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| STROKE IN THE YOUNG: NEWER CONCEPTS IN ETIOPATHOGENESIS AND RISK FACTORS |
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| Year : 2018 | Volume
: 5
| Issue : 1 | Page : 26-32 |
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Stroke in the young: Newer concepts in etiopathogenesis and risk factors
Man Mohan Mehndiratta1, Prachi Mehndiratta2
1 Department of Neurology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India
2 Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA
| Date of Web Publication | 28-Jan-2019 |
Correspondence Address:
Man Mohan Mehndiratta
Department of Neurology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi - 110 002
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/astrocyte.astrocyte_48_18
Background: Stroke in young has become one of the major causes of mortality & morbidity lately. Incidence of stroke in young is on the rise. Recent studies show young stroke being one of the important differential diagnoses for any kind of acute lateralised neurological deficits in younger population. Along with various traditional risk factors, there are some emerging vascular, genetic and others unidentified risk factors implicated in the etiopathogenesis of stroke in young. Burden of the disease along with major long term socioeconomic impacts at the patients, their family & society level are enormous. Objective: Recognition of underlying vascular & genetic risk factors may improve physician's awareness & optimise the outcomes in young stroke patients. Recent advances in the imaging technologies and genetic testing may help the experts to develop effective guidelines for the prevention and treatment of young stroke patients. Conclusion: Considering the increasing burden of the disease, standardised methodology along with more research works have become an imperative need of time in order to decrease the morbidity & mortality in young stroke patients.
Keywords: Epidemiology, hemorrhagic stroke, ischemic stroke, risk factors, stroke, stroke in young
How to cite this article:
Mehndiratta MM, Mehndiratta P. Stroke in the young: Newer concepts in etiopathogenesis and risk factors. Astrocyte 2018;5:26-32 |
| Introduction | |  |
Stroke is a common cause of morbidity and mortality in the developed world and largely thought of as a disease of the elderly.[1] However, recently, epidemiologic studies have demonstrated that the entity is not uncommon among adolescents and young adults.[2],[3] Current estimates indicate that of all the stroke patients, 10%–15% strokes occur in young adults. Clearly, it deserves to be considered as a part of the differential diagnoses in patients presenting with acute neurological symptoms even in the young. Stroke in the young is the third most common cause of death worldwide and the fourth leading cause of disease burden.[4] This can be devastating both for the affected individual and the immediate family, and the social order due to production of individual disability and loss of productivity.
Even though diverse studies have used a varying cut-off for qualifying “young stroke,” the large consensus seems to favor 49 years as the upper limit of age for the segregation of young stroke.[5] Current epidemiological data suggest that stroke in the young may well be an independent entity, with diverse risk factors and etiologies.
| Incidence | | |
There is diversity in the incidence, etiology, and prognosis of stroke in young patients especially in developing countries.[6] Studies of Indian immigrants to industrialized countries show that Indians are more susceptible compared with Caucasians to coronary artery disease and stroke.[7] In a study of more than 1008 young patients (15–49 years) in Finland, stroke was more common with increasing age even in the young adult age group. A yearly incidence of stroke of 2.4 per 100,000 in the age group of 20–24 years and 32.9 per 100,000 in the age group of 45–49 years was observed in this study. The frequency of stroke was more in women 20–30 years of age and in men older than 35 years.[8] Strokes in the young have been attributed to factors such as race and ethnicity. Young blacks have significantly greater stroke incidences than young whites according to the Northern Manhattan Study.[9]
| Etiology | | |
Etiology of stroke has been described under the broad groups of ischemic, hemorrhagic, and venous categories.[10],[11] Ischemic causes include cardioembolic, vasculitis, genetic, and inherited diseases. It was observed that central venous thrombosis and rheumatic heart diseases are the leading causes of young stroke. In India, tubercular meningitis and bacterial meningitis still remain an important cause of stroke.[12]
In a retrospective study conducted on 127 young adults with stroke, stroke etiology was found to be cardioembolic in 29.3%, large artery atherosclerosis in 22%, inherited haematological conditions in 1.8% of patients, nonatherosclerotic vascular disease was found to be causative in 15.6%, and other miscellaneous causes were observed in 22% of patients. In almost 10% of the remaining cases, etiology was cryptogenic.[5] Among cardiac causes, rheumatic heart disease was identified as the most common etiology of stroke in the young.
Etiology remains undefined in almost 35% of stroke cases.[4],[5],[13] This may be explained by the insufficient extent and timing of investigation. The TOAST (Trial of ORG 10172 in acute stroke treatment) criteria for classification are the most commonly used though a newer classification system for more accurate etiology is the A-S-C-O (Atherosclerosis, Small-vessel disease, Cardiac source, Others). This is a phenotype-based classification, in which every patient is characterized by A-S-C-O. Each of the four phenotypes is graded 1, 2, or 3. This classification reduces the number of undetermined etiology.[14] Still, atherosclerosis, cardioembolic stroke, extracranial artery dissection, and migraine remain the important reasons for stroke in young.[1],[2],[3],[4],[5],[6],[7],[8],[9]
| Risk Factors | | |
Even though the modifiable risk factors are shared, there is a significant difference in the risk factors for stroke in young adults and older individuals [Table 1].
Conventional vascular risk factors
Numerous pathophysiologic factors and definite diseases have been linked to stroke in the young. Younger patients are still risked by classical vascular risk factors such as hypertension, dyslipidemia, and diabetes, and their role increases with age. Certain risk factors which may be considered minor for elderly can have a greater impact on etiology of strokes in the young. The modifiable risk factors are similar for both the groups, but the prevalence of these risk factors is not the same. The three most important risk factors described in a study in India were smoking (49%), dyslipidemia (46%), and hypertension (36%).[8],[15]
Smoking is an important risk factor for cerebral infarction in the young. Cerebral infarction is 1.6 times more common in young smokers (15–45 years old) than nonsmokers.[16],[17] Moreover, this risk increases with the duration and dose of exposure.[16],[17]
In a study describing the risk factors with demographic characteristics according to the gender and TOAST classification, transient ischemic attack and family history of stroke were important risk factors found in 26% and 15.7% of patients, respectively, besides hypertension (44.5%), dyslipidemia (26.1%), and diabetes (13.9%).[18] Hypertension, hyperglycemia, and tobacco use with low hemoglobin levels were the important risk factors in a study from north India.[19]
In Athens young stroke registry, a study conducted on 253 consecutive first-ever ischemic stroke young patients (<45 years) showed smoking (59%) and dyslipidemia (41%) as the leading vascular risk factors.[20] Another multicenter study evaluated differences in vascular risk factors in 3944 patients with first-ever ischemic stroke at age 15–49 years from 15 cities in 12 European countries from hospital registries or population-based studies on young adults.[21]
Migraine is another important risk factor for stroke in the young. A significantly higher risk of stroke was seen in migraine with aura.[22] Migraine with aura along with other risk factors such as age less than 45 years, smoking, and concurrent oral contraceptive use have compounding effect on the risk of stroke compared with people who had migraine without aura. Similar results were seen in a subgroup from the Women's Health Study after adjustment for major vascular risk factors.[23]
Increased incidence of stroke has been observed during pregnancy and puerperium with reasons undefined.[24] Different theories and studies explain that hypercoagulable state which causes changes in vessel wall function is typically observed in pregnancy. In pregnancy, it is more often seen in patients with eclampsia, a typical pregnancy-related disease, and the pathophysiology has been linked with nonhemorrhagic stroke-like episodes and cerebral vasoconstriction syndrome.[25]
Oral contraceptive use as a risk factor for stroke in young is still controversial and not clearly known. The risk for stroke increased fourfold for women who take pills with a high content of estrogen and doubled for those who take pills with low estrogen content. Whereas no increase in the risk of stroke among women using only progestogen contraceptives was seen in a meta-analysis conducted on six case–control studies.[26] In contrast, increased risk of ischemic stroke was observed in another meta-analysis with use of oral contraceptives. There appears to be a dose-dependent increase in risks and smaller estrogen dosage was associated with lower risk.[27]
Unfortunately, the most common complication of drug abuse in the young population is stroke. It accounts for almost 12% of cases of stroke in young.[28] Therefore, in young patients presenting with stroke, unless a precise diagnosis is made, screening for illicit drugs must be done. Vasoconstriction, platelet aggregation, cardiac arrhythmias, and embolism, which further lead to stroke, are seen after intravenous use of drugs such as cocaine or amphetamines.[29]
Uncommon causes of stroke in young
Specific diseases such as spontaneous arterial dissection though rare but common cause of stroke in young adults have been observed.[30] Extracranial internal carotid artery is commonly involved in cervical dissection, which starts a few centimeters after common carotid bifurcation or vertebral artery. Arterial stenosis or occlusion is often seen consequent to subintimal dissections. Rupture of these vessels results in hematoma. The predisposing factors are mostly head and neck trauma. There is a concomitance between vascular risk factors, such as hypertension, and genetic factors.[31]
Fibromuscular dysplasia (FMD) of carotid and vertebral arteries is another potential cause of stroke in young adults. FMD is a noninflammatory, nonatherosclerotic vascular disease which mainly affects the renal and carotid artery resulting in arterial stenosis, occlusion, aneurysm, and dissection.[32],[33] Most of the patients with FMD are at higher risk of stroke seen in approximately 15% of patients especially with spontaneous dissection of the carotid or vertebral artery.[34] Although a variety of genetic, hormonal, and mechanical factors have been implicated in the pathophysiology of FMD, it is still poorly understood. International registries of FMD are currently investigating the natural history, diagnosis, treatment, and potential role of genetics in FMD.
Systemic lupus erythematosus (SLE), the most common disease associated with antiphospholipid syndrome – a common immunological disorder, is associated with stroke in young.[35] Other connective tissue disorders in young include polyarteritis nodosa, cryoglobulinemia, primary vasculitis, eosinophilic granulomatosis with polyangiitis (formerly called Churg–Strauss syndrome), granulomatosis with polyangiitis (formerly known as Wegener's vasculitis), Behçet's disease, inflammatory bowel disease, and sarcoidosis. SLE manifests itself in hypertensive small-vessel disease, and recurrent stroke has been reported in SLE. It triggers the formation of blood clots, deposition of immune products, and leads to inflammatory changes in blood vessels which create a prothrombotic state and increase the chance of thromboembolism.[36],[37]
Infectious diseases are also important risk factors especially in developing countries. Late-stage syphilis can induce stroke through arteritis of the major brain vessels such as the middle cerebral artery or the deep perforating vessels (Nills–Alzheimer's arteritis), or through cardiac complications.[38] Around 0.3% cases of lyme-neuroborrelosis-associated stroke and cerebral vasculitis have been reported. Most of these patients are relatively young. Therefore, a high index of suspicion should be kept in mind in high endemic areas. Cases of stroke have also been reported in young patients affected by acute bacterial meningitis, tuberculous meningitis, varicella-zoster virus (VZV), cytomegalovirus, AIDS, cysticercosis, and Chagas disease caused by Trypanosoma cruzi.[39],[40],[41],[42],[43]
Fugate J et al. have shown association of hepatitis C virus infection with stroke.[44] Infectious endocarditis frequently leads to embolic stroke. VZV produces vasculopathy by direct invasion of cerebral arteries.[45] Nearly all central nervous system fungal infections have the tendency to occlude small blood vessels in meningitis and may also cause mycotic aneurysms. These further lead to inflammatory changes in cerebral vessels conspicuously in the distribution of small leptomeningeal vessels. Fungal infections with Exserohilum species which lead to ischemic stroke have been reported by spinal injections of contaminated methylprednisolone.[46]
Hematological diseases such as paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, erythrocytosis, leukemias, and intravascular lymphoma have been associated with risk of stroke in the young. These all increase the risk of thrombosis or hemorrhage. Among these hematological diseases, the strongest association has been observed for sickle cell disease (SCD).[47],[48] It leads to formation of thrombus in the cerebral vasculature, with intimal proliferation of the vessels, discontinuity of the internal elastic lamina, and proliferation of endothelial cells. Coagulation disorders predispose to venous strokes more than arterial strokes. Platelet function abnormality, inherited hemostatic abnormality, and vascular injury also promote thrombosis.[49]
Congenital cardiac anomalies also constitute significant percentage of stroke in young. Patent foramen ovale (PFO) is found in 15%–25% of the general population. It is a common remnant of the fetal anatomy. PFO combined with atrial septal aneurysms (ASA) has been identified as an important etiology of stroke in young.[50] ASA is an additional abnormality of the interatrial septum, which usually occurs in association with PFO. When present, it tends to occur in association with larger shunts and has been demonstrated to be associated with increased risk of recurrent stroke.[51] A study conducted in young patients with ischemic stroke and a normal cardiac examination demonstrated significantly greater prevalence of PFO in patients with stroke (40%) than in the control group (10%, P < 0.001).[52] However, this association was weaker or absent in older patients, and the real impact of PFO in stroke is still controversial. The same trend was observed in all age, gender, and race-ethnic subgroups.[53]
Atrial fibrillation (AF), though one of the major causes of cardioembolic stroke in elderly, is less associated with stroke in young. A prevalence of AF is less than 0.1% among young adults.[54] Similarly, low prevalence in young adults is seen in other abnormalities such as cardiomyopathy, valvular disease, and endocarditis.
Genetic factors for stroke in young
The etiological diagnosis of stroke in young adults needs a different and more complex diagnostic work-up than in elderly. Real impact of genetics is still unknown. Stroke is a heterogeneous multifactorial disorder. Studies have been conducted in twins, families, and animal models which provide evidence for a genetic contribution to stroke.[55] Ischemic stroke is caused by a combination of multiple genetic and environmental factors. No good preclinical biomarkers are still available for studying the molecular and physiological processes which lead to a stroke event.
Genetic relatedness and stroke association vary from 30% to 76% as shown by various studies [Table 2]. Heritability of 32% for stroke death and 17% for stroke hospitalization was seen in a study conducted by Bak S et al.[56] Evidence for a genetic contribution was summarized by Flossmann et al. across 9 cohort studies, 27 case–control studies, and 3 twin studies.[57] A positive family history of stroke was associated with an ≈30%–76% increase in stroke risk. In the Framingham Study, a parental history was associated with a 2.22-fold increase in risk in offspring (P < 0.05).[58]
Childhood stroke is more common with these single-gene disorders. More than 50 single-gene disorders are implicated with stroke in young. However, overall, these account for less than 1% of stroke cases in young adults.[58] Identification of genetic causes becomes important for appropriate counseling and management. Genetic diseases have been classified as monogenic and polygenic disease. Terni et al. in a review article have extensively enumerated the genetic relatedness to stroke.[59] The monogenic diseases include mitochondrial diseases, familial hemiplegic migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), Fabry's disease, other rare autosomal dominant small-vessel disease, homocystinuria, stroke, and vasculopathy associated with ADA2 mutation, sickle cell disease (SCD), and disorders of the connective tissue associated with stroke. Polygenic conditions include homocysteine metabolism defect, renin–angiotensin–aldosterone system, hemostasis, platelet glycoproteins, lipid metabolism, and matrix metalloproteinases.[58],[59],[60],[61] Individuals and families causing mendelian or mitochondrial disease have to be recognized. Mendelian diseases are recognized by their familial history, young age of onset, more severe clinical course, and higher recurrence rate when compared with sporadic disease. Mitochondrial-related strokes may be maternally inherited and are more life-threatening.[58]
Monogenic diseases account for less than 5% of all cases. Due to diagnostic constraints, these are still underreported. Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most common maternally inherited mitochondrial diseases. CADASIL is one of the most common and most widely studied among the monogenic diseases as the hereditary cerebral small-vessel disease. CADASIL is caused by dominant mutations in the NOTCH3 gene.[60] The estimated prevalence of CADASIL in young patients with stroke is very low.[61] It is also associated with modifiable vascular risk factors. The percentage of young developing stroke with CARASIL is also low.[62] CARASIL is linked to a mutations in the HtrAserine peptidase 1 (HTRA1) gene.[63]
Unconventional risk factors
It is well documented that low consumption of fruits and vegetables, sedentary lifestyles, and psychological stress are among the additional contributory factors for stroke in young.[64] Sedentary lifestyle, drug abuse, oral contraceptives, and the ratio of apolipoprotein B to apolipoprotein A1 are more recent subjects of investigation. Increased ratio of apolipoprotein a1 has been shown to be associated with carotid atheroma. Obesity, psychological stress, raised apoB/apoA 1 ratio, physical inactivity, and low fruit and vegetable intake are also associated with increased stroke. In addition, newer risk factors, including homocysteine and chronic infection (Chlamydia pneumoniae and periodontal disease), are being studied as predictors of ischemic stroke.[64]
| Management and Prognosis | | |
Controlling of hypertension and biochemical risk factors and avoiding smoking become the foremost factors to reduce the risk of stroke. Acute management, prognosis, and long-term strategies to prevent recurrence vary considerably depending on the etiology and type of stroke.[65] The diagnosis of many of the subtypes, such as cardioembolic stroke, atherothrombotic stroke, antiphospholipid antibody syndrome (APLA syndrome), and coagulopathies, requires detailed clinical, radiological, and laboratory evaluation.
Management of a young adult with an acute stroke is the main clinical challenge. Advancement in the diagnostic modalities has significantly improved in the past few decades. Cerebral vessels are better visualized with high-resolution magnetic resonance imaging machines. Cardiac anatomical structures and cardiac functions are analyzed in a better way.
Community-based studies have not been of immense help to predict the outcome and prognosis of stroke in young adults because of slightly low incidence. The severity of stroke and cardiac failure have been the main predictors of mortality as shown in the Athens Young Stroke Registry. The 10-year survival probability in young with stroke was 86.3% and of composite vascular events was 30.4%. Most of the patients were functionally independent at the end of the follow-up period.[65]
The Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) was a clinical trial aimed to assess the safety and efficacy of thrombolysis in 18- to 50-year-old patients with stroke compared with those age 51–80 years.[66] The main outcome measures were symptomatic intracerebral hemorrhage, mortality, and functional independence (modified Rankin Scale) at 3 months. The results suggest that thrombolysis is safe in young compared with older stroke patients and needs to be taken into consideration in treatment of this subpopulation of ischemic stroke patients.
| Prevention | | |
Prevention is the primary treatment strategy which will reduce the morbidity and mortality related to stroke. The American Heart Association and guidelines of the European Stroke Organisation cover the stroke prevention in detail, which are common for both young and elderly groups. No separate guidelines for stroke prevention in young are available. Public awareness regarding the warning symptoms of stroke among public needs to be strengthened. Stepping up of awareness drive is urgently required as there is poor recognition of early stroke symptoms, which leads to delay in hospitalization and early embolic therapy.
This group becomes important as stroke in the young has major long-term socioeconomic consequences. Our focus should be on primary and secondary stroke prevention and lifestyle modification like quitting smoking, reducing alcohol consumption, maintaining the body mass index, regular physical exercises, and adopting for a diet rich in fruits and vegetables.
| Conclusion | | |
Stroke in young adults is a major public health problem. The factors responsible for stroke in young adults are quite different from those that cause stroke in elderly. Classical vascular risk factors, arteriopathy, cardiac diseases, monogenic disorders, and multifactorial genetic contributions represent the potential causes of stroke in young. Hence, a different approach is required to investigate and manage these patients. Although atherosclerosis still contributes to a large proportion of stroke in both young and elderly, there is a need for aggressive risk management. In young, looking for PFO and atrial septal defect (ASD) should be essential in the investigation. Recognition of the underlined genetic disorders causing stroke is important for the correct management of the patient. Advances in the imaging technologies and genetic testing may increase the identification of the causes and mechanisms of stroke in young adults. The recent methods such as gene profiling, proteomics, genomics, and whole genome sequencing technologies which detect the functional changes induced by genetic variations and nongenetic factor may additionally help in addressing the causes of stroke in the young. Moreover, further multicentric population-based studies and randomized clinical trials in stroke in young patients may help develop effective guidelines for treatment and prevention of stroke in this important subpopulation. Looking toward the increasing incidence of stroke in the young, clearly there is an imperative need for further research to decrease the disease burden.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]
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