Capítulo II: Marco Teórico
2.4 Formación integral como misión de la universidad
STATUS EPILEPTICUS AFTER ADMISSION
No (n = 100) Yes (n = 9) P value Baseline CQ (pg/1) 227.5 (85.6-441.2) 75.1 (7.4-116.5) 0.02 Baseline DCQ (pg/1) 375.9(134.8-701.2) 81.9 (0-322.9) 0.07 AUC 0-12 CQ (pg.hr/1) (n = 43) 2170.1 (1089.5-4053.6) 470.3 (211.3-659.7) 0.009 AUC 0-12 DCQ (pg.hr/1) (n = 39) 4769.4(2420.3-6416.6) 1188.7 (392.5-1985.0) 0.06
Chloroquine (CQ); Desethylchloroquine (DCQ); Area under the concentration curve for 0-12 hours (AUC 0-12)
Results
Samples
Of 340 patients recruited to the main phenobarbitone prophylaxis study, 170 received placebo. Sufficient blood was available for measurement of CQ and DCQ on 109 (64%) of these patients. There was no difference in the frequency or duration of seizures between patients who had levels measured and those who did not (p > 0.1 for all comparisons). Chloroquine was detected in 100/109 (92%) of the baseline blood samples. Median (interquartile range) baseline concentrations were 214.9 pg/1 (79.4 - 427.3) for CQ and 349.3 pg/1 (90.3 - 594.7) for DCQ. Of 80 children who had 3 or more CQ levels taken during their hospital course, 29 (36%) were thought to have received CQ in the period immediately (< 24 hours) before hospital admission, since the concentration of CQ in their blood fell by more than 50% during the first 24 hours of admission (White 1988b). These children had median (interquartile range) baseline levels of CQ and DCQ that were significantly higher than those given chloroquine more than 24 hours prior to admission (CQ 374.9 pg/1 (278.6 - 888.3) versus 114.8 pg/1 (41.0 - 185.8), p = 0.0001; DCQ 580.1 pg/1 (312.3 - 1156.2) versus 284.1 pg/1 (52.6 - 518.9), p = 0.001).
Seizures
Table 7 compares the baseline characteristics of those who had seizures with those who did not. Overall, fifty four percent (59/109) of the children had one or more witnessed seizures after admission. Of the children with undetectable baseline blood levels of chloroquine, 6/9 (67%) had between 1 and 27 (median 5) seizures. Forty one percent (45/109) had a seizure lasting for 5 minutes or more, while 8% (9/109) had an episode of status epilepticus (seizure lasting for 30 minutes or more). Children who had received chloroquine less than 24 hours prior to admission had a similar frequency and duration of seizures to those who had received CQ earlier (p > 0.4 for all comparisons). There was no significant correlation between the total number of seizures after admission and median baseline concentrations of CQ (Spearman’s rho -0.089, p = 0.36) or DCQ (Spearman’s
rho -0,039, p = 0.69). Baseline levels of CQ and DCQ and the corresponding area under the concentration curves (AUCo-12) were not significantly associated with the occurrence of seizures lasting for 5 minutes or more (p > 0.5 for CQ, DCQ, and AUCo-12). Baseline
CQ levels and AUC0.12 were, however, significantly reduced in the nine children who had an episode o f status epilepticus (Table 8). Multivariate logistic regression analysis, taking into account factors likely to affect the risk of seizures in hospital (Table 7) failed to change the significance of these results.
Discussion
There are many possible explanations for the high incidence of seizures in childhood cerebral malaria. Fever, known to precipitate seizures in young children (Wallace 1988), is an almost universal feature of cerebral malaria, although many of the seizures in cerebral malaria occur at temperatures of below 38 degrees Centigrade (Crawley 1996). Hypoglycaemia (White, 1987) and hyponatraemia (English 1996b), both complications of severe malaria, may also induce seizures. Sequestration of parasitised red blood cells in the cerebral microvasculature, the histopathological hallmark of cerebral malaria, may cause seizures through hypoxia, or by initiating the release of excitotoxic mediators, such as quinolinic acid (Dobbie 2000).
Throughout Africa, chloroquine continues to be widely used for the treatment of febrile illnesses at the community level, as illustrated by this and by previous studies (Snow 1992; Marsh 1999). Baseline chloroquine concentrations in this study were generally at the low end of the therapeutic range, and were well below concentrations (2000pg/l and above) considered toxic (Riou 1988). The association between chloroquine and seizures has been described in both adults and children, at therapeutic concentrations (Torrey 1968; Fish 1988; Luijckx 1992) and following overdose (Cann 1961; Kiel 1964; Jaffe 1988; Riou 1988). Seizures may occur within a few hours of overdose (Cann 1961; Kiel 1964; Jaffe 1988), or between one day and several weeks after the start of treatment with therapeutic doses of chloroquine (Luijckx 1992). The concentration of chloroquine within the brain is approximately four times that of plasma (Titus 1989), and experimental evidence suggests that chloroquine may precipitate seizures by attenuation of gamma aminobutyric acid (GABA) pathways (Amabeoku 1992), and by the enhancement of dopaminergic neurotransmission (Amabeoku 1993).
In this study, however, there was no association between baseline levels, area under the concentration curve (which reflects both absorption and subsequent elimination) of chloroquine and its active metabolite desethylchloroquine, and the number of subsequent seizures in children with cerebral malaria. In the small sub-group of children who had
one or more episodes of status epilepticus, baseline levels of chloroquine and desethylchloroquine were reduced.
There are a number of limitations to this study. The dose and route of chloroquine administration were not known, and it was only possible to obtain a rough estimate of the time of administration in 73% of the patients. Information on seizures that occurred prior to admission was based on clinical history, which can be unreliable, and analysis was therefore confined to seizures that were witnessed by clinical staff in hospital. In addition, it is not known whether the reported association between chloroquine ingestion and seizures is a dose-related or idiosyncratic phenomenon. Although this study suggests that the seizures of childhood cerebral malaria are unlikely to be caused by chloroquine alone, more definitive evidence would come from prospective longitudinal studies. Such studies could assess the prevalence of seizures complicating cerebral malaria in relation to changing patterns o f chloroquine useage. The rapid spread of chloroquine resistance, and the urgent need to change to alternative antimalarial drugs, is likely to provide such an opportunity in the near future.