Chapter 17 – Ischemic Stroke in the Young and in Children




Chapter 17 Ischemic Stroke in the Young and in Children


Valeria Caso and Didier Leys


The proportion of first-ever stroke in young adults and children differs from country to country, ranging from <5% to 20% of all strokes [1]. Most strokes occurring in young patients are ischemic in origin.


They account from 2% to 12% of all strokes, depending on whether figures are provided from community- or hospital-based data.


In this chapter, we will mainly focus on the specificities of ischemic strokes in young adults. Owing to space limitations, we will not cover the issues of intracerebral and subarachnoid hemorrhages, spinal strokes, perinatal strokes, cerebral venous thrombosis, silent strokes, microbleeds, and cerebrovascular disorders that are not associated with a stroke, such as cervical artery dissection revealed by cranial nerve palsies.


The main specificities of ischemic strokes in young patients are their causes, the outcome, and possibility to occur during pregnancy. These specificities may influence the management of those patients. Therapeutic options should take into account the presumed cause, the natural history of the disease, and the long life expectancy.



Epidemiology


Figures depend on the definition of “young.” Three upper thresholds can be found in the literature, at 30, 45, and 55 years of age. The most frequently used upper age limit is 45 years. It realizes a good compromise between age category where common causes of cerebral ischemia, such as atheroma, atrial fibrillation, and lipohyalinosis, are very rare, and on the other hand a disorder that is not too rare. The incidence of ischemic strokes increases with age even in young people: most young people with stroke are between 40 and 45 years of age [2]. The incidence of ischemic stroke in young people varies between 60 and 200 new cases per year per million inhabitants [3], depending on the characteristics of the population and definition of “young.” This incidence remains stable over time and does not decline as does the incidence rate of ischemic stroke in other age categories. The number of admissions in hospitals for ischemic strokes in young people is increasing, together with an increase in risk factors and behavioral risk factors [4]. The incidence is higher in non-industrialized countries and in Black populations. In fertile women, stroke affects 30 per 100 000 pregnancies, with ischemia, cerebral venous sinus thrombosis, and hemorrhage causing roughly equal numbers and with highest risk peripartum and post-partum [5]. Population-based estimates of the incidence of stroke in children include hemorrhagic strokes in the range 2.3–13.0 per 100 000 children [6]. About 50% of incident strokes in children are ischemic, with a higher incidence in boys [6].



Overall incidence rates under the age of 45 range from 7 to 15 in 100 000 people/year for all strokes (ischemic and hemorragic), with higher rates reported in some countries.



Diagnostic Workup


The diagnostic workup does not differ from that of older patients except for the search for a cause. The same principles as those detailed in the recommendations of the European Stroke Organisation are valid also in young people, although they are not specific for this age category. Cervical and transcranial ultrasounds, magnetic resonance angiography of cervical and intracranial arteries, continuous ECG monitoring, and transthoracic and transesophageal echocardiography should be performed according to the same rules as in older patients, and will therefore not be detailed in this chapter.


Cerebral ischemia occurring during pregnancy requires the same diagnostic workup as in non-pregnant women. However, magnetic resonance imaging is the investigation of choice over CT and percutaneous angiography, although its safety profile for the fetus has never been evaluated. Gadolinium enhancement is not, however, recommended, as its effects on the fetus remain unknown.


The patient’s interview can provide information on the potential cause of cerebral ischemia. It should be repeated, with the patient and close relatives. It should focus on the following features:




  • presence of cervical pain or headache that may have occurred before stroke (in favor of a dissection)



  • presence of pulsatile tinnitus (in favor of a dissection)



  • recent intake of illicit substances (in favor of toxic angiopathies)



  • recent intake of vasoconstrictive drugs (in favor of toxic angiopathies)



  • history of migraine with aura (in favor of migrainous infarct)



  • history of definite systemic inflammatory disorder, or suggestive clinical features such as photosensitivity, arthritis, pericarditis, pleuritis, repetitive spontaneous miscarriage, oral or genital aphtosis, unexplained fever, anemia, thrombopenia, proteinuria (in favor of cerebral vasculitis)



  • family history of ischemic stroke occurring in young patients (in favor of genetic causes, such as CADASIL)



  • family history of migraine with aura, severe depression, or dementia occurring in young patients (in favor of CADASIL)



  • personal history of irradiation (in favor of post-irradiation arteriopathy)



  • any personal medical history that may orientate towards a specific etiology of cerebral ischemia.


Skin examination is an important step in the search of a cause. It should be performed in a patient naked, and requires the advice of a dermatologist when necessary. The examination should focus on the search for:




  • features of abnormal skin elasticity, varicose veins, spontaneous ecchymosis, abnormal scars (in favor of Ehlers-Danlos disease)



  • papulosis (in favor of malignant atrophic papulosis, so-called Degos disease)



  • livedo racemosa (in favor of Sneddon disease)



  • neurofibromas and “taches café au lait” (in favor of von Recklinghausen disease)



  • angiokeratomas (in favor of Fabry disease)



  • facial lentiginosis (possibly associated with cardiac myxoma).


Fundoscopic examination is necessary, as it may identify signs of:




  • hypertensive retinopathy



  • cholesterol emboli



  • perivascular retinitis (in favor of Eales disease)



  • multiple retinal ischemia (in favor of Susac’s syndrome).


    The biological workup should include:




  • in all patients, the same biological workup as in older patients: blood cell count, glucose level, cholesterol and triglyceride levels, erythrocytes sedimentation rate, fibrinogen, and C-reactive protein



  • in selected patients in the absence of a clearly identified cause of cerebral ischemia:




    • activated cephalin time (when increased, should lead to a search of lupus anti-coagulant)



    • serology for syphilis and human deficiency virus



    • electrophoresis of proteins



    • dosage of anti-phospholipid antibodies in case of multiple spontaneous miscarriages, deep venous thrombosis, false positivity of syphilitic serology, or systemic disorder



    • search for congenital thrombophilia in the presence of personal or family history of multiple venous thrombosis (proteins C and S, anti-thrombin III, resistance to activated protein C, mutation of factor V Leiden, mutation of thrombin gene), but these causes of thrombophilia are rarely causes of cerebral ischemia except in case of cerebral venous thrombosis.




Diagnostic workup must include a large variety of symptoms and a careful examination of other systems (skin, retina), as well as a search for systemic diseases.



Causes of Ischemic Strokes in the Young


There are huge differences in the breakdown of etiologies depending on the centers and countries where the data are collected [7]. Despite an extensive diagnostic workup, the cause of cerebral ischemia remains undetermined in up to 45% of patients [7]. However, even in specialized centers it may happen that the diagnostic workup is negative because it is not extensive enough or performed too late after the onset. The most frequent cause in Western countries is cervical artery dissection, and in non-industrialized countries valvulopathies. In this chapter we will present the etiologies according to the TOAST classification [8], although the first three categories (large-vessel atherosclerosis, cardioembolism, and small-vessel occlusion) are rare in young patients.



Large-Vessel Atherosclerosis


Large-vessel atherosclerosis accounts for less than 10% of cerebral ischemia before the age of 45 years, and is found mainly in men between 40 and 45 years of age. Atherosclerosis has no specificity concerning the clinical presentation, diagnosis, and predisposing factors. Smoking is a major risk factor in this age category, and a family history is frequent, suggesting a genetic predisposition.



Cardioembolism


The main causes of cardioembolism in young patients are listed in Box 17.1. A few of them deserve further details.




Box 17.1 Main Cardiac Sources of Cerebral Ischemia in Young Adults





  • High-risk cardiopathies




    • atrial fibrillation associated with cardiopathy, or vascular risk factors or previous systemic emboli



    • mitral stenosis



    • mechanical prosthetic valve



    • infectious endocarditis



    • marastic endocarditis



    • intracardiac thrombus



    • acute myocardial infarction



    • ventricular akinesia



    • dilated cardiomyopathy



    • intracardiac tumor (myxoma, papillary fibro-elastoma)



    • paradoxical emboli through a patent foramen ovale (PFO) or inter-atrial communication



    • congenital cardiopathies with cyanosis



    • IASA plus PFO



    • complication of catheterism and cardiac surgery.




  • Low-risk cardiopathies




    • lone atrial fibrillation



    • mitral valve prolapse



    • mitral calcification



    • bioprosthesis



    • aortic stenosis



    • bicuspid aortic valve



    • Lambl excrescence



    • isolated IASA



    • isolated PFO.



Atrial fibrillation is associated with a very low risk of cerebra emboli in young people when occurring in the absence of underlying cardiopathy (lone atrial fibrillation) and of vascular risk factors. However, it confers a high risk of cerebral emboli when there are risk factors for stroke, especially high blood pressure, or an underlying cardiopathy, such as mitral stenosis or cardiomyopathy. Given the often paroxysmal and asymptomatic nature of atrial fibrillation, it may not be detected in acute stroke. Long-term monitoring with an insertable cardiac monitor has been reported to be more effective than conventional follow-up for detecting atrial fibrillation in patients with cryptogenic stroke [9].


Infectious endocarditis is not always associated with fever. At an early stage, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) may reveal vegetations. When negative, these investigations should be repeated.


Patent foramen ovale is present in 10–20% of young patients with cerebral ischemia [10]. It may be familial, especially in women [11]. PFO consists of a communication between right and left atrium which becomes functional when the pressure in the right atrium becomes higher than in the left one (e.g. pulmonary embolism, Valsalva maneuver). PFO may be diagnosed by TTE or TEE with contrast, or transcranial Doppler with contrast. When there is a causal relationship, possible mechanisms of cerebral ischemia are paradoxical emboli (requiring deep venous thrombosis, pulmonary embolism, and cerebral ischemia without other potential cause), local thrombosis in the PFO (most likely hypothesis, but almost never proven), or paroxysmal atrial fibrillation. However, the presence of a PFO is frequent in practice and the causal relationship is unlikely in many patients. The risk of recurrence after a first ischemic stroke in the presence of an isolated PFO does not differ from that of ischemic stroke patients of similar age who have no PFO [12]. Evidence of a right-to-left shunt by transcranial Doppler with contrast enhancement is, in most cases, a marker of the presence of a PFO. However, sometimes the cause of the right-to-left shunt is not a PFO, but a pulmonary arteriovenous malformation, which is a rare disorder that occurs mainly in patients with Rendu-Osler-Weber disease. Evidence of a shunt without evidence of a PFO should therefore lead to a search for pulmonary arteriovenous malformation.


Interatrioseptal aneurysm (IASA) is a protrusion of the interatrial septum in either atrium. It is rare in the absence of PFO [12]. Diagnostic criteria are, on TEE, an excursion of 10 mm or more during cardiac contraction, and a basis of at least 15 mm [12]. Presence of IASA is more frequent in young patients who have had an ischemic stroke of unknown cause, but in the absence of associated PFO, the presence of an IASA is not a marker of increased risk of recurrence [12]. Paroxysmal atrial fibrillation and local thrombosis in the IASA are the most likely mechanisms of cerebral ischemia when a causal relationship exists.


The association PFO/IASA (Figure 17.1) in patients aged 55 years or less who have had an ischemic stroke of unknown cause, is a marker of increased risk of recurrence under aspirin [12]. In the FOP-ASIA study [12], after 4 years of follow-up, the rate of recurrent strokes was 15.2% (95% confidence interval [CI] 1.8–28.6%) in patients with PFO and IASA, whereas it was only 2.3% (95% CI 0.3–4.3%) in those with isolated PFO, 4.2% (95% CI 1.8–6.6%) in those without PFO and IASA, and 0.0% in those with isolated IASA. Therefore, the coexistence of PFO and IASA is associated with a 4.2-fold increased risk of recurrence (95% CI 1.5–11.8). In 2012/2013, three randomized controlled trials (RCTs) failed to demonstrate the superiority of PFO closure over medical treatment in the secondary prevention of cryptogenic stroke, but, in 2017, three trials [1215] reported fewer recurrent cryptogenic strokes with PFO closure than with anti-thrombotic treatment alone.





Figure 17.1 Transesophageal echography showing a patent foramen ovale and an interatrioseptal aneurysm.


Mitral valve prolapse is a protrusion of one or two mitral valves in the left atrium found in 2–6% of people in the community [16]. However, diagnostic criteria often lacked precision in studies and its responsibility in cerebral ischemia remains very controversial. The risk of cerebral emboli in patients with mitral valve prolapse is very low except in case of associated atrial fibrillation or endocarditis.


Intracardiac myxoma (Figure 17.2) is the most frequent intracardiac tumor. Its prevalence is 10 per 1 million inhabitants and is usually located in the left atrium. In less than 50% of cases it leads to systemic emboli associated with fatigue, weight loss, fever, and sometimes cardiac signs such as dyspnea, murmur, or variations in blood pressure. Most myxomas remain asymptomatic and are revealed by an ischemic stroke. The presence of facial lentiginosis (rare autosomal dominant disorder) may be associated with a myxoma.





Figure 17.2 Transesophageal echography showing a left atrial myxoma (arrow).


Papillary fibro-elastoma is a benign tumor which is usually located on a cardiac valve difficult to distinguish from a vegetation.


Peripartum cardiomyopathies are very rare in Western countries, but are reported quiet frequently in sub-Saharan countries during the last month of pregnancy and during the post-partum period [17]. The clinical presentation is that of a cardiac failure, often associated with cerebral emboli [17]. This disorder is multifactorial and is associated with a high mortality rate.



Small-Vessel Occlusion


Lacunar infarcts are small infarcts of less than 15 mm located in the deep white matter, basal ganglia, and brainstem. They are the consequence of the occlusion of a single deep perforating intracerebral artery of less than 400 µm in diameter. These perforators have no collaterals and their occlusion always leads to an infarct. The short-term outcome is usually good, but the risk is cognitive decline and dementia in case of recurrences.


Lipohyalinosis of the deep perforators: Arterial hypertension is the most important risk factor for lipohyalinosis of the deep perforators, but such hypertensive arteriolopathies are very rare before the age of 45 years.


CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a genetic disorder of small deep perforating arteries identified on the basis of clinical, MRI (Figure 17.3), and genetic criteria [18]. CADASIL is due to a mutation of the NOTCH3 gene on chromosome 19 [19], leading to an accumulation in the wall of small perforators leading to a progressive occlusion. CADASIL is associated with migraine with aura, depression, multiple subcortical infarcts, and, at the end stage, dementia with pseudobulbar palsy [18]. White matter changes are always already severe on MRI when the first symptoms occur usually during the third decade of life [18], leading to death within 20 years after the first symptoms.





Figure 17.3 Brain MRI of a CADASIL patient showing severe white matter abnormalities and lacunas.



Other Definite Causes of Cerebral Ischemia


The following causes are actually the most frequent causes of cerebral ischemia when a cause can be identified.



Diseases of Large Arteries




  • Cervical artery dissections are the leading cause of cerebral ischemia in the young in Western countries when a cause can be clearly identified [2]. In most cases no trauma can be identified, or the trauma is mild and a causal relationship between a trivial trauma and dissection is even disputable. The most likely hypothesis to explain most cases is that of a trivial trauma of the daily life [20] occurring on an artery prone to dissect for genetic [21] or infectious reasons [20]. Inherited elastic tissue disorders, especially Ehler-Danlos de type IV, predispose to dissections, but they are rare and probably underdiagnosed in practice. The association with intracranial aneurysms and cases occurring in a same family are rare, but, when they occur, are in favor of elastic tissue disorder. Recurrences of stroke and of dissections are rare except during the first days [20], and the overall outcome can be considered as good except when stroke was severe at the acute stage [20]. Nowadays the diagnosis should be possible using exclusively non-invasive investigations, especially Doppler ultrasonography and MRI, both techniques being able to show the mural hematoma [20] (Figure 17.4).



  • Post-irradiation cervical arteriopathies in young persons are often due to irradiation for hematological disorders, and less frequently to throat cancers. Patients always have radiodermitis in the area of irradiation. The arterial lesion is atheroma, irradiation being a local factor of atheroma. The outcome is usually more dependent on the underlying disorder that led to irradiation than on irradiation arteriopathy per se, especially in asymptomatic cases [21].



  • Cervical fibromuscular dysplasia of cervical arteries is associated with a low risk of ischemic stroke, except in case of dissection. It can be isolated or associated with other locations such as renal arteries. It may be found in patients with Recklinghausen disease or elastic tissue disorder.



  • Intracranial dissections are very rare and difficult to diagnose. They may occur in children and are often revealed by cerebral ischemia, but may also lead to subarachnoid hemorrhage, especially when located in the vertebra-basilar territory. Their prognosis is usually poor, but benign cases, if they exist, may remain undiagnosed.



  • Moyamoya disease is a progressive intracranial vasculopathy that usually becomes symptomatic in children or young adults and may lead to ischemia, hemorrhage, or both. Angiography shows a tight stenosis or occlusion of the intracranial carotid arteries associated with intracerebral neo-vessels. Any disorder that can lead to progressive stenosis or occlusion of intracranial carotid arteries in children or in young adults may be a cause of Moyamoya.



  • Secondary vasculitis occurring in a context of systemic disorder: Such vasculitis may occur in a patient whose systemic disorder is already known, or may be the first manifestation.




    • Systemic disorders where cerebral vasculitis is usually not the most prominent feature (panarteritis nodosa, Churg-Strauss syndrome, systemic lupus erythematosus, Sjögren syndrome, Behçet syndrome, sarcoidosis, Crohn disease, ulcerative rectocolitis) are usually diagnosed on the basis of other manifestations of the disease and, depending on the type of systemic disorder, either a neuropathological proof (e.g. sarcoidosis) or association of diagnostic criteria (e.g. systemic lupus erythematosus).



    • Takayasu disease is a chronic inflammatory disease that involves progressively the aorta and the brachiocephalic arteries. It occurs prominently in women before 45 years of age. Cerebral ischemia may be due to progressive stenosis or occlusion of the cervical artery when they arise from the aortic arch.



    • Buerger disease, so-called thromboangiitis obliterans, is a segmental inflammatory vasculitis involving arteries of intermediate and small calibers and also superficial veins. This is usually a disorder involving peripheral arteries, which may exceptionally involve cerebral arteries.



    • Eales disease is an inflammatory vasculitis that involves prominently retinal arteries and very rarely cerebral arteries. The causal relationship with cerebral ischemia is uncertain.



    • Acute multifocal placoid pigment epitheliopathy is a bilateral primary disorder that may rarely be associated with cerebral vasculitis and lead to permanent visual deficits. The clinical picture is that of a decreased visual acuity and fever. The diagnosis is based on evidence of specific lesions at fundoscopy and inflammatory CSF. Intravenous corticosteroids and immunosuppressant therapy are requested.



    • Köhlmeier-Degos disease, or malignant atrophic papulosis, is a systemic vasculitis that involves prominently the skin. The severity of the disease is due to the consequences of the vasculitis involving the brain or the bowel.




  • Secondary vasculitis occurring in a context of infectious disorder: Such vasculitis may occur in patients with bacterial infections (syphilis, tuberculosis, Lyme disease, etc.), viral infections (ophthalmic herpes zoster, HIV, etc.), parasites (malaria, cysticercosis, etc.), or mycotic infections (aspergillosis, candidosis, cryptococcosis, etc.).



  • Primary vasculitis of the central nervous system are granulomatous inflammatory non-sarcoidosic non-infectious vasculitis with giant cells, restricted to the leptomeningeal and cerebral arteries [22]. The incidence is approximately 2.4 new cases per year per 1 million inhabitants [22]. They occur in both genders around 40 years of age. The first symptom is usually headache, followed by subacute focal neurological deficits, sometimes transient, and seizures [22]. Cerebral infarcts are usually multiple, cortical, and sometimes associated with hemorrhages. Fever is possible. There is no systemic biological sign of inflammation. The CSF may be normal, but is usually characterized by an increased number of lymphocytes with or without oligoclonal bands. Brain imaging is suggestive when it shows on (1) CT or MRI scans multiple infarcts of small size in cortical areas, with or without associated hemorrhages, and (2) conventional angiography or MRA multiple beadings in intracranial arteries in various territories [22]. This finding is not specific and the proof of diagnosis is provided by a biopsy of leptomeningeal arteries. In the absence of treatment (corticosteroids sometimes associated with cyclophosphamide for at least 1 year) or in case of failure of treatment, the outcome is poor with occurrence of cognitive decline, dementia, and a high mortality rate [22]. It is possible that primary vasculitis of the central nervous system is a heterogeneous entity that consists actually of several subsets of diseases [22].



  • Sneddon syndrome is a potential cause of recurrent cerebral ischemia. Each episode is usually of mild severity, but their repetition may lead to dementia. This diagnosis should be discussed each time a young patient has recurrent episodes of cerebral ischemia of mild severity preceded by livedo racemosa, which is a purple livedo, involving the trunk and the most proximal part of the limbs, which does not disappear with cutaneous warming, opposite to the more trivial livedo reticularis. Anti-phospholipid antibodies are usually associated. Although there is not a high level of evidence, oral anti-coagulation is recommended by experts.



  • Post-partum cerebral angiopathy is a rare entity that occurs usually in the first 2 weeks after delivery. Despite a severe clinical presentation, the outcome is usually excellent [23]. The clinical presentation consists of a combination of severe headache, vomiting, epileptic seizures, and focal neurological deficits. The angiography (either conventional or preferably magnetic resonance angiography) shows multiple beadings in large intracranial arteries that disappear spontaneously within a few weeks [23] (Figure 17.5). It might be a variety of toxic angiopathy favored by estrogen withdrawal, the use of vasoconstrictive drugs, and possibly bromocriptine [23].



  • Other acute reversible cerebral angiopathies have been reported. They have the same clinical presentation and outcome as the post-partum type. Possible etiologies are toxic (vasoconstrictive drugs, illicit substances such as cocaine or amphetamines), reversible hypertensive encephalopathies, pheochromocytoma, carcinoid tumors, or vasospasm after subarachnoid hemorrhage.



  • Eclampsia is the main cause of maternal mortality and preterm birth in Western countries [24]. The clinical presentation consists of headache, visual impairment, confusion or coma, epileptic seizures, and focal neurological deficits. The HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) is a subtype of eclampsia [24]. MRI shows in FLAIR sequences or in T2 sequences multiple hyperintense signals, isolated or more frequently confluent, more prominent in posterior areas, bilateral, located at the junction between the cortex and the subcortical white matter [24]. These abnormalities completely disappear after a few days or weeks. Cerebral infarcts may lead to residual deficits, but in most patients who survive the acute stage the long-term outcome is favorable.



  • Unruptured aneurysms of intracranial arteries may be a cause of cerebral ischemia secondary to a local intra-saccular thrombosis and subsequent distal emboli.


Sep 22, 2020 | Posted by in NEUROLOGY | Comments Off on Chapter 17 – Ischemic Stroke in the Young and in Children
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