PINTO, Antonio

TUTTOLOMONDO, Antonino

Antonino Tuttolomondo

Antonio Pinto

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Future Neurology

Ischemic stroke subtypes and the implications for stroke management

Archivio istituzionale della ricerca - Università di Palermo

567ISSN 1479-6708Future Neurol. (2014) 9(6), 567–570part of10.2217/FNL.14.53 © 2014 Future Medicine LtdCOMMENTARYIschemic stroke subtypes and the implications for stroke managementAntonino Tuttolomondo*,1 & Antonio Pinto1 1Internal Medicine & Cardioangiology Ward, Dipartimento Biomedico di Medicina Interna & Specialistica, University of Palermo, Italy*Author for correspondence: Tel.: +39 091 6552197; bruno.tuttolomondo@unipa.itKEYWORDS   • subtype • stroke • TOAST classificationIn their review article entitled “Why identification of stroke syndromes is still important,” Kumar and Kaplan affirmed “Within the broad category of brain ischemia, subtypes also vary dramatically in cause: from systemic hypoperfusion to atherosclerotic large artery disease to penetrating artery disease to dissection to emboli arising from the heart valves or atria, to emboli arising from the aorta to paradoxical emboli to occlusion of cerebral and dural sinus veins to hypercoagulabil-ity. These subtypes are as different as grapes and watermelons: two substances contained within the large category of fruits” [1].There is much truth in this picturesque statement since ischemic stroke is far from being a single disease. It combines several clinical syndromes that are sometimes very different, with differing pathophysiology, clinical manifestations, neuroradiological findings and localization. This complexity requires an approach that, despite the limi-tations of a Linnaean taxonomy approach to biological material, over time has led to various attempts at classification of cerebral ischemia based on clinical and anatomic, and now finally on a pathophysiological basis. The aim of these efforts is likely tied to achieving a classification model that is as close as possible to the phenomenologi-cal reality of ischemic stroke in order to improve the diagnostic and therapeutic approach to ischemic stroke, a disease in which these elements are worthy of an implementation of neuroimaging tech-niques, since the use of systemic and intra-arterial thrombolysis have only partially improved in recent years.Categorization of subtypes of ischemic stroke has undergone considerable study, and in the past, classifications have been based primarily on risk factor profiles, clinical features of the stroke and the find-ings of brain imaging studies: computed tomography or MRI, but clinical and brain imaging findings in brain ischemia are not often specific for any particular subtype of ischemic stroke.In 1993, Adams et al. developed a system for the diagnosis of subtype of ischemic stroke that uses components of existing diagnostic schemes for the “The classification in subtypes of ischemic stroke appears therefore to have important pathogenic, clinical and epidemiological implications as well as from a diagnostic and clinical point of view.”“Determining the cause of stroke does influence choices for management and in particular it can have repercussions on epidemiological, pathogenic and therapeutic issues.”For reprint orders, please contact: reprints@futuremedicine.comFuture Neurol. (2014) 9(6)568COmmEntaRY Tuttolomondo & Pintofuture science groupTrial of Org 10172 in Acute Stroke Treatment (TOAST) [2].The TOAST classification system includes five categories: large-artery atherosclerosis, car-dioembolism, small-artery occlusion (lacune), stroke of other determined etiology and stroke of undetermined etiology. Diagnoses are based on clinical features and on data collected by tests such as brain imaging (computed tomog-raphy/MRI), cardiac imaging (echocardiogra-phy, among others), duplex imaging of extra-cranial arteries, arteriography and laboratory assessments for a prothrombotic state.Determining the cause of stroke does influ-ence choices for management and in particu-lar it can have repercussions on epidemio-logical, pathogenic and therapeutic issues. Anticoagulation therapeutic choice could rep-resent a good example of the importance of pre-cise evaluation of stroke subtypes. The use of adjusted-dose warfarin for stroke patients with atrial fibrillation who do not have significant bleeding risk has been advocated in several professional guidelines [3–6], and the benefit has been demonstrated in clinical practice. However, not all strokes in patients with atrial fibrillation are cardioembolic in origin [7–9], and some evidence suggests that warfarin may not prevent noncardioembolic strokes [10]. It has also been shown that anticoagulation in patients with small-vessel cerebrovascular disease carries a higher risk of intracranial hemorrhage. Thus, it appears very important to consider stroke sub-type carefully to avoid starting anticoagulation with antivitamin K drugs.A recent study by Evans et al. including 386 acute stroke patients with atrial fibrilla-tion treated with adjusted-dose warfarin or aspirin had rates of recurrent stroke by subtype and major and minor bleeding complications as main outcome measures [11]. These authors showed that the rate of recurrent stroke was higher but that of major bleeding was lower with aspirin. They also showed that increased stroke rate with aspirin was due predominantly to cardioembolic recurrence in patients present-ing initially with cardioembolic stroke. The recurrence rate in aspirin-treated patients who presented with lacunar stroke and atrial fibrilla-tion was similar to that seen in patients receiv-ing warfarin. The findings of this study strongly indicate how determination of stroke subtype may be important in anticoagulation decisions for secondary prevention of stroke.Stroke subtype may also significantly differ due to the epidemiological relationship with dif-ferent cerebrovascular factors and some patho-physiological instances such as inflammatory activation degree of the acute phase. Precise classification of stroke also has epidemiologic involvement, and several studies have evaluated the role of cardiovascular risk factors and stroke subtypes.Our group conducted a study to evaluate cer-ebrovascular risk factor prevalence in diabetic stroke patients compared with nondiabetics, to analyze whether diabetics have a different prevalence of stroke subtypes as classified by the TOAST classification. We reported that diabe-tes was associated with lacunar ischemic stroke subtype and with a record of hypertension [12].Our group also conducted a study to evaluate immune-inflammatory activation in the acute phase of stroke in relation to time of symptom onset, diabetic state and diagnostic subtype. We reported significantly higher plasma lev-els of cytokines, selectins, adhesion molecules and PAI-1 and diabetic stroke patients exhib-ited higher plasma levels of PAI-1 compared with nondiabetic patients [13]. Lacunar strokes exhibited significantly lower levels of TNF-α and IL1-β P-selectin and ICAM-1 compared with nonlacunar strokes. Moreover, diabetic patients with lacunar strokes exhibited a minor grade of immune-inflammatory activation of the acute phase at 24–72 h and 7–10 days after stroke onset. The minor grade of immune- inflammatory activation of patients with lacunar strokes, particularly diabetics, could be related to the minor extension of the infarct size, owing to the typical microvascular disease of diabetic sub-jects which could also explain the better outcome of this subtype of ischemic stroke reported.In another recent study our group showed that among patients with acute ischemic stroke, patients with cardio-embolic subtype showed significantly higher plasma levels of TNF-α, IL-6 and IL1-β, whereas lacunar subtype showed significantly lower plasma levels of these cytokines [14].Our study further supports the hypothesis that inflammation may have an important role in the pathogenesis of ischemic strokes, but our findings also suggest a peculiar immune-inflammatory pattern in each subtype of acute ischemic stroke. Patients with cardio-embolic strokes, compared with other subtypes, showed a higher degree of acute neurological deficit “...our group showed that among patients with acute ischemic stroke, patients with cardio-embolic subtype showed significantly higher plasma levels of TNF-α, IL-6 and IL1-β, whereas lacunar subtype showed significantly lower plasma levels of these cytokines.”569Ischemic stroke subtypes & the implications for stroke management COmmEntaRYfuture science group www.futuremedicine.comon admission evaluated by SSS and a higher degree of immune-inflammatory activation of the acute phase. On the other hand in patients with lacunar stroke, compared with other sub-types, we observed a lower degree of acute neu-rological deficit on admission evaluated by SSS and a lower degree of immune-inflammatory activation of the acute phase. Nevertheless, patients with large artery atherosclerotic stroke (LAAS) subtype showed higher median plasma levels of some immune- inflammatory mark-ers (TNF-α, IL-6 and IL1-β) compared with lacunar subtype, but lower median plasma levels of these biomarkers compared with the cardioembolic-infarct subtype.Although several intervention trials with ACE-inhibitors, angiotensin receptor block-ers, other antihypertensives or statins have been shown, sometimes in primary prevention and mostly in a secondary prevention setting, a significant reduction of stroke incidence, yet few studies, with the exception of some such as SPARCL study [15], used a TOAST subtype oriented analysis. Therefore it is difficult to extrapolate the real benefit of pharmacological prevention strategies against atherothrombotic subtype that is represented by the LAAS and also with regard to lacunar subtype as an expres-sion of lipohyalinosis process which is a further aspect of atherosclerosis. More frequently stroke classification in clinical trials concerns prognosis with terms such as fatal or nonfatal that are less likely to reveal thrombotic or embolic type.The classification in subtypes of ischemic stroke appears therefore to have important pathogenic, clinical and epidemiological impli-cations as well as from a diagnostic and clinical point of view. Correctly classifying the TOAST subtype in the light of some recent studies also leads to a number of epidemiological and clini-cal considerations that take on a very impor-tant role in diagnostics and therapeutics. Proper assessment of initial stroke subtype in a clinical setting allows physicians to optimize second-ary prevention through the appropriate selec-tion of drug (anticoagulant or antiplatelet). The same approach could relate to the decision to use high doses of atorvastatin as indicated by the SPARCL study in the secondary preven-tion of ischemic stroke. Neither the SPARCL study nor other studies that have evaluated the effectiveness of statins in primary prevention of ischemic stroke have in fact opted for an assessment of the type that could be oriented to identify the subtype likely to show greater efficacy of the therapeutic estimate with high-dose atorvastatin in reducing the recurrence of atherosclerotic strokes (LAAS), unlike the other two types of ischemic stroke identified by the TOAST classification subtype as lacunar and cardioembolic that in the light of the epidemio-logical studies available so far do not seem to have a background of athero sclerosis. Ischemic stroke is a common multifactorial disease, which is affected by a number of genetic mutations and environmental factors. In a recent study we reported a relationship between pro-inflam-matory/anti-inflammatory (1/1 IL-1 variable number tandem repeat of 86 bp) and throm-botic-/fibrinolytic-gene single-nucleotide poly-morphisms (CC TPA genotype) and lacunar ischemic stroke that may contribute to delineate a possible stroke risk profile in subjects with cer-ebrovascular risk factors [16]. Future studies will be addressed to better tailor preventive strategies according to clinical subtypes of stroke to opti-mize drugs adapted to real thrombotic ischemic events. Each ischemic stroke subtype as reported by some studies is related to inflammation and arterial stiffness in a peculiar way, and to date no study has addressed the effects of secondary prevention with cardiovascular active drugs on these markers in relationship to TOAST sub-type, so this topic could represent a possible field of study [17–20].Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.No writing assistance was utilized in the production of this manuscript.References1 Kumar S, Caplan LR. Why identification of stroke syndromes is still important. Curr. Opin. Neurol. 20(1), 78–82 (2007).2 Adams HP Jr, Bendixen BH, Kappelle LJ et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Stroke 24(1), 35–41 (1993).3 Laupacis A, Albers G, Dalen J et al. Antithrombotic therapy in atrial fibrillation: Fifth ACCP consensus conference on antithrombotic therapy. Chest 114(Suppl.), 579S–589S (1998).Future Neurol. (2014) 9(6)570COmmEntaRY Tuttolomondo & Pintofuture science group4 Lip GY, Lowe GD. ABC of atrial fibrillation: antithrombotic treatment for atrial fibrillation. BMJ 312, 45–49 (1996).5 Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks of the Stroke Council of the American Heart Association. Guidelines for the management of transient ischemic attacks. Stroke 25, 1320–1335 (1994).6 Koudstaal PJ. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attacks. Cochrane Database Syst. Rev. 2, CD000187 (2000).7 Evans A, Perez I, Yu G, Kalra L. Secondary stroke prevention in atrial fibrillation: lessons from clinical practice. Stroke 31(9), 2106–2111 (2000).8 Bogousslavsky J, van Melle G, Regli F, Kappenberger L. Pathogenesis of anterior circulation stroke in patients with nonvalvular atrial fibrillation. Neurology 40(7), 1046–1050 (1990).9 Hart RG, Pearce LA, Miller VT et al. Cardioembolic vs noncardioembolic strokes in atrial fibrillation: frequency and effect of antithrombotic agents in the stroke prevention in atrial fibrillation studies. Cerebrovasc. Dis. 10(1), 39–43 (2000).10 Miller VT, Pearce LA, Feinberg WM, Rothrock JF, Anderson DC, Hart RG. Differential effect of aspirin vs warfarin on clinical stroke types in patients with atrial fibrillation. Neurology 46, 238–240 (1996).11 Evans A, Perez I, Yu G. Should stroke subtype influence anticoagulation decisions to prevent recurrence in stroke patients with atrial fibrillation? Stroke 32, 2828–2832 (2001).12 Tuttolomondo A, Pinto A, Salemi G et al. Diabetic and non-diabetic subjects with ischemic stroke: differences, subtype distribution and outcome. Nutr. Metab. Cardiovasc. Dis. 18(2), 152–157 (2008).13 Licata G, Tuttolomondo A, Corrao S et al. Immunoinflammatory activation during the acute phase of lacunar and non-lacunar ischemic stroke: association with time of onset and diabetic state. Int. J. Immunopathol. Pharmacol. 19(3), 639–646 (2006).14 Licata G, Tuttolomondo A, Di Raimondo D, Corrao S, Di Sciacca R, Pinto A. Immuno-inflammatory activation in acute cardio-embolic strokes in comparison with other subtypes of ischaemic stroke. Thromb. Haemost. 101(5), 929–937 (2009).15 Amarenco P, Goldstein LB, Szarek M et al. SPARCL Investigators Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke 38(12), 3198–3204 (2007).16 Tuttolomondo A, Di Raimondo D, Forte GI et al. Singlenucleotide polymorphisms (SNPs) of pro-inflammatory/anti-inflammatory andthrombotic/fibrinolytic genes in patients with acute ischemic stroke inrelation to TOAST subtype. Cytokine 58(3), 398–405 (2012).17 TuttolomondoA, Di Raimondo D, Pecoraro R, Arnao V, Pinto A, Licata G. Inflammation in ischemic strokesubtypes. Curr. Pharm. Des. 18(28), 4289–4310 (2012).18 Davì G, Tuttolomondo A, Santilli F et al. CD40 ligand and MCP-1 aspredictors of cardiovascular events in diabetic patients with stroke. J. Atheroscler. Thromb. 16(6), 707–713 (2009).19 Pinto A, Tuttolomondo A, Casuccio A et al. Immuno-inflammatorypredictors of stroke at follow-up in patients with chronic non-valvular atrialfibrillation (NVAF). Clin. Sci. (Lond.) 116(10), 781–789 (2009).20 Albanese A, Tuttolomondo A, AnileC et al. Spontaneous chronic subdural hematomas in youngadults with a deficiency in coagulation factor XIII. Report of three cases. J. Neurosurg. 102(6), 1130–1132 (2005).

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Ischemic stroke subtypes and the implications for stroke management

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