Dr Mirjam Janmaat at Department of Neurology, University Medical Center Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. E-mail: firstname.lastname@example.org
We report the case of a 4-year-old male with vertebrobasilar artery thrombosis for which he was treated with local intra-arterial urokinase 60 hours after onset of symptoms. Initially the patient had dysarthria and dysphagia. Brain magnetic resonance imaging (MRI) in a community hospital showed abnormalities in the pons, and vertebrobasilar artery thrombosis was suspected. The patient was transferred to the university hospital because of neurological deterioration. Just before thrombolysis, his physical examination revealed a downward ocular deviation, stretching of the arms, and spontaneous movements of the legs. Brain MRI showed recent ischaemia in the pons and caudal part of the mesencephalon, and magnetic resonance angiography showed occlusion of the basilar artery. Intra-arterial thrombolysis with urokinase (total dose 36 000U/kg) was performed 60 hours after onset of symptoms. After thrombolysis he was treated with heparin for 10 days, followed by aspirin. The patient recovered well. After 1 year he had only minor ataxia and performed all activities at school. Local vasculitis due to an infection with Borrelia burgdorferi was thought to be the cause of the local thrombosis. A review of the literature revealed 11 other case reports of successful local intra-arterial thrombolysis in children and adolescents with ischaemic stroke. This suggests that intra-arterial thrombolysis is feasible and safe in selected paediatric patients with ischaemic stroke.
The outcome of vertebrobasilar artery thrombosis (VBT) in adults is very poor, with mortality rates up to 90%.1 Data on paediatric VBT are scarce, but in general the outcome is also poor. VBT has no established therapy, although recanalization with thrombolytic agents may substantially improve outcome.2 The efficacy and safety of thrombolytic therapy in paediatric ischaemic stroke is still unproven and experience is limited, in particular with intra-arterial thrombolysis. Only a few case reports of intra-arterial thrombolysis in children and adolescents have been published.3–10
We report the case of a 4-year-old male with VBT, who successfully underwent intra-arterial thrombolysis 60 hours after onset of symptoms. In addition, we give a review of other reports of intra-arterial thrombolysis in children. Informed consent for publication of this case report was given by the father of the patient.
A 4-year-old male was transferred to the paediatric intensive care unit of the University Medical Center Groningen with the diagnosis of VBT. Two nights before, he had suddenly woken up crying, not able to speak or swallow, but still obeying simple commands. There was no history of a recent trauma of the head or neck. He was initially admitted to a general hospital where his neurological condition deteriorated within a few hours, with progressive drooling and inability to sit stably.
Magnetic resonance imaging (MRI) of the brain showed pontine abnormalities. Neurological examination on admission at our hospital revealed a crying and awake male not able to speak. His eye movements were conjugated with normal pupillary responses and no nystagmus was visible. He could make a fist with both hands and spontaneously moved his legs. There was ataxia of all limbs and trunk. The National Institutes of Health stroke scale (NIHSS) was 17 points at admission.
Repeated MRI 48 hours after onset showed lesions that appeared hyperintense on diffusion-weighted imaging and hypointense on apparent diffusion coefficient mapping in the pons and caudal part of the mesencephalon, compatible with recent ischaemia (Fig. 1a and 1b). Perfusion-weighted imaging was not available at that time. Magnetic resonance angiography showed complete occlusion of the basilar artery with exception of the distal part, as well as thrombosis of the distal part of the left vertebral artery (Fig. 1c). Axial images through the neck did not show signs of a vertebral artery dissection.
Despite anticoagulation therapy with low-molecular-weight heparin, the boy’s clinical condition deteriorated. He became somnolent and tetraplegic, with a vertical gaze palsy and spontaneous extension spasms of arms and legs. The NIHSS score increased to 30. It was then decided to perform local intra-arterial thrombolysis, approximately 60 hours after the onset of first symptoms. Because of the long interval between onset of symptoms and admission to our hospital, intravenous thrombolysis was not considered. A protocol for intra-arterial thrombolysis in paediatric stroke was not available; therefore the type and dosage of the thrombolytic agent were extrapolated from an adult protocol of intra-arterial thombolysis. This protocol was derived from the Prolyse in Acute Cerebral Thrombo-embolism (PROACT) II study.11 Using a transfemoral approach, a guidewire-controlled flow-independent microcatheter was placed near the thrombus. Boluses of 100 000U urokinase were given, alternated with continuous infusion. After four boluses, recanalization was achieved (Fig. 1d and 1e). The total amount of urokinase administered was 650 000U (36 000U/kg). Follow-up MRI the next day showed partial recanalization, with residual occlusion of the proximal part of the basilar artery but with filling of more than two-thirds of the artery through retrograde flow. Subcutaneous heparin was given for 10 days after thrombolysis, followed by aspirin 38mg once a day for 6 months.
Extensive investigations for an underlying cause of his stroke, including screening for coagulation, cardiac and autoimmune disorders, were all negative. Repeated cerebrospinal fluid examination showed immunoglobulin G and M antibodies against Borrelia burgdorferi, with a positive immunoblot in the serum. Therefore, in the absence of other causes, local vasculitis due to Borrelia burgdorferi infection was considered to be the cause of VBT in this boy and he was treated with intravenous cephalosporin for 2 weeks.
In the first 2 weeks after thrombolysis, his clinical condition dramatically improved. He became alert, with some residual dysarthria and gait ataxia. After 1 year, his fine motor skills were still minimally impaired but no other deficits were present. After 1 year, the modified Rankin scale score was 1. MRI at that time showed old ischaemic lesions of the pons (Fig. 1f). At 2-year follow-up, he was going to school for whole days.
Although there is no proven acute treatment for paediatric ischaemic stroke, children are occasionally treated with thrombolytic therapy. In this patient with VBT, local intra-arterial thrombolysis with urokinase 60 hours after onset of symptoms led to recanalization without complications and with a good clinical outcome.
The incidence of acute ischaemic stroke in children is estimated to be 2.5 to 7.8 per 100 000, which is much lower than in adults.12 Less than 10% is caused by thrombosis in the posterior cerebral circulation.4 Because of the low incidence of ischaemic stroke and VBT in children, diagnosis is often delayed, and as a consequence acute thrombolytic treatment in this age group is rarely used.
A meta-analysis of adult VBT stroke patients comparing systemic intravenous and intra-arterial recombinant tissue plasminogen activator treatment within 3 hours after onset showed that survival and outcome were equal between both treatment modalities.13
Within 3 to 6 hours after onset of symptoms, intra-arterial therapy with urokinase may be considered.11 However, the time window for local intra-arterial thrombolytic therapy may be even longer for VBT than for anterior circulation thrombotic events, which is also illustrated by our case report. Successful local thrombolytic treatment 24 hours or more after symptom onset in VBT with a stuttering course has been described.1,2 This prolonged therapeutic time window in posterior circulation stroke may be explained by the presence of collateral supply from the anterior circulation via the posterior communicating arteries.
Only a few case reports of intra-arterial thrombolysis in children and adolescents have been published. A summary of the cases found in the literature is given in Table I. The time from the first symptoms until treatment with thrombolytic therapy ranged from 2 to 72 hours. The functional outcome according to the modified Rankin scale was good to excellent in nine of the 12 patients. Four children were treated for a stroke in the anterior circulation and the others for stroke in the posterior circulation. There is no obvious difference in outcome between the groups, even though the mean time interval was lower in the anterior circulation group.
Table I. Published cases of stroke in children and adolescents treated with intra-arterial thrombolysis
Although no firm conclusions can be drawn from this small group of patients, local intra-arterial thrombolysis seems feasible and safe in a selected group of paediatric patients. In the present case, the decisive argument to thrombolyse our patient was the neurological deterioration together with the expected poor outcome of untreated VBT.
Issues that need to be clarified include the selection of the thrombolytic agent in terms of safety and effectiveness, the optimal dose of these agents, and response in different stroke subtypes (e.g. anterior and posterior circulation infarctions). To clarify these issues a randomized controlled trial would be preferable; however, because of the low incidence of paediatric ischaemic stroke, it is doubtful whether such a trial can be organized, and it would take a long time before the results were available. In the mean time, by registering all paediatric patients who receive thrombolytic therapy, the safety and outcome of these patients could be monitored and further studied.14
Our case report and those reported so far in the literature suggest that local intra-arterial thrombolysis may be considered in paediatric ischaemic stroke, especially in VBT, which has a poor prognosis if untreated, even after the established time-frame of 6 hours.