|Year : 2019 | Volume
| Issue : 3 | Page : 76-80
Etiopathogenic Factors of Cerebrovascular Disease in Young Adults: A Review of the Literature
Ezequiel Garcia-Ballestas1, Juan Camilo Medrano Carreazo1, Huber Said Padilla-Zambrano1, Amit Agrawal2, Jose Daniel Charry3, Luis Rafael Moscote-Salazar1
1 Center for Biomedical Research, Cartagena Neurotrauma Research Group Research Line, University of Cartagena, Cartagena, Colombia
2 Department of Neurosurgery, Narayana Medical College Hospital, Nellore, Andhra Pradesh, India
3 Research Department, Navarra University, Neiva, Huila, Colombia
|Date of Submission||07-Sep-2018|
|Date of Acceptance||28-Aug-2019|
|Date of Web Publication||28-Oct-2020|
Dr. Luis Rafael Moscote-Salazar
Center for Biomedical Research, Cartagena Neurotrauma Research Group Research University of Cartagena, Cartagena
Cerebrovascular disease (CVD) has been studied for many years, representing a cause of high morbidity and mortality; it has a great impact at a social, economic, and psychological level in the young adult population. There are different etiological factors that we do not find in the adult population, for that it is important to know how to differentiate them. There is no definitive etiological factor in this population given that the epidemiologic profile fluctuates considerably throughout regions and provinces, even if the same country is considered to make comparisons. CVD in young adults is caused by many etiological factors, predominantly the rare ones, such as cardioembolic, small vessel disease, due to thrombophilias, and undetermined cause. Despite being the main cause, the undetermined etiology is overestimated because it deserves for a detailed investigation in search of one of the rare causes, also, because of the lack of more complex studies in centers worldwide. No atherosclerotic large vessels diseases, such as cervicocephalic artery dissection, moyamoya disease, systemic vasculitis, and other rare syndromes should be considered to make an accurate diagnosis approach.
Keywords: Cerebrovascular disease, embolism, risk factors, stroke, stroke in young
|How to cite this article:|
Garcia-Ballestas E, Carreazo JC, Padilla-Zambrano HS, Agrawal A, Charry JD, Moscote-Salazar LR. Etiopathogenic Factors of Cerebrovascular Disease in Young Adults: A Review of the Literature. J Transl Crit Care Med 2019;1:76-80
|How to cite this URL:|
Garcia-Ballestas E, Carreazo JC, Padilla-Zambrano HS, Agrawal A, Charry JD, Moscote-Salazar LR. Etiopathogenic Factors of Cerebrovascular Disease in Young Adults: A Review of the Literature. J Transl Crit Care Med [serial online] 2019 [cited 2021 Dec 2];1:76-80. Available from: http://www.tccmjournal.com/text.asp?2019/1/3/76/299474
| Introduction|| |
Cerebrovascular disease (CVD) occupies the second to third place of the entities with higher mortality, is considered as the main cause of disability in the world and affects approximately 15 million patients each year worldwide, causing the death of one-third of the affected people. Approximately 80% of CVD are of the ischemic type. In young adults, this entity is rare,, and constitutes <10% of all patients with CVD., The risk and treatment factors for CVD in young adults vary according to geographic location because they are influenced by genetic, environmental, and accessibility factors in the health sector and the proportion of CVD varies from country to country between 5% and 20% regarding the types of CVD. The consequences of this disease are dramatic especially in young adults, and impacts in the family, psychosocial, and socioeconomic aspects, given that the production and economic rates have the highest peaks at these years of life, and for this reason, timely diagnosis and prevention in this group has a great importance. This article describes the etiological aspects of CVD and introduces some pathophysiological concepts regarding exclusively to the young adult population.
| Cerebrovascular Disease of Ischemic Type in Young Adults|| |
CVD is defined as a group of neurological alterations attributed to an acute and focal or global injury of the central nervous system attributed to a vascular abnormality. There are two types of CVD – ischemic type and hemorrhagic type. Ischemic CVD is an episode of neurological dysfunction caused by massive death of nerve cells based on pathological or clinical criteria, it is the first cause of disability worldwide; the second cause of death in countries of medium and high income; and the third cause in low-income countries. This entity marked variation according to geography, sex, race, and age.,, In Colombia, it occupies the seventh place in mortality and second place in frequency among CVDs. In the young adult, the ischemic CVD has a better prognosis, preserving a low percentage of recurrence and disability. In general, the incidence is proportional to age, so that in young adults, it is <10%; however, after the individual overpasses 35 years old, there has been strongly characterized a substantial increase in the incidence of ischemic CVD compared to all the young adult population. To note that, young people are considered to be the population between 15 and 45 years old, a few studies extend to 50 years, even up to 55 years.
Popular medical care is not enough exhaustive and interested in relation to ischemic CVD in young adults, probably due to its low prevalence in the population. However, its diagnosis is considered a challenge for professionals.,,, According to the Trial of ORG 10172 classification in acute stroke treatment, the ischemic extracellular volume is divided into atherosclerosis of large vessels, small vessel disease, cardioembolic, other determined causes, and cryptogenic. This has been widely accepted because it contributes to an early diagnosis. However, categorizing this subtype of cerebrovascular accident is hindered by the frequency of etiological factors in young adults according to geographic location. In countries such as Australia, Switzerland, and Norway, cardioembolic mechanisms were reported as the most frequent cause; in France. Nonatherosclerotic angiopathies, such as cephalic artery dissection, were reported in a greater proportion; in Spain, Brazil, Peru, and Finland those of undetermined cause, and in this way, the eventual publication of population studies reveals that there is no absolute etiological factor in young adults, because there are considerable discrepancies between regions. Moreover, there are also variations in the same country as the study carried out in Messina, located in Southern Italy, where hematological and autoimmune causes predominated, and in Turin, located in northern Italy, cardioembolic mechanisms predominated. Hence, we can conclude there is an heterogeneous distribution throughout locations.
Despite the large epidemiological difference, cardioembolic causes and cephalic artery dissection (nonatherosclerotic angiopathy) are usually alternated between the first and second place in order of frequency. It is necessary to clarify that in a large number of the studies cited above, the undetermined causes that occupy a large percentage are explained, in part, by the different ways of approaching the patient and establishing diagnoses to characterize an etiological agent in different institutions around the world, in fact, as the complexity of the institution increases, the diagnosis of CVD of undetermined causes decreases, due to different diagnostic approach of these institutions. For example, transesophageal echocardiography has shown a cardioembolic etiology in a patient whose diagnosis was of undetermined etiology. Then, the lack of transesophageal echocardiography in certain institutions may be guilty of having a different etiological distribution. There are other causes that although not frequent, require attention because in young adults, it is not usual to find the classic risk factors of CVD, and there could even be the absence of these., Within these etiologies, we find infections, genetics, coagulopathies, autoimmune, among others. The atherothrombotic cause is more frequent in the context of older adults, due to the determining role of age as a risk factor, so it will not be relevant in the present article, although industrialization and Western lifestyles, factors of risk for the disease in the young population, it will be becoming a topic of discussion of future research.
| Cardioembolic Etiology|| |
Cardioembolism is one of the main mechanisms of ischemic CVD in young adults. Its frequency varies widely across the studies,,,,,, however, the reported incidence varies between 20% and 30% in literature. Cardioembolic etiology is a diagnostic challenge, due to underlying congenital heart disease and atrial fibrillation, heart failure, coronary disease related to myocardial dysfunction, among others; which are very rare cardioembolic sources in the young adult population.
When CVD has previously been categorized as cryptogenic, there are reports that in subsequent studies, in which patients actually had a persistent foramen ovale (PFO), changing the management vision substantially. The postulates indicate that one-third of patients with cryptogenic CVD have this condition, so that the number of cases in this situation and the probability of presenting, amounts to figures that may be unforeseen for any clinician. In the general population, there is an estimated prevalence of PFO of 25%., Although CVDs attributed to PFO are much more frequent in adulthood, the proportion of these with respect to the total causes in young adults is undoubtedly higher, since the percentage of CVD in young adults is essentially lower than in adults. Regarding the cases of more advanced ages.
The mechanism of paroxysmal venous embolism is accepted to explain the pathophysiology of CVD in young adults, but not in older patients. This consists in the formation of a blood clot in the right heart that crosses to the left side through the foramen (right-left shunt) as a plunger., However, to be certain of this mechanism, it is necessary to have some of the conditioning factors, such as atrial anatomical variation (referring to the size of the foramen), the presence of an atrial septal aneurysm, or the anatomy of the Eustachian valve More Details; certain hemodynamic conditions, such as those caused by valvular disease or prosthesis of some kind; presence of the thrombus by high sensitivity studies, such as transesophageal echocardiography; and finally, genetic variables tending to hypercoagulability.
Other cardioembolic mechanisms in young adults are those generated by infectious agents capable of altering the cardiac function and conceiving embolism, as has been reported in Chagas disease caused by Trypanosoma cruzi, an endemic disease in South America. This disease is capable of producing cardiomyopathies, arrhythmias, and mural thrombi; potentially amblyogenic conditions, which are predisposing to development in the female sex. It was considered until a few years ago that chronic infection by Helicobacterpylori and Chlamydia pneumoniae had involvement in cardioembolic mechanisms of CVD, but the decreased risk reported in a population study refuted their cardioembolic relationship, and instead, supports the idea of the existence of an association between CVD and the chronic infection of these pathogens, but by mechanisms related to lipohyalinosis and production of lacunar infarcts, thus categorizing it within the subtype of CVD caused by small vessel disease.
| Large Vessel Disease|| |
Large vessel disease is reserved for processes in large vessels related, most commonly in the general population to atherosclerosis. These processes are frequent in older adults and very rare in young adults, for whom a heterogeneous range of etiologies is reserved, such as cervicocephalic artery dissection, inflammatory arterial disease, among others; therefore, in this section, reference will be made to all those nonatherosclerotic large vessel angiopathies.
Cervicocephalic artery dissection
It is defined as the separation of the layers of arterial walls creating a false lumen that allows blood to flow and expand, forming thrombi in it. It is the most common cause of ischemic CVD in young adults within the large vessel disease group., They generally share a traumatic history or may be related to a genetic defect of the connective tissue such as the Ehlers-Danlos syndrome More Details, Marfan syndrome, medial cystic necrosis; or less rarely, fibromuscular dysplasia. There are some triggers that could be taken into account to consider their etiological diagnosis in the face of an ischemic CVD in young adults, such as systemic disorders such as lupus, hypertension, or chronic infections such as syphilis or recent acute upper respiratory tract. The internal carotid artery is the site where dissections occur most frequently and about 90%–95% are unilateral, although if the triggering factor has been fibromuscular dysplasia, bilaterality reaches two-thirds. To confirm the etiological diagnosis, the presence of Horner's syndrome can be highly suggestive, since the lower cranial nerves IX–XII are the most affected. For the imaging study, a resonance, a tomography or an angiography have proved useful to confirm the diagnosis.
It is a cerebrovascular disorder caused by progressive stenosis of the supraclinoid internal carotid arteries and their proximal branches and the development of vessels near the site of the stenosis (moyamoya vessels). In this pathological entity, the perforating arteries in the basal ganglia and thalamus (lenticulostriate) undergo dilatation whose purpose is to achieve collateral circulation despite stenosis. It is a very rare cause of CVD, but mainly in the Asian population.,, It has been associated with defects in the ring finger protein 213 gene responsible for the angiogenesis and proliferation of endothelial colony-forming cells and endothelial vascular growth factors, of basic fibroblasts, β-1 transformant and of hepatocytes that result in stenosis and vascular disorders mentioned above.
There are two types of systemic vasculitis, infectious, and noninfectious, whose etiology is severely heterogeneous. Infectious is the product of edema produced by infections of the nervous system that cause ischemia. Occasionally, they are due to chronic meningitis, such as tuberculosis, fungi, syphilis, as well as arterial inflammation and thrombosis caused by viral infections in the case of herpes zoster, hepatitis C virus, and other pathogens such as CCCCCCCCCC mycoplasma, cytomegalovirus, borrelia, among others. Noninfectious vasculitis is mainly caused by systemic lupus erythematosus and includes a variety of possible causes of ischemic CVD and not only those of large vessels. There is also an isolated vasculitis, which affects only the blood vessels that supply the brain, whose diagnosis is confirmed by diffuse patterns of stenosis together with headache and other signs related to ischemic CVD.,
| Other Syndromes|| |
There are syndromes that tend to produce recurrent CVD and that occur mainly in the young adult population, such as Fabry syndrome, Susac syndrome, Sneddon syndrome More Details, autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), mitochondrial encephalopathy with myopathy, lactic acidosis and stroke-like episodes and endotheliopathy, retinopathy, nephropathy and hereditary stroke., Takayasu syndrome is a cause of ischemic CVD, mainly in women., All of these are prevalent with respect to CVD and deserve consideration in case of not finding a definitive etiologic factor in young adults, however, should be an exclusion diagnosis.
| Small Vessel Disease|| |
It includes all those angiopathies related to vessels of a smaller caliber that produce ischemic lesions <15 mm, known as lacunae, for which reason they are designated as lacunar infarcts. These are located in the vascular territory of a penetrating cerebral arteriole and produce any of the lacunar syndromes., It is not as frequent in young adults as the other etiological subtypes, since its classic risk factors are hypertension and diabetes mellitus, being much more frequent from 55 years onward; however, its appearance in young adults is strongly influenced by modifiable risk factors, such that with cardiovascular risk, the risk of ischemic CVD of the lacunar subtype can be estimated subjectively. As mentioned, there are chronic infections associated with the appearance of lacunar injuries, such as neurolues, neurocysticercosis, neuroborreliosis, HIV, H. pylori, and C. pneumonia., There has been an association between hospital infections and the formation of lacunar injuries so that the proinflammatory environment against infection contributes to the onset of lacunar infarction. With which it can be concluded that the aggressive management of an infection can contribute to improve a lacunar CVD status. Fabry disease, CADASIL, and some types of vasculitis also cause lacunar infarcts.
| Hematological Conditions|| |
Thrombophilias are all inherited coagulopathies which have an association to the development of CVD, although it is an extremely rare cause of this (0%–4% of CVD in the general population), they have a greater proportion in young adults. Among the major hematological disorders, the antiphospholipid syndrome is most commonly associated with prothrombotic coagulopathies., The search for sickle-cell anemia, erythrocytosis, leukemia, lymphomas, and purpura is very careful to have a complete vision and accurately accurate diagnoses.
| Cryptogenic or Undetermined Causes|| |
The majority of authors state that from one-third to half of the ischemic CVDs in young adults are of undetermined cause, relegating the cardioembolic causes and dissection of cervicocephalic artery to the background; however, the underestimation of these subtypes may be due to lack of availability of studies in different centers of study as aforementioned, since for cardioembolic causes, it is necessary to rule out by means of tests that usually exceed the capacity of endowment., In the face of a cryptogenic CVD, the most accurate attitude implies the search for the most remote causes in young adults, because the diagnosis of the cryptogenic subtype is merely exclusionary, as mentioned above, thrombophilias, cardiac anatomical abnormalities such as the PFO, atherosclerosis in rare locations, tachyarrhythmia and embolism of uncertain subclinical source, occult atrial fibrillation, and some genetic study or from infectious etiology driven by a relevant family or endemic background, respectively. It is important to have clarity about the types of study for each patient, because it is well-understood that in the cryptogenic variant are necessary from advanced vascular studies (angioplasty, Doppler monitoring of embolism, and vasculitis test), cardiac (cardiac telemetry for 2–4 weeks) and hematological (arterial and venous coagulation tests); to more specialized studies justified by previous results that include those aimed at investigating genetic disorders mentioned above, autoimmunity, brain biopsy, evaluation of cerebrospinal fluid, nonobserver dependent cardiac images (tomography or resonance), prolonged heart rhythm (1–3 years), and hidden hematologic neoplasms.
| Conclusion|| |
Ischemic CVD in young adults has substantial etiological differences compared to those widely known in older adults. It is a disease with marked variations according to geography, sex, race, and age so that in certain populations a subtype is more frequent than another. The socioeconomic, personal and family impact that this entity originates is an enough justification to pay attention to it, because the age ranges where the disease hits correspond to an active working age, prompting disability and devastating outcomes, and therefore, we must go in search of improvements in diagnosis and timely treatment. The cryptogenic subtype is commonly reported as the most frequent, although the simplest explanation of this phenomenon expresses the diversity of ways in which this disease is addressed and diagnosed worldwide, still having a strong socioeconomic influence. The cardioembolic etiological subtypes and the cephalic artery dissection interspersed the first and second place in different studies. The cardioembolic etiology is often diagnosed as cryptogenic because of the difficulty in examining a PFO. Atherosclerosis is not a frequent subtype in young adults. A thorough literary review of the etiology of ischemic CVD is necessary since among its causes, the existence of considerable differences in management and prognosis has been demonstrated.
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| References|| |
Smajlović D. Strokes in young adults: Epidemiology and prevention. Vasc Health Risk Manag 2015;11:157-64.
Maaijwee NA, Rutten-Jacobs LC, Schaapsmeerders P, van Dijk EJ, de Leeuw FE. Ischaemic stroke in young adults: Risk factors and long-term consequences. Nat Rev Neurol 2014;10:315-25.
Goeggel Simonetti B, Mono ML, Huynh-Do U, Michel P, Odier C, Sztajzel R, et al.
Risk factors, aetiology and outcome of ischaemic stroke in young adults: The swiss young stroke study (SYSS). J Neurol 2015;262:2025-32.
Yamamoto FI. Ischemic stroke in young adults: An overview of etiological aspects. Arq Neuropsiquiatr 2012;70:462-6.
Stroke-1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO task force on stroke and other cerebrovascular disorders. Stroke 1989;20:1407-31.
Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al.
An updated definition of stroke for the 21st
century: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:2064-89.
Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al.
Global and regional burden of stroke during 1990-2010: Findings from the global burden of disease study 2010. Lancet 2014;383:245-54.
Rodríguez-García J, Peñaloza-Quintero RE, Amaya-Lara JL, Amaya-Lara JL. Estimation of the global burden of disease in Colombia 2012: New methodological aspects. Rev Salud Pública 2017;19:235-40.
Peñaloza-Quintero RE, Salamanca-Balen N, Rodríguez-Hernández JM, Rodríguez-García J, Beltrán-Villegas AR. Estimación de la Carga de la Enfermedad para Colombia, 2010. Bogota: Pontificia Universidad Javeriana; 2014.
Jovićević M, Divjak I, Slankamenac P, Jovanović A, Ruzicka S, Dickov A, et al.
Non-atherosclerotic arteriopathy as the cause of ischemic stroke among young adults. Med Pregl 2010;63:324-32.
Rodríguez-García J, Peñaloza-Quintero RE, Amaya-Lara JL. Estimation of the global burden of disease in Colombia-2012: New methodological aspects. Rev Salud Publica (Bogota) 2017;19:235-40.
González-Gómez FJ, Pérez-Torre P, DeFelipe A, Vera R, Matute C, Cruz-Culebras A, et al
. Ictus en adultos jóvenes: Incidencia, factores de riesgo, tratamiento y pronóstico. Rev Clín Esp 2016;216:345-51.
Arboix A, Massons J, García-Eroles L, Oliveres M. Ictus en adultos jóvenes: Rasgos clínicos y frecuencia de presentación en 280 pacientes según el subtipo etiológico. Med Clin (Barc) 2016;146:207-11.
Adams HP Jr., Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, et al.
Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of org 10172 in acute stroke treatment. Stroke 1993;24:35-41.
Radu RA, Terecoasă EO, Băjenaru OA, Tiu C. Etiologic classification of ischemic stroke: Where do we stand? Clin Neurol Neurosurg 2017;159:93-106.
Phillips MC, Leyden JM, Chong WK, Kleinig T, Czapran P, Lee A, et al.
Ischaemic stroke among young people aged 15 to 50 years in Adelaide, South Australia. Med J Aust 2011;195:610-4.
Nacu A, Fromm A, Sand KM, Waje-Andreassen U, Thomassen L, Naess H, et al.
Age dependency of ischaemic stroke subtypes and vascular risk factors in Western Norway: The bergen norwegian stroke cooperation study. Acta Neurol Scand 2016;133:202-7.
Leys D, Bandu L, Hénon H, Lucas C, Mounier-Vehier F, Rondepierre P, et al.
Clinical outcome in 287 consecutive young adults (15 to 45 years) with ischemic stroke. Neurology 2002;59:26-33.
Varona JF, Bermejo F, Guerra JM, Molina JA. Long-term prognosis of ischemic stroke in young adults. Study of 272 cases. J Neurol 2004;251:1507-14.
Cabral NL, Freire AT, Conforto AB, Dos Santos N, Reis FI, Nagel V, et al.
Increase of stroke incidence in young adults in a middle-income country: A 10-year population-based study. Stroke 2017;48:2925-30.
Matos IE, Pinto-Casaverde L, Rosa CL, Torres-Ramírez L. Etiology of stroke in young adults from a series of patients at the Instituto Nacional de Ciencias Neurol. Rev Neuropsiquiatr 2016;79:16-22.
Putaala J, Kurkinen M, Tarvos V, Salonen O, Kaste M, Tatlisumak T, et al.
Silent brain infarcts and leukoaraiosis in young adults with first-ever ischemic stroke. Neurology 2009;72:1823-9.
Musolino R, La Spina P, Granata A, Gallitto G, Leggiadro N, Carerj S, et al.
Ischaemic stroke in young people: A prospective and long-term follow-up study. Cerebrovasc Dis 2003;15:121-8.
Cerrato P, Grasso M, Imperiale D, Priano L, Baima C, Giraudo M, et al.
Stroke in young patients: Etiopathogenesis and risk factors in different age classes. Cerebrovasc Dis 2004;18:154-9.
Ferro JM, Massaro AR, Mas JL. Aetiological diagnosis of ischaemic stroke in young adults. Lancet Neurol 2010;9:1085-96.
Bâsić Kes V, Zavoreo I, Demarin V. Etiology and diagnostic work-up in young stroke patients. Period Biol 2012;114:355-9.
Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: Incidental or pathogenic? Stroke 2009;40:2349-55.
Homma S, Sacco RL. Patent foramen ovale and stroke. Circulation 2005;112:1063-72.
Carod-Artal FJ, Gascon J. Chagas disease and stroke. Lancet Neurol 2010;9:533-42.
Heuschmann PU, Neureiter D, Gesslein M, Craiovan B, Maass M, Faller G, et al.
Association between infection with helicobacterpylori
and chlamydia pneumoniae and risk of ischemic stroke subtypes: Results from a population-based case-control study. Stroke 2001;32:2253-8.
Lau JT, Hunt JS Jr., Bruner DI, Austin AL. Cervical artery dissection and choosing appropriate therapy. Clin Pract Cases Emerg Med 2017;1:225-8.
Kim T, Oh CW, Bang JS, Kim JE, Cho WS. Moyamoya disease: Treatment and outcomes. J Stroke 2016;18:21-30.
Shang S, Zhou D, Ya J, Li S, Yang Q, Ding Y, et al.
Progress in moyamoya disease. Neurosurg Rev 2020;43:371-82.
Arboix A, Martí-Vilalta JL. Lacunar stroke. Expert Rev Neurother 2009;9:179-96.
Arboix A, Martí-Vilalta JL. New concepts in lacunar stroke etiology: The constellation of small-vessel arterial disease. Cerebrovasc Dis 2004;17 Suppl 1:58-62.
Mantero V, Scaccabarozzi C, Botto E, Giussani G, Aliprandi A, Lunghi A, et al.
Outcome in lacunar stroke: A cohort study. Acta Neurol Scand 2018;138:320-6.
Behrouz R. The risk of ischemic stroke in major rheumatic disorders. J Neuroimmunol 2014;277:1-5.
Liberman AL, Prabhakaran S. Cryptogenic stroke: How to define it? How to treat it? Curr Cardiol Rep 2013;15:423.
Saver JL. Clinical practice. Cryptogenic stroke. N
Engl J Med 2016;374:2065-74.