Eur J Pediatr DOI 10.

1007/s00431-012-1863-9

REVIEW

Therapy in pediatric stroke

B. Simma & I. Hliner & J. Luetschg

Received: 31 July 2012 / Revised: 3 October 2012 / Accepted: 6 October 2012 # Springer-Verlag Berlin Heidelberg 2012

Abstract The aim of this review is to summarize the existing literature on therapy and management of cerebrovascular insults in children and adolescents. As data sources, studies were identified by MEDLINE, PubMed, Cochrane Library, and relevant bibliographies for the topic pediatric stroke. We also reviewed guidelines for stroke in adults. As a result, pediatric stroke is underestimated. The annual incidence for all stroke entities (cerebral venous thrombosis and hemorrhagic and arterial ischemic stroke) is as high as for pediatric brain tumors, 315/100.000 children per year. A distinct etiology can be determined only in a minority of them. Underlying risk factors are multiple, mainly vasculopathies, congential heart diseases, coagulopathies, lipometabolic disorders, and sickle cell anemia. Current recommendations for therapy are based on adult studies, are preliminary, and discussed controversially. Antithrombotic therapy is uniformly recommended for the acute stage of pediatric stroke; no consensus exists on antiplatelet therapy with acetylsalicylic acid (ASA, aspirin) (5 mg/d), with ultra-fractionated or low-molecular-weight heparin. Thrombolysis using recombinant tissue plasminogen activator is not advised, despite the fact that current practice takes a different approach. None of the guidelines specify the duration of ASA for secondary prevention. Additional supportive therapy measures are osmotherapy and decompressive craniectomy. Oxygen in the absence of hypoxemia, intensive insulin therapy, antiepileptic drugs in the absence of clinical or electrographic seizures, corticosteroids, and GPIIb/IIIa-receptor antagonists should not be used outside clinical trials. In conclusions, current therapeutic guidelines for pediatric stoke are still based on consensus and expert and
B. Simma (*) : I. Hliner : J. Luetschg Department of Pediatrics, Academic Teaching Hospital, Landeskrankenhaus Feldkirch, Feldkirch 6800, Austria e-mail: burkhard.simma@lkhf.at

society opinions and differ between countries. Consensus prevails on the need for acute anticoagulation using either antiplatelets or heparin. Long-term treatment with acetylsalicylic acid in all or only high-risk patients and for how long remains the subject of debate. Lifelong secondary prevention has never been investigated in children or adults. All guidelines agree that there is no indication for thrombolysis in children outside clinical trials, although clinical practice in large centers differs. Keywords Pediatric stroke . Risk factors . Anticoagulation . Thrombolysis

List of abbreviations AHA American Heart Association AIS Arterial ischemic stroke ASA Acetylsalicylic acid CVT Cerebral venous thrombosis ICH Intracerebral hemorrhage LMWH Low-molecular-weight heparin rtPA Recombinant tissue plasminogen activator UFH Ultra-fractionated heparin

Introduction While stroke in children remains an underestimated disease, it has become better recognized in recent years. The World Health Organization defines stroke as [74] a state of rapidly developing clinical signs of focal or global disturbance of cerebral function, with clinical symptoms with no apparent cause other than of vascular origin Stroke is caused by the interruption of blood supply to the brain, usually a blood vessel bursts or is clogged by a clot [37].

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The annual incidence of pediatric stroke ranges from 0.5 1.0 for cerebral venous thrombosis (CVT) to 15 for hemorrhagic stroke and 213/100.000 children for arterial ischemic stroke (AIS) [3, 29, 64]. This corresponds with the incidence of pediatric brain tumors. The clinical and therapeutic management of stroke in the pediatric age group is based on adult studies and is preliminary or discussed controversially, like antithrombotic treatment and/or thrombolysis. Current recommendations are based on statements made by writing groups and societies from different countries, namely the UK [19, 20] and the United States [53, 56]. Although recommendations in these three guidelines largely agree, they also vary on some points. The purpose of this review is to discuss current therapeutic recommendations for pediatric stroke. In order to understand this topic, some aspects of the etiology and underlying risk factors need to be highlighted.

Method A PubMed search using the keywords therapy, management, treatment, pediatric stroke in children excluding neonates, neonatal, congenital, adult identified 168 articles of interest published since the year 2000. Twelve clinical trials and 23 case reports but no controlled studies or meta-analysis were found. Six guidelines and 47 reviews were retrieved. These articles were manually screened by two of the authors (BS, JL). Inclusion criteria were clinical studies in peer-reviewed journals and case reports for therapeutic interventions. We excluded reviews based on single cases, and those guidelines not related to the topic (e.g., resuscitation, atherosclerosis). Additional publications were identified via citations in these articles. The authors included 11 clinical trials [5, 9, 12, 15, 30, 36, 52, 61, 62, 65, 68], five guidelines [19, 20, 51, 53, 56], and seven reviews [10, 13, 17, 35, 57, 74] congruent with the topic therapy in pediatric stroke. Additional references are publications about epidemiology [3, 25, 29], clinical symptoms [1, 64], risk factors [4, 68, 14, 21, 26, 27, 3846, 4850, 54, 60, 66, 71, 72], and references for supportive therapy [24, 55, 59, 63, 67] on this topic. We also cited clinical trials [3133, 47, 70, 73] and guidelines [2, 11, 18, 23, 28] for therapy in adult stroke from different countries (US, Europe).

circulation of intracerebral arteries (hemiparesis, facial palsy) are the main complaints, whereas seizures and symptoms of the posterior circulation (Arteriae vertebrobasilares) like dysphasia, headache, and nausea are less common [1, 64]. Note that aphasia is often misdiagnosed or mistaken as confusion, anxiety, or oppositional behavior. Risk factors for AIS can be divided into vasculopathy (stenosis, dissection, occlusion, Moyamoya disease, OMIM 252350, 607151, 608796, 614042) (15 %50 %) [4, 64], congenital heart disease (25 %) [44, 64], coagulopathy (40 %) [39, 40, 43] including lipometabolism disorders (20 %85 %) [60, 64], infection (meningitis, varicella) (30 %50 %) [6, 42], genetic disease (Down syndrome, OMIM 190685, Fabry disease, OMIM 301500), metabolic stroke (1 %), iron deficiency anemia [45], and sickle cell anemia, OMIM 603903 (5 %30 %). Congenital heart disease has been recognized but may be underestimated in its importance as a cause of thromboembolic events: Stroke can be seen prior to cardiac surgery in 8 %20 %, due to any bypass surgery in 10 %20 % [46, 49], balloon procedure in 40 % (!) [50], Fontan procedure in 2 %16 % [14], and due to heart transplantation in 25 % [48] of patients. On the subject of coagulopathy as a risk factor for AIS, two metaanalyses have been published (Table 1): elevated lipoprotein (a) is the most common risk factor, followed by factor V Leiden, OMIM 612309, prothrombin mutation G20212A, and antiphospholipid antibodies. Lipoprotein data are derived from only four studies, and delayed blood sampling can cause transient low levels of several coagulant factors (antithrombin, protein C or S). Thus, debates about whom to examine for thrombophilia, when, and for what reason will continue [39, 69]. Progesterone interacts with coagulation, platelet aggregation, fibrinolytic proteins, and vascular endothelial function, and each nanomole-per-liter elevation of serum progesterone increases the risk for AIS
Table 1 Risk factors for arterial ischemic stroke (AIS) and cerebral venous thrombosis (CVT) OR (95% CI) for AIS >2 risk factors Factor II G20210A Factor V Leiden Lipoprotein (a) Protein C deficiency Protein S deficiency Antithrombin III deficiency Antiphospholipid antibodies ns not significant Kenet G et al (2010) [15] and Trenor CC et al (2010) [25] 18 (6.5; 54) 2.6 (1.7; 4.1) 3.7 (2.8; 4.8) 6.5 (4.5; 9.6) 11 (5.1; 23.6) Ns Ns 6.9 (3.7; 13.4) OR (95% CI) for CVT ns ns 2.7 (1.7; 4.3) 6.3 (1.6; 25.4) 5.3 (1.5; 18.2) 18.4 (3.3; 104)

Arterial ischemic stroke (AIS) Symptoms and risk factors Clinical symptoms of AIS are characterized by a sudden loss of neurologic function [64]. Symptoms of the anterior

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by 30 %50 % [54], which might explain its male predominance in a ratio of 1:2 [72], despite the fact that progesterone level does not differ between the whole group of boys as compared with girls. In contrast, in animal studies, progesterone given within hours after a stroke decreases the amount of inflammation, preserves the myelin sheaths, and reduces the extent of the infarct [63]. No human studies using progesterone as a therapeutic option for stroke have been published to date.

Therapy Acute therapy Antiplatelet/anticoagulation Acute therapy for pediatric AIS is anticoagulation (Table 2), by means of antiplatelet therapy with acetylsalicylic acid (ASA, aspirin) (5 mg/d) [20], either with ultra-fractionated (UFH) or low-molecularweight heparin (LMWH) [53, 56]. However, to date, the literature contains only studies on the safety [12, 62, 65] but not the efficacy or superiority of one or the other drug. Intravenous UFH offers the advantage of optimal drug targeting and prompt reversal with protamine in the event of overdosing. A protocol for systemic heparin administration is provided in Table 3 [51]. LMWH (enoxaparin) is given subcutaneously at 1 mg/kg in children (1.5 mg/kg in neonates) every 12 h to aim for an anti-factor Xa level of 0.5 1.0 U/mL in a sample drawn 4 to 6 h after administration of the last dose [56, 58]. More than 10 % of the centers use both therapeutic strategies simultaneously, although there is no published basis for this [30]. In addition, up to 15 % of the children did not receive any treatment within the first 48 h because of late presentation, contraindication [9], or lack of in-hospital guidelines [30]. Duration of initial therapy is not limited by UK guideline [20], or therapy switches to aspirin after 1 week when the cause is determined [56], or cardioembolic stroke and dissection are excluded [53].

In pediatric cardiac patients, potential therapeutic regimes are vague (Table 2): anticoagulation [20] or LMWH [53] should be discussed or therapy of the heart problem [56]. In patients with extra-cranial arterial dissection, anticoagulation [20], LMWH [53], or UFH/ LMWH [56] is recommended. In a case series of 30 children with AIS, the prevalence of right-to-left shunting through a patent foramen ovale was significantly greater as compared with that of a control group [7]. Because no controlled studies exist, optimal treatment is unclear [21], and a patent foramen ovale should be closed only in those who suffered a recurrent paradoxic embolism due to aneursymal atrial septal defects [37]. For pediatric patients undergoing specific cardiac procedures, anticoagulation by heparin is recommended either intra- (BlalockTaussig shunt, endovascular stents) or postoperatively (Norwood, Glenn, Fontan procedure, ventricular assist device placement) followed by either aspirin (Blalock Taussig shunt, Norwood, Glenn), coumarine (Fontan), no therapy (endovascular stent), or a combination with antiplatelets (ventricular assist device placement). In children with dilated cardiomyopathy or mechanical prosthetic valves, lifelong prophylaxis with coumarine and in patients with biological valves prophylaxis with aspirin for 3 months is described [28, 53, 56]. Children with atrial fibrillation should receive coumarine. Varicella-related stroke occurs in 1:15.000 children with varicella or in 30 % of children with AIS. It should be diagnosed if the patient suffered from varicella in the preceding 12 months, has a unilateral stenosis of one great vessel, and a positive varicella polymerase chain reaction test and/or IgG in the lumbar puncture [6, 13, 37]. Besides the anticoagulation treatment mentioned above, patients may be treated with acyclovir (500 mg/m2) for 7 days, and even longer in immunocompromised children, and with corticosteroids (prednisone 6080 mg/day) for 3 to 5 days [37]. In general, outcome is good, and spontaneous improvement can be seen [37], which is why this therapy is discussed [6, 13, 37]. Progressive and non-progressive

Table 2 Acute arterial ischemic stroke (AIS): guidelines for therapy UK guidelines 2004 General Aspirin 5 mg/kg Chest guidelines 2008 Aspirin 15 mg/kg/day or UFH or LMWH until cardioembolic stroke and dissection are excluded, followed by aspirin as maintenance LMWH for >6 weeks LMWH for >6 weeks Exchange transfusion to HbS<30 % AHA 2008 UFH or LMWH (1 mg/kg every 12 h) for up to 1 week until cause is determined, followed by aspirin as maintenance Therapy for heart problem UFH or LMWH, then anticoagulation with coumarine Exchange transfusion to HbS<30 %

Cardiac Dissection Sickle-cell disease

Anticoagulation should be discussed Anticoagulation Exchange transfusion to HbS<30 %

From de Veber G et al (2008) [7]

Eur J Pediatr Table 3 Protocol for systemic heparin Aim, aPTT 6085 s0anti-factor Xa 0.350.70 U/mL Loading dose 75 U/kg in 10 min (optional) Initial dosage 20 (>1 year of age) to 30 U/kg/h (<1 year of age) aPTT Adjustment (U/kg/h): <50 s, bolus 50 U/kg +10 5059 +10 6085 0 8695 96120 >120 10 10 15

used in children, mainly those with cardiac problems [53]. Adequate data in children on its use either alone or in combination with ASA or clopidrogel are lacking [56]. Thrombolysis Therapy of stroke in adults is defined by a clear and distinct protocol: acute and specific treatment by means of thrombolysis and early prevention with ASA [2, 23, 28]; rtPA should be given within a time window of 4.5 h after onset of first clinical signs for intravenous and 6 h for intraarterial use and in thrombosis of the basilar artery even 6 to 12 h. Drug of choice is alteplase in a dosage of 0.9 mg/kg. Intravenously, the first 10 % should be given as a bolus, the remaining 90 % over 1 h. Intravenous administration between 3 and 4.5 h shows an additional clinical benefit [32], and alteplase is now licensed in Europe. If a great supratentorial vessel or the basilar artery is occluded, immediate IV thrombolysis is a bridge to a recanalization attempt using either local intraarterial lysis, placement of a stent, or embolectomy (bridging concept) [28]. Mechanical embolectomy is a therapeutic option in the treatment of mainly brainstem ischemia administered by devices licensed only for adults [15, 68]; it is reported in the literature in a very few children and adolescents. Clearly defined guidelines have not yet been published [15]. In children, two studies have been published on the use of thrombolysis (Table 4): A retrospective survey [36] found 46 (1.6 %) of 2,904 children, exclusively males with no underlying medical conditions, who were thrombolysed. The mortality rate was 19 %; the paper provides no data on complications like cranial bleeding or neurological deficit. In a prospective study [5] conducted by the International Pediatric Stroke Study (IPSS) group, 15 (2 %) of 687 children were thrombolysed, nine intravenously and six intraarterially. Median time to treatment after the first clinical symptoms was 3.3 (2.052.0)h for intravenous and 4.5
Table 4 Data on thrombolysis in children Thrombolysis 46/2,904 (1.6 %) Retrospective 46/46 (100 %) 0 24/46 (52 %) 9/46 (19 %) IPSS 15/687 (2 %) Prospective 6/15 (40 %) 13/15 (86 %) 9/15 (60 %) 4/15 (25 %) 2/15 (13 %) 12/13 (92 %)

Adapted from Michelson AD et al (1995) [32]

primary angitis of the central nervous system may present as well as AIS [35]. Improvement in diagnosis leads to increased recognition of this disease entity. However, no accurate incidence rate is available, and treatment options are reported to be high doses of glucocorticoids, possibly in combination with immunosuppressive agents (cyclophosphamide) [35, 56]. Secondary prevention Secondary prevention by means of ASA in adults (25 mg/ kg/day) (except UK) should be started early [20, 53, 56], but not before, and at least 4 h after thrombolysis is planned or was performed [28]. The risk of bleeding due to thrombolysis will be minimally elevated if a patient is already on ASA. None of the guidelines specify the duration of ASA prevention. Only the Chest guideline recommends, once dissection and cardioembolic causes are excluded, daily ASA prophylaxis for a minimum of 2 years [20]. In adults, lifelong prevention is state-of-the-art, although the benefit of such treatment for a period of more than 4 years has never been investigated [28]. Most recurrent strokes occur within 1 year after the first event, and the 5-year cumulative recurrence rate is 25 %40 % for any cerebrovascular event (stroke or transient ischemic attack) and 15 %20 % for stroke [26, 66]. None of the children with a normal cerebrovascular bed will have a recurrent stroke [26], whereas two thirds of those with abnormal cerebral vessels had at least one recurrent stroke [26, 27]. Therefore, ASA prophylaxis may be extended beyond the 2 to 4 years, depending on the risk factors, such as recurrent stroke, transient ischemic attack, and persistent vasculo- and coagulopathy or congenital heart disease [56]. In the case of a recurrent stroke while on ASA, the antiplatelet agent should be changed to clopidogrel [53]. Dipyramidole (25 mg/kg/day) is increasingly

Male Risk factors/associated medical conditions IV thrombolysis Complications (cranial bleeding) Mortality Neurological deficit

Janjua et al (2007) [4], Amlie-Lefond et al. for the International Pediatric Stroke Study (IPSS) Group (2009) [45]

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(3.824.0)h for intraarterial alteplase. Associated risk factors were documented in 13 (86 %) and intracranial bleeding in four (25 %) children, although none was reported as symptomatic. Two (13 %) children died, but none due to thrombolysis, while 12 of the remaining 13 children (92 %) survived with a neurological deficit. When compared with the 14 patients (ten IV, four IA) reported as case reports [5], the patients in the IPSS cohort were mostly younger, waited longer for treatment, and had poorer outcome. This suggests a publication bias towards more favorable outcome in the case reports published. A recent publication by the Swiss Neuro Pediatric Stroke Registry [9] reports that thrombolysis was performed in five (4 %) of 128 pediatric stroke patients in a 9-year period. No other demographic or outcome data were provided. All three published guidelines uniformly state that thrombolysis is not advised in children outside clinical trials. In teenagers, no consensus exists on its use. However, off-label use is practiced in the United States in children older than 3 years of age [personal communication from R. Ichord, Philadelphia] and in teenage children in Switzerland [personal communication from M. Steinlin, Bern].

guideline [20], but the Chest ACCP and AHA guidelines [53, 56] recommend either LMWH or UFH heparin until recanalization is seen [20] or until up to 3 to 6 months [53, 56]. In children in whom no improvement is documented, thrombectomy or surgical decompression [53] or, in selected children, administration of a thrombolytic agent may be considered [56]. Local thrombolysis by means of urokinase provides better functional outcome, but a higher risk of secondary complications like hemorrhage or seizure [73] as compared with systemic heparin. With regard to thrombus propagation and survival, recent studies in children [41, 52] and a Cochrane review in adults [17] conclude that anticoagulation in children with UFH is safe [17] and shows important clinical benefits in adults [17, 39]. For patients with CVT and hemorrhage, published guidelines range from no statement [20] or a recommendation for no anticoagulation [53] to the opposite recommendation for anticoagulation with either UFH or LMWH (Table 5) [56].

Hemorrhagic stroke Clinical symptoms of hemorrhagic stroke are sudden onset of massive, severe headache, focal neurological deficits, altered mental status, and seizures [8]. Causes are vascular malformation (aneurysm, cavernous, arteriovenous malformation), tumor (50 %75 %) but also underlying disease (10 %20 %) or trauma (25 %). In up to 20 % of hemorrhagic strokes, no cause was found [25]. Hemorrhage from arteriovenous malformation has a 25 % mortality rate. The overall recurrence rate is 10 %15 %, and all these patients showed a structural and/or vascular abnormality [8, 25]. Rebleeding will occur in 6 % of patients within the first 6 months and thereafter in 3 % per year [25]. The conclusions are thus as follows: 1. Every patient should have a complete workup to search for vascular abnormalities. 2. Because of the accumulating risk, arteriovenous malformation should always be treated, and,

Cerebral venous thrombosis (CVT) Clinical symptoms of CVT in children are diverse and nonspecific, most commonly including the triad headache, emesis, and depressed mental status plus seizures [10, 57]. Potential causes are systemic diseases like infection, dehydration, iron deficiency anemia, and prothrombotic abnormalities [10]. The estimated number of unknown or undiagnosed cases is high and may double the stated incidence of 0.51.0/100.000 children per year. Almost all (70 %100 %) patients will have more than one risk factor, and up to 60 % have prothrombotic abnormalities. Venous infarction occurs in half, and the rate of recurrence is lower than 5 % of patients [38]. Recommended acute therapy in all guidelines is antithrombotic therapy (Table 5): It is not specified in the UK

Table 5 Cerebral venous thrombosis (CVT): guidelines for therapy UK guidelines 2004 Cerebral CVT w/o ICH No improvement With ICH Anticoagulation until recanalization for up to 6 months Chest guidelines 2008 Initial UFH or LMWH, then LMWH or warfarin for 36 months Thrombolysis, thrombectomy, or surgical decompression Do NOT anticoagulate, repeat imaging d5-7. Anticoagulate if thrombus progresses. AHA 2008 Initial UFH or LMWH, then warfarin for 36 months Local thrombolysis can be considered. Initial UFH or LMWH, then warfarin for 36 months

Adapted from de Veber G et al (2008) [7]

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3. Because of the low rate of early rebleeding, definitive treatment should be performed on an elective basis [37]. Embolization may obliterate malformations or facilitate surgery by reducing the size of the malformation. The type of surgery depends on the size, venous drainage, and localization of the hemorrhage and demands critical evaluation and special experience. Patients with a cerebellar hemorrhage >3 cm in diameter benefit from early evacuation of the hematoma [11]. Other recommendations are again derived from adult studies [11], like osmotherapy or decompressive craniectomy for elevated intracranial pressure, although no controlled study on these approaches exists. A promising therapy with potential application in children is recombinant activated factor VII (eptacog alfa [activated], ATC code B02BD0), which is licensed by the Food and Drug Administration and the European Medicines Agency and promotes hemostasis. An adult study shows that treatment within 4 h reduces the size of the hematoma, decreases mortality, and may improve neurological outcome, despite a non-significant increase in the frequency of adverse thromboembolic events [47]. Aneurysms should be actively screened in asymptomatic children with a family history of more than one first-degree relative who suffered a hemorrhagic stroke (risk 1 %8 %), in children with an autosomal dominant polycystic kidney disease, OMIM 600666 (risk 1 %9 %), EhlersDanlos syndrome type IV (vascular type), OMIM 130050 or alpha1-antitrypsin deficiency, OMIM 613490. An initial study with magnetic resonance imaging and angiography should be repeated at the age of 21 years [37]. For the case of a positive finding, the recommendations do not give any advice on further procedure.

Table 6 General therapeutic measures Effective therapy Normothermia, normal oxygenation, normotension Euvolemia (1,800 ml/m2/day) Normoglycemia (4.48.3 mmol/L) Hb>6.2 mmol/L Osmotherapy (mannitol or hypertonic saline) Decompressive craniectomy Ineffective therapy Oxygen in the absence of hypoxemia GP-IIb/IIIa-receptor antagonists outside clinical trials Antiepileptic drugs in the absence of clinical or electrographic seizures Intensive insulin therapy Corticosteroids Hypothermia

Outcome Pediatric stroke has a mortality of around 10 % and is therefore among the top ten causes of childhood mortality. Recurrence rate ranges from <5 % for CVT to 15 %20 % for hemorrhagic stroke and AIS [26, 66]. Three quarters of the survivors have long-term neurological deficits [64]. However, no gold standard exists for comparison of the outcome in different pediatric stroke studies [22].

Other supportive and ineffective therapy Every child who suffers a stroke should receive a certain basic supportive therapy (Table 6): normal maintenance fluid (1,800 ml/m2/day), normothermia, normal oxygenation, no hyperoxygenation, normotension and normogylcemia (4.4

8.3 mmol/L), and hemoglobin levels should be higher than 6.2 mmol/L [56]. Osmotherapy with mannitol or hypertonic saline [53, 56] and decompressive craniectomy [8, 59, 61] can be considered in patients with clinical signs of herniation or elevated intracranial pressure. In adults, decompressive craniectomy significantly decreases mortality (from 70 %80 % to 20 % 40 %), without increasing the rate of neurological impairment in survivors. Three prospective adult trials (93 patients, 1860 years of age) calculate the number needed to treat to be two for one more survivor [70]. The benefit of surgery was similar when performed before or after 24 h, without any additional benefit seen 48 h after the insult. A major drawback is the negative outcome in adults with diffuse traumatic brain injury, of whom significantly more patients died, were in a vegetative state or severely disabled following decompressive craniectomy [16]. In summary, it is advised that decompressive craniectomy be performed in children before 48 h in cases of extensive stroke in the area of the middle cerebral artery [8, 28, 31, 61]. Moreover, monitoring of intracranial pressure may delay life-saving treatment and is unlikely to have any additional benefit [24, 55, 67]. Elevated body temperature can be seen in up to 25 % of patients suffering a stroke and is certainly associated with a poorer neurological outcome [28, 34, 56]. It is also known that induced hypothermia reduces the extent of the infarct in animal studies. In human adults, however, pooled data (eight trials, 423 patients) show no difference in terms of outcome. Therefore, cooling for stroke cannot currently be recommended outside clinical trials [18]. Thrombocyte aggregation inhibitors other than ASA, for example, GP-IIb/IIIa-receptor antagonists or radical scavengers, should not be used [56]. Prophylactic antiepileptic treatment in the absence of clinical or electrographic seizures,

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intensive insulin therapy, and corticosteroids are not recommended [56]. The risk of stroke in children may be quadrupled in cases of hyperhomocysteinemia, OMIM 603174 [71]. However, adults do not benefit from homocysteine reduction by means of vitamin B6, B12, and folic acid [28]. Thrombolysis by means of other drugs, like desmoteplase, has demonstrated improved reperfusion and better outcome in a small phase II study but could not be confirmed in a larger phase III study [33]. Intravenous streptokinase increases mortality and the risk of secondary hemorrhage [28]. In summary, current therapeutic guidelines for pediatric stoke are still based on consensus and expert and society opinions, and differ between countries, which emphasizes the need for larger prospective trials. Consensus prevails on the need for acute anticoagulation using either antiplatelets or heparin. Long-term treatment with acetylsalicylic acid in all or only high-risk patients and for how long remains the subject of debate. Lifelong secondary prevention has never been investigated in adults or children. All guidelines agree that there is not enough evidence for or against thrombolysis in children, although clinical practice in large centers differs.

Conflict of interest The authors disclose no conflicts of interest.

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