Cryptogenic stroke. A non-diagnosis | Medicina Clínica (English Edition)

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A non-diagnosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "116" "paginaFinal" => "122" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Raquel Gutiérrez-Zúñiga, Blanca Fuentes, Exuperio Díez-Tejedor" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Raquel" "apellidos" => "Gutiérrez-Zúñiga" ] 1 => array:2 [ "nombre" => "Blanca" "apellidos" => "Fuentes" ] 2 => array:4 [ "nombre" => "Exuperio" "apellidos" => "Díez-Tejedor" "email" => array:1 [ 0 => "exuperio.diez@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Neurología y centro de Ictus, Área de Neurociencias IdiPAZ, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Ictus criptogénico. Un no diagnóstico" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 781 "Ancho" => 2167 "Tamanyo" => 82013 ] ] "descripcion" => array:1 [ "en" => "Progression of the cryptogenic stroke concept. ESUS: embolic stroke of undetermined source." ] ] ] "textoCompleto" => "Stroke is considered cryptogenic when an etiologic diagnosis is not found.<a class="elsevierStyleCrossRef" href="#bib0280">1</a> But in clinical practice, a cryptogenic stroke is a hodgepodge containing multiple and different possible causes which were not identified in the etiological study or whose pathogenic role is not sufficiently recognized. These include paroxysmal atrial fibrillation (PAF), patent foramen ovale (PFO), carotid artery atherosclerosis without stenosis or aortic arch atheroma, as well as other less common causes or little known as inflammatory processes, genetic alterations or hypercoagulability, among others. In addition, depending on the classification used, different diseases can be recognized as causes of a cerebral infarction.The possible implications of the diagnosis of cryptogenic stroke need to be taken into account, since admitting that we do not know the cause of the stroke suffered by the patient also involves the uncertainty about the risk of recurrence, which some series estimate that can reach up to 30% of the cases.<a class="elsevierStyleCrossRef" href="#bib0285">2</a> It also influences the efficacy of secondary prevention, since the specific treatment is not applied to the cause, since we do not know it. Another aspect, not sufficiently valued, is that not identifying the cause of the stroke can compromise the patient's confidence in the medical team and also condition a lower adherence to preventive treatment. On the other hand, another implication of the diagnosis of cryptogenic stroke is the need to expand the study with high resolution neuroimaging to study the pathology of the extra- or intracranial arterial wall as well as the prolonged heart rhythm monitoring.In this review we analyze the concept of cryptogenic stroke considering the different classifications, delving into the different diagnostic techniques for the identification of the underlying cause and exposing the trends of its therapeutic approach.Concept: definition and progressThe different etiological classifications for cryptogenic stroke have improved as knowledge about cerebrovascular disease has expanded, with the aim of minimizing the number of stroke patients in whom the aetiology is unknown<a class="elsevierStyleCrossRef" href="#bib0290">3</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Normally, a stroke is considered cryptogenic when no cause is found for it, when 2 or more possible causes coexist or when a complete diagnosis is not made<a class="elsevierStyleCrossRefs" href="#bib0295">4–7</a> once the diagnostic process has been completed. The first classification is the Trial Org-10172 Acute Stroke Treatment (TOAST)<a class="elsevierStyleCrossRef" href="#bib0295">4</a> classification, designed for use in clinical trials. It was validated in only 20 cases, of which 7 were classified as cryptogenic strokes, showing a moderate observer agreement (kappa index between 0.42 and 0.54).<a class="elsevierStyleCrossRefs" href="#bib0300">5,8–10</a> The main drawback of its use in clinical practice is that a large number of strokes are left undiagnosed, since minor cardioembolic sources or arterial stenosis <50% are not considered causes. This is why the Stop-Stroke Study-TOAST (SSS-TOAST) classification was created, which incorporated improvements in the use of neuroimaging and epidemiological criteria to support the most probable diagnosis, which contributed to reduce the percentage of strokes classified as cryptogenic down to 4% and modified the classification of some entities such as aortic arch atheroma that becomes part of the cardioembolic group, and eliminates mitral valve prolapse and left ventricular segmental wall motion abnormalities.<a class="elsevierStyleCrossRef" href="#bib0330">11</a> This classification included the development of an on-line tool to facilitate the etiological diagnosis in clinical practice, changing its name to Causative Classification System (CCS).<a class="elsevierStyleCrossRef" href="#bib0305">6</a> Classification of atherosclerosis; small-vessel disease; cardiac pathology; other causes (ASCO) later modified as ASCOD to include the category of arterial dissection, was created with the aim of indicating the most probable aetiology of a stroke based on the available evidence from the diagnostic tests performed and the characteristics of the patient, without omitting any of the other possible entities present in the patient. Five categories are considered (atherothrombotic, small vessel, cardioembolic, dissection and others) and, within these groups, levels of diagnostic certainty are established based on the possibility that the identified entity is the direct cause of the stroke and the degree of existing evidence that said disease is the cause of the stroke.<a class="elsevierStyleCrossRefs" href="#bib0335">12,13</a> The novelty of this classification is that the concept of cryptogenic stroke does not exist as such. In this classification, arterial stenosis <50% and aortic arch atheroma are considered as uncertain causes and the presence of PFO as an unlikely cause.<a class="elsevierStyleCrossRefs" href="#bib0335">12,13</a> However, it is too complex, so its use has not been generalized in clinical practice.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>In 2014, the concept of embolic strokes of undetermined source (ESUS), which is defined as a non-lacunar stroke detected on computed tomography (CT) or magnetic resonance imaging (MRI), in the absence of both a stenosis >50% of the vessel that supplies the infarcted area as well as a major cardioembolic cause and after having ruled out other etiologies.<a class="elsevierStyleCrossRef" href="#bib0345">14</a> Different potential causes of embolism are included within this term, such as minor cardioembolic sources, atherosclerotic plaques <50% of vessel lumen stenosis, aortic arch atheroma and paradoxical embolism due to abnormal communication of the arterio-venous system. However, this construct is not new, since the SSS-TOAST classification includes a section of cryptogenic embolism that includes these potential causes, and, in the ASCOD classification, this type of pathologies has a causal significance assigned based on the evidence of related published studies.<a class="elsevierStyleCrossRefs" href="#bib0330">11,15</a> In addition, in our opinion, it is a step backwards to include in the same group different aetiologies with different pathogenic basis.The Cerebrovascular Diseases Study Group of the Spanish Society of Neurology (GEECV-SEN) published a diagnostic classification in 1998<a class="elsevierStyleCrossRef" href="#bib0355">16</a> which was later updated in 2006. It was designed for clinical practice application, incorporating elements of the TOAST and Lausanne classification.<a class="elsevierStyleCrossRef" href="#bib0310">7</a> It includes a cryptogenic stroke category divided into 3 sections: (a) those in which a cause is not found after an exhaustive study, (b) coexistence of 2 aetiologies and (c) that situation in which the study has been insufficient.The main problem with these classifications is that the same disease, depending on the classification used, can be considered as a cause or not of a cryptogenic stroke (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) and, therefore, the subsequent management of the patient will be different.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>For this reason, the need to reserve the cryptogenic term for those cases in which, after an extensive history-taking and adequate complementary studies, no cause is found (a true cryptogenic aetiology) is increasingly evident, completely separating from this group the strokes in which there is a concurrence of several causes or those in which a complete diagnosis is not made (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<a class="elsevierStyleCrossRef" href="#bib0285">2</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>EpidemiologyIt is estimated that, in Spain, the percentage of stroke of undetermined aetiology is 23.1%. Of these, almost 65% have been classified as cryptogenic based on an inadequate or insufficient study, 23% due to the combination of several possible causes and only 12% due to the lack of aetiology after an exhaustive diagnostic process (true cryptogenic strokes).<a class="elsevierStyleCrossRef" href="#bib0360">17</a>Overall, the incidence of cryptogenic stroke varies according to the series. In young patients (15–45 years of age) their incidence varies between 8.3% and 62.4% depending on whether the presence of PFO is considered an aetiology,<a class="elsevierStyleCrossRefs" href="#bib0280">1,18</a> whereas, in elderly patients, the incidence varies between 20% and 40% when using the TOAST classification.<a class="elsevierStyleCrossRef" href="#bib0280">1</a> An example of the differences in the estimation of the frequency of cryptogenic stroke based on the etiological classification used is the North Dublin population study, in which the TOAST, ASCO and CCS classifications were compared. In a cohort of 381 patients with a first cerebral infarction, the percentage of cryptogenic strokes was 39% when the TOAST criteria were applied, 26% for the CCS and, in the case of ASCO, 42% of the patients did not have a cause with a grade 1 evidence.<a class="elsevierStyleCrossRef" href="#bib0350">15</a>Diagnostic approachInitial evaluationA true cryptogenic stroke is a diagnosis of exclusion. The first step for the diagnosis includes the performance of complementary tests that allow us to identify the most probable causes (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). These include haematological and biochemical laboratory studies; it will be necessary to perform a neuroimaging study using CT and/or brain MRI; a study of the cerebral vasculature and of supra-aortic trunks using non-invasive techniques (Doppler/transcranial and carotid duplex, angio-CT or angio-MRI) and a cardiological study including electrocardiogram (ECG), 24h Holter monitoring and echocardiography.<a class="elsevierStyleCrossRef" href="#bib0310">7</a> If no cause is found after this first line regarding a cryptogenic stroke, the GEECV-SEN guidelines recommend performing a transoesophageal echocardiogram for the correct evaluation of valves, cardiac cavities and ventricular function.<a class="elsevierStyleCrossRef" href="#bib0310">7</a> Transthoracic echocardiography (TTE) is better than transoesophageal echocardiography (TEE) in the assessment of the left ventricle, while TEE is superior to TTE for the assessment of the left atrium, the presence of PFO and the assessment of aneurysm or thrombus associated with it.<a class="elsevierStyleCrossRef" href="#bib0280">1</a> In addition, TEE can analyze the aortic arch to identify the presence of atherosclerotic plaques at this level and study their characteristics.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>If after these assessments we cannot identify the cause of the stroke, it will be necessary to carry out genetic, serological, immunological, toxicological and even histological and cerebrospinal fluid studies to identify rare causes of cryptogenic stroke<a class="elsevierStyleCrossRefs" href="#bib0310">7,11,13,19</a> especially in young patients in whom unusual causes are more frequent.<a class="elsevierStyleCrossRef" href="#bib0365">18</a> In addition, it is important to consider during the diagnostic process transitory situations, such as PAF, infections, reversible cerebral vasoconstriction syndromes or dissections that, at the time of the etiological study, if delayed, can be underdiagnosed (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0365">18,20,21</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>In selected patients it will be necessary to use other diagnostic techniques, such as high-resolution MRI for the study of the vascular wall, serological or imaging techniques for the detection of occult neoplasms or prolonged cardiac monitoring. To direct the diagnostic efforts in one way or another, the pattern found in the Diffusion Weighted Imaging (DWI) sequences of the cerebral MRI may be useful: an extensive infarction of cortical localization may be due to a cardioembolic mechanism (especially if there are previous infarctions of the same characteristics in different territories seen in the T2 FLAIR sequences) or due to a situation of hypercoagulability due to a tumour cause (especially if this pattern is found acutely in multiple territories); a pattern of multiple small and scattered restriction foci in DWI sequence (increased signal foci in DWI) may be due to a tumoral cause, to paradoxical emboli or of the aortic arch; or, if this same pattern occurs in a single area, it will be more likely due to an atheromatous embolism (due to an unstable plaque); and finally, if an infarction is found in a deep area, it will be, most likely, a lacunar infarction.<a class="elsevierStyleCrossRef" href="#bib0385">22</a>With the techniques available and the tests to be performed, most of the major cardioembolic causes of cerebral infarcts can be diagnosed. However, PAF (AF of at least 30s in the ECG record that spontaneously reverts to sinus rhythm in less than 48h)<a class="elsevierStyleCrossRef" href="#bib0390">23</a> is found within these, which, with the complementary tests carried out routinely (ECG, Holter 24h, monitoring in stroke units) is detected only in 7.7% of patients in the emergency department and 5.1% during hospitalization.<a class="elsevierStyleCrossRef" href="#bib0395">24</a> PAF comprises between 25% and 62% of AF cases, and its intermittent nature sometimes results in an inadequate diagnosis.<a class="elsevierStyleCrossRef" href="#bib0400">25</a> It is known that the incidence of stroke is similar in patients with PAF than in those with permanent AF<a class="elsevierStyleCrossRef" href="#bib0405">26</a> and this diagnosis has important therapeutic implications in the secondary prevention of new episodes (these patients should be treated with oral anticoagulants instead of antiplatelet agents).<a class="elsevierStyleCrossRefs" href="#bib0390">23,27</a> Therefore, in those patients in whom a cardioembolic source is suspected, it is necessary to expand the study in search for this disease.In recent years, clinical trials have been conducted to test the efficacy of prolonged cardiac monitoring in patients with cryptogenic stroke.In the EMBRACE study, involving 576 patients with cryptogenic stroke who were randomized to prolonged cardiac monitoring using a belt with electrodes around the chest for 30 days or a conventional study (24h Holter monitoring), AF of more than 30s was found in 16% of the patients monitored, compared to 3.2% in the control group.<a class="elsevierStyleCrossRef" href="#bib0415">28</a> The advantage of this type of device is its non-invasive nature, with a very favourable risk-benefit balance for the patient. However, in this study, the inclusion of patients was performed in an average of 75 days after suffering the episode of interest (stroke or transient ischaemic attack), so the percentage of patients with occult AF is probably underestimated. A second study, CRYSTAL-AF, showed the superiority of the Reveal® implantable device after a cryptogenic stroke for the detection of AF versus conventional management (8.9% of AF detected versus 1.4% at 6 months and 12.4% compared to 2% at 12 months).<a class="elsevierStyleCrossRef" href="#bib0420">29</a>The clinical practice guidelines of the American Stroke Association recommend prolonged cardiac monitoring for 30 days in cryptogenic strokes (class 2 grade B)<a class="elsevierStyleCrossRef" href="#bib0410">27</a> and the European Society of Cardiology (European Society of Cardiology) recommends monitoring for at least 72h in all strokes (class 1 grade B) and consider prolonged monitoring (class 2 grade B).<a class="elsevierStyleCrossRef" href="#bib0390">23</a>However, in routine clinical practice, perform this type of monitoring on all cryptogenic strokes is not profitable. A model has been recently proposed to explain the pathogenesis of stroke associated with paroxysmal AF, in which attention is focused on atrial disease, regardless of the rhythm disorder.<a class="elsevierStyleCrossRef" href="#bib0425">30</a> Thus, age and vascular risk factors (HBP, possibly DM, genetic factors, coronary disease or obesity) could trigger a series of morphological and functional changes in the atrium (remodelling, fibrosis, hypocontractility) that would lead to AF and this would perpetuate the atrium's pathological changes.<a class="elsevierStyleCrossRefs" href="#bib0390">23,30</a> In addition, some markers of these changes in the atrium (atrial enlargement),<a class="elsevierStyleCrossRef" href="#bib0430">31</a> changes of the left atrium in the ECG,<a class="elsevierStyleCrossRef" href="#bib0435">32</a> sustained supraventricular tachycardia)<a class="elsevierStyleCrossRef" href="#bib0440">33</a> have been associated with an increased risk of cryptogenic stroke regardless of AF.<a class="elsevierStyleCrossRef" href="#bib0425">30</a> The ASSERT study in 2780 patients with a pacemaker or implantable defibrillator demonstrated that the presence of atrial tachyarrhythmias (excluding AF) of more than 6min is associated with an increased risk of developing AF (HR: 5.56) and of suffering a cryptogenic stroke (HR: 2.49) than those without these alterations, during a mean follow-up period of 2.5 years.<a class="elsevierStyleCrossRef" href="#bib0445">34</a> With the adequate selection of patients (over 60 years of age, suspicion of strokes of embolic source and/or negative 24h Holter monitoring prior to prolonged cardiac monitoring), the detection rate of PAF can be increased from 5.3% to an average of 10.9% with prolonged cardiac monitoring (14.3% in a 4-day record until 20% in 30-day records).<a class="elsevierStyleCrossRef" href="#bib0400">25</a> Therefore, it could be interesting to focus advanced cardiac studies related to PAF screening in those patients in whom an embolic stroke source is suspected and with data in favour of atrial disease.The presence of unstable atherosclerotic plaques, with ulceration, necrosis and rupture are etiological causes for stroke, either due to local occlusion or due to an arterio-arterial embolism mechanism, even in patients with a stenosis of less than 50%.<a class="elsevierStyleCrossRef" href="#bib0280">1</a> The detection of this type of plaques improves with 3D ultrasound or high-resolution MRI.<a class="elsevierStyleCrossRefs" href="#bib0450">35–37</a> With the use of Doppler or duplex ultrasound, available in most Neurosonology laboratories, atherosclerotic plaques can be identified and their composition, texture, presence of ulceration and size can be studied.<a class="elsevierStyleCrossRef" href="#bib0465">38</a> However, this technique has some limitations, such as low sensitivity, decreased accuracy as the vessel stenosis caused by said plaque increases or the interobserver variability.<a class="elsevierStyleCrossRefs" href="#bib0450">35,39</a> With the development of 3D ultrasound, the image quality is improved, with a better characterization of the plaque being possible, thus increasing the possibility of detecting ulcers.<a class="elsevierStyleCrossRefs" href="#bib0475">40,41</a> However, this technique has not yet been validated for use in all Neurosonology laboratories.<a class="elsevierStyleCrossRef" href="#bib0450">35</a>In recent years the role of MRI in the study of atherosclerotic plaque ulceration has been analyzed. Recently, a study analyzed the characteristics of symptomatic and asymptomatic carotid atherosclerotic plaques, which generated moderate (between 30% and 70%) and severe (more than 70%) stenosis by a 3Tesla MRI and the use of contrast (gadolinium). They observed that all (100%) patients with moderate stenosis who had suffered a stroke in the area dependent on that artery there was a thinning or rupture of the fibrous capsule with a lipid centre compared to 32% and 36% among the patients asymptomatic for these findings, respectively; and the presence of intraplaque haemorrhage in 86% of patients with symptomatic stenosis versus 32% of asymptomatic.<a class="elsevierStyleCrossRef" href="#bib0485">42</a> However, these techniques are expensive and are not available in many hospitals. However, we must consider these aspects before diagnosing a stroke as cryptogenic, because we could be ruling out an atheromatous disease which could, in fact, be the actual cause of it.With respect to aortic arch atheroma, TEE is the technique of choice for the diagnosis of atherosclerotic plaques in the aortic arch and ascending aorta.<a class="elsevierStyleCrossRef" href="#bib0490">43</a> The vulnerable atherosclerotic plaques, defined as those of more than 4mm, with ulceration and mobile component have been shown to be associated with the risk of ischaemic stroke,<a class="elsevierStyleCrossRef" href="#bib0495">44</a> but as explained above, depending on the classification used, these plaques are considered to be an obvious, possible cause of stroke or unrelated to cryptogenic stroke (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).Treatment in secondary preventionThe current European and American clinical practice guidelines do not make specific recommendations regarding the preventive treatment of cryptogenic stroke,<a class="elsevierStyleCrossRefs" href="#bib0375">20,21</a> whereas the GEECV-SEN guidelines recommend preventive treatment with antiplatelet agents (acetylsalicylic acid or AWS) (level of evidence 3–4, grade C).<a class="elsevierStyleCrossRef" href="#bib0310">7</a> The rest of the usual stroke recommendations are also applicable in the case of cryptogenic stroke, including the control of cerebrovascular risk factors, the use of statins and antihypertensives for the control of blood pressure.<a class="elsevierStyleCrossRefs" href="#bib0280">1,7,27,45</a>The “ESUS” construct was created under the hypothesis that there is an unidentified embolic cause in most cryptogenic strokes, and therefore, patients diagnosed with ESUS could benefit from anticoagulant therapy. However, prior to the publication of this concept, some clinical trials were conducted in which anticoagulant treatment was inferior to antiplatelet agent treatment for the prevention of recurrences in patients with stroke of unknown aetiology. The WARSS clinical trial, which included a total of 2206 patients with stroke not caused by a major cardioembolic source or of atherothrombotic aetiology, was randomized to warfarin or AWS 375mg/day for 2 years. No significant differences were found in the recurrence rate of stroke or death, with higher frequency of major bleeding in the warfarin group, although not statistically significant.<a class="elsevierStyleCrossRef" href="#bib0505">46</a> Therefore, the concept of ESUS makes the same mistake again, that of including various etiological causes under the same definition, in order to test the efficacy of direct-acting oral anticoagulants, with lower rates of intracranial haemorrhage than warfarin and, in some studies, with bleeding rates superimposable to ASA. The AVERROES study demonstrated the superiority of apixaban over ASA in the prevention of new embolic episodes without higher bleeding rates, but in patients already diagnosed with AF, with a clear indication of anticoagulant treatment.<a class="elsevierStyleCrossRef" href="#bib0510">47</a> The NAVIGATE studies are currently being carried out (rivaroxaban vs AWS, ClinicalTrials.gov Identifier: <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02313909">NCT02313909</a>),<a class="elsevierStyleCrossRef" href="#bib0515">48</a> RE-SPECT-ESUS (dabigatran vs AWS, ClinicalTrials.gov Identifier: <a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02239120">NCT02239120</a>)<a class="elsevierStyleCrossRef" href="#bib0520">49</a> and ATTICUS (apixaban vs AWS, ClinicalTrials.gov Identifier <a id="intr0020" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02427126">NCT02427126</a>).<a class="elsevierStyleCrossRef" href="#bib0525">50</a> In all of them, the efficacy of one of direct-acting oral anticoagulants against ASA is compared in the prevention of new strokes in patients whose cryptogenic stroke meets the diagnostic criteria of ESUS. At present, all are still ongoing except NAVIGATE, which has ended early after an interim analysis showed no superiority of rivaroxaban over ASA, with higher rates of side effects (<a id="intr0025" class="elsevierStyleInterRef" href="https://www.jnj.com/media-center/press-releases/navigate-esus-study-stopped-early-due-to-comparable-efficacy-in-treatment-arms">https://www.jnj.com/media-center/press-releases/navigate-esus-study-stopped-early-due-to-comparable-efficacy-in-treatment-arms</a>). Therefore, we should not make the mistake of assuming that anticoagulation should be the standard treatment for cryptogenic stroke, as it is a hodgepodge that includes various diseases that may not benefit from this treatment. In the Athens registry, where the strokes were classified according to the ESUS diagnostic criteria, 10% of these met diagnostic criteria and, among them, 30% showed AF in the extension study.<a class="elsevierStyleCrossRef" href="#bib0530">51</a> That is, up to 70% of patients who meet ESUS diagnostic criteria would have another aetiology that may not benefit from empirical anticoagulation.With respect to patients with stroke and PFO, depending on the etiological classification we use, it will be considered as a cause or not.<a class="elsevierStyleCrossRefs" href="#bib0310">7,11,13</a> In any case, at present, the American Stroke Association recommends antiplatelet therapy for patients with stroke and PFO (level of evidence 3, grade A) and only anticoagulation is recommended in those cases in which, in addition to PFO, a source of venous embolism has been found (level of evidence 1, grade A), together with its closure, depending on the risk of recurrence of the embolic source (level of evidence 2b, grade C).<a class="elsevierStyleCrossRef" href="#bib0410">27</a> The European Stroke Organization recommends anticoagulation in the event that a PFO is found associated with atrial septal aneurysm (ASA) or a venous embolic source (level of evidence 4)<a class="elsevierStyleCrossRef" href="#bib0500">45</a> and the GEECV-SEN recommends antiplatelet therapy in cases of PFO and if a source of venous embolism is associated (such as deep vein thrombosis), anticoagulant treatment is recommended during the first 3 months after the stroke and subsequently continuing with ASA in cases of isolated PFO. If in addition to a source of venous embolism an ASA coexists with PFO, it is recommended to continue with anticoagulants and only consider the percutaneous closure of the PFO in recurrent cases (level of evidence 3–4, grade C).<a class="elsevierStyleCrossRef" href="#bib0310">7</a>The RE-SPECT clinical trial (in which 980 patients with cryptogenic stroke and PFO were included, randomized to treatment by means of percutaneous closure of PFO together with antiplatelet treatment for the following 5 months or to receive antiplatelet treatment only) did not find significant benefit associated with PFO closure compared to medical treatment except in those patients in whom an ASA coexisted or the size of the PFO was significant.<a class="elsevierStyleCrossRef" href="#bib0535">52</a> However, 6-year results have been published recently, demonstrating the superiority of percutaneous closure over medical treatment, reducing the recurrence rate of cryptogenic aetiology stroke by 66%.<a class="elsevierStyleCrossRef" href="#bib0540">53</a>Recurrence riskThe risk of recurrence of cryptogenic stroke varies according to published series, from 4.8% at 3 months to 33% at 5 years in a series published in the year 2000<a class="elsevierStyleCrossRef" href="#bib0545">54</a>; or up to 30% per year in a study published in 2003.<a class="elsevierStyleCrossRef" href="#bib0285">2</a> In the latter, a higher recurrence rate is observed compared to previously published series and relate this recurrence to the presence of moderate stenosis (<50%) in the cryptogenic stroke's artery and the presence of significant atheromatosis (>50%) in other arteries; establishing the hypothesis that the patients who experience recurrences could have an atheromatous disease at a different stage than those who meet criteria for atherothrombotic stroke according to the TOAST classification.In a study that analyzed recurrence rates of cryptogenic stroke according to the MRI's lesion pattern in a cohort of 241 patients, it was found that those who had a single lesion had lower recurrence rates (4.4%) versus those with a pattern of multiple lesions (8%), with the possibility of an embolic disease being the underlying cause in the latter (PAF not detected, PFO and ASA, occult neoplasm, aortic arch atheroma). In addition, the values of D-dimer and pro-BNP were higher in patients with a multiple infarction pattern in MRI.<a class="elsevierStyleCrossRef" href="#bib0550">55</a>These differences in the frequency of recurrence of cryptogenic stroke support our opinion that under this name different pathologies are included, which have not been recognized or identified, but, nevertheless, have an important role in the pathogenesis of ischaemic stroke.ConclusionCryptogenic stroke is a “non-diagnosis” behind which a large number of different aetiologies are underlying, so that no type of treatment can be induced, and in which it is necessary to deepen the etiological study by means of appropriate diagnostic techniques, taking into consideration the characteristics of each patient.Conflict of interestsThe authors declare no conflict of interest.The authors declare that they have participated as investigators in the RE-SPECT ESUS<a class="elsevierStyleCrossRef" href="#bib0520">49</a> and NAVIGATE<a class="elsevierStyleCrossRef" href="#bib0515">48</a> clinical trials." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1075770" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1022089" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1075771" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1022090" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Concept: definition and progress" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Diagnostic approach" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Initial evaluation" ] ] ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Treatment in secondary prevention" ] 8 => array:2 [ "identificador" => "sec0030" "titulo" => "Recurrence risk" ] 9 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusion" ] 10 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflict of interests" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-12-21" "fechaAceptado" => "2018-01-05" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1022089" "palabras" => array:4 [ 0 => "Cryptogenic stroke" 1 => "Advance Cardiac monitoring" 2 => "Atherosclerotic plaques" 3 => "Patent foramen oval" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1022090" "palabras" => array:4 [ 0 => "Ictus criptogénico" 1 => "Monitorización cardíaca prolongada" 2 => "Placa de ateroma" 3 => "Foramen oval permeable" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The term cryptogenic stroke refers to a stroke for which there is no specific attributable cause after a comprehensive evaluation. However, there are differences between the diagnostic criteria of etiological classifications used in clinical practice. An improvement in diagnostic tools such advances in monitoring for atrial fibrillation, advances in vascular imaging and evidence regarding the implication of patent foramen oval on the risk of stroke specially in young patients are reducing the proportion of stroke patients without etiological diagnosis. We carried out a critical review of the current concept of cryptogenic stroke, as a non-diagnosis, avoiding the simplification of it and reviewing the different entities that could fall under this diagnosis and reviewing the different entities that could fall under this diagnosis; and therefore avoid the same treatment for differents entities with uncertains results." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El ictus criptogénico se define como aquel para el que no encontramos una etiología. Sin embargo, existe cierta heterogeneidad en los criterios para definir un ictus criptogénico entre las diferentes clasificaciones etiológicas de uso habitual. Los avances en sistemas de monitorización y detección de fuentes cardioembólicas, el avance de las técnicas de neuroimagen para la caracterización de la placa de ateroma, así como la mayor evidencia de la implicación del foramen oval permeable en el riesgo de ictus en pacientes jóvenes, hacen que cada vez menos ictus queden sin un diagnóstico etiológico. Realizamos una revisión crítica del concepto de ictus criptogénico como un «no diagnóstico», resaltando la importancia de realizar un estudio diagnóstico completo, evitando simplificaciones que pueden llevar a agrupar diferentes entidades que, aunque no identificadas, podrían subyacer al ictus criptogénico y, por tanto, a aplicar el mismo tratamiento preventivo a todas ellas, con resultados inciertos." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Gutiérrez-Zúñiga R, Fuentes B, Díez-Tejedor E. Ictus criptogénico. Un no diagnóstico. Med Clin (Barc). 2018;151:116–122." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 781 "Ancho" => 2167 "Tamanyo" => 82013 ] ] "descripcion" => array:1 [ "en" => "Progression of the cryptogenic stroke concept. ESUS: embolic stroke of undetermined source." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1001 "Ancho" => 2328 "Tamanyo" => 126532 ] ] "descripcion" => array:1 [ "en" => "Cryptogenic stroke classification proposal." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "TIA: transient ischaemic attack; ASA: atrial septal aneurysm; ASCOD: ASCO (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection); AT: atherothrombotic; CCS: Causative Classification System; CE: cardioembolic; DM: diabetes mellitus; ESUS: embolic stroke of undetermined source; PFO: permeable foramen ovale; GEECV-SEN: Study Group of Cerebrovascular Diseases of the Spanish Society of Neurology; HT: hypertension; CI: cerebral infarction; SSS-TOAST: Stop-Stroke Study-TOAST; PTE: pulmonary thromboembolism; TOAST: Trial Org-10172 Acute Stroke Treatment; DVT: deep vein thrombosis." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TOAST classification<a class="elsevierStyleCrossRef" href="#bib0295">4</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">GEECV-SEN<a class="elsevierStyleCrossRef" href="#bib0310">7</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ASCOD classification<a class="elsevierStyleCrossRef" href="#bib0340">13</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SSS-TOAST classification CCS<a class="elsevierStyleCrossRef" href="#bib0330">11</a> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ESUS<a class="elsevierStyleCrossRef" href="#bib0345">14</a> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PFO \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CE if no other cause \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cryptogenic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CE C1 -PFO+thrombus in situ -PFO+Concomitant PTE -PFO+Previous DVT C2 -PFO+ASA -PFO+Concomitant PTE or DVT (not prior) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Possible CE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ESUS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aortic arch atheroma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cryptogenic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cryptogenic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AT A1: -Thrombo-mobile A2: -Plaque >4mm not mobile \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Possible CE \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ESUS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Atheromatosis <50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cryptogenic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AT If more than 2: -Age >50 years -HT -DM -Smoking -Hypercholesterolemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AT A1: -With intraluminal thrombus A2: -Ipsilateral stenosis 30–50% A3 -Ipsilateral stenosis <30% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AT Evident: -If there is ulceration or thrombosis Possible: -Yes >2 amaurosis fugax, TIA or CI in the same area in the last month \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ESUS \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1836233.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic controversies according to the different classifications." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "ALT: alanine transaminase; AST: aspartate transaminase; TEE: transoesophageal echocardiography; TTE: transthoracic echocardiography; AP: alkaline phosphatase; GGT: gamma-glutamyl transpeptidase; HbA1c: glycosylated haemoglobin; HDL: high density lipoprotein; INR: international normalized ratio; LDL: low density lipoprotein; CRP: C-reactive protein; CW: Circle of Willis; MRI: magnetic resonance imaging; CT: computed tomography; TG: triglycerides; SAT: supra-aortic trunks; PTT: partial thromboplastin time; ESR: erythrocyte sedimentation rate.Source: According to the GEECV-SEN clinical practice guidelines recommendations.<a class="elsevierStyleCrossRef" href="#bib0310">7</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neuroimaging study \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cranial CT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Brain MRI \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Laboratory study \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Complete blood count \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ESR \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Platelets \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Coagulation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PTT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">INR \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fibrinogen \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Homocysteine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Study of genetic and acquired thrombophilia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Biochemistry \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Renal function (urea, creatinine) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liver function (AST, ALT, GGT, AP) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Glycemia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HbA1c \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lipid profile (HDL, LDL, TG) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Serum total protein test \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Uric acid \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CRP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cerebral vasculature study \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Carotid and transcranial Doppler/duplex \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Angio-CT SAT and CW \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Angio-MRI SAT and CW \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cardiology study \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">TTE and/or TEE \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">24h Holter monitoring \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Prolonged cardiac monitoring \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Screening for occult neoplasm \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1836235.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic study of cerebral infarction." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CADASIL: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASIL: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; ITP: idiopathic thrombocytopenic purpura; TTP: thrombotic thrombocytopenic purpura; CNS: central nervous system; TB: tuberculosis; HIV: human immunodeficiency virus; VZV: varicella zoster virus." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Inflammatory vasculopathies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CNS vasculitis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Systemic vasculitis with CNS involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Arteritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Giant cells \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Takayasu disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Infectious \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HIV, VZV, syphilis, TBC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Non-inflammatory vasculopathies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ehlder-Danlos \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fibromuscular dysplasia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Radiation-induced vasculopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Moya-Moya disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sneddon syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Lupus and other collagenopathies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Genetic causes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CADASIL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CARASIL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Retinocerebral arteriopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Small vessel disease due to mutations of COL-4A1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fabry disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">MELAS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hypercoagulability conditions \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Genetic prothrombotic states \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Antiphospholipid syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sickle cell disease \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Hyperhomocysteinemia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">ITP, TTP \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Neoplasms (especially blood-related, lymphomas) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Erythrocytosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Other \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reversible cerebral vasoconstriction syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reversible posterior leukoencephalopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pregnancy and puerperium (hypercoagulability, eclampsia/preeclampsia) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recreational drugs (cocaine, amphetamines) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1836234.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Uncommon causes of cerebral infarction." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:55 [ 0 => array:3 [ "identificador" => "bib0280" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cryptogenic stroke" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A.C. Fonseca" 1 => "J.M. Ferro" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/ene.12673" "Revista" => array:7 [ "tituloSerie" => "Eur J Neurol" "fecha" => "2015" "volumen" => "22" "paginaInicial" => "618" "paginaFinal" => "623" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25597418" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0300289610001444" "estado" => "S300" "issn" => "03002896" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0285" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Frequency and mechanisms of stroke recurrence after cryptogenic stroke" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "O.Y. Bang" 1 => "P.H. Lee" 2 => "S.Y. Joo" 3 => "J.S. Lee" 4 => "I.S. Joo" 5 => "K. 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Chilukuri" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Stroke" "fecha" => "2001" "volumen" => "32" "paginaInicial" => "1091" "paginaFinal" => "1098" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11340215" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0305" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke system" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Ay" 1 => "T. Benner" 2 => "E.M. Arsava" 3 => "K.L. Furie" 4 => "A.B. Singhal" 5 => "M.B. 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Cryptogenic stroke. A non-diagnosis

Ictus criptogénico. Un no diagnóstico

Raquel Gutiérrez-Zúñiga, Blanca Fuentes, Exuperio Díez-Tejedor

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exuperio.diez@salud.madrid.org

Corresponding author.

Servicio de Neurología y centro de Ictus, Área de Neurociencias IdiPAZ, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain

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since admitting that we do not know the cause of the stroke suffered by the patient also involves the uncertainty about the risk of recurrence&#44; which some series estimate that can reach up to 30&#37; of the cases&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">2</span></a> It also influences the efficacy of secondary prevention&#44; since the specific treatment is not applied to the cause&#44; since we do not know it&#46; Another aspect&#44; not sufficiently valued&#44; is that not identifying the cause of the stroke can compromise the patient&#39;s confidence in the medical team and also condition a lower adherence to preventive treatment&#46; On the other hand&#44; another implication of the diagnosis of cryptogenic stroke is the need to expand the study with high resolution neuroimaging to study the pathology of the extra- or intracranial arterial wall as well as the prolonged heart rhythm monitoring&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In this review we analyze the concept of cryptogenic stroke considering the different classifications&#44; delving into the different diagnostic techniques for the identification of the underlying cause and exposing the trends of its therapeutic approach&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Concept&#58; definition and progress</span><p id="par0020" class="elsevierStylePara elsevierViewall">The different etiological classifications for cryptogenic stroke have improved as knowledge about cerebrovascular disease has expanded&#44; with the aim of minimizing the number of stroke patients in whom the aetiology is unknown<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">3</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Normally&#44; a stroke is considered cryptogenic when no cause is found for it&#44; when 2 or more possible causes coexist or when a complete diagnosis is not made<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">4&#8211;7</span></a> once the diagnostic process has been completed&#46; The first classification is the <span class="elsevierStyleItalic">Trial Org-10172 Acute Stroke Treatment</span> &#40;TOAST&#41;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">4</span></a> classification&#44; designed for use in clinical trials&#46; It was validated in only 20 cases&#44; of which 7 were classified as cryptogenic strokes&#44; showing a moderate observer agreement &#40;kappa index between 0&#46;42 and 0&#46;54&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">5&#44;8&#8211;10</span></a> The main drawback of its use in clinical practice is that a large number of strokes are left undiagnosed&#44; since minor cardioembolic sources or arterial stenosis &#60;50&#37; are not considered causes&#46; This is why the <span class="elsevierStyleItalic">Stop-Stroke Study</span>-TOAST &#40;SSS-TOAST&#41; classification was created&#44; which incorporated improvements in the use of neuroimaging and epidemiological criteria to support the most probable diagnosis&#44; which contributed to reduce the percentage of strokes classified as cryptogenic down to 4&#37; and modified the classification of some entities such as aortic arch atheroma that becomes part of the cardioembolic group&#44; and eliminates mitral valve prolapse and left ventricular segmental wall motion abnormalities&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">11</span></a> This classification included the development of an <span class="elsevierStyleItalic">on-line</span> tool to facilitate the etiological diagnosis in clinical practice&#44; changing its name to <span class="elsevierStyleItalic">Causative Classification System</span> &#40;CCS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">6</span></a> Classification of atherosclerosis&#59; small-vessel disease&#59; cardiac pathology&#59; other causes &#40;ASCO&#41; later modified as ASCOD to include the category of arterial dissection&#44; was created with the aim of indicating the most probable aetiology of a stroke based on the available evidence from the diagnostic tests performed and the characteristics of the patient&#44; without omitting any of the other possible entities present in the patient&#46; Five categories are considered &#40;atherothrombotic&#44; small vessel&#44; cardioembolic&#44; dissection and others&#41; and&#44; within these groups&#44; levels of diagnostic certainty are established based on the possibility that the identified entity is the direct cause of the stroke and the degree of existing evidence that said disease is the cause of the stroke&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">12&#44;13</span></a> The novelty of this classification is that the concept of cryptogenic stroke does not exist as such&#46; In this classification&#44; arterial stenosis &#60;50&#37; and aortic arch atheroma are considered as uncertain causes and the presence of PFO as an unlikely cause&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">12&#44;13</span></a> However&#44; it is too complex&#44; so its use has not been generalized in clinical practice&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">In 2014&#44; the concept of <span class="elsevierStyleItalic">embolic strokes of undetermined source</span> &#40;ESUS&#41;&#44; which is defined as a non-lacunar stroke detected on computed tomography &#40;CT&#41; or magnetic resonance imaging &#40;MRI&#41;&#44; in the absence of both a stenosis &#62;50&#37; of the vessel that supplies the infarcted area as well as a major cardioembolic cause and after having ruled out other etiologies&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">14</span></a> Different potential causes of embolism are included within this term&#44; such as minor cardioembolic sources&#44; atherosclerotic plaques &#60;50&#37; of vessel lumen stenosis&#44; aortic arch atheroma and paradoxical embolism due to abnormal communication of the arterio-venous system&#46; However&#44; this construct is not new&#44; since the SSS-TOAST classification includes a section of cryptogenic embolism that includes these potential causes&#44; and&#44; in the ASCOD classification&#44; this type of pathologies has a causal significance assigned based on the evidence of related published studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">11&#44;15</span></a> In addition&#44; in our opinion&#44; it is a step backwards to include in the same group different aetiologies with different pathogenic basis&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The Cerebrovascular Diseases Study Group of the Spanish Society of Neurology &#40;GEECV-SEN&#41; published a diagnostic classification in 1998<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">16</span></a> which was later updated in 2006&#46; It was designed for clinical practice application&#44; incorporating elements of the TOAST and Lausanne classification&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">7</span></a> It includes a cryptogenic stroke category divided into 3 sections&#58; &#40;a&#41; those in which a cause is not found after an exhaustive study&#44; &#40;b&#41; coexistence of 2 aetiologies and &#40;c&#41; that situation in which the study has been insufficient&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The main problem with these classifications is that the same disease&#44; depending on the classification used&#44; can be considered as a cause or not of a cryptogenic stroke &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; and&#44; therefore&#44; the subsequent management of the patient will be different&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">For this reason&#44; the need to reserve the cryptogenic term for those cases in which&#44; after an extensive history-taking and adequate complementary studies&#44; no cause is found &#40;a true cryptogenic aetiology&#41; is increasingly evident&#44; completely separating from this group the strokes in which there is a concurrence of several causes or those in which a complete diagnosis is not made &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">2</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0045" class="elsevierStylePara elsevierViewall">It is estimated that&#44; in Spain&#44; the percentage of stroke of undetermined aetiology is 23&#46;1&#37;&#46; Of these&#44; almost 65&#37; have been classified as cryptogenic based on an inadequate or insufficient study&#44; 23&#37; due to the combination of several possible causes and only 12&#37; due to the lack of aetiology after an exhaustive diagnostic process &#40;true cryptogenic strokes&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">17</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Overall&#44; the incidence of cryptogenic stroke varies according to the series&#46; In young patients &#40;15&#8211;45 years of age&#41; their incidence varies between 8&#46;3&#37; and 62&#46;4&#37; depending on whether the presence of PFO is considered an aetiology&#44;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">1&#44;18</span></a> whereas&#44; in elderly patients&#44; the incidence varies between 20&#37; and 40&#37; when using the TOAST classification&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">1</span></a> An example of the differences in the estimation of the frequency of cryptogenic stroke based on the etiological classification used is the North Dublin population study&#44; in which the TOAST&#44; ASCO and CCS classifications were compared&#46; In a cohort of 381 patients with a first cerebral infarction&#44; the percentage of cryptogenic strokes was 39&#37; when the TOAST criteria were applied&#44; 26&#37; for the CCS and&#44; in the case of ASCO&#44; 42&#37; of the patients did not have a cause with a grade 1 evidence&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Diagnostic approach</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Initial evaluation</span><p id="par0055" class="elsevierStylePara elsevierViewall">A true cryptogenic stroke is a diagnosis of exclusion&#46; The first step for the diagnosis includes the performance of complementary tests that allow us to identify the most probable causes &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; These include haematological and biochemical laboratory studies&#59; it will be necessary to perform a neuroimaging study using CT and&#47;or brain MRI&#59; a study of the cerebral vasculature and of supra-aortic trunks using non-invasive techniques &#40;Doppler&#47;transcranial and carotid duplex&#44; angio-CT or angio-MRI&#41; and a cardiological study including electrocardiogram &#40;ECG&#41;&#44; 24<span class="elsevierStyleHsp" style=""></span>h Holter monitoring and echocardiography&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">7</span></a> If no cause is found after this first line regarding a cryptogenic stroke&#44; the GEECV-SEN guidelines recommend performing a transoesophageal echocardiogram for the correct evaluation of valves&#44; cardiac cavities and ventricular function&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">7</span></a> Transthoracic echocardiography &#40;TTE&#41; is better than transoesophageal echocardiography &#40;TEE&#41; in the assessment of the left ventricle&#44; while TEE is superior to TTE for the assessment of the left atrium&#44; the presence of PFO and the assessment of aneurysm or thrombus associated with it&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">1</span></a> In addition&#44; TEE can analyze the aortic arch to identify the presence of atherosclerotic plaques at this level and study their characteristics&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">If after these assessments we cannot identify the cause of the stroke&#44; it will be necessary to carry out genetic&#44; serological&#44; immunological&#44; toxicological and even histological and cerebrospinal fluid studies to identify rare causes of cryptogenic stroke<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">7&#44;11&#44;13&#44;19</span></a> especially in young patients in whom unusual causes are more frequent&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">18</span></a> In addition&#44; it is important to consider during the diagnostic process transitory situations&#44; such as PAF&#44; infections&#44; reversible cerebral vasoconstriction syndromes or dissections that&#44; at the time of the etiological study&#44; if delayed&#44; can be underdiagnosed &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">18&#44;20&#44;21</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">In selected patients it will be necessary to use other diagnostic techniques&#44; such as high-resolution MRI for the study of the vascular wall&#44; serological or imaging techniques for the detection of occult neoplasms or prolonged cardiac monitoring&#46; To direct the diagnostic efforts in one way or another&#44; the pattern found in the <span class="elsevierStyleItalic">Diffusion Weighted Imaging</span> &#40;DWI&#41; sequences of the cerebral MRI may be useful&#58; an extensive infarction of cortical localization may be due to a cardioembolic mechanism &#40;especially if there are previous infarctions of the same characteristics in different territories seen in the T2 FLAIR sequences&#41; or due to a situation of hypercoagulability due to a tumour cause &#40;especially if this pattern is found acutely in multiple territories&#41;&#59; a pattern of multiple small and scattered restriction foci in DWI sequence &#40;increased signal foci in DWI&#41; may be due to a tumoral cause&#44; to paradoxical emboli or of the aortic arch&#59; or&#44; if this same pattern occurs in a single area&#44; it will be more likely due to an atheromatous embolism &#40;due to an unstable plaque&#41;&#59; and finally&#44; if an infarction is found in a deep area&#44; it will be&#44; most likely&#44; a lacunar infarction&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">22</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">With the techniques available and the tests to be performed&#44; most of the major cardioembolic causes of cerebral infarcts can be diagnosed&#46; However&#44; PAF &#40;AF of at least 30<span class="elsevierStyleHsp" style=""></span>s in the ECG record that spontaneously reverts to sinus rhythm in less than 48<span class="elsevierStyleHsp" style=""></span>h&#41;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">23</span></a> is found within these&#44; which&#44; with the complementary tests carried out routinely &#40;ECG&#44; Holter 24<span class="elsevierStyleHsp" style=""></span>h&#44; monitoring in stroke units&#41; is detected only in 7&#46;7&#37; of patients in the emergency department and 5&#46;1&#37; during hospitalization&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">24</span></a> PAF comprises between 25&#37; and 62&#37; of AF cases&#44; and its intermittent nature sometimes results in an inadequate diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">25</span></a> It is known that the incidence of stroke is similar in patients with PAF than in those with permanent AF<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">26</span></a> and this diagnosis has important therapeutic implications in the secondary prevention of new episodes &#40;these patients should be treated with oral anticoagulants instead of antiplatelet agents&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">23&#44;27</span></a> Therefore&#44; in those patients in whom a cardioembolic source is suspected&#44; it is necessary to expand the study in search for this disease&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In recent years&#44; clinical trials have been conducted to test the efficacy of prolonged cardiac monitoring in patients with cryptogenic stroke&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">In the EMBRACE study&#44; involving 576 patients with cryptogenic stroke who were randomized to prolonged cardiac monitoring using a belt with electrodes around the chest for 30 days or a conventional study &#40;24<span class="elsevierStyleHsp" style=""></span>h Holter monitoring&#41;&#44; AF of more than 30<span class="elsevierStyleHsp" style=""></span>s was found in 16&#37; of the patients monitored&#44; compared to 3&#46;2&#37; in the control group&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">28</span></a> The advantage of this type of device is its non-invasive nature&#44; with a very favourable risk-benefit balance for the patient&#46; However&#44; in this study&#44; the inclusion of patients was performed in an average of 75 days after suffering the episode of interest &#40;stroke or transient ischaemic attack&#41;&#44; so the percentage of patients with occult AF is probably underestimated&#46; A second study&#44; CRYSTAL-AF&#44; showed the superiority of the Reveal&#174; implantable device after a cryptogenic stroke for the detection of AF versus conventional management &#40;8&#46;9&#37; of AF detected versus 1&#46;4&#37; at 6 months and 12&#46;4&#37; compared to 2&#37; at 12 months&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">29</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The clinical practice guidelines of the <span class="elsevierStyleItalic">American Stroke Association</span> recommend prolonged cardiac monitoring for 30 days in cryptogenic strokes &#40;class 2 grade B&#41;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a> and the <span class="elsevierStyleItalic">European Society of Cardiology</span> &#40;European Society of Cardiology&#41; recommends monitoring for at least 72<span class="elsevierStyleHsp" style=""></span>h in all strokes &#40;class 1 grade B&#41; and consider prolonged monitoring &#40;class 2 grade B&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">23</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">However&#44; in routine clinical practice&#44; perform this type of monitoring on all cryptogenic strokes is not profitable&#46; A model has been recently proposed to explain the pathogenesis of stroke associated with paroxysmal AF&#44; in which attention is focused on atrial disease&#44; regardless of the rhythm disorder&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">30</span></a> Thus&#44; age and vascular risk factors &#40;HBP&#44; possibly DM&#44; genetic factors&#44; coronary disease or obesity&#41; could trigger a series of morphological and functional changes in the atrium &#40;remodelling&#44; fibrosis&#44; hypocontractility&#41; that would lead to AF and this would perpetuate the atrium&#39;s pathological changes&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">23&#44;30</span></a> In addition&#44; some markers of these changes in the atrium &#40;atrial enlargement&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">31</span></a> changes of the left atrium in the ECG&#44;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">32</span></a> sustained supraventricular tachycardia&#41;<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">33</span></a> have been associated with an increased risk of cryptogenic stroke regardless of AF&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">30</span></a> The ASSERT study in 2780 patients with a pacemaker or implantable defibrillator demonstrated that the presence of atrial tachyarrhythmias &#40;excluding AF&#41; of more than 6<span class="elsevierStyleHsp" style=""></span>min is associated with an increased risk of developing AF &#40;HR&#58; 5&#46;56&#41; and of suffering a cryptogenic stroke &#40;HR&#58; 2&#46;49&#41; than those without these alterations&#44; during a mean follow-up period of 2&#46;5 years&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">34</span></a> With the adequate selection of patients &#40;over 60 years of age&#44; suspicion of strokes of embolic source and&#47;or negative 24<span class="elsevierStyleHsp" style=""></span>h Holter monitoring prior to prolonged cardiac monitoring&#41;&#44; the detection rate of PAF can be increased from 5&#46;3&#37; to an average of 10&#46;9&#37; with prolonged cardiac monitoring &#40;14&#46;3&#37; in a 4-day record until 20&#37; in 30-day records&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">25</span></a> Therefore&#44; it could be interesting to focus advanced cardiac studies related to PAF screening in those patients in whom an embolic stroke source is suspected and with data in favour of atrial disease&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The presence of unstable atherosclerotic plaques&#44; with ulceration&#44; necrosis and rupture are etiological causes for stroke&#44; either due to local occlusion or due to an arterio-arterial embolism mechanism&#44; even in patients with a stenosis of less than 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">1</span></a> The detection of this type of plaques improves with 3D ultrasound or high-resolution MRI&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">35&#8211;37</span></a> With the use of Doppler or duplex ultrasound&#44; available in most Neurosonology laboratories&#44; atherosclerotic plaques can be identified and their composition&#44; texture&#44; presence of ulceration and size can be studied&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">38</span></a> However&#44; this technique has some limitations&#44; such as low sensitivity&#44; decreased accuracy as the vessel stenosis caused by said plaque increases or the interobserver variability&#46;<a class="elsevierStyleCrossRefs" href="#bib0450"><span class="elsevierStyleSup">35&#44;39</span></a> With the development of 3D ultrasound&#44; the image quality is improved&#44; with a better characterization of the plaque being possible&#44; thus increasing the possibility of detecting ulcers&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">40&#44;41</span></a> However&#44; this technique has not yet been validated for use in all Neurosonology laboratories&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">35</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In recent years the role of MRI in the study of atherosclerotic plaque ulceration has been analyzed&#46; Recently&#44; a study analyzed the characteristics of symptomatic and asymptomatic carotid atherosclerotic plaques&#44; which generated moderate &#40;between 30&#37; and 70&#37;&#41; and severe &#40;more than 70&#37;&#41; stenosis by a 3<span class="elsevierStyleHsp" style=""></span>Tesla MRI and the use of contrast &#40;gadolinium&#41;&#46; They observed that all &#40;100&#37;&#41; patients with moderate stenosis who had suffered a stroke in the area dependent on that artery there was a thinning or rupture of the fibrous capsule with a lipid centre compared to 32&#37; and 36&#37; among the patients asymptomatic for these findings&#44; respectively&#59; and the presence of intraplaque haemorrhage in 86&#37; of patients with symptomatic stenosis versus 32&#37; of asymptomatic&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a> However&#44; these techniques are expensive and are not available in many hospitals&#46; However&#44; we must consider these aspects before diagnosing a stroke as cryptogenic&#44; because we could be ruling out an atheromatous disease which could&#44; in fact&#44; be the actual cause of it&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">With respect to aortic arch atheroma&#44; TEE is the technique of choice for the diagnosis of atherosclerotic plaques in the aortic arch and ascending aorta&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a> The vulnerable atherosclerotic plaques&#44; defined as those of more than 4<span class="elsevierStyleHsp" style=""></span>mm&#44; with ulceration and mobile component have been shown to be associated with the risk of ischaemic stroke&#44;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">44</span></a> but as explained above&#44; depending on the classification used&#44; these plaques are considered to be an obvious&#44; possible cause of stroke or unrelated to cryptogenic stroke &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment in secondary prevention</span><p id="par0110" class="elsevierStylePara elsevierViewall">The current European and American clinical practice guidelines do not make specific recommendations regarding the preventive treatment of cryptogenic stroke&#44;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">20&#44;21</span></a> whereas the GEECV-SEN guidelines recommend preventive treatment with antiplatelet agents &#40;acetylsalicylic acid or AWS&#41; &#40;level of evidence 3&#8211;4&#44; grade C&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">7</span></a> The rest of the usual stroke recommendations are also applicable in the case of cryptogenic stroke&#44; including the control of cerebrovascular risk factors&#44; the use of statins and antihypertensives for the control of blood pressure&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">1&#44;7&#44;27&#44;45</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The &#8220;ESUS&#8221; construct was created under the hypothesis that there is an unidentified embolic cause in most cryptogenic strokes&#44; and therefore&#44; patients diagnosed with ESUS could benefit from anticoagulant therapy&#46; However&#44; prior to the publication of this concept&#44; some clinical trials were conducted in which anticoagulant treatment was inferior to antiplatelet agent treatment for the prevention of recurrences in patients with stroke of unknown aetiology&#46; The WARSS clinical trial&#44; which included a total of 2206 patients with stroke not caused by a major cardioembolic source or of atherothrombotic aetiology&#44; was randomized to warfarin or AWS 375<span class="elsevierStyleHsp" style=""></span>mg&#47;day for 2 years&#46; No significant differences were found in the recurrence rate of stroke or death&#44; with higher frequency of major bleeding in the warfarin group&#44; although not statistically significant&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">46</span></a> Therefore&#44; the concept of ESUS makes the same mistake again&#44; that of including various etiological causes under the same definition&#44; in order to test the efficacy of direct-acting oral anticoagulants&#44; with lower rates of intracranial haemorrhage than warfarin and&#44; in some studies&#44; with bleeding rates superimposable to ASA&#46; The AVERROES study demonstrated the superiority of apixaban over ASA in the prevention of new embolic episodes without higher bleeding rates&#44; but in patients already diagnosed with AF&#44; with a clear indication of anticoagulant treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a> The NAVIGATE studies are currently being carried out &#40;rivaroxaban vs AWS&#44; ClinicalTrials&#46;gov Identifier&#58; <a id="intr0010" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02313909">NCT02313909</a>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> RE-SPECT-ESUS &#40;dabigatran vs AWS&#44; ClinicalTrials&#46;gov Identifier&#58; <a id="intr0015" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02239120">NCT02239120</a>&#41;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">49</span></a> and ATTICUS &#40;apixaban vs AWS&#44; ClinicalTrials&#46;gov Identifier <a id="intr0020" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT02427126">NCT02427126</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">50</span></a> In all of them&#44; the efficacy of one of direct-acting oral anticoagulants against ASA is compared in the prevention of new strokes in patients whose cryptogenic stroke meets the diagnostic criteria of ESUS&#46; At present&#44; all are still ongoing except NAVIGATE&#44; which has ended early after an interim analysis showed no superiority of rivaroxaban over ASA&#44; with higher rates of side effects &#40;<a id="intr0025" class="elsevierStyleInterRef" href="https://www.jnj.com/media-center/press-releases/navigate-esus-study-stopped-early-due-to-comparable-efficacy-in-treatment-arms">https&#58;&#47;&#47;www&#46;jnj&#46;com&#47;media-center&#47;press-releases&#47;navigate-esus-study-stopped-early-due-to-comparable-efficacy-in-treatment-arms</a>&#41;&#46; Therefore&#44; we should not make the mistake of assuming that anticoagulation should be the standard treatment for cryptogenic stroke&#44; as it is a hodgepodge that includes various diseases that may not benefit from this treatment&#46; In the Athens registry&#44; where the strokes were classified according to the ESUS diagnostic criteria&#44; 10&#37; of these met diagnostic criteria and&#44; among them&#44; 30&#37; showed AF in the extension study&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">51</span></a> That is&#44; up to 70&#37; of patients who meet ESUS diagnostic criteria would have another aetiology that may not benefit from empirical anticoagulation&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">With respect to patients with stroke and PFO&#44; depending on the etiological classification we use&#44; it will be considered as a cause or not&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">7&#44;11&#44;13</span></a> In any case&#44; at present&#44; the <span class="elsevierStyleItalic">American Stroke Association</span> recommends antiplatelet therapy for patients with stroke and PFO &#40;level of evidence 3&#44; grade A&#41; and only anticoagulation is recommended in those cases in which&#44; in addition to PFO&#44; a source of venous embolism has been found &#40;level of evidence 1&#44; grade A&#41;&#44; together with its closure&#44; depending on the risk of recurrence of the embolic source &#40;level of evidence 2b&#44; grade C&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a> The <span class="elsevierStyleItalic">European Stroke Organization</span> recommends anticoagulation in the event that a PFO is found associated with atrial septal aneurysm &#40;ASA&#41; or a venous embolic source &#40;level of evidence 4&#41;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a> and the GEECV-SEN recommends antiplatelet therapy in cases of PFO and if a source of venous embolism is associated &#40;such as deep vein thrombosis&#41;&#44; anticoagulant treatment is recommended during the first 3 months after the stroke and subsequently continuing with ASA in cases of isolated PFO&#46; If in addition to a source of venous embolism an ASA coexists with PFO&#44; it is recommended to continue with anticoagulants and only consider the percutaneous closure of the PFO in recurrent cases &#40;level of evidence 3&#8211;4&#44; grade C&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">7</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The RE-SPECT clinical trial &#40;in which 980 patients with cryptogenic stroke and PFO were included&#44; randomized to treatment by means of percutaneous closure of PFO together with antiplatelet treatment for the following 5 months or to receive antiplatelet treatment only&#41; did not find significant benefit associated with PFO closure compared to medical treatment except in those patients in whom an ASA coexisted or the size of the PFO was significant&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">52</span></a> However&#44; 6-year results have been published recently&#44; demonstrating the superiority of percutaneous closure over medical treatment&#44; reducing the recurrence rate of cryptogenic aetiology stroke by 66&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">53</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Recurrence risk</span><p id="par0130" class="elsevierStylePara elsevierViewall">The risk of recurrence of cryptogenic stroke varies according to published series&#44; from 4&#46;8&#37; at 3 months to 33&#37; at 5 years in a series published in the year 2000<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">54</span></a>&#59; or up to 30&#37; per year in a study published in 2003&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">2</span></a> In the latter&#44; a higher recurrence rate is observed compared to previously published series and relate this recurrence to the presence of moderate stenosis &#40;&#60;50&#37;&#41; in the cryptogenic stroke&#39;s artery and the presence of significant atheromatosis &#40;&#62;50&#37;&#41; in other arteries&#59; establishing the hypothesis that the patients who experience recurrences could have an atheromatous disease at a different stage than those who meet criteria for atherothrombotic stroke according to the TOAST classification&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In a study that analyzed recurrence rates of cryptogenic stroke according to the MRI&#39;s lesion pattern in a cohort of 241 patients&#44; it was found that those who had a single lesion had lower recurrence rates &#40;4&#46;4&#37;&#41; versus those with a pattern of multiple lesions &#40;8&#37;&#41;&#44; with the possibility of an embolic disease being the underlying cause in the latter &#40;PAF not detected&#44; PFO and ASA&#44; occult neoplasm&#44; aortic arch atheroma&#41;&#46; In addition&#44; the values of D-dimer and pro-BNP were higher in patients with a multiple infarction pattern in MRI&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">55</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">These differences in the frequency of recurrence of cryptogenic stroke support our opinion that under this name different pathologies are included&#44; which have not been recognized or identified&#44; but&#44; nevertheless&#44; have an important role in the pathogenesis of ischaemic stroke&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusion</span><p id="par0145" class="elsevierStylePara elsevierViewall">Cryptogenic stroke is a &#8220;non-diagnosis&#8221; behind which a large number of different aetiologies are underlying&#44; so that no type of treatment can be induced&#44; and in which it is necessary to deepen the etiological study by means of appropriate diagnostic techniques&#44; taking into consideration the characteristics of each patient&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The authors declare that they have participated as investigators in the RE-SPECT ESUS<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">49</span></a> and NAVIGATE<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> clinical trials&#46;</p></span></span>"
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          "identificador" => "xres1075770"
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              "identificador" => "abst0005"
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        1 => array:2 [
          "identificador" => "xpalclavsec1022089"
          "titulo" => "Keywords"
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          "identificador" => "xres1075771"
          "titulo" => "Resumen"
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          "identificador" => "xpalclavsec1022090"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Concept&#58; definition and progress"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Epidemiology"
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        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Diagnostic approach"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Initial evaluation"
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        7 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Treatment in secondary prevention"
        ]
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          "identificador" => "sec0030"
          "titulo" => "Recurrence risk"
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        9 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Conclusion"
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          "identificador" => "sec0040"
          "titulo" => "Conflict of interests"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2017-12-21"
    "fechaAceptado" => "2018-01-05"
    "PalabrasClave" => array:2 [
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Cryptogenic stroke"
            1 => "Advance Cardiac monitoring"
            2 => "Atherosclerotic plaques"
            3 => "Patent foramen oval"
          ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1022090"
          "palabras" => array:4 [
            0 => "Ictus criptog&#233;nico"
            1 => "Monitorizaci&#243;n card&#237;aca prolongada"
            2 => "Placa de ateroma"
            3 => "Foramen oval permeable"
          ]
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The term cryptogenic stroke refers to a stroke for which there is no specific attributable cause after a comprehensive evaluation&#46; However&#44; there are differences between the diagnostic criteria of etiological classifications used in clinical practice&#46; An improvement in diagnostic tools such advances in monitoring for atrial fibrillation&#44; advances in vascular imaging and evidence regarding the implication of patent foramen oval on the risk of stroke specially in young patients are reducing the proportion of stroke patients without etiological diagnosis&#46; We carried out a critical review of the current concept of cryptogenic stroke&#44; as a non-diagnosis&#44; avoiding the simplification of it and reviewing the different entities that could fall under this diagnosis and reviewing the different entities that could fall under this diagnosis&#59; and therefore avoid the same treatment for differents entities with uncertains results&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El ictus criptog&#233;nico se define como aquel para el que no encontramos una etiolog&#237;a&#46; Sin embargo&#44; existe cierta heterogeneidad en los criterios para definir un ictus criptog&#233;nico entre las diferentes clasificaciones etiol&#243;gicas de uso habitual&#46; Los avances en sistemas de monitorizaci&#243;n y detecci&#243;n de fuentes cardioemb&#243;licas&#44; el avance de las t&#233;cnicas de neuroimagen para la caracterizaci&#243;n de la placa de ateroma&#44; as&#237; como la mayor evidencia de la implicaci&#243;n del foramen oval permeable en el riesgo de ictus en pacientes j&#243;venes&#44; hacen que cada vez menos ictus queden sin un diagn&#243;stico etiol&#243;gico&#46; Realizamos una revisi&#243;n cr&#237;tica del concepto de ictus criptog&#233;nico como un &#171;no diagn&#243;stico&#187;&#44; resaltando la importancia de realizar un estudio diagn&#243;stico completo&#44; evitando simplificaciones que pueden llevar a agrupar diferentes entidades que&#44; aunque no identificadas&#44; podr&#237;an subyacer al ictus criptog&#233;nico y&#44; por tanto&#44; a aplicar el mismo tratamiento preventivo a todas ellas&#44; con resultados inciertos&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Guti&#233;rrez-Z&#250;&#241;iga R&#44; Fuentes B&#44; D&#237;ez-Tejedor E&#46; Ictus criptog&#233;nico&#46; Un no diagn&#243;stico&#46; Med Clin &#40;Barc&#41;&#46; 2018&#59;151&#58;116&#8211;122&#46;</p>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Progression of the cryptogenic stroke concept&#46; ESUS&#58; <span class="elsevierStyleItalic">embolic stroke of undetermined source</span>&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Cryptogenic stroke classification proposal&#46;</p>"
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        "etiqueta" => "Table 1"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">TIA&#58; transient ischaemic attack&#59; ASA&#58; atrial septal aneurysm&#59; ASCOD&#58; ASCO &#40;atherosclerosis&#59; small-vessel disease&#59; cardiac pathology&#59; other causes&#59; dissection&#41;&#59; AT&#58; atherothrombotic&#59; CCS&#58; <span class="elsevierStyleItalic">Causative Classification System</span>&#59; CE&#58; cardioembolic&#59; DM&#58; diabetes mellitus&#59; ESUS&#58; <span class="elsevierStyleItalic">embolic stroke of undetermined source</span>&#59; PFO&#58; permeable foramen ovale&#59; GEECV-SEN&#58; Study Group of Cerebrovascular Diseases of the Spanish Society of Neurology&#59; HT&#58; hypertension&#59; CI&#58; cerebral infarction&#59; SSS-TOAST&#58; <span class="elsevierStyleItalic">Stop-Stroke Study</span>-TOAST&#59; PTE&#58; pulmonary thromboembolism&#59; TOAST&#58; Trial Org-10172 Acute Stroke Treatment&#59; DVT&#58; deep vein thrombosis&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">TOAST classification<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">4</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">GEECV-SEN<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ASCOD classification<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">13</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">SSS-TOAST classification<br>CCS<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">11</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ESUS<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">14</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PFO&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CE if no other cause&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cryptogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">CE<br><br>C1<br>-PFO<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>thrombus in situ<br>-PFO<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Concomitant PTE<br>-PFO<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Previous DVT<br><br>C2<br>-PFO<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>ASA<br>-PFO<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Concomitant PTE or DVT &#40;not prior&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Possible CE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ESUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aortic arch atheroma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cryptogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cryptogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AT<br><br>A1&#58;<br>-Thrombo-mobile<br>A2&#58;<br>-Plaque &#62;4<span class="elsevierStyleHsp" style=""></span>mm not mobile&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Possible CE&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ESUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Atheromatosis &#60;50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cryptogenic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AT<br>If more than 2&#58;<br>-Age &#62;50 years<br>-HT<br>-DM<br>-Smoking<br>-Hypercholesterolemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AT<br><br>A1&#58;<br>-With intraluminal thrombus<br><br>A2&#58;<br>-Ipsilateral stenosis 30&#8211;50&#37;<br><br>A3<br>-Ipsilateral stenosis &#60;30&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AT<br><br>Evident&#58;<br>-If there is ulceration or thrombosis<br>Possible&#58;<br><br>-Yes &#62;2 amaurosis fugax&#44; TIA or CI in the same area in the last month&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ESUS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Diagnostic controversies according to the different classifications&#46;</p>"
        ]
      ]
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        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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            "identificador" => "at2"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">ALT&#58; alanine transaminase&#59; AST&#58; aspartate transaminase&#59; TEE&#58; transoesophageal echocardiography&#59; TTE&#58; transthoracic echocardiography&#59; AP&#58; alkaline phosphatase&#59; GGT&#58; gamma-glutamyl transpeptidase&#59; HbA1c&#58; glycosylated haemoglobin&#59; HDL&#58; <span class="elsevierStyleItalic">high density lipoprotein</span>&#59; INR&#58; <span class="elsevierStyleItalic">international normalized ratio</span>&#59; LDL&#58; <span class="elsevierStyleItalic">low density lipoprotein</span>&#59; CRP&#58; C-reactive protein&#59; CW&#58; Circle of Willis&#59; MRI&#58; magnetic resonance imaging&#59; CT&#58; computed tomography&#59; TG&#58; triglycerides&#59; SAT&#58; supra-aortic trunks&#59; PTT&#58; partial thromboplastin time&#59; ESR&#58; erythrocyte sedimentation rate&#46;</p><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Source&#58; According to the GEECV-SEN clinical practice guidelines recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">7</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Neuroimaging study</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Cranial CT</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Brain MRI</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Laboratory study</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Complete blood count</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ESR</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Platelets</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Coagulation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>PTT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>INR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Fibrinogen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Homocysteine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Study of genetic and acquired thrombophilia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Biochemistry</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Renal function &#40;urea&#44; creatinine&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Liver function &#40;AST&#44; ALT&#44; GGT&#44; AP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Glycemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HbA1c&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Lipid profile &#40;HDL&#44; LDL&#44; TG&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Serum total protein test&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Uric acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>CRP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Cerebral vasculature study</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Carotid and transcranial Doppler&#47;duplex</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Angio-CT SAT and CW</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Angio-MRI SAT and CW</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Cardiology study</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">TTE and&#47;or TEE</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">24</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">h</span> Holter monitoring&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Prolonged cardiac monitoring</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Screening for occult neoplasm</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">CADASIL&#58; cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy&#59; CARASIL&#58; cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy&#59; MELAS&#58; mitochondrial myopathy&#44; encephalopathy&#44; lactic acidosis&#44; and stroke-like episodes&#59; ITP&#58; idiopathic thrombocytopenic purpura&#59; TTP&#58; thrombotic thrombocytopenic purpura&#59; CNS&#58; central nervous system&#59; TB&#58; tuberculosis&#59; HIV&#58; human immunodeficiency virus&#59; VZV&#58; varicella zoster virus&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Inflammatory vasculopathies</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CNS vasculitis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Systemic vasculitis with CNS involvement</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Arteritis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Giant cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Takayasu disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Infectious</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HIV&#44; VZV&#44; syphilis&#44; TBC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Non-inflammatory vasculopathies</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Ehlder-Danlos</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Fibromuscular dysplasia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Radiation-induced vasculopathy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Moya-Moya disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Sneddon syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Lupus and other collagenopathies</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Genetic causes</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">CADASIL</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Retinocerebral arteriopathy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Small vessel disease due to mutations of COL-4A1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Fabry disease</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Genetic prothrombotic states</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Antiphospholipid syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Sickle cell disease</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hyperhomocysteinemia</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">ITP&#44; TTP</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neoplasms &#40;especially blood-related&#44; lymphomas&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Erythrocytosis</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Other</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Reversible cerebral vasoconstriction syndrome</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Reversible posterior leukoencephalopathy</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Pregnancy and puerperium &#40;hypercoagulability&#44; eclampsia&#47;preeclampsia&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Recreational drugs &#40;cocaine&#44; amphetamines&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Uncommon causes of cerebral infarction&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
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            0 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cryptogenic stroke"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46;C&#46; Fonseca"
                            1 => "J&#46;M&#46; Ferro"
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                      "doi" => "10.1111/ene.12673"
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                        "tituloSerie" => "Eur J Neurol"
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                        "volumen" => "22"
                        "paginaInicial" => "618"
                        "paginaFinal" => "623"
                        "link" => array:1 [
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              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Frequency and mechanisms of stroke recurrence after cryptogenic stroke"
                      "autores" => array:1 [
                        0 => array:2 [
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                          "autores" => array:6 [
                            0 => "O&#46;Y&#46; Bang"
                            1 => "P&#46;H&#46; Lee"
                            2 => "S&#46;Y&#46; Joo"
                            3 => "J&#46;S&#46; Lee"
                            4 => "I&#46;S&#46; Joo"
                            5 => "K&#46; Huh"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/ana.10644"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Neurol"
                        "fecha" => "2003"
                        "volumen" => "54"
                        "paginaInicial" => "227"
                        "paginaFinal" => "234"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12891675"
                            "web" => "Medline"
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                      "titulo" => "Advances in the diagnosis of etiologic subtypes of ischemic stroke"
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                          "autores" => array:1 [
                            0 => "H&#46; Ay"
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                  ]
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                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "Curr Neurol Neurosci Rep"
                        "fecha" => "2010"
                        "paginaInicial" => "140"
                        "paginaFinal" => "220"
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                      "titulo" => "Classification of subtype of acute ischemic stroke"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Adams"
                            1 => "H&#46; Adams"
                            2 => "B&#46; Bendixen"
                            3 => "B&#46; Bendixen"
                            4 => "L&#46; Kappelle"
                            5 => "L&#46; Kappelle"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Stroke"
                        "fecha" => "1993"
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                        "paginaFinal" => "41"
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