|Ahead of print
Risk factors, clinical characteristics, and outcomes of recurrent pediatric stroke: A study from Bangladesh
Kanij Fatema, Md Mizanur Rahman
Department of Pediatric Neurology, Institute of Pediatric Neurodisorder and Autism (IPNA), Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
|Date of Submission||19-Jul-2020|
|Date of Decision||27-Aug-2020|
|Date of Acceptance||01-Oct-2020|
|Date of Web Publication||12-Jul-2021|
Department of Pediatric Neurology, Institute of Pediatric Neurodisorder and Autism (IPNA), Bangabandhu Sheikh Mujib Medical University, Dhaka.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objective: Stroke is relatively rare in children, but it can lead to significant morbidity and mortality. Understanding the risk factors related to stroke will optimize the outcomes in children. Published cohorts of children with stroke recurrence rates are variable. This study has been done to determine the risk factors, clinical features, and outcomes of recurrent pediatric stroke in a developing country. Materials and Methods: We enrolled 98 children with stroke: 16 children were excluded due to incomplete investigations and were lost to follow-up. This study was conducted in a tertiary care hospital in Dhaka, Bangladesh from January 2017 to December 2019. Detailed investigations regarding stroke, physical examination, and targeted investigations were done. Results: We studied 82 patients: Among them, 52 had their 1st attack, and 30 had recurrent attacks of stroke. The age range of onset of stroke was 4.78 ± 3.90 and 5.30 ± 4.25 in the first and recurrent stroke, respectively. In this study, 36.5% of the enrolled children presented with a recurrence of stroke, whereas the rest presented with the first episode of stroke. The most common cause of recurrent stroke was intracranial vasculopathy, with the most common being vascular narrowing and moya moya disease (MMD). Protein C deficiency was observed more frequently in recurrent stroke. No significant difference was found in the risk factors of the first and recurrent stroke. During follow-up, patients with recurrent stroke developed cognitive decline, epilepsy, and speech disorder more frequently. Conclusion: In children with recurrent stroke vasculopathy, particularly MMD and protein C deficiency were observed more frequently. Moreover, in this group, sequelae-like cognitive dysfunction, speech disorder, and epilepsy were observed more frequently.
Keywords: Childhood, recurrent, risk factors, stroke
| Introduction|| |
Stroke in children is not unusual. Compared with patients with adult stroke, stroke in children is not easy to identify immediately due to varying signs and symptoms and more nonlocalizing features. Pediatric stroke has a high percentage of death and disability. It is one of the top 10 causes of death in children. Those who survive stroke may develop permanent neurological deficits. The sequel of stroke is observed in 50% to 80% of patients with pediatric stroke. Thus, pediatric stroke has a substantial long-term medical and financial burden on families and the society.,,
In a recent population-based study, the incidence of pediatric stroke was 5.9 per 100,000 children. Among them, 3.3/lakh were ischemic stroke, and 1.8/lakh were hemorrhagic stroke. A significant number of pediatric strokes have recurrence. This stroke mostly occurs in the case of arterial ischemic stroke (AIS). Recurrent AIS is defined as clinically symptomatic AIS events manifested as acute focal neurological deficits with infarction in a vascular distribution in neuroimaging, which begins in more than 24 hours after the onset of the first stroke.
In different previous studies, the 1-year cumulative recurrence rate of pediatric stroke was 6.8% to 15% and the 5-year cumulative recurrence rate was 15%.,, The understanding and identification of the risk factors of stroke are critical for the timely initiation of targeted therapy and for improving strategies for secondary stroke prevention. From previous studies on childhood recurrent stroke, it has been revealed that arteriopathies are the major predictors of recurrence. Other contributing factors are infection, cardiac diseases, and coagulopathy.,
The study of stroke, particularly of recurrent stroke, in the pediatric population is limited. Thus, the aim of the study was to highlight the possible risk factors, clinical profile, investigation profile, treatment, and outcomes of patients with recurrent pediatric stroke in a developing country such as Bangladesh.
| Materials and Methods|| |
This study was conducted in a tertiary care hospital in Bangladesh from January 2017 to December 2019. Children from 6 months to 18 years were taken as study subjects. Demographic information of the patients was obtained, including age and sex. Patients were divided into two categories: ischemic stroke and hemorrhagic stroke. The cases with hemorrhagic transformation of ischemic stroke were enrolled as mixed stroke. Again, they were divided into two types: first attack and recurrent attack of stroke. Informed written consent was obtained from the guardian of all the patients. Permission was obtained from the institutional review board.
Recurrent stroke was diagnosed on the basis of two criteria: (1) imaging evidence of a new acute infarction/hemorrhage in a territory of the brain that was unaffected on baseline parenchymal imaging; and (2) new or worsening clinical signs and symptoms corresponding to the new area of infarction/ hemorrhage. Hemorrhagic stroke after the index AIS was also considered a form of recurrence and was defined as a symptomatic intracerebral or subarachnoid hemorrhage. Transient ischemic attacks (TIAs) were recorded, but they were not incorporated in our definition of recurrent stroke.
Detailed history regarding the presenting features, number of recurrence, risk factors, or underlying disease conditions was taken and recorded. In every patient, the following investigations were done: complete blood count (CBC), iron profile, prothombin time, activated partial thromboplastin time (APTT), liver function test, renal function test, thyroid profile (FT4, TSH), ANA, and anti DS-DNA. In all patients, an magnetic resonance imaging of the brain and an magnetic resonance angiography were done. In case of hemorrhagic stroke serum factor VIII, IX and von Willebrand factor (VWF) were done. In case of ischemic stroke, antiphospholipid antibody, anticardiolipin antibody, serum homocysteine, antithrombin III, factor V labile, Protein C, and Protein S level were investigated. In a suspected case of metabolic disease, tandem mass spectrometry (TMS) and gas chromatography mass spectrometry (GCMS) were done. In a probable case of cerebral sinuvenous thrombosis (CSVT), magnetic resonance venography (MRV) was done.
In case of ischemic stroke, antithrombotic therapy was given in the form of heparin or warfarin in selected cases. Antiplatelet drug aspirin was given for prevention of secondary strokes. In case of hemorrhagic stroke, treatment was given according to the cause (factor replacement, plasma infusion etc.). Patients were followed up for a period of 6 months up to 3 years.
| Result|| |
Clinical demography of the studied children
In this study, 98 children with stroke were enrolled; 16 children were excluded due to incomplete investigations and were lost to follow-up. Finally, 82 patients had been studied. Among them, 52 had their 1st attack and 30 had recurrent attacks of stroke. The mean age of the studied children was 4.97 ± 4.01 year, and the age range was 6 months to 18 years. The age of onset of stroke was earlier in patients with recurrent stroke. A male predominance was observed in both groups; however, in the recurrent stroke group, it was more (4:1) [Table 1].
[Table 1] shows that there was no statistically significant difference between the age of children and the age of onset of stroke in both groups. Only patients with ischemic stroke had a recurrent attack (30); 88.46% of patients with 1st stroke and 93.3% of patients with recurrent stroke had anterior circulation involvement.
Type of stroke in the studied subject
Among the studied subjects, 52 had their 1st attack and 30 had recurrent attacks. Overall, 27 patients had 2 attacks and the rest had 3 or more attacks. One patient had four attacks, which was the highest number of attacks. In patients with ischemic stroke, 43 had their 1st attack and 30 had recurrent attacks. None of the patients with hemorrhagic and mixed stroke had recurrent attacks. Regarding the circulation involved, most of the patients in both groups had anterior circulation stroke (88.46% in 1st stroke and 93.3% in recurrent stroke) [Table 1].
Clinical manifestations of the studied subject
The most frequently occurring clinical feature was hemiparesis (82.7% in 1st stroke and 86.7% in recurrent stroke). Seizure was also common, occurring in more than one third of the patients in both groups. Other features observed were cranial nerve palsy (mostly facial nerve, in some patients 3rd, 4th, 9th, and 10th cranial nerves were involved), dysphasia/aphasia, vomiting, headache, loss of consciousness, ataxia, visual impairment, nuchal rigidity, and papilloedema. No significant difference was observed between the 1st stroke and recurrent stroke in view of clinical features. However, aphasia, loss of consciousness, visual impairment, and papilloedema were observed more frequently in recurrent strokes [Table 2].
[Table 2] shows the clinical features of the 1st stroke and recurrent stroke. No significant difference was observed in both groups. The most frequent clinical features were hemiparesis, seizure, cranial nerve palsy, and aphasia.
[Table 3] shows that in AIS, the most common cause was internal vusculopathy. Infection and cardiac causes were also important. Interestingly 14 patients had no risk factors and 2 patients had multiple risk factors. Among the vascular causes of stroke, the most common were narrowing of the vessels and MMD.
|Table 3: Risk factors of studied subjects with arterial ischemic stroke (AIS) (n = 73)|
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Risk factors of the study subjects
In 73 patients with AIS, the most common cause was intracranial vasculopathy, comprising about 36.2% in the case of 1st stroke. However, in the case of recurrent stroke, 66.7% patients had vasculopathy. Other important risk factors were infection, cardiac diseases, coagulation disorders, and extracranial vasculopathy. No consequential difference was observed between the two groups. In the cases with vascular stroke (39), nonspecific vascular abnormality was present in 47.4% of patients with 1st stroke and in 55% of patients with recurrent stroke. The vascular abnormality observed here was mainly a narrowing or stenosis of blood vessels (not MMD). Other important types of vascular abnormality were MMD, postvaricella angiopathy, arteriorvenous malformation (AVM), Takayasu arteritis (TA), migraine, CSVT and vusculitis. Among the studied subjects, three patients had cardiac problems, and all these problems were observed in patients with 1st stroke. The patterns of cardiac problems were Tetrallogy of Fallot (TOF), rheumatic vulvular disease, and atrial septal defect (ASD). Eight patients of the study group had coagulopathy (7.69% in 1st stroke and 10% in recurrent stroke). In the case of recurrent stroke, three patients had protein C deficiency, and one had iron deficiency anemia (IDA); however, in the case of 1st stroke, two patients had antiphospholipid antibody syndrome, one had IDA, and one had protein C deficiency. The risk factors in hemorrhagic stroke were hemophilia (2), leukemia (2), AVM (1), and thrombocytopenia (1). None was in the recurrent stroke group. Most of the patients in the study groups had a single risk factor (53.8 % in 1st stroke and 66.7% in recurrent stroke). However, multiple risk factors were present in 19.2% of patients with 1st stroke and in 20% of patients with recurrent stoke. Interestingly, in 26.9% of patients with 1st stroke and in 13.3 % of patients with recurrent stroke, no risk factor had been detected [Table 3].
The patients who came to the hospital immediately after a stroke were admitted; attention was given to maintain airway, breathing, and blood pressure. None of the patients was treated with thrombolytic therapy. Antithrombotic therapy was given to 3 patients with warfarin; aspirin was given to 33 patients. In the case of recurrent stroke, warfarin was given to six patients, heparin to two patients, and both to two patients. Here, all 30 patients got maintenance arpirin to prevent further stroke. The patients with cardiac risk factors were treated with cardiology consultation [Table 4].
|Table 4: Distribution of the study subjects by treatment in patients with AIS and CSVT (n = 8)|
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[Table 4] shows the specific treatment of patients with AIS. Here, antithrombotic treatment was given with warfarin and heparin. Aspirin was used as antiplatelet therapy.
There was a significant difference in the recovery of patients with 1st stroke and those with recurrent stroke. Complete recovery occurred in only two patients (6.66%) with recurrent stroke whereas it occurred in 17 patients (32.69%) with 1st stroke. Among the complications, most patients had residual hemiparesis on follow-up. The other complications observed were epilepsy, speech disorder, cognitive dysfunction, behavioral abnormality, and learning disorder. Speech disorder, cognitive dysfunction, and epilepsy were present significantly more in patients with recurrent stroke [Table 5].
[Table 5] shows the outcomes of the studied subjects. Patients with complete recovery were significantly more in the 1st stroke group than in the recurrent stroke group (P < 0.05). Speech disorder and cognitive dysfunction were significantly more in the cases with recurrent stroke.
| Discussion|| |
Pediatric stroke is an important cause of disability; however, its etiology is often undetected. A significant number of patients have recurrence of pediatric stroke. Certain risk factors are responsible for recurrent stroke. Data regarding the risk factors and predictors of recurrent stroke are scarce till date.,, Conditions associated with the 1st stroke include vasculopathies, congenital and acquired heart disease, sickle cell diseases, prothombotic states, and infection. Vascular etiology showed fourfold odds in causing recurrent stroke, as observed in some studies. According to some authorities, stenosis of cerebral vessels and multiple infarcts in neuroimaging possess a higher risk of recurrence. The information about recurrent stroke can help to ascertain the investigation and management strategy, thereby diminishing the chances of further stroke.
In this study, 53.8% of patients with 1st stroke and 66.7% of patients with recurrent stroke had a single risk factor. A good number of patients had multiple risk factors and these were almost identical in both groups. In pediatric stroke, a significant number of patients may not have identified a risk factor. For instance, in a study by Ganesan et al., about half of the patients did not have any risk factor. Again, in a study done by Ghofrani et al., 40.1% of the cases had an undetermined risk factor. In our study, the undetermined risk factor was almost twice in 1st stroke in relation to recurrent stroke (26.9% versus 13.3%). This may be explained by more detailed follow-up investigations of the patients with recurrent stroke.
The identified risk factors of pediatric stroke vary in different studies; they also differ in various regions. In a study done by Lyle et al., they reported that the most common risk factor of AIS was congenital heart disease, sickle cell disease, arterial dissection, and MMD. In another study done by Lo et al., the common risk factors were congenital heart disease and infections such as sepsis and meningitis/encephalitis. Meanwhile, in the patients with AIS of this study, the most common risk factor was intracranial vasculopathy. It was almost double in recurrent stroke (36.2% in 1st stroke and 66.7% in recurrent stroke). The most prevalent form of vasculopathy in this study was arterial stenosis, occurring in almost half of the patients in both groups. Arterial stenosis was also the most common risk factor in the study done by Goffrani et al. and Fullerton et al. The etiology of isolated vessel stenosis in children remains unknown and may be heterogeneous. It may be congenital or acquired. The congenital causes are like hypoplastic arteries seen in PHACE (posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta, cardiac defects, and eye abnormalities) syndrome. These may be either transient or progressive. Thus, these patients need clinical and neuroimaging follow-up. For example, two of our cases had transient cerebral arteriopathy, which was associated with varicella infection.
MMD is a progressive cerebrovascular occlusive disease of the bilateral internal carotid arteries that leads to a compensatory abnormal vascular network at the base of the brain. It is an important cause of recurrent stroke in children. In one study by Lee et al., in a total of 174 children with MMD, 90% presented with ischemic stroke, 7.5% with transient ischemic attack, and 2.5% with hemorrhagic stroke. One-third of patients had moya moya syndrome. Stroke recurrence was 20% over a median follow-up of 13 months, and 9% had multiple recurrences. Here, we also observed that more children with MMD were in the recurrent stroke group (35% in the recurrent stroke group and 15.8% in the 1st stroke group in children with vasculopathy). Here, other forms of vasculopathy such as AVM, TA, migraine, CSVT, and vasculitis were also observed.
Cardiac diseases are an important cause of pediatric stroke. In children with a cardiac repair or catheterization, nearly 50% of strokes occur within 72 hours. Long-standing cyanotic lesions cause polycythemia and anemia, both of which increase the risk of thromboembolism and cerebral infarction. Moreover, embolic clots can arise in children with cardiomyopathies, rheumatic heart disease, prosthetic valves, or valvular vegetation from endocarditis. In previous published studies, congenital and acquired heart disorders accounted for about 10–40% of pediatric ischemic stroke.,,,, In most of the studies, it was the second common cause of pediatric stroke. In our study, it was the third common cause, comprising about 6.4% of the studied subject. The percentage was less in comparison to the published studies. Our patients had TOF, ASD, and rheumatic heart disease.
Another important cause of stroke in pediatric age is coagulopathy. Prothrombotic disorders should be suspected in case of early stroke or recurrent stroke. It may be acquired in case of renal and liver diseases or it may be congenital. In this study, we had eight patients with coagulopathy. Congenital protein C deficiency was common here in patients with recurrent stroke. The other causes found were antiphospholipid antibody syndrome and IDA. In a study done by deVeber et al., the other prothrombotic risk factors were antithrombin III deficiency, elevated lipoprotein (a) etc., which were absent in this study. It has been mentioned that prothombotic disorders are increasingly associated with recurrence, which has been observed in our study also (10% in recurrent stroke and 7.69% in 1st stroke). We had six cases of hemorrhagic stroke, but we did not have any in the recurrent stroke group. Among them, two had hemophilia, two had leukemia, and the others had AVM and thrombocytopenia. These findings have similarity with a previously published paper.
For developing countries, the IDA is a significant risk factor of AIS in otherwise healthy children. In previous studies, it had been seen that children with IDA have a 10-fold increased risk of AIS than those without IDA. Further, children with IDA accounted for more than half of the stroke cases in children without an underlying medical illness. The CSVT is more associated with IDA then AIS. Two cases of AIS and one case of CSVT in our study had IDA. There are three mechanisms that can explain the association between IDA and childhood ischemic stroke: (i) a hypercoagulable state directly related to iron deficiency and/ or anemia; (ii) thrombocytosis secondary to IDA; and iii) anemic hypoxia, whereby a mismatch between oxygen supply and end-artery oxygen demand leads to ischemia and infarction.
In the International Pediatric Stroke Study, about 24% of AIS patients had infection. However, vaccination seems to be protective in the case of stroke. Patients with recent infection were observed to have a sixfold increased risk of stroke. The most common infection causing stroke was upper respiratory tract infection. Children with few or no vaccinations have a sevenfold increased risk of stroke. In our study, 17% of patients with 1st stroke and 3.3% of patients with recurrent stroke had a recent history of infection. Most of the patients here had upper respiratory tract infection, and some had gastroenteritis. This had similarity with the study done by Fullerton et al., where they found that recent infection and poor vaccination status were not related to recurrence of pediatric stroke.
In pediatric stroke, the clinical manifestations are often subtle. Thus, diagnosis is delayed and often missed. Therefore, both localizing and nonlocalizing features should be emphasized and stroke should be excluded. In this study, hemiparesis occurred in 82.7% of cases with 1st stroke and in 86.7% of cases with recurrent stroke. The other clinical features were seizure, cranial nerve palsy, dysphasia/aphasia, vomiting, headache, loss of consciousness, ataxia etc. This had similarity with other studies., It is worth mentioning here that the neurological features are age related in children. Older infants with AIS usually present an acute focal neurological deficit typically with hemiparesis, whereas school-aged children present speech, sensory, or visual deficits. Diffuse symptoms are common in children. In some studies, up to 50% patients presented with diffuse symptoms such as headache, lethargy, confusion etc. In this study also, a significant number of patients presented with diffuse clinical manifestations such as headache, aphasia, vomiting, loss of consciousness, ataxia etc.,
There is little consensus regarding the treatment of pediatric AIS with antithrombotic therapy and antiplatelet therapy. In a retrospective population-based cohort study of AIS patients, only 51% were treated with aspirin or anticoagulation, and the 1-year cumulative recurrence rate was 15%. In another study of 212 children with AIS, 46% were treated with an antithrombotic agent, and the 5-year cumulative recurrence rate was 18%. In another study where 87% patients were treated with an antithrombotic agent after the baseline stroke, 1-year cumulative recurrence rate was 12%. In our study, during the 1st attack, 3 patients were treated with warfarin and 33 patients were treated with aspirin. In the case of recurrent stroke, six patients were treated with warfarin, two with heparin, and two with both. Here, all patients were treated with aspirin. We used limited antithrombotic drugs due to limited facility of monitoring.
The mortality of children with stroke is lower than in adults, but it causes significant long-term sequelae in children. In previous studies, it had been observed that 55% of the children developed sequelae, and 15% died. In our study, none of the patients died, and 19 (30%) out of 82 had completely recovered; patients with recurrent stroke had significantly lower complete recovery in comparison to patients with 1st stroke. Cognitive dysfunction and speech disorder were significantly more in recurrent stroke.
Regarding the demographic features, we did not find any significant difference in 1st stroke and recurrent stroke in age of the patient, age of onset, and sex. However, in patients with recurrent stroke, the age of onset seemed to be earlier. A male predominance was observed in both groups.
This study has some limitations. The first was the short time of follow-up of the patients and the loss to follow-up. The second was the lack of repeated imaging in all cases. The third was that we had only included patients who were referred to a tertiary care center. Thus, a further long-time prospective nationwide study is needed.
| Conclusion|| |
This study provides the information regarding risk factors and clinical features of patients with pediatric stroke. We highlighted the features of recurrent stroke here, which is the least studied in this age group. We did not find any significant differences in the risk factors of the patients with 1st stroke and those with recurrent stroke. However, vasculopathy, particularly MMD and protein C deficiency, was observed more frequently in recurrent stroke. Complete recovery was less in patients with recurrent stroke; regarding sequel, speech dysfunction, epilepsy, and cognitive dysfunction were observed more frequently in patients with recurrent stroke.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]