Abstract
Background Ischemic stroke is one of the most common causes of death and disability. The most common independent cause is cervical artery dissection, which represents around 20% of all cases of ischemic stroke in young adults. Risk factors for dissection include male gender, migraine (particularly with aura), hyperhomocysteinemia, recent infection, recent history of minor cervical trauma, young age, current smoking status, increased leucocyte count, and shortened activated partial thromboplastin time, whereas hypercholesterolemia and being overweight appear protective.
Patients and Methods This retrospective study was based on data of all patients aged 18 to 49 who were hospitalized in the University Medical Centre Maribor for ischemic stroke between 2010 and 2019 inclusive. The results of the research were analyzed by IBM SPSS Statistics 28 software. For statistical significance, a cut-off value of p < 0.05 was used.
Results The study includes 196 patients with 198 events of ischemic stroke. Dissection of cervical arteries was presented in 16 (8.2%) cases. The presence of arterial hypertension proved to have a relation with the presence of a dissection; patients with dissection are less likely to suffer from arterial hypertension. Duration of hospitalization in the group with dissection lasted significantly longer than in the group without dissection.
Conclusions Dissection of cervical or intracranial artery is an important cause of ischemic stroke, especially in young adults. Therefore, it should be considered in young adults with presentation of stroke who lack traditional and modifiable risk factors.
Keywords: ischemic stroke, dissection, stroke, cervical artery dissection, young adults, risk factors
Ischemic stroke (IS) represents 71% of all strokes. It is one of the most common causes of death and disability. 1 IS in young adults is usually defined as an IS which occurs in adults aged between 18 and 50 years or 18 and 55 years. Its incidence is 7 to 8/100,000 in Europe and 100/100,000 in Sub-Saharan Africa. IS in young adults represents 10 to 18% of all IS. 2 3 4
Even though there are many causes of IS in young adults, the cause cannot be determined in around 40% of cases. 5 6 The most common independent cause is cervical artery dissection (CAD), which represents around 20% of all cases of IS in young adults. 5 7 In some but not all observational studies, it has been associated with a high risk of recurrent stroke. 8 Generally, IS and transient ischemic attack (TIA) occur in 67 to 77% of CAD patients. 9
A classification of CAD depends on the type of involved artery (vertebral or carotid), location (extracranial or intracranial), and pathophysiology (spontaneous or traumatic). 9 The most common type is extracranial internal carotid dissection, which typically occurs 2 to 3 cm above the bifurcation. In population-based studies the mean age of occurrence is approximately 45 years and there appears to be a slight gender predisposition favoring males. 10 11 Furthermore, there seems to be seasonal variation, with dissection more likely to occur in winter. 11 Risk factors for CAD include migraine (particularly with aura), hyperhomocysteinemia, recent infection, and recent history of minor cervical trauma, whereas hypercholesterolemia and being overweight appear protective. 7 11 12 13 Other risk factors for CAD include young age, current smoking status, increased leucocyte count, and shortened activated partial thromboplastin time. Some results show that hypertension and diabetes mellitus are also protective factors. 9 12 Other list hypertension as a risk factor for CAD. 14 There are some contradictory studies about certain genetic connective tissue conditions, such as Ehlers-Danlos syndrome, Marfan syndrome, osteogenesis imperfecta, and fibromuscular dysplasia, being connected to CAD. 7 10 11 13
The most likely mechanism of stroke is artery-to-artery embolism of a thrombus or fragments of a thrombus that form in the false lumen. Other possible mechanisms include hypo-perfusion causing watershed infarctions if there is severe vessel narrowing, occlusion of the dissected vessel, or, less commonly, the intimal flap occluding the ostium of a branch of the dissected vessel. 9 11
A triad of CAD symptoms includes ipsilateral pain of the head, neck, and face, Horner's syndrome and ischemic symptoms (cerebral or retinal), although the manifestation of all the symptoms listed above is rare and may be observed only in less than one-third of patients. Carotid artery dissection is associated with a higher frequency of Horner's syndrome, cranial nerve damage (XII, XI, X), tinnitus, ataxia, nausea, and visual symptoms. Symptoms of vertebral artery dissection include posterior neck pain or occipital headache followed by posterior circulation ischemia (vertigo, ipsilateral facial dysesthesia). CAD is asymptomatic in around 5% of all cases. 9
Generally, patients developing IS as a result of CAD have greater rates of functional independence 3 months after the event compared with the other stroke causes. Severe disability at hospital admission is the most clinically relevant predictor of death. 9
Patients and Methods
This retrospective study was based on data of all patients who were hospitalized in the University Medical Centre Maribor for IS between 2010 and 2019 inclusive. These patients were aged between 18 and 49 inclusive at the time of the event. If a single person suffered more than one event of stroke in that time, the second event had been taken and labeled as a relapse. Individuals who did not fit the time or age interval were excluded. Patients who suffered other types of stroke, e.g., hemorrhagic stroke or venous sinus thrombosis, were also excluded.
The data were obtained from the database of hospital's patients—MEDIS and, besides dissection, it contained gender, age, location of the lesion according to circulation, year of hospitalization, number of days of hospitalization, relapse, National Institutes of Health Stroke Scale (NIHSS) score at admission, NIHSS score at discharge, difference between the scores, modified Rankin Scale (mRS) score (at discharge), and risk factors for IS, such as family history, obesity, experience of TIA, arterial hypertension, diabetes mellitus and HbA1c, dyslipidemia, migraine, malignant disease, infection, alcohol abuse, smoking cigarettes, illicit drug use, pregnancy, hormonal therapy, immunosuppressive therapy, immunoglobulin therapy, Down syndrome, Marfan syndrome, morphological changes of heart, heart congestion, arrhythmias, increased value of homocysteine, decreased values of vitamin D, B12, folates, protein C and protein S, factor V Leiden mutation, prothrombin gene mutation, presence of antibodies (anti-b2GPI-IgM, anti-cardiolipin-IgM, cryoglobulin, myeloperoxidase, antineutrophil cytoplasmic antibodies, antinuclear antibodies, anti-dsDNA, lupus anticoagulant), and primary angiitis of the central nervous system.
Events that occurred in patients with clinically proven ischemic or hemorrhagic stroke in the past were marked as relapses. Lesions in carotid artery, anterior or medial cerebral artery or their branches were grouped into “anterior circulation.” Lesions in posterior cerebral artery, basilar or vertebral artery or their branches were grouped into “posterior circulation.” Those with an IS or TIA in parents or siblings were considered to have positive family history. The days in the University Medical Centre Maribor were regarded as the number of days of hospitalization. Obesity was defined by BMI ≥30. The group of people with diabetes was divided into patients with type 1 diabetes and patients with type 2 diabetes. Values for normal HbA1c were determined as NGSS <6.0% and IFCC < 42 mmol/L. Dyslipidemia was considered for values of total cholesterol >5.7 mmol/L, high-density lipoprotein <0.9 mmol/L, low-density lipoprotein >4.9 mmol/L, or triglyceride> 1.7 mmol/L. Malignant diseases of any type in the period of 5 years before stroke were considered as malignant diseases. In the group of infectious diseases, the events with clinically or laboratory proven infection during hospitalization or a week before the event were counted. Alcohol abuse was divided into groups of harmful drinking and occasional drinking. Smoking was considered as regular smoking of cigarettes at the time of the event or in the past. Peroral contraceptives, therapy with sex hormones, and erythropoietin therapy were considered as hormonal therapy. Heart or ascending aorta aneurism, patent foramen ovale, myxoma, changes of heart valves, heart hypertrophy, and heart dilatation were all considered as morphological changes of heart. Heart rhythm disorders were divided into two groups—atrial fibrillation and other rhythm disorders. For increased homocysteine the values above 15 μmol/L were considered, for decreased vitamin D the values below 47.7 nmol/L, for decreased vitamin B12 the values below 132 pmol/L, for decreased folates the values below 6.1 nmol/L, and for decreased protein C and protein S the values below 70 IU/dL were considered. The disease outcome was determined by NIHSS and mRS scales.
The results of the research were analyzed by IBM SPSS Statistics 28 software. For statistical significance, a cut-off value of p < 0.05 was used.
Results
The study includes 196 patients with 198 events of IS. Dissection of cervical arteries was presented in 16 (8.2%) cases.
Considering distribution through time, there was one case of IS caused by dissection in 2012, 2014, and 2019, two cases per year in 2010, 2013, and 2017, three cases in 2015, and four cases in 2016. Time distribution is shown in Fig. 1 .
Fig. 1.
Time distribution of ischemic stroke cases.
None of the patients with dissection of cervical arteries were obese, had a relapse of IS, had diabetes or malignant disease, used illicit drugs, were pregnant, took immunosuppressive or immunoglobulin therapy, had Down or Marfan syndrome, had patent foramen ovale, had atrial fibrillation, increased homocysteine or decreased vitamin D, vitamin B12, folates, protein C, protein S, had factor V Leiden mutation or prothrombin mutation. None of those patients died in the hospital.
Out of 16 cases of cervical or cerebral artery dissections, 13 (81.3%) were present in anterior circulation and three (18.8%) in posterior circulation. There were 10 (62.5%) male and six (37.5%) female patients. One of them (6.3%) had a history of TIA. Family history was present in two patients; one of them (6.3%) had a positive family history for stroke before the age of 50 and the other (6.3%) had a positive family history for stroke in the year of 50 or later; 14 (87.5%) had a negative family history. Hypertension was present in three (18.8%) patients with dissection. There were seven (43.8%) patients with dyslipidemia and two (12.5%) patients with migraine. There were four (25.0%) patients with recent infection. Among those with dissection there were eight (50.0%) occasional alcohol users and none harmful drinkers. There were four(25.0%) cigarette smokers. One (6.3%) patient was taking hormonal therapy. There were three (18.8%) patients with morphological changes of heart, including one (6.3%) aneurism of heart or ascending part of aorta, one patient with heart valve changes (6.3%), two (12.5%) cases of heart hypertrophy, and one (6.3%) heart dilatation. Protein S was lowered in one (6.3%) patient. Non-infectious inflammatory factors were present in two (12.5%) patients. Frequencies of risk factors are shown in Fig. 2 .
Fig. 2.
Frequencies of risk factors for ischemic stroke.
Relations between the variables mentioned above were statistically analyzed. Only the presence of arterial hypertension proved to have a relation with the presence of a dissection; patients with dissection are less likely to suffer from arterial hypertension χ 21 = 6.371, p = 0.012.
Mean (SD) age of patients that suffered from a dissection was 39.25 (7.497) years compared with 41.74 (7.251) in the group with IS without dissection. Median (interquartile range [IQR]) NIHSS value at admission in the group with dissection was 8.00 (10.50) compared with 5.00 (5.00) in the group without dissection. Median (IQR) NIHSS value at discharge in the group with dissection was 4.00 (4.75) compared with 2.00 (2.00) in the group without dissection. Median (IQR) difference between NIHSS scores at discharge and at admission was −3.50 (7.25) in the group with dissection compared with −2.00 (4.00) in the group without dissection. Median (IQR) mRS score (at discharge) was 2.00 (2.00) in the group with dissection compared with 1.00 (1.00) in the group without dissection. Median (IQR) duration of hospitalization was 26.00 (16.75) days in the group with dissection compared with 16.00 (14.00) days in the group without dissection.
Statistically significant difference between the two groups was duration of hospitalization. In the group with dissection, it lasted significantly longer than in the group without dissection ( U = 816, p = 0.004).
Discussion
Among all cases of IS dealt with in this study the dissection of cervical extra- or intracranial artery was present in 8.2% cases, which is a little less than most findings of other worldwide studies. Many of them observe that dissection contributes to around 10 to 25% of IS in young adults. 7 A study from Colombia reported CAD as one of the main causes of IS in young adults as 23.6% of IS patients were diagnosed with CAD. 15 There were 23.7% cases of CAD among patients with IS in an American study and 15% in Helsinki study. 12 16 Another study states that CAD as a main cause for IS represents 2.5% of causes for stroke in whole population, as in younger population aged up to 45 years it represents 5 to 22% of causes for IS. 10 Another study from the United States stated that dissection was the most common cause of the other determined cause category in young adults, accounting for 13% of ischemic infarction in patients aged 18 to 45 years and up to 20% in patients under the age of 25. 17
The majority of patients that encountered IS because of a dissection (62.5%) were male. The gender predisposition is also visible in other studies, where there were 53 to 57% men. 7 18 A study in Colombia reported that 29.8% of all male patients and 17.3% of all female patients with IS had CAD. 15 Some studies that did not focus solely on IS in young adults report even higher percentages of male predominance in incidence of dissections in patients with IS with 69.9% of patients being male. 8 On the other hand, some reports from the North American population suggest that more women (50–52%) encounter CAD as a cause of IS. 18
The mean (SD) age of patients with CAD was 39.25 (7.497) years, whereas in other studies it was higher at approximately 44 or 45 years. 7 11 Some studies presented even lower age of patients with mean (SD) age being 34.9 years (6.7), but these included patients aged 15 to 45 years and not up to 49 years as was the case in our study. 12 Age seems to play an important role in CAD caused IS as some studies report a significant percentage difference in CAD presence in group of IS patients under 50 years of age compared with older group with 18 versus 0.6%. 19
Some reports stated that patients with IS caused by CAD have less relatives that suffered from IS compared with other causes, 9 however, our study showed no significant difference between family history in patients with or without dissection as it was positive in 16 (8.9%) patients without CAD and two (12.6%) patients with CAD.
Many risk factors for CAD remain unclear. Our study showed that patients with CAD were less likely to have AH, which is concordant with results of some analyses. 12 The percentage of AH in patients with CAD was 18.8% compared with 26.6% in those studies. 12 On the other hand, many studies report that AH may be a risk factor for CAD. 14
Some studies also implied that patients with CAD were more likely to be younger and were less likely to have diabetes, or history of stroke. 12 The latter did not show any statistically significant differences between the two groups in our study.
Some studies implied that migraine could possibly be related with CAD and subsequently IS, 12 20 but our study showed no significant difference in history of migraine between groups with and without CAD.
Percentages of some risk factors were 0% for diabetes compared with 6.3% in other studies, 12 43.8% for dyslipidemia compared with 10.1% in other analyses, 12 12.5% for migraine history compared with 26.6% in other studies, 12 0% for congestive heart failure compared with 1.3% in other literature, 12 0% for obesity compared with 29.1% in other studies, and 0% for malignant disease compared with 2.3% in other analyses. 12
Main significant difference between the two groups shown in our study was the duration of hospitalization. Mean duration was 26.00 (16.75) days in the group with dissection compared with 16.00 (14.00) days in the group without dissection. That could be due to an additional diagnosis or treatment procedures as there was no significant difference in disability (NIHSS at admission, NIHSS at discharge, mRS).
Our study showed no significant difference between NIHSS at admission in groups with and without NIHSS. Median (IQR) value for NIHSS at admission was 8.00 (10.50). Other studies reported slightly lower mean (SD) NIHSS values with 5.5 (6.9) at admission. 12
The results of our study showed no statistically significant difference between outcomes of NIHSS and mRS at discharge. According to some studies, patients developing IS as a result of CAD have greater rates of functional independence at 3 months compared with the other stroke causes. 9 Clinical outcomes of CAD were comparable to strokes due to other etiologies, according to other studies. 12
Mortality level for IS patients with CAD appears to be low, as studies report it to be between 2 and 5%. 9 Mortality rate among patients with CAD in our study was even lower, as it was 0%.
Limitations
There were some limitations to our study; sampling was performed by convenience, which resulted in the impossibility to make general statements with statistical rigor on the population. The sample was also very small which resulted in limited statistical analyses—some expected values were low; this may had led to the p-value not being accurate. The study was also retrospective—the authors could not collect the data directly from the patients but had to interpret findings from medical database. Some data could be incorrect as it is subjective and not possible to confirm, e.g., medical history of smoking, alcohol abuse, and use of illicit drugs.
Conclusion
Dissection of cervical or intracranial artery is an important cause of IS, especially in young adults. Therefore, it should be considered in young adults with presentation of IS who lack traditional and modifiable risk factors. We observed arterial hypertension to be inversely related to IS caused by dissection, and time of hospitalization in patients with a dissection to be longer than in those who did not have it. More studies about risk factors connected to CAD should be conducted.
Conflict of Interest None declared.
Compliance with Ethical Standards
The ethics committee from University Medical Centre in Maribor, Slovenia approved the study (UKC-MB-KME-45/21).
Authors' Contributions
All authors contributed to the study conception and data collection. Analyses were performed by L.J. and R.A. The first draft of the manuscript was written by L.J. and R.A. All authors read and approved the final manuscript.
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