Results

PATIENT CHARACTERISTICS

A total of 38 children were identified, ranging in age from 6 months to 15 years (median, 6 years). There were 22 boys. In 24 cases, MRI studies were available from the first week after the acute stroke; six patients were scanned within one month and five within one year of the stroke. Three patients were imaged much later: after five, six, and eight years. One child had an acute deterioration after making an initial recovery; in this instance the scan obtained after the second event was analysed. Four children had had previous strokes and bilateral lesions. In two of these cases, areas of infarction that had occurred “silently” (without any corresponding clinical event) were apparent on T2 weighted MRI at the time of a second, clinical stroke. Eleven children fell into the symptomatic stroke category (indicated with an asterisk in table 1). Table 1 summarises further clinical details.

INFARCT SIZE AND TERRITORY

The lesion volumes ranged from 1 cm³ to 244 cm³, which represented a range of 0.12% to 21.52% of ICV. Figure 1 illustrates the topographical characteristics of the lesions for individual patients. Figure 2 shows the allocation of lesions into large, moderate, and small categories (defined according to the 33rd and 67th centiles for mean values of %ICV infarcted (1.03% and 5.29% ICV)) by each observer.

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Figure 1

Line drawings of a transaxial section through the brain at the level of the IIIrd ventricle illustrating the lesion characteristics for individual patients. Each figure represents one patient and the figures are arranged in ascending order of lesion size.

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Figure 2

Per cent intracranial volume (%ICV) infarcted measured by observers 1 and 2, plotted on a logarithmic scale to illustrate the allocation of the small lesions. The horizontal lines indicate the 33rd and 67th centiles for the values of mean %ICV infarcted, according to which lesions were allocated into “small”, “moderate”, and “large” categories.

Twenty one of the lesions involved the cortex and the remaining 17 lesions were confined to subcortical structures. All but one of the lesions that involved the cortex also involved subcortical structures (fig 1).

REPRODUCIBILITY AND AGREEMENT

Table 2 summarises the data on the reproducibility of the measurements of ICV and infarct volume within and between the two observers. The reproducibility of volume measurements for small lesions was much poorer than for large lesions, as is evident in fig 2 and table 2; the large number of relatively small lesions in our study tended to increase the mean per cent difference between observers for values of lesion volume.

There was agreement between the observers on the allocation of the lesions into the three groups in 33 of 38 cases. In the five cases where lesions were allocated into different categories, the differences in the %ICV volume infarcted between the two observers was 1.29%, 1.44%, 0.18%, 0.14%, and 0.13%; therefore, these differences were very small, indicating that these values lay around the cut off points for the groups (fig 2). The final allocation of individual patients into the categories was based on the mean value for %ICV infarcted.

RELATION BETWEEN LESION SIZE, LOCATION, AND OUTCOME

Twelve children had a good outcome and 26 children had a poor outcome, as defined previously. Two children died as a result of intractable intracranial hypertension in the acute phase of stroke; they were included in the poor outcome category.

The relation between infarct size, location, and outcome, summarised in table 1 and fig 3, is not simple. In a logistic regression model there were no significant relations between infarct size category (p = 0.90), infarct location (p = 0.88), the presence of a previous risk factor (p = 0.39), and outcome for the group as a whole.

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Figure 3

(A) Outcome related to infarct size category for the 34 children with unilateral lesions (see methods for definitions of infarct size and outcome categories). Of the eight children with previous risk factors, one had good outcome and seven had poor outcome; one had a small lesion and seven had large lesions. (B) Outcome related to mean per cent intracranial volume (%ICV) infarcted and lesion location. See results section for definition of “cortical” and “subcortical” infarct locations.

Considering the subgroups of children with unilateral cortical lesions (n = 18) and unilateral subcortical lesions (n = 16) individually, lesion volume did not significantly influence outcome in either group (logistic regression, p = 0.28 for those with cortical lesions; logistic regression, p = 0.5 for those with subcortical lesions).

However, it was apparent that there was a relation between infarct volume and outcome for the largest lesions. Children who infarcted more than 10% ICV were significantly more likely to have a moderate or severe level of residual disability (Fisher’s exact test, p = 0.036) (fig 3). In all these cases the lesions involved cortical tissue.

All the children who had bilateral lesions fell into the poor outcome category. One was in the small lesion category, one in the moderate lesion category, and two were in the large lesion category. Both the children who died had large lesions.

All of the seven children with small lesions and poor outcome had lesions that involved the basal ganglia. Five of them had lesions confined to these structures.

As a group, children with symptomatic stroke (those with a previous risk factor) had larger lesions then those with idiopathic stroke (χ², p = 0.02). However, this was not predictive of a worse outcome.

Discussion

Our findings indicate that, in children with MCA territory infarcts, although the functional sequelae of small lesions might be variable, infarction of more than 10% ICV is associated with pronounced residual deficits.

There are methodological constraints inherent in measuring infarct volumes in the manner described here. The reproducibility of measuring individual volumes in the our study was compromised by subjectively defining the lesion boundaries, both in the acute and chronic stages. This was especially difficult in the case of small lesions, as is apparent from the data presented in table 2, where relatively small absolute differences in measurement resulted in large percentage differences in repeated measurements. In contrast, the reproducibility of the ICV measurements was good.

The natural history of cerebral infarction on MRI is for signal hyperintensity and swelling on T2 weighted images to be apparent around six to 12 hours after symptom onset.11 Chronic infarcts show signal hyperintensity and tissue atrophy on T2 weighted imaging. In the early stages of evolution of a cerebral infarct, tissue swelling makes definition of lesion boundaries difficult; in more chronic lesions, atrophy may cause similar problems. Although automated or semi automated image analysis techniques might improve reproducibility,3 12 the accuracy with which such techniques measure the true volume of damaged tissue is questionable. Moreover, absolute values for infarct volume at any stage in the lesion’s evolution must be viewed with some scepticism because early measurement might overestimate and late measurement might underestimate the actual volume of damaged tissue. Because swelling is more apparent around large lesions than small ones, lesion size might also be an important factor determining the variation in individual lesion volumes during the evolution of the lesion. Our patients comprised a heterogeneous group in terms of the timing of imaging in relation to the neurological insult. Although most of them were imaged acutely, in a few cases there was an interval of several years between the event and the MRI study. However, as we were studying the relative rather than the absolute effects of lesion volume on outcome (by categorising lesions into small, moderate, and large), we believe that inclusion of all the patients was valid.

In a recent study examining the relation between lesion volume and outcome in adults with cortical MCA territory stroke, Saunders and colleagues3 showed a significant relation between lesion volume on T2 weighted MRI obtained within 72 hours of the onset of symptoms and outcome. The population in this study was relatively elderly (mean age, 66.5 years) and of the nine patients who died, none appear to have died as a direct result of the stroke (although at least two died of secondary illnesses, such as pulmonary embolism). Compared with this group, our patients formed a more heterogenous group, which included patients with purely subcortical infarction, and death or disability were more directly attributable to the acute stroke.

Lovblad and colleagues12 found that in adults with MCA territory infarction, the volume of lesions on T2 weighted MRI at a chronic time point correlated well with indices of stroke severity and functional outcome. Although that study included some patients with purely subcortical lesions, these associations were stronger in the subgroup of patients with cortical MCA lesions. It was noted that the correlation between lesion size and clinical status was less for smaller lesions than for large ones. The relative frequency of small, subcortical lesions in our study might partly account for the discrepancies between our findings and those of Lovbladet al. The methodological difficulties discussed previously might also have some bearing on this. Comparison of our results with those of the two studies above, however, must also take into account the differing effects of basal ganglia injury in adults and children, as discussed below.

Unlike adult stroke patients, in whom the profile of risk factors is relatively homogenous, children who suffer ischaemic stroke are a heterogeneous group. Symptomatic stroke or stroke in children with a pre-existing medical condition (such as congenital heart disease) has been reported to previously be a risk factor for poor outcome.4 6 7 Although this might be associated with factors relating to the underlying diagnosis (such as chronic hypoxia) it is noteworthy that these children tended to have larger lesions. Compensatory mechanisms might be less efficient in children whose cerebral perfusion is under chronic stress. In children with cardiac disease, embolic occlusion might cause occlusion of arterial trunks, resulting in larger lesions. However, as is apparent from our data, the relation between the presence of a risk factor for stroke and lesion size, lesion location, and outcome is not a simple one. Neurological co-morbidity from the pre-existing risk factor needs to be considered; however, given the small numbers of patients in our study we were unable to examine these questions in further detail.

Idiopathic ischaemic stroke in childhood has been reported previously to be confined frequently to basal ganglia structures.4 In our group, 15 of the 27 patients without previous medical diagnoses had lesions confined to the basal ganglia, without cortical involvement. Five of them had had chickenpox within the six months preceding the stroke; the relation between preceding varicella and basal ganglia infarction in childhood has been described elsewhere.13

We found that some children with relatively small lesions confined to the basal ganglia had pronounced residual deficits. Unlike adult patients, children have been shown to develop residual dystonia after basal ganglia infarction.4 14 15 Hand function tends to be the worst affected, although progressive dystonia can lead to more generalised disability. Previous reports suggest that striatocapsular infarction in adults might be associated with pronounced cognitive and motor sequelae.16 17 There is also evidence that language function,18 behaviour, and attention19 might be affected in children with subcortical lesions. Although striatocapsular infarction is a relatively common pattern in childhood stroke, its psychometric correlates have not been explored in detail. Our data suggest that the residual sequelae after basal ganglia infarction can lead to pronounced functional impairment and support more detailed characterisation of this group of patients.

Although, anecdotally, outcome after stroke in childhood is thought to be good, it is clear from previous publications that most children are left with residual deficits and that there is an appreciable mortality.20 21 This argues for a role for acute stroke treatments in the prevention of disability in the paediatric stroke population. The recent trials of acute stroke treatments in adults have shown that very large numbers of patients are required to evaluate treatments that have a finely balanced risk–benefit ratio. Although the estimated incidence of ischaemic stroke in childhood varies widely from 0.6 to 8/100 000/year,20 21 compared with ischaemic stroke in adults (which has an incidence of 180/100 000/year22) patient numbers are small. Some means of categorisation of patients into prognostic groups would facilitate trials of treatment in smaller groups of patients.

In our group of patients, infarction of more than 10% of the ICV was associated with pronounced disability or death in all cases. This suggests that a threshold exists for lesion size, above which outcome is universally poor. The clinicopathological stroke syndrome of “malignant middle cerebral artery infarction” is characterised by large MCA territory infarcts. This has been shown to have a very poor prognosis in adult patients.23 24 It appears from our study that a similar clinicopathological syndrome is identifiable in children. Our data suggest that by combining information from lesion volume and topography, a group of children with ischaemic stroke who would be predicted to have poor outcome could be identified and enrolled in future therapeutic trials.