Having analyzed the data on 143 patients aged from 0 to 17 years old with CVD (the age median of 5 years old, in 68 boys (48%) and 75 girls (52%)), the same authors concluded that all types of CVD occur equally often both in boys and girls, with the exception of TIAs, which are recorded in girls three times more frequently than in boys. The authors also note a high percentage (13%) of recurrent strokes in children, while the highest risk of a recurrent CVD is recorded during the first 2 weeks after the disease onset [8].
According to data of the Emergency Call Service of Moscow, in 2012 there were 157 ambulance responses on calls to children and teenagers with the ACVD diagnosis, and in 2013 – 179 [4].
Employees of the FSBEI of Higher Professional Education «Urals State Medical University» analyzed the stroke in children living in the area of Yekaterinburg (with population of 1.5 million people) and Sverdlovsk region (4.5 million people). The following parameters were assessed: the stroke registration rate in the years from 1995 till 2015; the morbidity rate during the last five years, including children of the first year of life; gender distribution characteristics; incidence rate of fatal outcomes and recurrences in 162 children with IS and 73 children with TIA.
The study was held for 10 years. During this period, the information was distributed among the pediatric neurologists of the city and the region, who actively referred already followed-up and new pediatric patients with diagnosed or suspected ischemic ACVD to hospitals. We suppose that practically all patients with the onset of IS or TIA occurring in childhood were included into this database, and this permits to regard this study as an epidemiological survey.
According to the data obtained, during the last five years the morbidity rate was: 3.4 (2011), 4.9 (2012), 4.9 (2013), 4.6 (2014) and 5.0 (2015) per 100,000 of the pediatric population annually. Fig. 1 shows the total number of registered children with strokes on a specified territory during the last 20 years since 1995, when neuroimaging (brain CT) and emergency diagnosing became possible.
It must be emphasized that the obtained indicators are closer to the lower threshold of values stated in literature (2—26.7 per 100,000 annually). At the same time, a distinct tendency for growing stroke registration incidence rate in children in the surveyed area, which can be observed during the last ten year period in all countries, where ACVD morbidity is registered among children.
Fig. 1. Incidence rate of ischemic stroke in children in 1995—2015 in the area of Yekaterinburg and Sverdlovsk region (population: 6 million people).
The average age of children with IS manifestation at the age of below one year was 19.5±1.2 weeks (we revealed 7 infants with fetal / perinatal onset of IS) and at the age of above one year – 6.2±0.4 years. For TIA this parameter was 11.8±0.3 years.
The gender distribution of patients was even, and matched the literature data: boys with IS constituted 62.7% (n=102), and boys with TIA – 45.2% (n=33).
Based on literature data, the average risk of recurrent strokes in children is 20%, while in children with a single revealed risk this parameter is within 8%, and in children with a combination of two or more risks it grows at an exponential rate and reaches 42% [145; 148].
According to data of the FSBEI of Higher Professional Education «Urals State Medical University», the recurrence is also recorded on the levels of 14.2% (n=23) and 70.4% (n=50) for IS and TIA respectively. The average incidence rate of recurrent ISs was 1.6±1.1 (1—2 episodes of IS compared to 2—19 incidents of TIA), the average incidence rate of TIA was 3.4±0.5 incidents (from 2 to 20 episodes). It is the low level of ACVD detectability in childhood, which is supposed to cause the lack of timely and comprehensive examination, correct diagnosing and timely application of secondary prevention measures. For example, there was a patient registered, who had suffered 6 TIAs and 2 ISs, before he was subjected to a comprehensive examination, which diagnosed the moya-moya disease.
The disability status was given to 61.2% (n=90) and 9.1% (n=4) of patients from 125 and 62 children with IS and TIAs respectively, whose catamnesis was known. It should be noted that the disability in the group of children with TIAs was caused by a non-neurologic deficiency: two children had an acknowledged moya-moya disease, one had a chronic renal insufficiency, and one – a congenital heart defect.
The mortality in a group of children with IS was 3.3% (n=4, 2 boys and 2 girls); all the patients, who had suffered TIAs, were alive by the moment of the last follow-up visit (minimum 2 years of follow-up).
Thus, the literature data and the results of limited epidemiological surveys in Russia permit to conclude that ischemic strokes are a relatively rare disease in pediatric practice, although they are characterized by a high rate of recurrence, disability and mortality.
2. Pediatric stroke classifications
As already stated above, the ratio between hemorrhagic and ischemic strokes in children essentially differs from that in an adult age group. There is no unanimous opinion on the ratio between these variants in children. Apparently, the prevalence of an ischemic or a hemorrhagic ACVD variant in every new survey is associated with the specialization profile and medical care type in a healthcare facility.
Also, there are discrepancies in determination of a stroke variant in a child. For instance, the national research community failed to agree whether periventricular ischemia as well as intraventricular and subarachnoid hemorrhages can, by way of a morphological substrate of perinatal impairment of infants’ nervous systems, be considered to be equivalents of ischemic or hemorrhagic ACVDs (by analogy with adult patients). Authors of foreign clinical manuals on diagnostics and treatment of strokes say that they excluded infants with such lesions from analyzed literature sources. Based on provided epidemiological indicators, it also becomes evident that the researchers did not include patients with perinatal encephalopathy into their analysis scope [183; 107; 146; 220; 280].
It is well known that an ischemic stroke is broken up into the following categories:
• complete stroke – a cerebrovascular disease, which results in the formation of a sustained neurologic deficiency; ischemic lesions of cerebral tissue are detected by spiral computed tomography (CT) and magnetic resonance imaging (MRI) of brain;
• minor stroke – an acute development of a neurologic deficiency with subsequent complete regression within 2—3 weeks; small ischemic lesions may be detected by CT and MRI of brain;
• evolving stroke or stroke in evolution – an acute development of cerebral ischemia accompanied by a gradual growth of the neurologic deficiency during several days.
A separate nosological form of ACVD is transitory ischemic attacks (TIAs), which are characterized by a sudden development of a neurologic or retinal deficiency of ischemic nature, which is related to a specific artery territory and which regresses completely within 24 hours. TIAs occur considerably more frequently than strokes. Regarding their incidence rate, TIAs are subdivided into rare (1—2 times per year), mid-frequent (3—6 times per year) and frequent (once per month or more frequently) [17]. TIAs may be a manifestation of a chronic cerebral ischemia (insufficiency) with a high risk of subsequent development of a massive IS. Thus, a TIA may be considered an antecedent of IS.
The international terminology used for describing a pediatric stroke includes the following notions:
1. fetal (prenatal, intra-uterine) stroke – before the child birth;
2. perinatal stroke (when the disease develops during the period from the 28-th gestational week till the end of the first month following the birth);
3. pediatric stroke – at the age of 1 month following the birth until 18 years old [37; 148].
Presently, in children it is proposed to single out the following pathogenetic types of an ischemic stroke: hemodynamic, metabolic, embolic and occlusive.
There is no generally accepted and acknowledged by all specialists classification of CVDs in children. Above, we have presented a classification, which considers the age, when the stroke onset occurred.
Regarding the periodization of the disease itself, national specialists prefer to rely on the time frames formed in adult practice.
Groups of experts attempt to propose the pathogenetic variants of a pediatric stroke classification, yet they fail to end the discussions. For instance, they propose an anatomical classification named CASCADE (Childhood AIS Standardized Classification and Diagnostic Evaluation), which considers the localization and/or source of thrombosis/embolism of brain arteries (minor cerebral arteries, major cerebral arteries, aorta and cervical arteries, heart) [57]. The development of CASCADE classification was aimed at creating an analog of TOAST (Trial of ORG 10172 in Acute Stroke Treatment) accepted in adult practice, which was practically achieved [76]. However, the criteria specified in it can be hardly met or, in fact, cannot be met at all: e.g., they imply a histological acknowledgement of changes in cerebral vessels. Another essential drawback of this classification is deemed to be ignoring the embolic variant of IS and thrombophilic states in it.
3. Aetiopathogenesis and risks
A pediatric stroke is heterogeneous in aetiopathogenesis. If in adults strokes are associated most frequently with atherosclerosis of brachiocephalic arteries (BCA) [26; 27], the etiology of strokes in children is diverse and complex [40]. In literature there is a quite exhaustive list of diseases and syndromes, which are fraught with a risk of cerebral ischemia in childhood, adolescence and youth. According to data of the American Heart Association & American Stroke Association (2012), half of all children, who had suffered a stroke, had risks [219].
Complexity and diversity of etiology imply a wide circle of specialists, who must keep an alert eye on strokes in their routine practice.
Heart diseases (congenital and acquired) present one of the most significant risks equal to about 20—30% of the causes of ischemic strokes in childhood [161]. A combination of left-heart embolisms (or paradoxical embolism in right-to-left cardiac shunt) and cardiac decompensation is important in pathogenesis of cardioembolic variant of an ischemic stroke [1; 7; 22; 52]. There is a description of cases of paradoxical embolism into the cerebral vessels of children and young people in the background of an atrial septal defect, open foramen ovale, in cases of arteriovenous malformations of pulmonary vessels and neurocutaneous syndromes [280]. While this problem was in focus, the attention was again attracted to minor cardiac abnormalities. Regarding patients with vague etiology of stroke, it is, primarily, recommended to rule out sources of hidden or paradoxical embolism as an open foramen ovale, a mitral valve prolapse and an atrial septal aneurysm [1; 52; 56; 38]. The literature data state that imaging reveals «silent» brain infarctions in 25% of patients with mitral stenosis. Also, clinically «silent» ischemic lesions of brain tissue are found in 20% of newborns with heart diseases on a pre-surgery stage and in 17.4% – on a post-surgery stage [63; 181; 221]. Presently, several studies were held with the attempted prognostication of strokes in infants with congenital heart diseases. A significant role of duration and an intensity of hypoxia in newborns, resuscitation procedures, prematurity and duration of waiting for surgical intervention were indicated as ACVD risks at pre-surgery and post-surgery stages [62; 112; 161; 181; 183; 210].
Cardiac arrhythmias are considered to be a very rare cause of strokes in childhood and youth, as opposed to adults. Nevertheless, it should be kept in mind regarding children with hyperthyreosis, rheumatic heart diseases, after surgical interventions and in the structure of Kearns-Sayre syndrome.
Cardiac myopathy as a manifestation of systemic diseases occurs in congenital myopathies (Duchenne, Becker, Emery-Dreifuss, etc.), Friedrich’s ataxia, mitochondrial diseases. With this pathology, both embologenic and hemodynamic variants of an ischemic stroke are possible. In some cases, a myocardial infarction and a stroke may develop simultaneously, which points at the similarity of pathogenetic processes leading to inadequate perfusion [7].
Hypercoagulation states are presently considered to be the most common causes of ischemic strokes in childhood – their contribution reaches 87% [3; 16; 138; 144; 170; 265]. However, a universally acknowledged screening protocol for thrombophilic state in a child with CVD has not been developed yet, and some researchers dispute the role of multigenic thrombophilias as risks of strokes and TIAs in children [82; 121; 142; 184; 194; 282].
During the last decade a large number of thrombophilic mononucleotide genic polymorphisms were described. Carriership of proaccelerin, prothrombin, plasminogen activator inhibitor and fibrinogen is considered to be most significant clinically [61; 138]. F5 genotypes: 1691 G> A and AA (Leyden mutation) as well as F2: 20210 G> A and AA are currently the only ones, whose prothrombotic effect is acknowledged in newborns. Besides, there is a good reason to suppose that with the carriership of thrombogenic mutations and polymorphisms in children the risk degree differs according to their age [5; 56; 138].
Presently, there are no doubts regarding the connection of hyperhomocysteinemia and MTHFR677C> T mutation with cerebrovascular and cardiovascular diseases [5; 16; 61; 280]. Homocystein acts as a prothrombotic factor due to activation of coagulation factors XII and V, increase in tissue factor expression and suppression of thrombomodulin expression. Besides, the rise of homocystein in blood leads to vascular endothelium damages, which reveals in neurotoxic and proatherosclerotic effects and contributes to the emergence of resistance to activated protein C [3; 31; 66; 267; 276; 290]. During the latest years, the role of hyperhomocysteinemia in damaging the vascular walls was proven as well as its prothrombotic and pro-atherosclerotic effects and its effect on the vasomotoric regulation [3; 32; 290].
The MTHFR enzyme gene provides for homocystein metabolism with the participation of a folic acid. The greatest practical significance belongs to a mononucleotide replacement of cytosine with thymine at position 677 of gene, thus leading to a replacement of alanine amino acid residue with valine in the catalytic core of methylene tetra hydro folate reductase enzyme (MTHFR). Individuals, homozygous by this allelic mutation, display a decrease of the enzyme activity by 60—70%, and heterozygous – by 35% [28; 159; 275]. It should be noted that all available data concern either fundamental aspects of the pathology study, or the population of adult patients.