The sections above have dealt with possible mechanisms by which brain damage may be incurred or overcome, several have implications for the design and analysis of the current study.
Cerebral Insults
One approach referred to in studying the effects of cerebral insult is to link the site of specific lesions with specific deficits (Lezak 1983). The information available on the site of lesions in children post-cerebral has come from EEG readings and CT scans (Newton et al 1994, Crawley et al 1996, Peshu et al in prep). The most common EEG finding during illness in a recent study in Kenya of 65 children with cerebral malaria (Crawley et al 1996) was of discharges in the posterior parieto-temporal region. In 15 children the discharges were generalised across both hemispheres. EEG's were normal in all children who showed no gross neurological sequelae at one month post discharge. CT scans were also performed at one month post discharge on 7 children with neurological sequelae. In 5 of these the focus of damage was again the parieto-temporal region, in 3 cases localised in only one hemisphere, with no preference to either left or right. In the remaining 2 children, atrophy was generalised. The implication for cognitive functioning is that the parieto-temporal region is associated with vision, touch and the co-ordination of complex cognitive tasks, and lesions here have commonly resulted in impairment on constructional tasks (e.g. copying shapes using drawings, blocks or sticks). The exact nature of the impairment in completing these tasks appear to depend on the hemisphere involved (Lezak 1983).
In another series of 14 children CT scans were performed while the children were still unconscious, all at least 36 hours post admission (Newton et al 1994). in 8 the scans were reported as normal. In the other 6 there was evidence of diffuse brain swelling. 2 of these had no evidence of brain damage, and follow-up scans
performed 1 2 - 1 2 0 days later showed complete resolution of the abnormalities. Follow-up scans of the remaining 4, whose original scans had shown evidence of brain damage, showed cerebral atrophy and infarction, which was associated with significant neurological sequelae. The damage was either diffuse, or affected the boundary zones between the anterior and middle cerebral arteries, or the middle and posterior cerebral arteries. This implies that whilst a generalised impairment is likely to be found in some children, in others the deficit may be highly specific, but its nature could vary between individuals.
Coma
There are a number of features of C.f\/I. which could be related to the onset of coma, including a deficient oxygen supply to the brain, associated with the sequestration there of mature parasites (Looareesuwan 1992). Typically coma in cerebral malaria lasts between two hours and 14 days, with a median of 30 hours. A coma length in excess of 120 hours which has been found to be associated with neurological sequelae (Brewster et al 1990, Crawley et al 1996). Length of coma is also likely to be an important variable in the development of cognitive sequelae, as is depth of coma.
Seizures
A recent study in Kenya (Waruiru et al 1996) found that 69% of all seizure activity in children admitted to a general paediatric ward was attributable to malarial disease. This might explain the greater prevalence of seizure activity in children in Sub-Saharan Africa as compared to figures for Europe and North America (see above). Seizures have been found to occur in 85% of admissions with a diagnosis of cerebral malaria (Crawley et al 1996). The majority occur with no other sign of neurological involvement (Waruiru et al 1996). In this latter group the majority of seizures, 84%, were found to be complex, with no clear relationship with fever. These two factors indicate that they are not purely febrile seizures, and that the presence of P.falciparum may be a direct cause (Waruiru et al 1996).
In cerebral malaria when seizures occur in conjunction with neurological involvement, status epilepticus becomes a more common feature, though fits still vary in their number and duration. 25% of children studied by Crawley et al had seizures with minimal clinical manifestations, and around 50% presented as grand mal seizures (Crawley et al 1996). In both of these groups seizures appeared to be associated with coma. Evidence from EEGs and CT scans taken on children in the study indicate an association between seizure activity, structural abnormalities and the posterior parieto-temporal region.
The occurrence of multiple and prolonged seizures in cerebral malaria has been associated with the development of neurological sequelae (Molyneux et al 1989, Bondi 1992 and Peshu et al in prep.) Given the association found between seizures and sequelae in the absence of malaria (Aicardi & Chevrie 1983) one might expect to find a significant proportion of C.M. children with some form of cognitive impairment, amongst those both with and without observable neurological sequelae. The literature does not suggest whether it is more likely that the impairments are generalised or specific, although where the focus is the parieto-temporal region impairments of information processing is indicated (Luria 1973, Gaddes & Edgell 1993).
Hvpoqivcaemia
In a series of 698 children with a primary diagnosis of malaria the prevalence of hypoglycaemia, (measured as a blood glucose level of less than 2.2 mmol per litre) was found to be 13% (Marsh et al 1995). Estimates of the prevalence increases to 34% in children also with impaired consciousness (Brewster 1990). Hypoglycaemia has been associated with both an increased risk of mortality, and of neurological sequelae following C.M.. Prevalence estimates range between 22.5% in those who died, and 64% of those who survived with neurological sequelae (Brewster 1990, Bondi 1992, Marsh et al 1995).
Studies of the effect of hypoglycaemia on cognitive functions have used subject groups which are not directly comparable to a C.M. patient group. Not only are
they generally from an older population, but also include subjects who have had multiple episodes. The sequelae found might therefore be the result of a chronic condition rather than an acute episode (Deary 1992), as experienced in C.M. (Boivin et al 1993). However, an association has been found in research on meningitis between glucose levels in the cerebral spinal fluid and IQ scores (Taylor et al 1990), in a population more comparable in age and disease history. Hypoglycaemia might therefore also have a role in the onset or severity of cognitive sequelae in C.M..
Hyperpyrexia
This appears to be a little studied phenomenon of C.M. In a series of 1816 children with malaria it was found to have a prevalence of 10.6%, with only a relative risk of 0.5 associated with mortality (Marsh et al 1995). Although it is likely that hyperpyrexia is associated with the onset of febrile seizures in malaria, as it is with other illnesses (Crawley et al 1996), there is no evidence of any association with longer term outcome.
Malnutrition
As protein energy malnutrition is associated with impairments in the human immunologic responsiveness, malnutrition might be expected to be associated with an increased risk of developing malarial disease (Grimble 1994, Schlesinger et al 1994). However the nature of the relationship between nutrition and malaria has yet to be established, the literature being contradictory on the subject. Earlier research, in the 60's and 70's, suggested that a poor nutritional status may actually be a protective factor against the development of severe malaria (reviewed in McGregor 1982). A later review suggested that the results were uncertain, and that the topic required more rigorous methodology, with investigations on a much larger scale than had previously been carried out (Greenwood et al 1991). Just such a large scale study, carried out more recently in Kenya, found under-nutrition, whether measured by weight for age, weight for height or mid-upper arm circumference, to be a significant risk factor in the development of severe disease (Marsh personal communication). As under-
nutrition is also a risk factor in the development of cognitive deficits (see earlier section for details) it increases the importance of having information on the early nutritional status of children when investigating the development of children who have had cerebral malaria.
The relationship may also work the other way, as with other severe infections, whereby an episode of severe malaria.may cause an episode of malnutrition. However, while there is evidence that episodes of malaria infection are associated with periods of retarded growth, there is little to suggest that severe malarial disease has a longer term impact on nutritional status and growth (McGregor 1982).
Anaemia
The anaemia which is commonly associated with malaria is caused by a combination of the destruction of existing red cells, and the failure to produce sufficient replacement cells. It is more common in children under 3 years of age, whilst cerebral malaria more commonly occurs in children over that age. Iron deficiency anaemia is associated with chronic malaria parasitisation rather than with an acute episode of malaria infection (McGregor 1982), and is therefore of limited relevance to the current study. However it has been suggested that the anaemia present in malaria could compound the effects of any cerebral insult by reducing still further the cerebral oxygen being transported. In support of this hypothesis severe anaemia has been found to be closely associated with the development of neurological sequelae (Brewster et al. 1990, Hendrickse 1987). This support is limited, and in direct contrast to other studies, which have included a much larger series, and which have found no such association (Molyneux et al 1989, Marsh et al 1995).
To summarise, the link between anaemia and cognitive development appears to be as a result of the iron deficiency associated with the anaemia. Assuming then that acute malarial infection is not associated with iron deficiency, and that malarial anaemia is not associated with a negative neurological outcome, the
presence or absence of anaemia during the course of the severe infection is therefore unlikely to be an important risk factor for cognitive impairment. However, as the study population is known to be one where iron deficiency anaemia is common, it is important to have some measure of underlying iron status which can be used in the matching of controls.
Other Parasitic Infections
The debilitating affect of parasitic infections on cognitive function is likely to be a feature of the chronic nature of such infections, rather than related to a single infection, and chronic malaria parasitisation may share similar mechanisms and effects. In some ways the situation with cerebral malaria is therefore less complex than with chronic parasitic infections, in that there is a discrete episode of illness associated with organic brain damage. Nevertheless the important methodological issues raised by the literature on parasitic infections remain relevant to the current study, and need to be addressed when selecting appropriate assessment tools. These primarily relate to the co-existence of multiple risk factors common in populations were the disease is prevalent, such that other aspects of health and general environment may be confounding the effects of the malarial disease process itself.
Socio-Economic Status
At several points in the preceding sections it has been proposed that poor outcome may be a consequence of a generally impoverished environment rather than directly as a consequence of the course of one specific disease/infection (Kvalsvig 1988). The majority of children exposed to malaria infection live within just such an impoverished environment, and this needs to be taken into account in the assessment of outcome, by making some assessment of socio-economic status.
In the current study area no information exists as to which socio-economic indicators relate to the prediction of cognitive performance. The measures used
to represent SES will therefore be primarily selected because there is information relating them to the development of severe malarial disease (Marsh et al 1995). Results will need to analyse the extent to which these variables, and the supplementary questions asked about current socio-economic status, are able to stratify the group as a whole, and the extent to which they relate to measures of performance.
Summary And Development of Hypotheses a) theoretical guidelines
The Vygotsky -Luria descriptions of abnormal development suggest that the consequence of brain insult will be a qualitatively different pattern of functioning. This could be evident in a different pattern of strengths and weaknesses across a range of tasks, such as a different balance of processing strengths. Qualitatively different performance is also likely to result in a different pattern of errors within different tasks. By implication children’s whose performance is found to differ in this way would be expected to require a different educational approach to the mainstream.
b) research evidence
By making a link between the descriptions of the range of possible outcomes of brain insult, and the evidence from studies of the neurological outcome and patho-physiology of C.M., two possible cognitive outcomes in a population of affected children are suggested. They are illustrated in Figure 8.1.
Fig 8.1 Hypothetical Distributions of Performance
Distribution
Distribution A would be more likely to occur should cognitive impairments be found only in a minority of children. This distribution would be suggestive of a "critical level" of damage. Therefore impairments may well be of an extreme nature, and outcome confined to Gaddes and Edgell's "Brain Damaged" group, (described in Figure 7.1).
Distribution B would follow from the situation where the majority of survivors are affected. In this instance there is likely to be a continuum of deficit, such that subtle impairments predominate, with the majority of children falling into Gaddes and Edgell's "Borderline Dysfunction" or "Specific Learning Disability" grouping. Should this distribution emerge the 'hidden' nature of the impairments would explain why the extent of the problem had previously been undetected when impairment was defined solely on the basis of gross neurological sequelae.
Given the evidence from the CT scans of survivors, which showed a marked variability in the location of damage (Newton et al 1994, Crawley et al 1996, Peshu et al in prep), it seems unlikely that the pattern of impairments will be characterised by specific difficulties common amongst all children.
Hypotheses
The evidence provided in the literature on the experience of other encephalopathies and brain insult in childhood suggests:
1. That there will be only a minority of survivors whose performance is significantly affected by the illness episode.
and
2. That these children will be identifiable by
a) the severity of symptoms of the illness episode b) neurological impairment on discharge
The Vygotsky-Luria theoretical framework, which describes disruptions to development as altering, and not simply limiting, subsequent cognitive functioning, suggests:
3. That these children will be identifiable by a qualitatively different pattern of strengths and weaknesses in their performance and behaviour.
The study will therefore be designed to investigate the relationship between insult and outcome as illustrated below.
Insult
Neurological Status on Discharge
no impairment
impairment
> 4^