Cerebral stroke is a rare disease in children, with an estimated incidence between 2 to 13/100000 and a significant impact on morbidity and mortality. The clinical presentation and risk factors present in almost half of cases in children and adolescents are not the same as in adults. The diagnosis of cerebral stroke in children is often delayed because the signs and symptoms may be subtle and nonspecific. History and physical examination should exclude diseases or underlying predisposing factors. Neuroimaging is crucial in defining the diagnosis, other tests are needed depending on the clinical picture. In the paper are presented practical directions on how to diagnose and manage arterial stroke in children, according to various international guidelines on this topic.
We will focus on the challenges involved in the diagnosis and treatment of arterial ischemic stroke, highlighting recent advances in the field and critical areas where further research is needed . A discussion of perinatal arterial ischemic stroke was excluded from this article because it has different clinical presentation, risk factors and risk of stroke recurrence than ischemic stroke in older children.
Pediatric stroke is an important cause of long term disability, because after, children could present significant neurological deficits. This condition is also associated with notable costs of health care. An often quoted fact is that, in children, strokes can occur as frequently as brain tumors. However, the data suggest that strokes are more common than brain tumors in this group of patients, with an incidence of 2-13 per 100,000 children/year (Ciccone S, 2011).
The World Health Organization defines stroke as “rapidly developing clinical syndrome with focal or global disturbance of cerebral function, lasting more than 24 hours or leading to death with no obvious nonvascular cause” (Aho K et all, 1980 ). In recent paperworks, there is a tendency to integrate a reference to neuroimaging, now considered essential for defining the origin of neurovascular symptoms. A modern definition would be ” a clinical syndrome characterized by neurological deficit related to perfusion territory of a cerebral artery and neuroradiology evidence of ischemic lesions” ( JV Hunter , 2008).
The estimated incidence of ischemic stroke in children older than 28 days of life is variable, but according to a large prospective study conducted in France over a period of eight years, the average is 13/100.000 children/year for all stroke, 7.9/100,000 children/year for ischemic stroke and 5.1/100,000 children/year for hemorrhagic strokes(Giroud M, 1995). About 20% of affected children die after an ischemic stroke, while more than 50% of those who survived remain with neurological sequelae, most commonly being hemiparesis(Ciccone S , 2011). Cumulative, the recurrence rate of stroke was 15% for 1 year, 19% for 5 years, and up to 41% for 5 years (Ganesan V , 2007). Boys had a higher risk than girls and black children were at higher risk than white children and Asian (partly explained by the fact that sickle cell anemia is present more frequently). Age peak is located in the first year of life (for both ischemic and hemorrhagic stroke), when can happen approximately one third of child stroke .
Recognition of stroke in children by parents and medical staff is often delayed , highlighting the need for increased awareness and education about this condition. Moreover, various other neurological conditions look alike stroke in these patients, definite diagnosis requiring MRI.
In older literature it was indicated that the average time from symptom onset to hospital presentation for children with AIS was 24 hours (Gabis LV, 2002). More recent paperwork suggest that a big part of the diagnosis delay for children with this condition is now showing in hospitals. Rafay et al and other contributors found out that, while the average prehospital delay from onset of symptoms to presentation to the hospital in case of pediatric AIS was 1.7 h, the average delay in hospital presentation to diagnosis for these cases was 12.7 hours ( Rafay MF , 2009).
A risk factor is present in almost half of the children at the time of stroke. Common risk factors in childhood are congenital heart disease, sickle cell anemia, infections and various prothrombotic conditions. There are studies which emphasize the importance of infections: it seems that at least one third of cases of childhood stroke occur in such a context. A fifth of children with ischemic stroke of unknown origin has previously shown a history of chickenpox( Miravet E, 2007).
1. Disease History
Clinical history should include the presence of sickle cell disease and congenital heart disease, head or neck trauma(may be associated with intracranial hemorrhage and dissection), recent infection (especially chickenpox), vasculitis, blood disorders and cerebrovascular disease, coagulopathy or immunological disorders among first-degree relatives.
How and how quickly symptoms develop, it is of great importance. Up to one third of children who had an ischemic stroke have a history of recent events compatible with transient ischemic stroke(DeVeber G, 2002).
2. Clinical presentation
A complete physical and neurological exam, which includes monitoring vital signs, will identify neurological damage and allows presumptive diagnosis of topography of the vessel involved . Should be sought signs of systemic diseases that increase the risk of stroke .
Clinical stroke varies by age, the artery involved and cause. While in early childhood the symptoms are usually nonspecific, in older children the most common symptoms are neurological deficits such as acute hemiplegia.
Symptoms, with the artery involved, are presented in the following table, vascular territory of the middle cerebral artery being the most commonly affected(Lopez- Vicente M, 2010).
The diagnosis of stroke in children is often delayed because the signs and symptoms may be subtle and nonspecific. There can be a slight weakness of a limb, difficulty with motor coordination and sensory disorders, initially attributed to causes other than stroke .
When a child shows an acute neurological deficit before diagnosis of arterial ischemic stroke was put, it is important to exclude other cerebrovascular disease(hemorrhagic stroke, cerebral venous sinus thrombosis). Common causes of acute hemiplegia are Todd’s paralysis, in which case the focal seizures usually preced monoparesis or hemiplegia and hemiplegic migraine, in which the hemiplegia is preceded by visual and sensitivity disturbances and followed by headache. It is also necessary meningoencephalitis to be excluded(usually associated with fever, headaches and altered consciousness).
Acute neurological deficits can be caused by tumors, central nervous system disorders , including acute disseminated leucoencefalita, cerebellum disorder, reversible posterior leukoencephalopathy, which alternates the hemiplegia, metabolic disorders, epilepsy and psychogenic diseases(Shellhaas RA, 2006).
The first step to detect stroke consists of including this option in the differential diagnosis of an acutely ill child. Early diagnosis allows immediate initiation of appropriate therapy.
1. Imaging diagnosis
Native computed tomography (CT) can be carried out promptly and quickly in an emergency. It may properly exclude hemorrhagic stroke or parenchymal abnormalities that cause mass effect and may reveal a low-density lesion in arterial ischemic stroke and venous sinus thrombosis. In general, CT does not require sedation, but the sensitivity of this method for detection of acute ischemic arterial stroke is low. In fact, a study conducted in 2009 found that ischemic stroke was not visualized on cerebral native CT on 62 of 74 children with this condition (84%); All these children had confirmation of stroke by MRI (Srinivasan J, 2009). This procedure must be called every time magnetic resonance imaging (MRI) is not available.
MRI is, in fact, the “golden standard” of imaging modalities for investigating arterial ischemic stroke in infants and children due to its sensitivity and specificity. MR is useful in differentiating stroke of pathologies that “mimic” this pathology, but is rarely available in case of emergency. The efficiency of MRI diagnosis can be improved by perfusion techniques, which measures, by bolus of contrast material based on gadolinium, relative cerebral blood flow, volume and transit time.
Diffusion-weighted MRI is the most sensitive method for diagnosing acute ischemic stroke; children less than 8 years may need sedation or anesthesia. One challenge associated with imaging of stroke in children and adolescents is therefore proper disposal of a team, available at all times for emergency sedation of patients. Angiography MR is a noninvasive way to detect big vascular abnormalities and it is as effective as the classic cerebral arteriography in identifying large ischemic lesions in most patients. If the pattern of brain injury suggests a venous infarction, urgent vascular imaging should include MR venography too.
CTA and CTV disadvantages compared to MRA and MRV include patient exposure to ionizing radiation and iodinated contrast agents. However, CTA also presents another difficulty: the administration of intravenous contrast should be done with precision to get a high quality image. To a hild with a small intravenous line, it may not be possible to inject the contrast fast enough to allow imaging. Another problem associated with CTA is that some awake children move when the contrast agent is injected, and this movement can reduce scan quality. The advantages of CTA over MRA are related to widespread availability in many centers (Bowen BC, 2007).
Conventional digital angiography remains the golden standard for vascular imaging in establishing a definitive diagnosis of vasculitis of small vessels, Moyamoya disease, arterial stenosis or cervicocephalic arterial dissection (ET Chappell, 2003).
2. Other investigations
It might be useful a complete blood count, determination of levels of iron, prothrombin time, partial thromboplastin time, erythrocyte sedimentation rate, and antinuclear antibodies (Ciccone S, 2011).
Investigation of the second cover (indicated after 48 hours)
They are generally required to assess and manage the dynamics of the patient as appropriate.
Electrocardiogram and transthoracic or transesophageal echocardiography are always necessary in children with known or suspected congenital heart disease and who suffered ischemic stroke. Echocardiography may be helpful to diagnose patent foramen ovale, this anomaly having an incidence of up to four times higher in children with undetermined stroke etiology than in the general population (Calder K, 2003).
Hemoglobin electrophoresis and a complete evaluation for thrombophilia (deficiency of protein C and protein S, antithrombin III, plasminogen, von Willebrand antigen, factor VIII, factor XII, factor V Leiden, activated protein C resistance, prothrombin 20210 gene, homocysteine, methylene-tetra-hydro-folate-reductase, lipoprotein A and antiphospholipid antibodies) are reasonable investigation for all children who underwent arterial ischemic stroke (Nestoridi E, 2002).
It can be achieved broader diagnostic tests based on clinical suspicion, including cerebrospinal fluid analysis, lipid profile, tests for varicella zoster virus and human immunodeficiency virus, and screenings for metabolic disorders. However, in most cases, their results will not have a major impact on emergency care.
Treatment guidelines performed on stroke in children are all limited by the lack of studies (with the notable exception of studies focusing on sickle cell disease), this being a direction that needs further research. There are not strong evidence-based guidelines for the care of patients with acute ischemic stroke in pediatrics (except sickle cell anemia). Therefore, the treatment recommendations of this condition in children are extrapolated from adult guidelines.
Children with acute ischemic stroke should be immediately admitted in a clinical unit where continuous monitoring is possible. Only in selected cases, the treatment is needed in intensive care units.
1. Emergency management
General emergency approach includes simple measures such as maintaining respiratory and cardiovascular functions, aggressive treatment of infections, seizures, maintaining normoglycaemia and oxygen supplementation to maintain SaO2> 95% within the first 24 hours of the stroke accident (correction of hypoxemia is more important in people with ischemic stroke than other types of stroke, because of ischemic penumbra concept) (JK Lynch, 2004). However, there is no clear evidence that oxygen supplementation is beneficial for children who are not hypoxemic. Also, there is no established role for hyperbaric oxygen therapy except those with air embolism after cardiac surgery. Even in the absence of clinical trials in children with stroke, there is experimental evidence according to which fever can worsen the effects of a brain injury, therefore fever control after ischemic stroke seems reasonable. However, although therapeutic hypothermia has been studied as a neuroprotective technique, there is insufficient evidence that hypothermia improves outcome to justify its use (Mackay MT, 2007).
Medical or surgical treatment of intracranial hypertension syndrome, when present, is important because children have a greater risk of herniated tonsils due to cerebral edema. Hyperventilation is a short-term solution which should be used under imminent hernia until definitive therapy can be offered (decompressive neurosurgery) (Jordan LC, 2008).
2. Anticonvulsants and EEG monitoring
Seizures are a common complication of stroke in children, affecting <25% of children with arterial ischemic stroke (LC Jordan, 2011). Pediatric stroke guidelines do not recommend the prophylactic use of anticonvulsants in ischemic stroke, but they are also not making recommendations for hemorrhagic stroke. Note that there are no studies of prophylactic use of anticonvulsants performed in children with stroke (ES Roach, 2008).
Continuous EEG monitoring is often used in intensive care units, although the benefit of this technique remains unproven. A study of 100 children who had continuous EEG monitoring for a wide range of clinical indications, not necessarily for stroke, showed the need for initiation or titration anticonvulsant dose in 43 patients. In many of these cases, the indication for EEG monitoring was extended due to lack of response after clinical seizures (NS Abend, 2011). The application of these data in children with acute ischemic stroke without a history of seizures is unclear. However, continuous EEG monitoring should be considered in children who have persistent altered mental state which is not clearly explained by stroke, or has changes in vital signs that are suggestive for seizures, but can not be captured on a routine EEG.
3. Anticoagulant and anti-aggregation platelet agents therapy
The choice of anticoagulant and anti-aggregation platelet agents is controversial and there is little data to guide this decision in children.
As anticoagulant therapy, both unfractionated heparin and low molecular weight heparin (LMWH) have been used in children with arterial ischemic stroke. Current guidelines recommend the use of anticoagulant in children with arterial dissection or cardioembolic stroke, demonstrated or being in state of diagnosis, until the exclusion or confirmation of cardiac etiology of arterial dissection. Heparin should be used in children with a high risk of recurrence and a low risk of secondary hemorrhage (LC Jordan, 2011).
According to international medical literature, LMWH in doses of 1 mg / kg every 12 hours is a safe start of therapy for ischemic stroke in infants and children. Hemorrhagic stroke must be excluded before the start of administration. Low molecular weight heparin offers several advantages over standard unfractionated heparin and oral anticoagulants: lower risk of heparin-induced thrombocytopenia, fewer drug interactions, fewer adverse effects on bone when long-term administered and small costs. Moreover, LMWH is administered subcutaneously and it demonstrates a predictable age-dependent pharmacokinetics and lower need for monitoring, therefore reducing the need for multiple venous punctures (ES Roach, 2008). Enoxaparin (1 mg/kg subcutaneously for children older than two months, or 1.5 mg/kg in infants less than 2 months) is most commonly used LMWH in children. In children with heart embolism, LMWH is administered for 3 to 6 months (P Monagle, 2008).
Regarding anti-aggregation platelet, even in the absence of randomized studies of aspirin use in acute treatment of arterial ischemic stroke in children, most experts believe that it is useful for secondary stroke prevention. The standard dose is between 1 and 5 mg/kg/day for 3 to 5 years after the acute event, taking into account the increased risk of Reye syndrome. Clopidogrel, used in doses of approximately 1 mg/kg/day, had good results in children who can not take aspirin (Soman T, 2006).
Thrombolysis with tissue plasminogen activator (tPA) is not commonly used today, and most guidelines do not recommend the treatment in children less than 18 months, although it is, along with the surgical removal of the thrombus, the only treatment that limits brain damage after a stroke. There is no consensus regarding the use on older children who meet standard adult tPA therapy (ES Roach, 2008). In addition, the diagnosis of stroke in children is usually determined by the time required for intravenous or intra-arterial tPA administration (between 3 and 6 hours after onset) (Jordan LC, 2011).
In children who had arterial ischemic stroke associated with a Sickle cell disease, antiplatelet agents and anticoagulants are usually not recommended. However, transfusions are recommended to reduce HbS to <30%. This approach includes both secondary and primary stroke prevention. There is no scientific-sustained evidence which indicates that acute transfusion in case of first arterial ischemic stroke is as effective as chronic transfusions, although they are commonly performed in clinical practice (Jordan LC, 2011).
Generally, the choice between antiplatelet and anticoagulant therapy for children with this pathology varies geographically (centers in the United States use anticoagulant therapy more frequently than centers in Australia, Europe and Canada). Some researchers argue that these geographical differences in care do not permit a balance that could be at the basis of a randomized trial on aspirin versus anticoagulants. (Goldenberg NA, 2009).
4. Surgery therapy
Hemicraniectomy can be a lifesaver in adults faced with extended arterial ischemic stroke and a rapid deterioration in the level of consciousness or shows signs and symptoms of impending herniation. In children, no formal studies of the benefit of hemicraniectomy in the same conditions exist. In a study conducted in 2011 on 10 children with malignant middle cerebral artery infarction, seven had undergone hemicraniectomies (Glasgow score between 4 and 9). All of them survived and experienced a moderate recovery (all seven had hemiparesis, but walking and fluent speech were possible despite left infarctions). The three children who died, did not suffer hemicraniectomies and died due to increased intracranial pressure. Researchers who conducted the study recommended taking in consideration of hemicraniectomy in children with malignant middle cerebral artery infarction, even in the presence of deep coma (Smith, 2011).
These are present in more than half of the children who had arterial ischemic stroke. Motor deficits are most easily observed in these children, while the cognitive deficits are more subtle.
Up to 25% of children with acute stroke will have convulsions. However, no clear data are available on the persistence of seizures and development of epilepsy. Cortical lesions and persistence of crisis more than 2 weeks after the acute event were identified as risk factors for secondary epilepsy (Everts R, 2008).
The young age, male gender and bihemispheric infarct are considered to be adverse prognostic factors after arterial ischemic stroke (Ciccone S, 2011).
- Except for sickle cell disease, stroke is relatively rare in children. Moreover, the risk and clinical presentation factors are distinct, compared to adults, leading to delayed diagnosis
- There are many challenges in the assessment and treatment of these children, including non-recognition by families and health care providers, the frequent need of anesthesia for MRI diagnosis and lack of treatment studies, beside sickle cell disease
- There is no uniform approach of treatment. Until randomized pediatric clinical trials based-data become available, the treatment guidelines for acute care of children with stroke will remain extrapolated from adult guidelines
- General supportive measures for arterial ischemic stroke should include fever control, maintaining a normal level of oxygen, control of hypertension and normalization of glucose levels. In the absence of additional data which could confirm the safety and efficacy, hypothermia should not be used in these children, unless in the context of a clinical trial. There is no evidence that the use of supplemental oxygen is beneficial in children with stroke in the absence of hypoxemia
- In the absence of clinical or electroence-phalographic seizures, prophylactic antiepileptic drugs in children with ischemic stroke is not necessary
- There are treatment studies needed for arterial ischemic stroke therapy, including safety studies of treatment with tPA, as well as studies comparing anticoagulants and antiplatelet efficacy in secondary stroke prevention.
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