown.

Mendelian randomization (MR) uses genetic variants to represent a certain exposure. Such genetic variants are used as instrumental variables, which are randomly distributed in the general population by nature [ 8 , 9 ]. A major advantage of using MR is that one can infer causal relationships between risk factors (exposure) and diseases (outcome) without environmental or reverse confounders [ 10 ]. In this study, we aim to use MR analyses to explore whether genetically predisposed circulating VEGF levels increase the risk of IS, and specifically, three subtypes of IS, in the absence of confounders and reverse causations. Depicting this causality would provide insights into using VEGF neutralizing antibodies as a primary prevention of IS.

Study Design

We carried out MR analysis with a two-sample design, employing summary statistics from two extensive genome-wide association studies (GWAS) [ 11 , 12 ]. Each of the individual studies obtained approval from the respective local institutional review board or ethics committee. In this current study, we exclusively extracted summarized data from consortia. Ethics approval was deemed unnecessary, given that all analyses were conducted utilizing publicly accessible databases [ 13 ]. A genetic variant serves as a valid instrument when it met the main assumption of MR: (1) it should be strongly associated with the risk factor, (2) it must not be tied to any confounding factors, and (3) its impact on the outcome should come only through its effect on the exposure.

Genetic Instruments for Circulating VEGF Levels

Genetic association estimates of genome-wide significant single nucleotide polymorphisms (SNPs) ( p  < 5 × 10 −8 ) with predicted serum VEGF levels (per log-transformed pg/mL) were obtained from a GWAS including 16,112 samples of European ancestry based on the 1000 Genomes reference data [ 11 ]. It is the most comprehensive GWAS of circulating VEGF and the instruments have been widely used in multiple MR studies confounding different outcomes, including ischemic heart disease [ 7 , 14 ]. The serum VEGF levels were measured using commercial ELISA assays. Participants’ age ranged from 30.4 to 76.2 years old. All SNPs were clumped with a 10,000-kB window to a threshold of r 2  < 0.1 to ascertain independence between genetic variants according to the 1000 Genomes (EUR) reference data from SNP Annotation and Proxy Search ( http://www.broad.mit.edu/mpg/snap/ldsearchpw.php ). We utilized the online database Phenoscanner to investigate potential pleiotropy of the instruments concerning confounding traits. This included traits such as hypertension medical history, patient’s blood lipid status, and diabetes status [ 15 ]. Proxies (with r 2  > 0.80) for SNPs not present in the outcome dataset were determined utilizing the LDproxy tool on the National Cancer Institute LDlink platform ( https://ldlink.nih.gov/?tab=ldproxy ). The robustness of the instrument was indicated by the F-statistic. All SNPs exhibited F-statistic values exceeding 10, indicating a low likelihood of introducing substantial weak instrument bias in the MR analyses. Any paralimbic SNPs were excluded.

Summary Statistics Data for Ischemic Stroke

A multi-ancestry GWAS conducted by the GIGASTROKE consortium, encompassing 62,100 and 1,234,808 cases of European ancestry and controls, was used to derive the evaluation of genetic relationship between SNP and outcome [ 16 ]. This is the latest and largest comprehensive GWAS, which has been applied in most MR studies [ 17 ]. IS cases were diagnosed on the basis of clinical and imaging criteria. In accordance with the Acute Stroke Treatment (TOAST) criteria, IS was categorized into the following subtypes: large-artery stroke (LAS, n  = 6399), cardioembolic stroke (CES, n  = 10,804), and small-vessel ischemic stroke (SVS, n  = 6811). Replication analyses were conducted within the MEGASTROKE Consortium, comprising 40,585 cases and 406,111 controls. All cases of IS were categorized into LAS ( n  = 4373), CES ( n  = 7193), and SVS ( n  = 5369) [ 12 ].

Compliance with Ethics Guidelines

The summary-level datasets utilized in our study were retrieved from de-identified public datasets or studies. All included studies had received prior approval from the appropriate ethics committee, and informed consent was obtained from all participants involved in the original studies [ 11 , 12 , 16 ]. Ethical approval was not required for our study as we exclusively utilized summary-level data. The study complied with the Declaration of Helsinki.

Mendelian Randomization Power Calculation

To assess the adequacy of the participant size for conducting MR analyses, we performed power calculations using a published calculator. A total of 10 SNPs of VEGF levels explained the variance which ranged from 19% to 52%. Rs34528081 was clumped to ascertain independence and excluded from the instruments. Under the assumption that the remaining nine SNPs contributed only 19% of the variance, we performed power calculations using an online tool ( https://shiny.cnsgenomics.com/mRnd/ ).

Statistical Analysis

The primary outcome was defined as any IS, with secondary outcomes including LAS, CES, and SVS. With regards to individual SNPs, MR estimates were computed using the ratio of coefficients method, and their standard errors were derived using the delta method. Primary analysis involved amalgamating the ratio estimates under a random-effects model inverse-variance weighting (IVW) approach. Additionally, the findings were complemented by employing MR-Egger regression and a penalized weighted median for a comprehensive assessment [ 18 , 19 , 20 ].

The MR-Egger intercept test was used to estimate the horizontal pleiotropic effects. The MR-Egger estimates were calculated to adjust for pleiotropy, which is the phenomenon where a single genetic variant affects multiple traits or outcomes. In this test, if the intercept value for the MR-Egger regression significantly deviates from zero ( P  < 0.05), it suggests the presence of horizontal pleiotropy, which indicates that the genetic variant is influencing the outcome through pathways unrelated to the main exposure of interest [ 18 ]. In addition to other analyses, we utilized the penalized weighted median estimates to enhance robustness. This method penalizes the weights of candidate instruments in the weighted regression model, taking into account heterogeneous ratio estimates. Funnel plots were utilized for a visual inspection of heterogeneity, with any observable asymmetry around the vertical line raising the possibility of directional pleiotropy. This graphical approach provided an additional layer of scrutiny to detect potential biases or anomalies in the MR estimates. Moreover, we applied the MR pleiotropy residual sum and outlier (MR-PRESSO) method as an additional step to corroborate the presence of potential outliers in our MR analyses [ 21 ]. This method enhanced the robustness of our findings by identifying and addressing any influential data points that might impact the validity of the results.

To communicate the outcomes effectively, we exponentiated all results to present odds ratios (ORs) and their accompanying 95% confidence intervals (CIs) for stroke. These values reflect the association per logarithmic increase in circulating VEGF levels, offering a comprehensive perspective on the impact of VEGF in the context of stroke risk. To account for multiple testing, we applied a Bonferroni correction and set a significance threshold of α = 0.05/4 (one exposure and four outcomes). P  values ranging from 0.05 to 0.0125 indicate potential causal significance between the exposure and outcome. All statistical analyses were performed using R version 4.0.0, with the utilization of the R packages TwoSampleMR and MR-PRESSO.

Nine SNPs were performed as instruments for analyzing ischemic stroke (Supplementary Table  1 ). The power calculation indicated a statistical power ranging from 85% to 100% for detecting an OR of 0.9 or 1.1. Each of the instrumental variables displayed significant associations with circulating VEGF levels and demonstrated independence from the majority of confounding factors. All instruments were also independent of the outcomes. Figure  1 a illustrates MR causal effect estimates for the risk of stroke per log-transformed increase in circulating VEGF levels. In summary, the application of the IVW method did not reveal a substantial causal link between VEGF levels and the occurrence of IS (OR 1.01, 95% CI 0.99–1.04, P  = 0.39), CES (OR 1.04, 95% CI 0.97–1.12, P  = 0.28), LAS (OR 1.02, 95% CI 0.95–1.09, P  = 0.62), and SVS (OR 0.98, 95% CI 0.91–1.04, P  = 0.46). Replication analysis using MEGASTROKE exhibited consistent results with that of GIGASTROKE (Fig.  1 b). The causal effects of singe instrument are described in Supplementary Table  3 .

Causal effect of VEGF on the risk of ischemic stroke and its subtypes estimated using four MR methods. a GIGASTROKE; b MEGASTROKE. The causal effect from VEGF to outcomes is expressed as OR per unit. Error bars represent the 95% CIs of the estimates. The odds ratios (OR) are per genetically predicted 1 SD increase in genetically predicted per standard deviation (SD) increase in log odds of the circulating VEGF. SNP single nucleotide polymorphism, GWAS genome-wide association study, VEGF vascular endothelial growth factor, IVW inverse-variance weighted, OR odds ratio, CIs confidence intervals, MR-PRESSO MR pleiotropy residual sum and outlier

The conclusions drawn from the penalized weighted median method align with those derived from our analyses using the same method. Moreover, the MR-Egger regression intercept provided no substantial evidence of horizontal pleiotropy ( P  > 0.05), reinforcing the robustness of our findings (Table  1 ). There were no outliers detected in the analyses of funnel plot (shown as Fig.  2 a, b), and this observation was corroborated by the results of the MR-PRESSO outlier test.

Funnel plot of four MR methods. a GIGASTROKE; b MEGASTROKE. SNP single nucleotide polymorphism, GWAS genome-wide association study, VEGF vascular endothelial growth factor, IVW inverse-variance weighted, MR-PRESSO MR pleiotropy residual sum and outlier, SE standard error

In this two-sample MR study, we explored the causal relationship between circulating VEGF levels and risks of IS using genetic instrumental variables. Our findings suggest that a high level circulating VEGF is unlikely to result in any IS or its subtypes, specifically LAS, CES, and SVS. The findings remained robust in sensitivity analyses with different MR methods. In clinical practice, high circulating VEGF levels may not be a predictor of ischemic stroke.

The hypothesis of VEGF causing atherosclerotic stroke is deduced from its role in atherogenesis. An atherosclerotic plaque is a hypoxic and inflammatory environment. Both features upregulate VEGF expression to promote angiogenesis and relieve ischemia, but the newly generated vessels could lead to intraplaque hemorrhage and eventually plaque rupture [ 2 ]. However in real-world experiences, a prospective community-based study including 3041 participants reported a complex, inverted U-shaped relation between serum VEGF level and incidence of cardiovascular diseases, as the incidence increases with serum VEGF going up but then drops at the highest quartile of VEGF levels [ 22 ]. Such population-based studies were inevitably to suffer from epidemiological confounders, including patients’ age, gender, comorbidities of coronary artery diseases [ 22 ], myocardial infarction [ 23 ], and diabetes mellitus [ 24 ], which are all known to influence VEGF levels.

Using MR analyses that eliminate the aforementioned confounders and reverse causations, the largely null results of our study provided evidence that high circulating VEGF does not cause IS or its subtypes. This result is consistent with a previous MR study focusing on VEGF’s relationship with ischemic heart disease (IHD) [ 7 ]. That MR study enrolled 60,801 patients with IHD and 123,504 controls, only to find no positive effect of VEGF on IHD risks [ 7 ]. Another recent MR study involving 41 cytokines and growth factors identified VEGF as a possible cause of CES ( p  < 0.05), but its p  value did not meet the Bonferroni correction threshold [ 25 ]. It also reported no causality between VEGF and any IS, LAS, or SVS [ 25 ].

The biggest strength of this study lies within the rigorous assumptions of MR analyses. We satisfied all three key assumptions that validate an MR study [ 26 ]. First, for the relevance assumption, the adopted instrumental variables in our study were associated with circulating VEGF levels and incidence of IS in two large GWAS [ 11 , 12 ]. The large sample size substantially compensated for the potential weak instrumental bias. Second, in terms of the independence assumption, it is established that genetically predisposed serum VEGF accounts for the majority of serum VEGF levels. Acute-onset conditions, including acute coronary syndrome and stroke, may cause temporal fluctuations in VEGF levels, but could not be held accountable for the chronic and slow progression of atherosclerotic plaques. Last, regarding the exclusion restriction, MR-Egger test suggested no evidence of heterogeneity, and the MR-PRESSO method found no outliers, suggesting that the genetic variants under discussion only affect the outcome through their effects on the VEGF levels. Another strength is the robustness of our findings, as we applied four methods and all gave negative results. We also distinguished between different subtypes of IS, especially LAS, which theoretically could be caused by elevated VEGF. Though our largely null finding negated the causal relationship between VEGF and IS, the biomarker role of VEGF in IS diagnosis should not be repudiated. The upregulation of VEGF is likely to be the outcome instead of the cause of ischemia.

A notable limitation of this study is that we failed to distinguish subgroups of VEGFs. VEGFs are a group of growth factors that primarily include VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor (PlGF) [ 2 ]. Among them, VEGFA is considered as the most relevant, as it originates from almost all vascularized tissues in humans, and loss of a single VEGF allele results in embryonic death in mice [ 5 ]. However, no strong genetic variables have been identified to predict serum VEGFA levels. Another limitation is that all participants were of European descent. Different populations have different genetic characteristics, and some genetic variations may be prevalent in one population but scarce or absent in another as a result of recent emergence and limited dissemination [ 27 , 28 ]. Hence, the generalizability of our results to other ethnic groups may be potentially limited, and this is also a common limitation in MR studies [ 29 , 30 ].

Future studies should investigate the differences between lacunar and non-lacunar strokes, since they require different treatment intensities and have diverged prognosis [ 31 ]. Secondly, the specific link between VEGFA and IS remains to be elucidated in future studies, once such variables are recognized.

Our two-sample MR study provides genetic evidence that high serum VEGF levels do not increase the risk of IS. Therefore, high VEGF levels may not predict the risk of stroke under clinical circumstances. Future studies should explore the relationship between VEGFA and IS.

Data Availability

All data pertinent to this study are comprehensively detailed within this paper, and the origin of publicly accessible data is explicitly disclosed.

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Acknowledgements

We are grateful to all members of LJ lab for their help with this manuscript.

Medical Writing and Editorial Assistance

The authors did not employ medical writing or editorial assistance for the preparation of this paper.

This work was supported by the Beijing Scientific and Technologic Project [grant number Z201100005520019], the National Natural Science Foundation of China [grant number 82171303], Beijing Hospitals Authority’s Ascent Plan [grant number DFL20220702], the National Natural Science Foundation of China [grant number 82301468], Beijing Municipal Administration of Hospitals Incubating Program [grant number PX2021034]. The Rapid Service Fee was funded by the authors.

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Xiao Zhang, Xinzhi Hu, and Shiyuan Fang contributed equally to this work and share first authorship.

Authors and Affiliations

Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing, 100053, China

Xiao Zhang, Jiayao Li, Ran Xu, Yan Ma, Liqun Jiao & Tao Wang

Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK

Xiao Zhang & Zhichao Liu

China International Neuroscience Institute (China-INI), 45 Changchun Street, Beijing, 100053, China

Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, 100730, China

Xinzhi Hu & Shiyuan Fang

Department of Neurology, Peking Union Medical College Hospital, Beijing, 100730, China

Shiyuan Fang

Department of Computer Science, City University of Hong Kong, Kowloon, 999077, Hong Kong SAR

Neuroendovascular Program, Massachusetts General Hospital, Boston, MA, 02114, USA

Adam A. Dmytriw

Department of Neurosurgery, Tai’an Central Hospital, 29 Longtan Road, Tai’an, 271000, Shandong, China

Department of Interventional Neuroradiology, Xuanwu Hospital, Capital Medical University, No. 45 Changchun Street, Xicheng District Beijing, 100053, China

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Tao Wang and Liqun Jiao developed the initial ideas for this study and formulated the study designs. Xiao Zhang, Xinzhi Hu, and Shiyuan Fang performed data analysis and original drafts. Liqun Jiao, Tao Wang, Ran Xu, Adam A. Dmytriw, and Yan Ma were consulted about clinical issues. Xiao Zhang, Xinzhi Hu, Shiyuan Fang, Jiayao Li, Zhichao Liu, Weidun Xie, Ran Xu, Adam A. Dmytriw, Kun Yang, Yan Ma, Liqun Jiao, and Tao Wang were responsible for the revision of the draft. All authors read and approved the final version of the manuscript prior to submission.

Corresponding authors

Correspondence to Liqun Jiao or Tao Wang .

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Conflict of interest.

Shiyuan Fang relocated to a new institution following her graduation and the completion of this paper; her new affiliation is Department of Neurology, Peking Union Medical College Hospital, Beijing, China. We have included her both primary and updated affiliation addresses in this manuscript. Other authors have nothing to disclose. The authors declare no competing interests.

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Prior Publication : This manuscript is based on work that was previously reported by Choi SH et al., Malik R et al., and Mishra A et al. in PLoS Genetics , Nature Genetics , and Nature , respectively [ 11 , 12 , 16 ].

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Zhang, X., Hu, X., Fang, S. et al. Vascular Endothelial Growth Factor and Ischemic Stroke Risk: A Mendelian Randomization Study. Neurol Ther (2024). https://doi.org/10.1007/s40120-024-00601-0

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Research paper

Late functional improvement after lacunar stroke: a population-based study, aravind ganesh.

Centre for Prevention of Stroke and Dementia, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK

Sergei A Gutnikov

Peter malcolm rothwell, associated data.

jnnp-2018-318434supp001.pdf

Recovery in function after stroke involves neuroplasticity and adaptation to impairments. Few studies have examined differences in late functional improvement beyond 3 months among stroke subtypes, although interventions for late restorative therapies are often studied in lacunar stroke. Therefore, we compared rates of functional improvement beyond 3 months in patients with lacunar versus non-lacunar strokes.

In a prospective, population-based cohort of 3-month ischaemic stroke survivors (Oxford Vascular Study; 2002–2014), we examined changes in functional status (modified Rankin Scale (mRS), Rivermead Mobility Index (RMI), Barthel Index (BI)) in patients with lacunar versus non-lacunar strokes from 3 to 60 months poststroke, stratifying by age. We used logistic regression adjusted for age, sex and baseline disability to compare functional improvement (≥1 mRS grades, ≥1 RMI points and/or ≥2 BI points), particularly from 3 to 12 months.

Among 1425 3-month survivors, 234 patients with lacunar stroke did not differ from others in 3-month outcome (adjusted OR (aOR) for 3-month mRS >2 adjusted for age/sex/National Institutes of Health Stroke Scale score/prestroke disability: 1.14, 95% CI 0.75 to 1.74, p=0.55), but were more likely to demonstrate further improvement between 3 months and 1 year (aOR (mRS) adjusted for age/sex/3-month mRS: 1.64, 1.17 to 2.31, p=0.004). The results were similar on restricting analyses to patients with 3-month mRS 2–4 and excluding recurrent events (aOR (mRS): 2.28, 1.34 to 3.86, p=0.002), or examining BI and RMI (aOR (RMI) adjusted for age/sex/3-month RMI: 1.78, 1.20 to 2.64, p=0.004).

Patients with lacunar strokes have significant potential for late functional improvement from 3 to 12 months, which should motivate patients and clinicians to maximise late improvements in routine practice. However, since late recovery is common, intervention studies enrolling patients with lacunar strokes should be randomised and controlled.

Introduction

Functional improvement after neurological lesions like stroke or demyelination is driven by neural recovery, through structural and functional plasticity, 1 and/or by the individual’s physiological and psychosocial adaptation to activities with residual impairments. 2 3 Although the capacity for neuroplasticity is known to be influenced by the nature of the initial injury, 4 the differential implications of lesion location and stroke subtype for overall functional improvement remain uncertain. For instance, one might consider patients with lacunar strokes, affecting subcortical structures, 5 as potentially having a greater capacity for functional improvement than those with non-lacunar strokes, given their intact cortex recruitable for plasticity and adaptive strategies. On the other hand, the damage to densely packed tracts might leave patients with lacunar stroke less capable of meaningful improvement despite cortical plasticity or adaptation. Some studies suggest that certain lacunar syndromes might have a greater capacity for recovery, 6 while others report no differences in recovery at discharge in cortical or subcortical strokes. 7 Of the few studies that have examined recovery beyond the acute phase, one found no differences, 8 while another suggested that patients with lacunar stroke fare worse, 9 but they were limited by small sample size and/or retrospective design. Most studies have also focused on neurological recovery (improvement in specific impairments like motor strength), but elucidating changes in functional improvement (daily activities) is also clinically relevant, as both recovery and adaptive capabilities could be harnessed in rehabilitation.

The potential for patients with lacunar strokes to demonstrate late improvement has also been suggested in some studies of restorative therapies that specifically enrolled patients with small subcortical strokes, 10–15 although not all had a control group. 13–15 However, given the paucity of published data on differences between stroke subtypes in late recovery trajectories, it is uncertain how much late improvement can be expected simply on the basis of untreated natural history. 16 To better inform patients and clinicians about prognosis in routine practice, and inform the design and interpretation of rehabilitation studies, we compared functional improvement beyond 3 months in patients with lacunar versus non-lacunar strokes in a prospective, population-based cohort (Oxford Vascular Study, OXVASC).

The OXVASC population comprises 92 728 patients registered with about 100 general practitioners (GPs) in 9 practices across Oxfordshire. The study methods have been published. 17 Recruitment has been ongoing since April 2002. Patients with suspected transient ischaemic attack (TIA) or stroke are ascertained using overlapping methods of ‘hot’ and ‘cold’ pursuit, including daily rapid-access ‘TIA/stroke clinic’ to which participating GPs and the local emergency department (ED) refer all unhospitalised individuals with suspected TIA/stroke; daily searches of ward admissions (medical, cardiology, stroke, neurology), ED attendance register and in-hospital bereavement office death records; and monthly searches of death certificates, coroners’ reports (for out-of-hospital deaths), GP and hospital diagnostic/discharge codes, and brain/vascular imaging referrals. Direct assessment has shown ascertainment is near complete. 18

Patients with ischaemic stroke recruited from April 2002 to March 2014 were included. Patients were assessed urgently by study clinicians and considered for inclusion. Stroke was diagnosed per the WHO definition. 19 Neurological impairment, medical history and risk factors were assessed. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). All cases were reviewed by a senior neurologist (PMR) daily and imaging was reviewed by the study neuroradiologist. Patients received no interventions beyond standard care.

Patients had face-to-face follow-up with a study nurse/physician either in a hospital clinic or at home at 1 month, 3 months, 6 months, 1 year and 5 years. At each visit, functional status was assessed using the modified Rankin Scale (mRS), Rivermead Mobility Index (RMI) and Barthel Index (BI). The mRS is a 7-point disability scale ranging from 0 (no symptoms) to 6 (death). 20 The RMI assesses 15 functional mobility tasks and ranges from 0 (cannot perform any) to 15 (can perform all). 21 The BI assesses activities of daily living and ranges from 0 (dependent for all) to 20 (independent for all). 22 These scales are often used as outcome measures in trials of poststroke restorative therapies. 23 Raters were trained in mRS assessment using an instructional DVD with written materials produced by the University of Glasgow, previously used in large-scale trials, 20 and underwent additional training and observation for RMI and BI assessments. Prestroke mRS and BI were determined at enrolment.

Patients who moved out of the study area were followed up by telephone. Additional information was obtained from carers in patients with significant speech or cognitive impairment. Recurrent vascular events were identified by daily OXVASC ascertainment, follow-up interviews and review of GP/hospital diagnostic codes. All deaths were also recorded from death certificates, coroners’ reports and the National Health Service Central Register. Poststroke healthcare resource use was obtained until 1 May 2017, including hospital-based rehabilitation (with length of stay, LOS) and community-based rehabilitation (physiotherapy, speech/language, occupational therapy).

Statistical analyses

Only patients surviving ≥3 months after their first (‘index’) stroke in the study period were included to focus on functional improvement beyond the 90-day endpoint favoured by acute stroke trials. Analyses were censored at 1 May 2017.

We classified strokes as lacunar/non-lacunar using the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria for small-vessel occlusion. 24 As sensitivity analyses, we also examined recovery trends in patients with lacunar stroke syndrome (LACS) per the Oxfordshire Community Stroke Project classification who did not necessarily meet the TOAST criteria for small-vessel aetiology. 25

We plotted 3-month mRS against the initial NIHSS score to examine early functional improvement in the first 3 months poststroke. We then examined functional improvement beyond 3 months by plotting changes in mRS from 3 months to 6 months, 6 months to 1 year, and from 1 year to 5 years for patients with lacunar versus non-lacunar strokes, further stratifying patients by age (<75 and >75 years).

Any drop in mRS is meaningful, as long-term mortality and dependency rise with each scale increment, 26 so patients were deemed to show functional improvement if the score decreased by ≥1 grades. Logistic regression was used to model the association of lacunar versus non-lacunar stroke with mRS improvement in each time-period, adjusted for age/sex/baseline score for that time-period (eg, 3-month mRS for improvement from 3 months to 1 year; 1-year mRS for 1–5 years). Patients with mRS=0 at the beginning of each time-period were excluded from respective regressions since they could not show improvement. To minimise bias of the 1-year functional improvement analysis in favour of patients with lacunar strokes from their lower mortality, while avoiding survivorship bias, we used the most recent mRS prior to death (ie, 6-month mRS) whenever available for patients who died within 1 year, and otherwise excluded 1-year deaths. To focus on patients with mild-to-moderate disability who might be recruited in rehabilitation trials, we repeated the analysis using only patients with 3-month mRS 2–4. To verify that differences were not reflecting non-stroke-related disability, we repeated these regressions, progressively excluding patients with recurrent vascular events, prestroke mRS >2 and relevant comorbidities (peripheral vascular disease, heart failure, valve disease, cancer).

We validated our findings by repeating these analyses with the RMI and BI. The RMI’s minimal clinically important difference (MCID) is not established, but test–retest studies suggest that increases by ≥1 points are reliable, so this was deemed indicative of functional improvement on logistic regression. 27 The BI’s MCID is 1.85 points, so increases by ≥2 points were deemed indicative of functional improvement. 22 Patients with 3-month RMI=15 and BI=20 were excluded as they could not show improvement.

Statistical analyses used STATA V.13.1. Trends in ordinal data were compared using non-parametric Wilcoxon rank-sum tests corrected for ties, and dichotomous variables were compared using χ 2 tests. Significance was set at p<0.050.

Of 1606 patients with ischaemic stroke, 181 (11.3%) died within 3 months. Baseline data were available for 1403 (98.5%) of the 1425 3-month survivors. Patients with lacunar stroke were younger than non-lacunar stroke patients, more often men, had lower initial NIHSS score and were less likely to have premorbid disability ( table 1 ). There was no difference between patients with lacunar and non-lacunar strokes in thrombolysis (NIHSS adjusted OR (aOR): 0.67, 95% CI 0.08 to 5.44, p=0.71) or community-based rehabilitation (NIHSS aOR: 0.97, 0.63 to 1.49, p=0.88). Although patients with lacunar stroke seemed less likely to receive hospital-based rehabilitation ( table 1 ), this difference was no longer seen on adjusting for stroke severity (NIHSS aOR: 0.77, 0.53 to 1.12, p=0.18; mean LOS if NIHSS score ≥5: lacunar=54.9 days, non-lacunar=63.9, p=0.57). Over 5 years of follow-up, there were fewer deaths among lacunar strokes but no differences in recurrent vascular events or poststroke depression ( table 1 ; flow diagram in  online supplementary figure I ). Complete mRS data were available for 1403 (98.5%) and RMI/BI data for 1228 (86.2%) 3-month survivors. There was no difference between lacunar and non-lacunar stroke patients with missing RMI/BI data (n=197) in the distribution of NIHSS scores (p trend =0.58), 3-month mRS (p trend =0.14) or improvement on mRS from 3 months to 1 year (p trend =0.36).

Characteristics of 3-month survivors of ischaemic stroke

*Significant differences at p<0.05. We compared ordinal/continuous variables using the Wilcoxon rank-sum (Mann-Whitney U) and dichotomous variables using χ 2 tests.

Results in bold represent significant p values.

BI, Barthel Index; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale.

Supplementary data

Patients with lacunar stroke did not differ from non-lacunar strokes in 3-month functional improvement (OR for mRS >2 adjusted for age/sex/initial NIHSS score/thrombolysis/prior disability=1.14, 95% CI 0.75 to 1.74, p=0.55; online supplementary figures II, III ). Three-month RMI and BI ( online supplementary figures IV, V ) were also not different after adjusting for age/sex/NIHSS score/prior disability (adjusted coefficient (RMI): 0.03, –0.48 to 0.53, p=0.92; adjusted coefficient (BI): 0.42, –0.18 to 1.02, p=0.17), and patients with lacunar stroke were no less likely to have 3-month RMI <15 or BI <20 (aOR: 1.14, 0.80 to 1.62, p=0.46).

Patients with lacunar strokes were, however, much more likely to show improvement by ≥1 mRS grades between 3 months and 6 months (71/214 (33.2%) vs 242/1052 (23.0%); 3-month mRS 2–4: 49/114 (43.0%) vs 160/621 (25.8%), p<0.001; online supplementary figure VI ), even adjusting for age/sex/3-month mRS (aOR: 1.55, 1.11 to 2.18, p=0.01, n=1206). These patients were also more likely to demonstrate improvement between 6 months and 1 year (39/198 (19.7%) vs 139/973 (14.3%); 3-month mRS 2–4: 24/96 (25.0%) vs 87/557 (15.6%), p=0.02; online supplementary figure VII ). Consequently, improvement between 3 months and 1 year was also more common for lacunar strokes (75/214 (35.1%) vs 251/992 (25.3%), aOR: 1.64, 1.17 to 2.31, p=0.004, n=1206; table 2 and  online supplementary figure VIII ). This difference remained on examining only those with 3-month mRS of 2–4 (57/114 (50.0%), 182/590 (30.9%), p <0.001,  figure 1 ), excluding recurrent events (aOR: 2.28, 1.34 to 3.86, p=0.002, n=488), adjusting for premorbid disability (aOR: 2.11, 1.23 to 3.61, p=0.007), and further excluding patients with premorbid disability or relevant chronic conditions ( figure 2 ).

Logistic regression models for the association of lacunar versus non-lacunar stroke with functional improvement per mRS, RMI and/or BI between 3 months and 1-year poststroke, adjusted for age, sex and 3-month score on the relevant measure, in 3-month survivors of ischaemic stroke

For the model examining improvement in any of the three scales, we adjusted for the initial stroke severity (NIHSS score). These models exclude patients who could not show improvement by definition, namely those with 3-month mRS=0 (n=137), 3-month RMI=15 (n=378) or 3-month BI=20 (n=674), with 93 patients meeting all three criteria.

aOR, adjusted OR; BI, Barthel Index; mRS, modified Rankin Scale; NA, not applicable; NIHSS, National Institutes of Health Stroke Scale; RMI, Rivermead Mobility Index.

Changes in modified Rankin Scale (mRS) between 3-months and 1-year post-stroke for 3-month survivors of lacunar versus non-lacunar strokes with 3-month mRS of 2, 3, 4, and 2 to 4 (pooled), potentially recruitable for trials of recovery therapies. On the x-axis, 0 indicates no change in mRS, positive points to the right indicate mRS worsening, while negative points to the left indicate improvement. Results of non-parametric tests for trend significance (P trend) are shown above. Results for 3-month mRS 3-4 were combined because there were only 15 lacunar strokes with 3-month mRS=4.

Changes in mRS between 3-months and 1-year post-stroke for 3-month survivors of lacunar versus non-lacunar stroke, (A) including all patients with 3-month mRS of 2 to 4, and then progressively excluding patients with: (B) recurrent vascular events over follow-up, (C) pre-morbid mRS>2, and (D) relevant comorbidities including peripheral vascular disease, heart failure, valve disease, and/or cancer. P-values are from Wilcoxon rank-sum tests for trend.

Similar trends were observed for functional improvement per RMI/BI between 3 months and 1 year ( online supplementary figure IX ). Of 225 patients with 3-month mRS ≥1 and 3-month RMI <15 or 3-month BI <20 whose mRS score improved between 3 months and 1 year, 161 (71.6%) also showed an improvement in the RMI and/or BI (OR for patients with improved mRS also showing improved RMI/BI: 3.44, 2.46 to 4.80, p<0.0001; BI: 7.50, 4.81 to 11.7, p<0.0001). Patients with lacunar strokes were also significantly more likely to show improvement on RMI/BI between 3 months and 1 year, adjusted for age/sex/3-month RMI/BI (aOR: 1.55, 1.06 to 2.26, p=0.02, n=799; table 2 ). This difference remained on adjusting for recurrent events and premorbid BI (aOR: 1.59, 1.09 to 2.33, p=0.02; aOR (RMI): 1.80, 1.21 to 2.67, p=0.004) or excluding patients with recurrent events and/or premorbid disability ( online supplementary figures X, XI ). Patients with lacunar stroke were also more likely to improve between 3 months and 1 year on ≥1 of the three scales (mRS/BI/RMI) adjusted for age/sex/NIHSS score (aOR: 1.70, 1.26 to 2.28, p=0.001, n=1251; table 2 ), even on restricting to patients with 3-month mRS of 2–4 and excluding those with recurrent events (aOR: 2.32, 1.34 to 4.02, p=0.003, n=488) .

Beyond 1 year, improvements on mRS were rarer in both groups (lacunar: 21/179 (11.7%), rest: 93/787 (11.8%), p=0.98;  online supplementary figure XII ) and no more likely for patients with lacunar strokes after adjusting for age/sex/1-year mRS (aOR (mRS): 0.84, 0.50 to 1.43, p=0.53, n=961, excluding deaths/recurrent events: 0.92, 0.51 to 1.69, p=0.80, n=484). Similarly, patients with lacunar stroke were no more likely than other 5-year survivors to show further improvement on RMI/BI beyond 1 year (aOR: 0.83, 0.46 to 1.47, p=0.51, n=590, excluding deaths/recurrent events: 0.77, 0.38 to 1.56, p=0.47, n=242; online supplementary figure XIII ).

Similar results were seen when performing these analyses with patients with LACS versus other syndromes, despite the greater similarity of their baseline characteristics ( online supplementary table I and figure XIV ). Patients with LACS strokes were no more likely to show early functional improvement within 3 months (aOR for 3-month mRS >2: 1.26, 0.89 to 1.77, p=0.19), but were significantly more likely to show late improvement between 3 months and 1 year (aOR (mRS): 1.37, 1.02 to 1.84, p=0.03), particularly between 3 months and 6 months (aOR: 1.62, 1.12 to 2.33, p=0.01, excluding recurrent events and prestroke mRS >2). Similarly, 1-year survivors were more likely to show improvement on RMI/BI between 3 months and 1 year, adjusted for age/sex/3-month RMI/BI/recurrent events (aOR (RMI/BI): 1.44, 1.03 to 2.01, p=0.03; aOR (RMI): 1.41, 1.01 to 1.98, p=0.04, n=760). Beyond 1 year, no differences in functional improvement were seen (aOR (mRS): 0.90, 0.66 to 1.24, p=0.53; aOR (RMI/BI): 0.72, 0.38 to 1.37, p=0.32).

By prospective assessment of disability using three commonly used scales in a population-based cohort study, we showed that patients with lacunar strokes have greater potential for late functional improvement in the first year poststroke. This difference remained significant in multiple sensitivity analyses and was not accounted for by differences in 3-month disability, premorbid or non-stroke-related disability, mortality, or recurrent events. Functional improvement beyond 1 year was rare and no more likely in patients with lacunar stroke. Our findings have implications for motivating and rehabilitating patients with lacunar stroke in clinical practice, for the design of restorative therapy trials, and for our understanding of functional recovery.

First, our findings should encourage clinicians to optimise late functional improvement in patients with lacunar stroke, and to consider this added potential for late improvement when discussing prognosis and rehabilitation options. These findings could be interpreted in support of piloting and focusing studies of non-acute stroke restorative therapies in patients with lacunar stroke. In addition to the lower mortality of lacunar strokes, 28 their greater potential for late functional improvement makes them especially appealing for enrolment in studies of new therapies. Such patient selection might improve detection of treatment effects that could be missed in a mixed sample of non-lacunar or cortical strokes. For example, analyses of a robot-based rehabilitation study 29 and a neutral trial of epidural motor cortex stimulation 30 found that responders were typically lacunar/subcortical strokes with intact motor system physiology, specifically cortical function and connectivity. On the other hand, the relatively lower rate of late functional improvement in patients with non-lacunar stroke in our cohort does not mean that interventions to improve recovery in this group are futile. One might also argue that if patients with lacunar stroke are likely to demonstrate late improvement without additional therapy, then attempts at restorative therapies may be better concentrated on patients with non-lacunar stroke whose functional improvements might otherwise plateau. Indeed, the apparent differences in potential for late functional improvement between patients with lacunar and non-lacunar strokes may reflect differences in engagement in rehabilitation; although both groups appeared to receive similar levels of inpatient and outpatient rehabilitation, patients with lacunar strokes may have engaged more effectively or aggressively in these sessions owing to factors like more intact cortex and/or lower cognitive impairment.

Second, our findings imply that studies of restorative therapies cannot assume that functional improvements seen in the first year poststroke are necessarily treatment-related, even if undertaken beyond 3 months poststroke. Studies focusing on patients with lacunar strokes should be randomised and controlled to ensure that improvement exceeds what is expected from their natural history. For instance, some early uncontrolled studies of repetitive transcranial magnetric stimulation have reported that patients with lacunar/subcortical strokes were most likely to improve, but this difference cannot necessarily be ascribed to a treatment response. 31 Similarly, if such therapies are tested in the general stroke population, the treatment and control groups should be balanced in their representation of lacunar strokes to prevent confounding by a greater capacity for late improvement in either group.

Third, our findings lend credence to the phenomenon of late recovery beyond 3 months poststroke and underscore the importance of further studying mechanisms of late subcortical or white matter recovery. Emerging evidence indicates that these mechanisms include time-dependent processes like cortical activation, network modulation, 32 contralesional cortical reorganisation, 33 enhanced interhemispheric connectivity, 34 and modulation of axomyelinic synapses to alter myelin properties or recruit companion glia. 35 MRI lesions shrink over 1 year in almost half of patients with lacunar strokes, 36 with axonal remodelling giving rise to poorly organised, randomly oriented axons in the initial poststroke months, followed by gradual organisation into single direction-oriented fibres. 37 These mechanisms may explain why our patients with lacunar stroke showed no difference in 3-month functional improvement rates versus non-lacunar stroke patients, but were more likely to show further improvement over the next 9 months. That these differences persisted on adjusting for age is compatible with recent evidence that white matter neuroplasticity, unlike cortical plasticity, does not diminish with age. 38

Although our analysis has several strengths, including generalisability from a population-based sample, there are some shortcomings. First, we assessed functional improvement using disability scales and did not serially determine neurological impairments using measures like the NIHSS or Fugl-Meyer Scale, which may be more sensitive to small improvements in deficits. 39 However, any insensitivity would likely cause similar underestimation of improvement in patients with lacunar and non-lacunar strokes, and a small improvement on an impairment-base scale may not translate into meaningful functional improvement in the patient’s daily activities. On the other hand, our use of functional outcome scales means that we cannot differentiate between improvement in neurological impairment and adaptation to impairment, as either of these processes can result in functional improvement. Additional studies using serial measurements of neurological impairment will therefore be required to further clarify the nature of this observed late functional improvement in lacunar strokes. Second, scales like the mRS can be confounded by non-stroke-related disability. However, between-group differences remained significant after adjusting for and/or excluding premorbid disability and excluding those with potentially disabling comorbidities. Third, the mRS and other scales have inter-rater variability, 20 but our findings were similar for the mRS and for the BI and RMI, and inter-rater variability would be unlikely to account for differences between lacunar and non-lacunar stroke. Fourth, we coded functional improvement as a binary outcome in logistic regressions for our main adjusted analyses; more sophisticated models of mRS/RMI/BI changes over time, such as multilevel models with random intercepts to account for repeated measures for each patient, may have better captured differences in the extent of improvement between patients with lacunar and non-lacunar strokes. However, we did examine functional improvement as a scalar outcome in univariate analyses (presented in the graphs), which while unadjusted were grouped by relevant parameters like 3-month mRS and age, and demonstrated significant differences between patients with lacunar and non-lacunar strokes as with the logistic regressions. Finally, we could not adjust for all psychosocial factors that might affect functional improvement, such as mood/anxiety, social support and economic status. However, we suspect that such interindividual variability is unlikely to have driven the between-group differences in our study.

In conclusion, patients with lacunar strokes have greater potential for late functional improvement in the first year poststroke, which should motivate patients and clinicians to maximise late improvements in routine practice. However, since late recovery is common, studies of restorative therapies that enrol patients with lacunar strokes should be randomised and controlled to reliably assess treatment effects. More detailed studies of late recovery of specific neurological deficits might help elucidate the nature of this late improvement.

Acknowledgments

We dedicate this paper to Rose M Wharton, a statistician and beloved member of the OXVASC team, who provided invaluable assistance in our analyses, but unfortunately passed away recently. We also acknowledge support from the John Radcliffe Hospital’s Acute Vascular Imaging Centre.

Collaborators: Rose M Wharton Oxford Vascular Study.

Contributors: AG collected the data, performed the analysis and interpretation, and wrote the manuscript. SAG contributed to data collection. PMR conceived and designed the study, provided supervision and funding, interpreted the data, and revised the manuscript.

Funding: OXVASC has been funded by the Wellcome Trust, Wolfson Foundation, and NIHR Oxford Biomedical Research Centre. PMR has received NIHR and Wellcome Trust Senior Investigator Awards. AG was funded by the Rhodes Trust.

Competing interests: None declared.

Patient consent: Not required.

Ethics approval: The study was approved by the Oxfordshire Research Ethics Committee.

Provenance and peer review: Not commissioned; externally peer reviewed.

Contributor Information

for the Oxford Vascular Study : Collaborators: Rose M Wharton