Introduction
Ischemic stroke is most frequent among the elderly; the average age of the patient is 70 years [1]. In contrast, it is much rarer in young individuals and children as only 3% of the strokes occur in patients under 40 years of age [2]. Frequently, the etiology of ischemic stroke in both age groups is different. In older patients, the stroke is most commonly associated with such classical cardiovascular risk factors as arterial hypertension, hyperlipidemia, diabetes, tobacco smoking, and cardiac disorders (atrial fibrillation, valvular disorders). In contrast, small vessel disease, atherosclerosis of large arteries, and cardiac disorders are not observed in younger patients with ischemic stroke; this is reflected by the diagnosis of the so-called cryptogenic stroke. In this group of patients, the ischemic stroke can be associated with other factors including a patent foramen ovale (PFO), thrombophilia, or vasculitis.
During fetal development, i.e. in the period when the pulmonary circulation is virtually inactive, the patent foramen ovale enables shunting of blood between the right and the left atrium. The foramen is closed postnatally in most cases; however, it remains patent in approximately 25% of individuals. In the case of the latter group, it may constitute a gate for so-called paradoxical embolism since it enables the transfer of embolus from venous system to the left atrium and further penetration into systemic circulation [3].
Antiphospholipid syndrome (APS) is an autoimmune disorder associated with the synthesis of autoantibodies against membrane phospholipids (aPI) and phospholipid-binding proteins. Antiphospholipid antibodies (aPI) affect the function of the coagulation system, increasing the risk of arterial thrombosis (stroke, myocardial infarct), venous thrombosis (venous thromboembolism), and the thrombosis of microcirculation vessels, as well as the risk of obstetrical failures resulting from changes in placental vessels. Aside from the abovementioned clinical criteria used in APS diagnosis, the syndrome can be associated with an array of other disorders. Clinical manifestation of APS can also comprise cardiac changes, leading to valvular injury and subsequent embolic complications in systemic circulation. Aside from clinical criterion, the diagnosis of APS requires satisfying at least one laboratory criterion, i.e. the presence of lupus anticoagulant (LAC), IgG and/or IgM anti-cardiolipin antibodies (aCI; moderate or high titer: > 40 GPL, MPL, or > 99th percentile), or IgG and/or IgM anti-beta-2-glycoprotein I antibodies (anti-B2GPI; titer > 99% percentile) [4].
The C667T and A1298C polymorphisms of MTHFR gene are associated with the reduced activity of the enzyme and elevated serum concentration of homocysteine (Hcy). Hcy was revealed as an independent risk factor of stroke, coronary heart disease, and peripheral artery atherosclerosis, as well as the risk factor of venous thromboembolism, neoplastic disease, and obstetrical failures [5-11]. Meta-analysis by Boushey et al. showed that a 5 μmol/L increase in Hcy concentration corresponds to a 1.5 odds ratio (OR) of cerebrovascular incidents (95% CI 1.3-1.9) [11].
Case report
A 31-year-old male was admitted to the Department of Angiology in the course of diagnosing thrombophilia as a result of recurrent cerebrovascular incidents and the presence of lupus anticoagulant (LAC) revealed accidently during a recent episode of ischemic stroke. The patient was diagnosed with transient ischemic attack (TIA) 8 years earlier, followed by the ischemic stroke of the occipital lobe and right cerebellar hemisphere. Analysis of patient’s family history revealed that his grandmother suffered from chronic venous insufficiency; however, none of his family members was diagnosed with venous thromboembolism. Moreover, the patient had no history of symptoms suggesting previous venous thrombosis or pulmonary thromboembolism. Magnetic resonance performed during the recent cerebrovascular episode revealed fresh ischemic lesions of the right occipital lobe and cerebellar hemisphere along with the chronic vascular lesions in both cerebellar hemispheres and right side of the pons, possibly resulting from the so-called silent brain infarct (SBI; fig. 1, 2). Doppler ultrasonography and CT angiography did not show any abnormalities of cerebral vessels. Transthoracic echocardiography (TTE) revealed normal heart chambers, with no indications of pulmonary hypertension, and normal systolic and diastolic function of the left ventricle. However, PFO was detected on transesophageal echocardiography (TEE) along with left-to-right shunt irreversible on Valsalva maneuver. No thrombotic changes were observed in the left atrium or its auricle. Holter monitoring did not document any echocardiographic abnormalities aside from few, sporadic additional excitations of supraventricular and ventricular origin as well as night bradycardia (down to 45 beats per min).
Figure 1. T2 weighted magnetic resonance image shows bilateral cerebellar hyperintense foci
Rycina 1. Ogniska hiperintensywne widoczne w obu półkulach móżdżku w obrazach T2 zależnych badania rezonansu magnetycznego głowy
Figure 2. T2 weighted magnetic resonance images shows right occipital hyperintense focus
Rycina 2. Ognisko hiperintensywne w prawej okolicy potylicznej widoczne w obrazach T2 zależnych badania rezonansu magnetycznego głowy
Physical findings included abdominal obesity (BMI 33 kg/m2), and elevated arterial blood pressure (140/90 mm Hg). Laboratory tests revealed hypercholesterolemia, hyperuricemia, and slightly elevated concentrations of aminotransferases (Tab. 1). Abdominal ultrasound showed enlargement of the liver with the signs of fatty liver disease. No signs of previous venous thrombosis of lower and upper limbs were documented on Doppler ultrasound performed during hospitalization. ABPM showed borderline elevation of arterial blood pressure corresponding to high normal pressure (a mean of 133/79 mm Hg for the whole period of monitoring). Examination for clotting abnormalities revealed a combined defect: the presence of lupus anticoagulant (LAC) and A1298C polymorphism of MTHFR gene (homozygote). Positive result of LAC testing was documented twice with 12-week interval, no earlier than 12 weeks after the recent cerebrovascular episode. The results of other laboratory parameters: antithrombin, C protein, S protein, factor VIII, factor Leiden, mutation of G20210A prothrombin gene, anti-cardiolipin antibodies (aCI), and anti-beta-2-glycoprotein I antibodies (anty-B2GPI) were normal (Tab. 1).
The combined therapy included warfarin (target INR: 2-3), and acetylsalicylic acid (150 mg/d). Additionally, supplementation with folic acid, vitamin B6, and vitamin B12 was recommended. Finally, the patient was referred to cardiosurgical center to consider surgical closing of PFO.
Table 1. Laboratory findings
Tabela 1. Parametry laboratoryjne
Badane parametry | Wartość | Norma |
Erytrocyty | 5,15 mln/ml | 4,5–5,5 mln/ml |
Hemoglobina | 14,9 g/dl | 14–18 g/dl |
Leukocyty | 8,17 tys/ml | 4–10 tys/ml |
Płytki krwi | 326 tys/ml | 140–440 tys/ml |
Kreatynina | 0,8 mg/dl | < 1,3 mg/dl |
Sód | 137 mmol/l | 136–146 mmol/l |
Potas | 4,3 mmol/l | 3,5–5,1 mmol/l |
Hs-CRP | 3,0 mg/l | < 5,0 mg/l |
Cholesterol całkowity | 241 mg/dl | < 180 mg/dl |
Cholesterol LDL | 166 mg/dl | < 115 mg/dl |
Cholesterol HDL | 40 mg/dl | > 40 mg/dl |
Triglicerydy | 161 mg/dl | < 150 mg/dl |
Homocysteina | 12,8 mmol/l | < 15 mmol/l |
Kwas moczowy | 8,2 mg/dl | < 7,2 mg/dl |
Glukoza na czczo | 81 mg/dl | < 100 mg/dl |
Glukoza 2 godziny po obciążeniu (75 g glukozy) | 80 mg/dl | < 140 mg/dl |
ALAT | 66 U/l | 0–45 U/l |
ASPAT | 56 U/l | 0–35 U/l |
Kwas moczowy | 8,2 mg/dl | 3,5–7,2 mg/dl |
TSH | 1,77 uIU/ml | 0,35–4,94 uIU/ml |
ANA | Ujemne | |
c-ANCA, p-ANCA | Ujemne | |
APTT | 38,8 sek | 25–37 sek |
Wskaźnik protrombiny | 102% | 80–114% |
INR | 1,0 | 0,9–1,3 |
Fibrynogen | 3,5 g/l | 1,8–3,5 g/l |
Antytrombina | 102% | 80–120% |
CRP | 133% | 70–140 |
Białko S (C?) aktywne wolnej frakcji | 129% | 75–130% |
Białko S stężenie wolnej frakcji | 120% | 74–146% |
Czynnik VIII | 86% | 70–150% |
LAC | LA1 test skriningowy 49 sek | 30,5–40,6 sek |
LA2 test potwierdzenia 34 sek | 26,4–34,5 sek | |
LA ratio 1,43 | 1,0–1,37 | |
LA1 test skriningowy 45 sek | ||
LA2 test potwierdzenia 28 sek | ||
LA ratio 1,59 | ||
aCI | IgG 3,7 GPL/ml IgM < 2,0 MPL/ml | |
Anty-B2GPI | IgG 2,1 Ru/ml IgM 7,88 Ru/ml | |
Czynnik Leiden G1691A | G-G negatywny | |
Mutacja genu protrombiny G20210A | G-G negatywny | |
Polimorfizm genu MTHFR C667T | C-C negatywny | |
Polimorfizm genu MTHFR A1297C | C-C zmutowana homozygota |
hs-CRP (high sensitivity C-reactive protein) – białko C-reaktywne o wysokiej czułości; LDL (low-density lipoprotein) – lipoproteina o niskiej gęstości; HDL (high-density lipoprotein) – lipoproteina o wysokiej gęstości; ALAT (alanine aminotransferase) – aminotransferaza alaninowa; ASPAT (aspartate aminotransferase) – aminotransferaza asparaginianowa; TSH (thyroid-stimulating hormone) – tyreotropina; ANA (anti-nuclear antibodies) – przeciwciała przeciwjądrowe; ANCA (anti-neutrophil cytoplasmic antibodies) – przeciwciała przeciw cytoplazmie neutrofilów; APTT (activated partial thromboplastin time) – czas częściowej tromboplastyny po aktywacji; INR (international normalized ratio) – międzynarodowy współczynnik znormalizowany; CRP (C-reactive protein) – białko C-reaktywne; LAC (lupus anticoagulant) – antykoagulant toczniowy; aCI (anticardiolipin antibodies) – przeciwciała antykardiolipinowe
Discussion
The following questions should be addressed in the hereby presented case of a young man with recurrent ischemic episodes of CNS: the reasons for the recurrent stroke/TIA along with the possibilities of their control or elimination, the risk of another episode of recurrent ischemia of CNS, and the EBM-based treatment that should be offered as a secondary prevention of stroke.
It is believed that there is a link between PFO and ischemic stroke in younger individuals. PFO is associated with 46% of cases of cryptogenic ischemic stroke diagnosed in patients under 55 years of age, 4 times more frequently than in the control group [3]. In contrast, the association between PFO and stroke has not been unambiguously confirmed in older age groups (> 55 years of age) [3]. The risk of paradoxical embolism associated with PFO seems to be modulated by an array of factors. The risk of stroke is higher in the case of large oval opening, aneurysm of inter atrial septum, conditions promoting the right-to-left shunt (pulmonary hypertension, right ventricular infarct, severe insufficiency of tricuspid valve), and in certain morphological variants of the right atrium (persistent Eustachian valve, Chiari’s network) [3]. Also, conditions promoting thrombosis in the venous system, such as thrombophilia, can constitute an important factor involved in the formation of paradoxical embolism in patients with PFO. The presence of a clot in the venous system of patient with cryptogenic stroke and PFO increases the probability of paradoxical embolism. Transient right-to-left shunt can occur both under physiological conditions (cough, Valsalva maneuver) and in various pathologies (pulmonary hypertension, right ventricular infarct, severe insufficiency of tricuspid valve), leading to the transfer of embolic material from the venous system to systemic circulation. The fact that the presence of embolic material is observed sporadically in the venous system of patients with cryptogenic stroke represents a weak point of the PFO theory of paradoxical embolism. Nevertheless, several studies confirmed higher prevalence of venous thrombosis in patients with cryptogenic stroke as compared to individuals with a stroke of established etiology [12, 13]. Pelvic vein thrombosis was documented in 20% of cryptogenic stroke cases included in the PELVIS trial; it was significantly more frequent than in the group of patients with a stroke of established etiology (4%) [13]. Extremely high fraction of patients with confirmed venous thrombosis documented in this study is particularly significant. Perhaps, pelvic veins, relatively rarely examined in everyday practice, may constitute the main source of paradoxical embolism in patients with PFO. It has been postulated that paradoxical emboli can be characterized by extremely small sizes precluding their detection by means of routine imaging methods; nevertheless, significant neurological signs can result even from the embolus of only 1 mm diameter [14].
Transesophageal echocardiography revealed patent foramen ovale in our patient, constituting a potential etiological mechanism of paradoxical embolism. Furthermore, two other abnormalities were detected during diagnostic process: antiphospholipid syndrome (APS) and the polymorphism of MTHFR gene, both promoting thrombosis and increasing the probability of paradoxical embolism causing stroke. Several studies confirmed higher prevalence of thrombophilia amongst patients with cryptogenic stroke and PFO [15-18]. However, diagnostic imaging did not reveal thrombotic changes in the venous system of our patient. Nevertheless, venous thrombosis cannot be definitely excluded as a cause of paradoxical embolism since the venous system was examined some time after the recent episode of cerebral ischemia, and, therefore, potential thrombotic lesions could have undergone recanalization. Furthermore, thrombotic changes could have been too small to give the signs of venous thrombosis or to be visualized by imagining studies; still they were large enough to cause the signs of CNS ischemia after entering systemic circulation via PFO. Thrombophilia, and particularly APS, can also promote the thrombosis of arterial system, including the cerebral arteries. Ischemic stroke or TIA belong to the most common consequences of APS and represent the initial manifestation of the syndrome in about 30% of patients [19]. Also, the recurrence of APS-related vascular thrombosis is most commonly manifested as a stroke or TIA. The presence of anti-cardiolipin antibodies and lupus anticoagulant was showed to be associated with the risk of stroke in young adults [20, 21]. Antiphospholipid antibodies could promote arterial thrombosis in our patient and underlie the recurrence of stroke/TIA, irrespective of PFO and the mechanism of paradoxical embolism. Elevated risk of stroke may also be associated with the presence of MTHFR polymorphism. The polymorphism of MTHFR is an established, but weak, risk factor of venous thrombosis and can increase the risk of paradoxical embolism in patients with PFO. Several studies documented the association between the MTHFR polymorphism and ischemic stroke in younger individuals; this relationship was associated with elevated concentration of Hcy, being the established risk factor of cardiovascular disorders [22-24]. It should be noted, however, that the MTHFR polymorphism is associated with only a slightly elevated risk of stroke. In one meta-analysis the odds ratio (OR) of stroke in the carriers of C677T polymorphism of MTHFR was estimated at 1.23 (0.61-1.47) [24]. In comparison, OR of stroke associated with the presence of lupus anticoagulant can be as high as 43.1 (12.2-152) [21]. Patients with congenital thrombophilia (Leiden factor, mutation of prothrombin gene, deficiency of antithrombin, protein S, and protein C, or MTHFR polymorphism) have an elevated risk of venous thrombosis. In contrast, these factors play a rather marginal role with regards to the risk of arterial thrombosis due to the different pathophysiology of coagulation in venous and arterial system. Other polymorphisms, e.g. polymorphism of fibrinogen gene, convertase, or platelet glycoproteins, can play a more important role in the case of arterial thrombosis [25]. The relationship between congenital thrombophilia and ischemic stroke was observed mostly in children and younger individuals < 40 years of age [26]. In contrast, no evident association between the ischemic stroke and congenital thrombophilia and/or APS was documented in older population [26, 27]. Consequently, testing for thrombophilia should be performed mostly in stroke patients below 40 years of age.
Proper diagnostics of the antiphospholipid syndrome are essential. In the case of our patient, the first positive result of lupus anticoagulant (LAC) testing was determined during his recent episode of stroke. It should be remembered that antiphospholipid antibodies can be observed transiently and remain undetectable on later testing. Consequently, according to the International Society on Thrombosis and Haemostasis recommendations, the presence of antiphospholipid antibodies should be confirmed at least twice within 12-week interval; moreover, they should be detected no earlier than 12 weeks after vascular episode and no later than 5 years thereafter [4]. In our patient, the tests for LAC, aCI, and anti-B2GPI were repeated 3 and 6 months after the recent stroke. All tests revealed the presence of LAC, along with the negative results for aCI and anti-B2GPI. The presence of LAC is the most specific (but less sensitive than aCI) criterion of APS; additionally, LAC is better correlated with the risk of thrombosis than aCI [28]. Defining proper protocol of management in patients with ischemic stroke and APS is challenging due to the small number of randomized clinical trials (RCT) dedicated to this group of patients. In the case of deep vein thrombosis co-existing with APS, there is a body of evidence supporting the necessity of moderately intense (INR 2-3), long-term therapy with vitamin K agonist (VKA) [28-30]. VKA and ASA seem to have a similar significance in reducing the risk of recurrent arterial episodes. The Antiphospholipid Antibodies and Stroke Study (APASS) trial did not show any differences between VKA (INR 1.4-2.8) and acetylsalicylic acid (325 mg) with regards to reducing the risk of recurrent stroke in patients who tested positive for antiphospholipid antibodies (aCI or LAC) [31]. It should be noted, however, that APASS included patients with stroke who were randomized on the basis of single positive testing for antiphospholipid antibodies; consequently, the study included a fraction of patients in whom these antibodies were present transiently. Furthermore, this study did not confirm that the presence of antiphospholipid antibodies increases the risk of recurrent stroke. Consequently, there is no evidence supporting the theory that the administration of VKA to patients with APS and a history of stroke are more beneficial than monotherapy with ASA. It should be remembered that the etiology of APS-associated stroke can be variable: the stroke can result from embolism (cardiogenic stroke, paradoxical stroke associated with PFO), thrombosis of microcirculation or small arteries (lacunar stroke), or thrombosis of the venous sinuses of the brain. According to some authors, VKA should constitute first line of therapy in patients with APS and stroke of embolic etiology or stroke associated with the thrombosis of venous sinuses [26]. There are three possible strategies that can be implemented whenever thrombosis of cerebral arteries recurs during VKA or ASA therapy: increasing the intensity of VKA therapy (INR 3-4), using combined therapy with VKA and ASA, or replacing VKA with non-fractioned or low molecular weight heparin [28]. Our patient experienced consecutive cerebrovascular episodes in the course of ASA treatment; consequently, combined therapy with warfarin (with target INR 2-3) and acetylsalicylic acid (150 mg/d) was implemented.
Another problem pertains to defining the proper protocol of management of PFO detected on echocardiographic examination. The possible strategies of management in patients with cryptogenic stroke and PFO include: administration of ASA, anticoagulant therapy with VKA, combined therapy with ASA and VKA, and transdermal or surgical closure of PFO. To date, the superiority of any of abovementioned approaches was not confirmed with regards to the reduced risk of recurrent stroke/TIA in patients with PFO [32-37]. The only prospective, randomized trial – PICSS [32], which included patients with PFO and cryptogenic stroke, showed that the risk of recurrent stroke in warfarin-treated group was twice as low as in individuals given ASA. However, this difference did not prove significant. At the same time, warfarin group showed a significant increase in bleeding complications. Consequently, according to the American College of Chest Physicians and the American Heart Association guidelines, antiplatelet therapy (ASA) is preferred over VKA in patients with cryptogenic stroke and PFO, except for individuals with thrombophilia and deep vein thrombosis [38, 39].
Is invasive closure of PFO required in the case of our patient? Sparse clinical trials analyzing the effects of transdermal closure of PFO in patients with cryptogenic stroke did not confirm the superiority of the invasive treatment over pharmacotherapy (ASA, VKA) [35, 36]. The fact that the presence of PFO was not proved to increase the risk of recurrent cryptogenic stroke in patients treated pharmacologically (ASA, VKA) can be important in this matter [32]. One study revealed that transdermal closure of PFO is more beneficial than pharmacotherapy, but solely in the subgroup of patients with a history of more than one cryptogenic stroke [36]. Moreover, an extended 15-year follow-up confirmed a lower incidence of TIA in patients who were treated invasively, but without a significant effect on the risk of stroke and mortality [40]. According to the American Heart Association guidelines [39], the transdermal closure of PFO should be considered in patients in whom stroke recurred despite pharmacotherapy. One can hardly find any evidence-based data supporting transdermal closure of PFO in patients with thrombophilia and a history of stroke as thrombophilia usually constitutes an exclusion criterion in the case of clinical trials dealing with the problem in question [41, 42]. Due to the lack of strong evidence of benefits associated with transdermal closure of PFO, following consultation at the cardiosurgical center, we have temporarily resigned from invasive treatment, taking into account the preference of our patient and the fact that he is receiving combined therapy with ASA and VKA. Nevertheless, indications for PFO closure will be reconsidered if stroke/TIA recurs despite pharmacotherapy. There is a need for clinical trials analyzing the effects of PFO closure in patients with cryptogenic stroke and thrombophilia, in whom the presence of clotting abnormalities increases the risk of paradoxical embolism.
Does our patient require any specific pharmacotherapy due to the presence of 1297 C-C (homozygote) polymorphism of MTHFR gene? Fasting serum concentration of Hcy in our patient was at the upper limit of normal values. It should be remembered, however, that in the case of MTHFR polymorphism significant increase in Hcy concentration can be observed solely upon provocation with methionine. Noticeably, previous observational studies documented an increased risk of recurrent stroke with regards to Hcy concentrations below 15 mol/l [5]. Consequently, the concentration of Hcy observed in our patient can be already associated with an elevated risk of vascular complications.
Although the results of intervention studies suggest that supplementation with folic acid, vitamin B6, and vitamin B12 reduces blood concentration of Hcy, the effect of this reduction on the risk of cardiovascular episodes is still not fully understood. Numerous studies have confirmed a lack of significant effects of supplementation with folic acid, vitamin B6, and vitamin B12 on the risk of myocardial infarct and stroke [43, 44]. The lack of expected favorable results of interventional studies could result from the lack of adjustment to baseline concentrations of Hcy, folic acid, vitamin B12, and vitamin B6 on randomization. On the other hand, the results of HOPE 2 trial should be kept in mind; this study showed a 25% decrease in the risk of stroke (p = 0.03) in a group of high cardiovascular risk patients resulting from supplementation with folic acid (2.5 mg/d), vitamin B12 (1 mg/d), and vitamin B6 (50 mg/d) [45].
Also, the presence of classical risk factors of atherosclerosis: obesity (BMI 33 kg/m2), hyperlipidemia, and elevated arterial blood pressure should be considered in the case of our patient. Although atherosclerotic lesions were not observed due to his young age, the accumulation of numerous risk factors increases the probability of developing cardiovascular disorders in the future. This is well documented by the SCORE index, which quantifies the risk of cardiovascular mortality within a 10-year period. Currently, this patient’s SCORE index is 1%; however, it can reach as high as 6% (corresponding to high risk) by age 60 if the exposure to abovementioned risk factors remains unchanged. Consequently, lifestyle modification and long-term treatment with statins are required in the case of our patient.