- Email: [email protected]
Post-malaria neurological syndrome
THE LANCET
Post-malaria neurological syndrome
Nguyen Thi Hoang Mai, Nicholas P J Day, Ly Van Chuong, Deborah Waller, Nguyen Hoan Phu, Delia B Bethell, Tran Tinh Hien, Nicholas J White
Summary Background Neurolog ic al sig ns and sy mpt oms are common in malaria, but observations in Vietnam and Thailand have pointed to a discrete transient neurological syndrome after recovery from severe infections. Methods A prospec t ive st udy of t he post -malaria neurological syndrome (PMNS) was conducted at two centres in Vietnam over four years. Criteria for inclusion were recent symptomatic malaria infection with parasites cleared from blood (and in cases of cerebral malaria full rec overy of c onsc iousness) , and development of neurological or psychiatric symptoms within two months after the acute illness. Half of the patients with severe falciparum malaria had been taking part in a randomised trial of antimalarials. Findings Of 18 124 patients with falciparum malaria treated (1176 of whom had severe infections) 19 adults and three children had subsequent PMNS; in one patient it followed uncomplicated malaria and in 21 it followed severe malaria. The overall incidence (95% confidence interval) of PMNS after falciparum malaria at the main study centre was 1·2 per 1000 (0·7 to 1·8 per 1000) and relative risk (95% CI) for developing PMNS after severe versus uncomplicated falciparum malaria was 299 (40 to 2223). 13 patients had an acute confusional state or psychosis, six had one or more generalised convulsions, two had generalised convulsions followed by a long period of acute confusion, and one developed a fine tremor. At t he t ime of P M NS diag nosis all pat ient s w ere aparasitaemic. The syndrome was self-limiting, median duration 60 h (range 24–240). PMNS was associated with the use of oral mefloquine. In the randomised trial 4·4% (10/228) of patients with severe malaria who received mefloquine after parenteral treatment developed PMNS compared with 0·5% (1/210) of those who received quinine; relative risk 9·2 (95% CI 1·2 to 71·3, p=0·012). Interpretation Mefloquine is not the only risk factor for
Centre for Tropical Diseases (N T H Mai MD, L V Chuong MD, N H Phu MD, T T Hien MD) and Wellcome Trust Clinical Research Unit (N P J Day MRCP , D Waller BM , D B Bethell MB , Prof N J White FRCP ), Centre for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam; and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK (N P J Day, D Waller, D B Bethell, N J White) Correspondence to: Prof Nicholas J White, Wellcome Trust Clinical Research Unit, Centre for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam
Vol 348 • October 5, 1996
P M NS but it is a st rong one. W here an effec t ive alternative drug is available, mefloquine should not be used after treatment of severe malaria.
Lancet 1996; 348: 917–21
Introduction Of the many neurological manifestations and complications of malaria, the most common and important is the cerebral form of severe Plasmodium falciparum malaria. This is attributed to the sequestration of parasitised red blood cells in the brain, though how this process causes coma is incompletely understood.1,2 In most cases recovery is complete, although cerebral malaria is fatal in 15–20% of cases and a further 10% of children and 1–3% of adults have residual neurological sequelae.3,4 Hypoglycaemia resulting from malaria or quinine treatment can also cause coma and, if it is severe and protracted, may result in death or permanent brain damage.5 Use of mefloquine, chloroquine, and earlier mepacrine (quinacrine) for the prophylaxis or treatment of malaria has also been associated with an acute selflimiting neuropsychiatric syndrome,6–8 and lately a case of “central anticholinergic syndrome” associated with mefloquine treatment was described.9 Psychosis following cerebral malaria has been reported,10 and a delayed cerebellar syndrome following falciparum malaria has also been described, particularly in Sri Lanka.11 After observations in Vietnam and Thailand that a discrete neurological syndrome could follow recovery from falciparum malaria a prospective study was conducted. Here we report the clinical features and associations of this post-malaria neurological syndrome (PMNS) in 22 patients.
Patients and methods This prospective study was conducted over four years, to January, 1995, at the Centre for Tropical Diseases, Ho Chi Minh City, Vietnam, an infectious disease hospital which is a referral centre for much of southern Vietnam, and at the nearby Dong Nai Paediatric Centre. We included under PMNS any patient with symptomatic malaria infection (initial blood smear positive for asexual forms of malaria parasites), whose parasites had cleared from the peripheral blood and, in cerebral cases, had recovered consciousness fully, who developed neurological or psychiatric symptoms within two months after the acute illness. During part of the study period a double-blind trial of the treatment of severe adult malaria was carried out at one of the study centres,12 and any patients presenting with PMNS after recovery were included in the present series. In this treatment trial, patients were randomised to receive either intramuscular artemether (4 mg per kg initially, then 2 mg per kg eight hourly) or quinine (20 mg of hydrochloride salt per kg initially, then 10 mg per kg eight hourly) and when they could
917
THE LANCET
take oral medication they were randomised for a second time to receive either oral sulphadoxine-pyrimethamine (Fansidar; Roche, Basel) in a single dose of three tablets together with oral quinine sulphate (Government Pharmaceutical Organisation, Thailand) 10 mg per kg three times a day to complete seven days’ treatment, or a single dose of mefloquine (Lariam; Roche, Basel) 15 mg of base per kg. The second randomisation was independent of the first. The antimalarial treatment of patients not included in this prospective double-blind trial was at the discretion of the admitting physician.
Procedures On entry a full history was taken from each patient and his or her relatives, including an assessment of the patient’s premorbid neurological and psychiatric condition and any history of epilepsy. Details of the recent malaria episode were obtained from the hospital records or from the case forms of the prospective antimalarial drug trial. A full general, neurological, and mental state examination was conducted on admission by one of the investigators, the results being recorded in standard format. Each patient was re-examined 6-hourly until recovery. Blood was drawn for biochemical and haematological tests including blood glucose, electrolytes, liver and renal function tests, plasma mefloquine level, blood culture, full blood count, and thick and thin malaria blood smears. A lumbar puncture was performed, the opening pressure was measured, and cerebrospinal fluid (CSF) samples were taken for protein and glucose measurement, for cell counts, and for herpes simplex virus testing with a specific polymerase chain reaction.13 CSF was also inoculated into Aedes albopictus C6/36 cell line cells and a standard indirect immunofluorescence technique with hyperimmune mouse ascitic fluid was used to detect Japanese encephalitis virus (JEV). CSF and acute serum samples were also tested for the presence of JEV and dengue virus antibodies.14
Statistical analysis Continuous variables were compared between groups by use of the Mann-Whitney U unpaired and the Wilcoxon signed-rank paired tests as appropriate. Nominal data were compared by means of Fisher’s exact test. Exact 95% confidence intervals were calculated for proportions15 and medians.16 Logistic regression analysis was done with the Stata statistical software package (Statacorp, USA), using regression diagnostic tests devised by Lemeshow and Hosmer.17
Results During the study period 22 patients admitted to the two sites developed neurological or psychiatric symptoms after recovery from malaria and fulfilled the criteria for entry to the study. One patient had recovered from uncomplicated falciparum malaria, and the remainder from severe falciparum malaria. All cases followed infection with Plasmodium falciparum malaria; none followed P vivax infection although this parasite accounts for about 30% of malaria infections seen at the study sites.
Incidence of PMNS During the four-year study period 16 970 patients with uncomplicated falciparum malaria and 1065 patients with severe malaria were treated at one of the two study sites (Centre for Tropical Diseases), and 21 of these patients were diagnosed subsequently as having PMNS—ie, 1·2 per 1000 falciparum malaria cases overall (95% CI 0·7 to 1·8 per 1000). 20 cases followed severe malaria, an estimated incidence of 18·7 (95% CI 11·5 to 28·8) per 1000, and one followed uncomplicated falciparum malaria; relative risk 299 (40 to 2223) for 918
PMNS following severe compared with uncomplicated falciparum malaria. Three patients were children under the age of 15 (aged 6, 9, and 10 years), all recovering from severe malaria. At the two centres 363 children were admitted with severe malaria, all of whom were observed and treated on the study wards, an incidence for PMNS following severe childhood malaria of 8·3 per 1000 cases (exact 95% CI 1·7 to 24·0). In adult patients there were 18 cases of PMNS among 813 cases of severe malaria, giving an approximate incidence of 22·1 per 1000 (exact 95% CI 13·2 to 34·8) (p=0·16). These figures define the lower limit of the true incidence, because some patients were discharged home to regions of southern Vietnam far from the study hospitals, where any symptoms that developed subsequently might have been treated locally without the knowledge of the investigators. For the same reasons mild cases of PMNS may be under-reported. Thus the true incidence of the condition may have been underestimated and the clinical description skewed towards the severe end of the spectrum.
Clinical features Of the 22 cases of PMNS, 16 developed during the same admission as the malarial illness; six patients were readmitted after being discharged clinically well. 15 (68%) cases were male, with a mean (range) age of 29 (6 to 51) years. No patient had a previous history of neurological or psychiatric illness, although one patient was an intravenous opioid abuser positive for human immunodeficiency virus (HIV). The PMNS-defining neuropsychiatric manifestations were wide-ranging; 13 (59%) patients had either an acute confusional state or an acute psychosis, six (27%) had generalised convulsions, and two (9%) had generalised convulsions followed by an acute confusional state. One patient’s only neurological manifestation was a fine tremor which lasted 4 days. The median duration of these neuropsychiatric symptoms was 60 h (95% CI 48 to 109, range 24–240). During this period no patient had any focal neurological signs on examination, and all made a full recovery without sequelae. No relation was found between the type of PMNS symptomatology and either the antimalarial drug(s) used to treat the preceding malaria infection or the clinical characteristics of the malaria infection. Generalised convulsions—Eight (36%) patients had at least one generalised convulsion lasting in each case under a minute; three patients had multiple seizures. Two patients recovered full consciousness within minutes of the convulsions, but in four there was a subsequent period of coma lasting 36–72 h. The remaining two patients regained consciousness quickly but developed an acute confusional state (one immediately, one 24 h later) which lasted 5 and 10 days, respectively. Four patients had recovered from cerebral malaria, and three had had convulsions complicating their malaria. No focal neurological signs were detected in any of these patients post-ictally, none had a past history of epilepsy, and all eventually made a complete recovery. Psychotic or acute confusional episodes—15 patients (68%) developed symptoms of an acute confusional state
Vol 348 • October 5, 1996
THE LANCET
or acute psychosis. 12 had an acute confusional state with clouding of consciousness and inappropriate speech or behaviour, six of whom experienced florid visual hallucinations, and two developed a prolonged confusional state following generalised convulsions. Two patients with acute confusional states had periods of classic catatonia with waxy flexibility. Three patients developed acute psychotic symptoms without clouding of consciousness. Of these, two had serious and prolonged persecutory delusions (one attempted suicide), and the other became acutely manic and euphoric and experienced visual hallucinations.
Tremor —One patient developed a fine postural tremor of the arms and legs (frequency >10 Hz), which worsened on intention. Muscle tone was decreased symmetrically in all limbs, though there was no nystagmus and no ataxia. His plasma bilirubin was slightly raised (34 mol/L); transaminases were normal and there was no evidence of hepatic encephalopathy. The tremor lasted four days and then resolved spontaneously and completely. Other clinical features—Nine patients were febrile on diagnosis of PMNS, though none had any signs of systemic infection. No abnormalities were found in the cardiovascular and respiratory systems. Six patients still had hepatomegaly and one had hepatosplenomegaly. Laboratory features (table) —Peripheral blood smears were negative for malaria parasites at the time of diagnosis of PMNS in all patients. The opening pressure at lumbar puncture was normal (65–195 mm CSF) in all but one (230 mm CSF). In eight (36%) the CSF showed a leucocyte pleocytosis (>5 cells/L, range 8 to 80) with lymphocyte predominance, and in 13 (59%) the CSF protein concentration was raised (>50 mg/dL). There was no relation between CSF opening pressure, total protein, or white cell count and the PMNS symptomatology. Cerebrospinal fluid culture and serum and CSF antibody tests were negative for Japanese encephalitis, and PCR was negative for herpes simplex virus in all cases. Two patients had serum anti-dengue IgM antibodies consistent with recent dengue infection, although CSF antibodies were negative. Both developed an acute confusional state within three days of parasite clearance; in both cases the state lasted less than three days and resolved spontaneously. One patient was HIV positive and was hypoglycaemic with a blood glucose below 1 mmol/L at the time of diagnosis of PMNS. This patient had a convulsion followed by a prolonged coma which did not improve with hypertonic glucose administration. On lumbar puncture his CSF was clear, White blood cells ⫻106L, mean (95% CI) WBC>8000 ⫻106L (%) Haematocrit %, mean (95% CI) Sodium, mmol/L, mean (95% CI) Potassium, mmol/L, mean (95% CI) Creatinine, mol/L, median (95% CI, range) Bilirubin, mol/L, median (95% CI, range) Aspartate aminotransferase, mol/h per dL, median (95% CI, range) Alanine aminotransferase, mol/h, per dL, median (95% CI, range) Plasma mefloquine (ng/mL), mean (95% CI, range), n=17
10 800 (9400 to 12 200) 77% 28 (24 to 32) 131 (128 to 134) 3·8 (3·3 to 4·2) 115 (80 to 186, 62–1132) 27 (19 to 31, 10–75) 124 (73 to 200, 32–470) 135 (74 to 201, 40–490) 1382 (919 to 2134, 185–5207)
Table: Laboratory findings in post-malaria neurological syndrome
Vol 348 • October 5, 1996
though it contained 28 lymphocytes/L. Bacterial, fungal, and viral cultures were negative and eventual recovery was spontaneous and uncomplicated.
Features of the preceding malaria infection Of the 22 patients with PMNS, 21 were originally admitted with severe malaria18 and one had acute uncomplicated malaria. 13 patients had cerebral malaria (Glasgow coma score [GCS] <11), and three others were confused on admission (GCS 13 or 14). Overall during the acute admission 14 of the patients were jaundiced, 10 had severe anaemia, eight developed acute renal failure, four had one or more episodes of hypoglycaemia, and one was shocked. Six patients, all with cerebral malaria, had one or more generalised convulsions during their malaria infection. All patients were blood smear negative for malaria parasites and were fully conscious (GCS 15) immediately before the onset of PMNS. The median time from parasite clearance to onset of the PMNS-defining neurological symptoms was 96 h (95% CI 66 to 351, range 6 h to 60 days). In the 15 patients whose GCS fell below 15 during their episode of malaria the median time between recovery of the GCS to 15 and the onset of PMNS was 192 h (95% CI 52 to 389, range 24–1128). At the time of onset of PMNS residual manifestations of the malaria infection were evident in 12 (55%) patients; 10 were anaemic, six were still jaundiced, and six still had abnormal renal function (plasma creatinine >265 mol/L). Seven patients still had splenomegaly, and two had hepatomegaly. In those patients with residual abnormal renal function the median plasma creatinine was 610 mol/L (range 309–1129), though none had any systemic signs or symptoms of uraemia or evident disturbance of electrolyte balance. Similarly those patients who were still jaundiced had no signs or symptoms of acute liver failure. Relation of PMNS to preceding mefloquine treatment Overall 17 patients (77%) were treated at some stage in the illness with mefloquine, 10 (46%) with quinine, 13 (59%) with a qinghaosu derivative (artesunate seven and artemether six), and four (18%) with pyrimethamine/sulphadoxine. The median time from the end of antimalarial treatment to the onset of PMNS was 78 h (95% CI 31 to 180, range 11–1344). The relation between drug use and development of PMNS overall can be estimated only imprecisely because the details of previous treatment in the 18 124 malaria patients admitted to the hospitals who were not known to have developed PMNS are incomplete. Following severe malaria PMNS developed in 16 of 412 known mefloquine recipients compared with 4 of 764 patients who did not receive mefloquine (relative risk 7·4, 95% CI 2·5 to 22) and in one of 1012 patients who were prescribed mefloquine in uncomplicated malaria (relative risk following severe malaria 39·3, 5·2 to 295). This indicates synergy between the drug and disease severity in inducing PMNS (p=0·0009). All patients who were known to have received mefloquine had detectable plasma levels, whereas mefloquine was not detected in the plasma of the five patients without a history of mefloquine treatment. There was no relation between plasma mefloquine concentrations and any particular neuropsychiatric symptom. 11 patients with PMNS had 919
THE LANCET
been enrolled in the prospective comparison of intramuscular artemether and intramuscular quinine in severe falciparum malaria.12 A total of 516 cases were enrolled in this comparison during the study period, giving an incidence for PMNS following severe malaria of 21·3 per 1000 (exact 95% CI 10·7 to 37·8 per 1000), a similar value to the incidence estimate for the whole study period. In the first randomisation, five of the PMNS patients received quinine and six artemether. In the second randomisation, 10 of 228 patients who received mefloquine developed PMNS compared with only one of 210 patients who were randomised to receive quinine and sulphadoxine-pyrimethamine; relative risk 9·2 (95% CI 1·2 to 71), p=0·012. Thus 4·4% (95% CI 2·1 to 7·9) of patients with severe malaria who subsequently received mefloquine developed PMNS. Overall 17 out of 22 PMNS patients (77%) had received mefloquine. The median time from taking the mefloquine to onset of PMNS was 84 h (95% CI 32 to 246, range 0·5–1200). There was no significant difference between patients treated with mefloquine and those treated with other antimalarials in the time from parasite clearance or from the end of treatment to the onset of PMNS, or in the nature or duration of PMNS. A logistic regression analysis of data from the 516 severe malaria patients in the artemether/quinine trial12 did not identify any clinical features of the malaria infection or drug treatment other than mefloquine which predisposed to the development of PMNS. The significant association between mefloquine treatment and subsequent PMNS was found to be robust and not explicable by co-segregation of any other variable; odds ratio 9·4 (95% CI 1·2 to 76).
Discussion Although the manifestations of post-malaria neurological syndrome in this series are diverse, there are several common features. These include a negative blood smear at the onset of neurological or neuropsychiatric symptoms, recent recovery from P falciparum malaria with a preceding severe rather than moderate or mild infection, and complete recovery from PMNS without specific treatment within ten days. PMNS was associated strongly with mefloquine treatment, although this did not account for all cases or any particular clinical presentation. No specific predisposing factors other than mefloquine treatment and the severity of the falciparum malaria were identified. It is possible that the pathology of PMNS is linked directly to the neuropathological processes which are common in severe falciparum malaria. The brain is a favoured site of parasitised erythrocyte sequestration.2 In several necropsy series the findings of parasitised red blood cells blocking brain capillaries have not been limited to patients who died of the cerebral form of severe malaria (refs 19 and 20, and G Turner, personal communication). Falciparum malaria is associated specifically with convulsions even in uncomplicated malaria,21 so sequestration of parasitised erythrocytes in the brain may well occur in all patients with falciparum malaria. However, structural lesions such as infarcts or haemorrhages are difficult to reconcile with the extent of central nervous system dysfunction in PMNS, and its rapid resolution. An immune basis for this syndrome is possible; immunological mechanisms have been implicated also in 920
the pathogenesis of the delayed post-malaria cerebellar syndrome, which would be included in our broad definition of PMNS.22 Over half of the PMNS patients were febrile but they had no other evidence of infection. At lumbar puncture most patients had a slightly raised CSF protein and some had a CSF lymphocyte pleocytosis. Further immunopathological studies are needed to substantiate this hypothesis. Co-infection with a virus capable of causing encephalitis is another possible explanation for PMNS, though we found no laboratory evidence of Japanese B virus infection (the most common cause of encephalitis in this region) or herpes simplex infection, and recovery was usually rapid. Dengue is very common in southern Vietnam during the rainy (malaria) season, but this seldom causes encephalitis. Dengue virus IgM antibody was found in the serum, but not the CSF, of two PMNS patients but this was judged coincidental. Although metabolic abnormalities are well known to cause confusion and neurological dysfunction, we found no evidence for such causation except possibly in the patient with hypoglycaemia. The strong association between treatment with mefloquine and the development of PMNS suggests a role for mefloquine in the aetiology of this syndrome in most cases. Acute self-limiting neuropsychiatric reactions to mefloquine have been well described in the context of both malaria prophylaxis and treatment.23 The data from this study indicate synergistic neurotoxicity between the drug and disease, which increases with the severity of the infection. This interpretation is supported by observations from the western border of Thailand8 where eight neuropsychiatric reactions were reported in a series of 13 950 supervised mefloquine treatments for acute uncomplicated falciparum malaria, giving an incidence of 0·57 per 1000 mefloquine treated patients (exact 95% CI 0·25 to 11·3). This figure is comparable with the approximate PMNS incidence of 0·1% following uncomplicated falciparum malaria in the present series. It is about ten times higher than the estimated incidence in healthy individuals receiving mefloquine prophylaxis (1 in 15 000) but it is 31 times lower (95% CI 13·9 to 70) than the incidence of 17·8 (exact 95% CI 10·8 to 27·7) per 1000 following severe malaria in the present series. However, mefloquine is not the only risk factor for PMNS since five patients in the present series had definitely not received the drug. Because a proportion of the patients had already been discharged from hospital after recovery from malaria, is it possible that prejudice in the community against mefloquine led to differential reporting and a spurious association between malaria and mefloquine? This is highly unlikely, since in Vietnam at the time of this study mefloquine was not widely available and public awareness of any potential sideeffects would have been very low. The importance of mefloquine in the aetiology of PMNS was confirmed by the observations from the randomised controlled trial. All patients who developed PMNS in this trial did so while still in hospital (and the patients randomised to mefloquine were not observed in hospital for any longer than those randomised to quinine). This study indicated a relative risk of 9·2 of developing PMNS if mefloquine was used following severe malaria, and an absolute risk of approximately 5%. This risk is unacceptable, and where an effective alternative drug is available
Vol 348 • October 5, 1996
THE LANCET
mefloquine should not be used after treatment of severe malaria.
9 10 11
We thank the directors and staff of the Centre for Tropical Diseases (CTD) and Dong Nai Paediatric Centre for their support and in particular Tran Thi Hong Chau, Pham Phu Loc, Ha Vinh, Tom Solomon, and Cao Xuan Thanh Phuong for their invaluable help. We are also grateful to the doctors and nurses on the severe malaria ward and the paediatric intensive care unit at the CTD. Special thanks go to Dinh Xuan Sinh, Nguyen The Dung, Nguyen Minh Duong, Bui Minh Cuong, Nguyen Van Vinh Chau, Nguyen Thi Giac, and David Vaughan, Department of Virology, US AFRIMS component, Bangkok, Thailand. This study was funded by the Wellcome Trust of Great Britain.
12
13 14 15 16
References 1 2 3 4
5
6
7 8
Roman GC. Cerebral malaria: the unsolved riddle. J Neurol Sci 1991; 101: 1–6. White NJ, Ho M. The pathophysiology of malaria. Adv Parasitol 1992; 31: 83–172. Brewster D, Kwiatkowski D, White NJ. Neurological sequelae of cerebral malaria in children. Lancet 1990; 336: 1039–43. Warrell D, Looareesuwan S, Warrell M, et al. Dexamethasone proves deleterious in cerebral malaria: a double-blind trial in 100 comatose patients. N Engl J Med 1982; 306: 313–19. White NJ, Miller K, Marsh K, Berry C, Turner RC, Williamson DH, Brown J. Hypoglycaemia in African children with severe malaria. Lancet 1987; i: 708–11. Weinke T, Trautmann M, Held T, et al. Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 1991; 45: 86–91. Rouveix B, Bricaire F, Michon C, Franssen G, Le Bras J. Mefloquine and an acute brain syndrome. Ann Intern Med 1989; 110: 577–78. Luxemburger C, Nosten F, ter Kuile F, Frejacques L, Chongsuphajaisiddhi T, White NJ. Mefloquine for multidrugresistant malaria. Lancet 1991; 338: 1268.
Vol 348 • October 5, 1996
17 18
19
20
21
22
23
Speich R, Haller A. Central anticholinergic syndrome with the antimalarial drug mefloquine. N Engl J Med 1994; 331: 57–58. Sowunmi A. Psychosis after cerebral malaria in children. J Natl Med Assoc 1993; 85: 695–96. Silva HJD. Delayed cerebellar ataxia following falciparum malaria: lack of evidence for antibody mediation. Trans R Soc Trop Med Hyg 1992; 86: 608. Hien TT, Day NPJ, Phu NH, et al. A controlled trial of quinine or artemether in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996; 335: 76–83. Burke DS, Lorsumrudee W, Leake CJ, et al. Fatal outcome in Japanese encephalitis. Am J Trop Med Hyg 1985; 34: 1203–09. Powell KF, Anderson NE, Frith RW, Croxon MC. Non-invasive diagnosis of Herpes simplex encephalitis. Lancet 1991; 335: 357. Miettinen OS. Estimation of relative risk from individually matched series. Biometrics 1970; 26: 75–86. Mood A, Graybill F. Introduction to the theory of statistics. 2nd ed. New York: McGraw-Hill, 1963. Hosmer D, Lemeshow S. Applied logistic regression. New York: Wiley, 1989. World Health Organization. Control of tropical diseases. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990; 84 (suppl 2): 1–65. Pongponratn E, Riganti M, Punpoowong B, Aikawa M. Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. Am J Trop Med Hyg 1991; 44: 168–75. Macpherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria: a quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol 1985; 119: 385–401. Wattanagoon Y, Srivilairit S, Looareesuwan S, White NJ. Convulsions in childhood malaria. Trans R Soc Trop Med Hyg 1994; 88: 426–28. de Silva H, Hoang P, Silva ND, Jewell D, Peiris J. Immune activation during cerebellar dysfunction following Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 1992; 86: 129–31. Phillips-Howard P, ter Kuile F. CNS adverse events associated with antimalarial agents, fact or fiction? Drug Safety 1995; 12: 370–83.
921
Post-malaria neurological syndrome
Nguyen Thi Hoang Mai, Nicholas P J Day, Ly Van Chuong, Deborah Waller, Nguyen Hoan Phu, Delia B Bethell, Tran Tinh Hien, Nicholas J White
Summary Background Neurolog ic al sig ns and sy mpt oms are common in malaria, but observations in Vietnam and Thailand have pointed to a discrete transient neurological syndrome after recovery from severe infections. Methods A prospec t ive st udy of t he post -malaria neurological syndrome (PMNS) was conducted at two centres in Vietnam over four years. Criteria for inclusion were recent symptomatic malaria infection with parasites cleared from blood (and in cases of cerebral malaria full rec overy of c onsc iousness) , and development of neurological or psychiatric symptoms within two months after the acute illness. Half of the patients with severe falciparum malaria had been taking part in a randomised trial of antimalarials. Findings Of 18 124 patients with falciparum malaria treated (1176 of whom had severe infections) 19 adults and three children had subsequent PMNS; in one patient it followed uncomplicated malaria and in 21 it followed severe malaria. The overall incidence (95% confidence interval) of PMNS after falciparum malaria at the main study centre was 1·2 per 1000 (0·7 to 1·8 per 1000) and relative risk (95% CI) for developing PMNS after severe versus uncomplicated falciparum malaria was 299 (40 to 2223). 13 patients had an acute confusional state or psychosis, six had one or more generalised convulsions, two had generalised convulsions followed by a long period of acute confusion, and one developed a fine tremor. At t he t ime of P M NS diag nosis all pat ient s w ere aparasitaemic. The syndrome was self-limiting, median duration 60 h (range 24–240). PMNS was associated with the use of oral mefloquine. In the randomised trial 4·4% (10/228) of patients with severe malaria who received mefloquine after parenteral treatment developed PMNS compared with 0·5% (1/210) of those who received quinine; relative risk 9·2 (95% CI 1·2 to 71·3, p=0·012). Interpretation Mefloquine is not the only risk factor for
Centre for Tropical Diseases (N T H Mai MD, L V Chuong MD, N H Phu MD, T T Hien MD) and Wellcome Trust Clinical Research Unit (N P J Day MRCP , D Waller BM , D B Bethell MB , Prof N J White FRCP ), Centre for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam; and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK (N P J Day, D Waller, D B Bethell, N J White) Correspondence to: Prof Nicholas J White, Wellcome Trust Clinical Research Unit, Centre for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam
Vol 348 • October 5, 1996
P M NS but it is a st rong one. W here an effec t ive alternative drug is available, mefloquine should not be used after treatment of severe malaria.
Lancet 1996; 348: 917–21
Introduction Of the many neurological manifestations and complications of malaria, the most common and important is the cerebral form of severe Plasmodium falciparum malaria. This is attributed to the sequestration of parasitised red blood cells in the brain, though how this process causes coma is incompletely understood.1,2 In most cases recovery is complete, although cerebral malaria is fatal in 15–20% of cases and a further 10% of children and 1–3% of adults have residual neurological sequelae.3,4 Hypoglycaemia resulting from malaria or quinine treatment can also cause coma and, if it is severe and protracted, may result in death or permanent brain damage.5 Use of mefloquine, chloroquine, and earlier mepacrine (quinacrine) for the prophylaxis or treatment of malaria has also been associated with an acute selflimiting neuropsychiatric syndrome,6–8 and lately a case of “central anticholinergic syndrome” associated with mefloquine treatment was described.9 Psychosis following cerebral malaria has been reported,10 and a delayed cerebellar syndrome following falciparum malaria has also been described, particularly in Sri Lanka.11 After observations in Vietnam and Thailand that a discrete neurological syndrome could follow recovery from falciparum malaria a prospective study was conducted. Here we report the clinical features and associations of this post-malaria neurological syndrome (PMNS) in 22 patients.
Patients and methods This prospective study was conducted over four years, to January, 1995, at the Centre for Tropical Diseases, Ho Chi Minh City, Vietnam, an infectious disease hospital which is a referral centre for much of southern Vietnam, and at the nearby Dong Nai Paediatric Centre. We included under PMNS any patient with symptomatic malaria infection (initial blood smear positive for asexual forms of malaria parasites), whose parasites had cleared from the peripheral blood and, in cerebral cases, had recovered consciousness fully, who developed neurological or psychiatric symptoms within two months after the acute illness. During part of the study period a double-blind trial of the treatment of severe adult malaria was carried out at one of the study centres,12 and any patients presenting with PMNS after recovery were included in the present series. In this treatment trial, patients were randomised to receive either intramuscular artemether (4 mg per kg initially, then 2 mg per kg eight hourly) or quinine (20 mg of hydrochloride salt per kg initially, then 10 mg per kg eight hourly) and when they could
917
THE LANCET
take oral medication they were randomised for a second time to receive either oral sulphadoxine-pyrimethamine (Fansidar; Roche, Basel) in a single dose of three tablets together with oral quinine sulphate (Government Pharmaceutical Organisation, Thailand) 10 mg per kg three times a day to complete seven days’ treatment, or a single dose of mefloquine (Lariam; Roche, Basel) 15 mg of base per kg. The second randomisation was independent of the first. The antimalarial treatment of patients not included in this prospective double-blind trial was at the discretion of the admitting physician.
Procedures On entry a full history was taken from each patient and his or her relatives, including an assessment of the patient’s premorbid neurological and psychiatric condition and any history of epilepsy. Details of the recent malaria episode were obtained from the hospital records or from the case forms of the prospective antimalarial drug trial. A full general, neurological, and mental state examination was conducted on admission by one of the investigators, the results being recorded in standard format. Each patient was re-examined 6-hourly until recovery. Blood was drawn for biochemical and haematological tests including blood glucose, electrolytes, liver and renal function tests, plasma mefloquine level, blood culture, full blood count, and thick and thin malaria blood smears. A lumbar puncture was performed, the opening pressure was measured, and cerebrospinal fluid (CSF) samples were taken for protein and glucose measurement, for cell counts, and for herpes simplex virus testing with a specific polymerase chain reaction.13 CSF was also inoculated into Aedes albopictus C6/36 cell line cells and a standard indirect immunofluorescence technique with hyperimmune mouse ascitic fluid was used to detect Japanese encephalitis virus (JEV). CSF and acute serum samples were also tested for the presence of JEV and dengue virus antibodies.14
Statistical analysis Continuous variables were compared between groups by use of the Mann-Whitney U unpaired and the Wilcoxon signed-rank paired tests as appropriate. Nominal data were compared by means of Fisher’s exact test. Exact 95% confidence intervals were calculated for proportions15 and medians.16 Logistic regression analysis was done with the Stata statistical software package (Statacorp, USA), using regression diagnostic tests devised by Lemeshow and Hosmer.17
Results During the study period 22 patients admitted to the two sites developed neurological or psychiatric symptoms after recovery from malaria and fulfilled the criteria for entry to the study. One patient had recovered from uncomplicated falciparum malaria, and the remainder from severe falciparum malaria. All cases followed infection with Plasmodium falciparum malaria; none followed P vivax infection although this parasite accounts for about 30% of malaria infections seen at the study sites.
Incidence of PMNS During the four-year study period 16 970 patients with uncomplicated falciparum malaria and 1065 patients with severe malaria were treated at one of the two study sites (Centre for Tropical Diseases), and 21 of these patients were diagnosed subsequently as having PMNS—ie, 1·2 per 1000 falciparum malaria cases overall (95% CI 0·7 to 1·8 per 1000). 20 cases followed severe malaria, an estimated incidence of 18·7 (95% CI 11·5 to 28·8) per 1000, and one followed uncomplicated falciparum malaria; relative risk 299 (40 to 2223) for 918
PMNS following severe compared with uncomplicated falciparum malaria. Three patients were children under the age of 15 (aged 6, 9, and 10 years), all recovering from severe malaria. At the two centres 363 children were admitted with severe malaria, all of whom were observed and treated on the study wards, an incidence for PMNS following severe childhood malaria of 8·3 per 1000 cases (exact 95% CI 1·7 to 24·0). In adult patients there were 18 cases of PMNS among 813 cases of severe malaria, giving an approximate incidence of 22·1 per 1000 (exact 95% CI 13·2 to 34·8) (p=0·16). These figures define the lower limit of the true incidence, because some patients were discharged home to regions of southern Vietnam far from the study hospitals, where any symptoms that developed subsequently might have been treated locally without the knowledge of the investigators. For the same reasons mild cases of PMNS may be under-reported. Thus the true incidence of the condition may have been underestimated and the clinical description skewed towards the severe end of the spectrum.
Clinical features Of the 22 cases of PMNS, 16 developed during the same admission as the malarial illness; six patients were readmitted after being discharged clinically well. 15 (68%) cases were male, with a mean (range) age of 29 (6 to 51) years. No patient had a previous history of neurological or psychiatric illness, although one patient was an intravenous opioid abuser positive for human immunodeficiency virus (HIV). The PMNS-defining neuropsychiatric manifestations were wide-ranging; 13 (59%) patients had either an acute confusional state or an acute psychosis, six (27%) had generalised convulsions, and two (9%) had generalised convulsions followed by an acute confusional state. One patient’s only neurological manifestation was a fine tremor which lasted 4 days. The median duration of these neuropsychiatric symptoms was 60 h (95% CI 48 to 109, range 24–240). During this period no patient had any focal neurological signs on examination, and all made a full recovery without sequelae. No relation was found between the type of PMNS symptomatology and either the antimalarial drug(s) used to treat the preceding malaria infection or the clinical characteristics of the malaria infection. Generalised convulsions—Eight (36%) patients had at least one generalised convulsion lasting in each case under a minute; three patients had multiple seizures. Two patients recovered full consciousness within minutes of the convulsions, but in four there was a subsequent period of coma lasting 36–72 h. The remaining two patients regained consciousness quickly but developed an acute confusional state (one immediately, one 24 h later) which lasted 5 and 10 days, respectively. Four patients had recovered from cerebral malaria, and three had had convulsions complicating their malaria. No focal neurological signs were detected in any of these patients post-ictally, none had a past history of epilepsy, and all eventually made a complete recovery. Psychotic or acute confusional episodes—15 patients (68%) developed symptoms of an acute confusional state
Vol 348 • October 5, 1996
THE LANCET
or acute psychosis. 12 had an acute confusional state with clouding of consciousness and inappropriate speech or behaviour, six of whom experienced florid visual hallucinations, and two developed a prolonged confusional state following generalised convulsions. Two patients with acute confusional states had periods of classic catatonia with waxy flexibility. Three patients developed acute psychotic symptoms without clouding of consciousness. Of these, two had serious and prolonged persecutory delusions (one attempted suicide), and the other became acutely manic and euphoric and experienced visual hallucinations.
Tremor —One patient developed a fine postural tremor of the arms and legs (frequency >10 Hz), which worsened on intention. Muscle tone was decreased symmetrically in all limbs, though there was no nystagmus and no ataxia. His plasma bilirubin was slightly raised (34 mol/L); transaminases were normal and there was no evidence of hepatic encephalopathy. The tremor lasted four days and then resolved spontaneously and completely. Other clinical features—Nine patients were febrile on diagnosis of PMNS, though none had any signs of systemic infection. No abnormalities were found in the cardiovascular and respiratory systems. Six patients still had hepatomegaly and one had hepatosplenomegaly. Laboratory features (table) —Peripheral blood smears were negative for malaria parasites at the time of diagnosis of PMNS in all patients. The opening pressure at lumbar puncture was normal (65–195 mm CSF) in all but one (230 mm CSF). In eight (36%) the CSF showed a leucocyte pleocytosis (>5 cells/L, range 8 to 80) with lymphocyte predominance, and in 13 (59%) the CSF protein concentration was raised (>50 mg/dL). There was no relation between CSF opening pressure, total protein, or white cell count and the PMNS symptomatology. Cerebrospinal fluid culture and serum and CSF antibody tests were negative for Japanese encephalitis, and PCR was negative for herpes simplex virus in all cases. Two patients had serum anti-dengue IgM antibodies consistent with recent dengue infection, although CSF antibodies were negative. Both developed an acute confusional state within three days of parasite clearance; in both cases the state lasted less than three days and resolved spontaneously. One patient was HIV positive and was hypoglycaemic with a blood glucose below 1 mmol/L at the time of diagnosis of PMNS. This patient had a convulsion followed by a prolonged coma which did not improve with hypertonic glucose administration. On lumbar puncture his CSF was clear, White blood cells ⫻106L, mean (95% CI) WBC>8000 ⫻106L (%) Haematocrit %, mean (95% CI) Sodium, mmol/L, mean (95% CI) Potassium, mmol/L, mean (95% CI) Creatinine, mol/L, median (95% CI, range) Bilirubin, mol/L, median (95% CI, range) Aspartate aminotransferase, mol/h per dL, median (95% CI, range) Alanine aminotransferase, mol/h, per dL, median (95% CI, range) Plasma mefloquine (ng/mL), mean (95% CI, range), n=17
10 800 (9400 to 12 200) 77% 28 (24 to 32) 131 (128 to 134) 3·8 (3·3 to 4·2) 115 (80 to 186, 62–1132) 27 (19 to 31, 10–75) 124 (73 to 200, 32–470) 135 (74 to 201, 40–490) 1382 (919 to 2134, 185–5207)
Table: Laboratory findings in post-malaria neurological syndrome
Vol 348 • October 5, 1996
though it contained 28 lymphocytes/L. Bacterial, fungal, and viral cultures were negative and eventual recovery was spontaneous and uncomplicated.
Features of the preceding malaria infection Of the 22 patients with PMNS, 21 were originally admitted with severe malaria18 and one had acute uncomplicated malaria. 13 patients had cerebral malaria (Glasgow coma score [GCS] <11), and three others were confused on admission (GCS 13 or 14). Overall during the acute admission 14 of the patients were jaundiced, 10 had severe anaemia, eight developed acute renal failure, four had one or more episodes of hypoglycaemia, and one was shocked. Six patients, all with cerebral malaria, had one or more generalised convulsions during their malaria infection. All patients were blood smear negative for malaria parasites and were fully conscious (GCS 15) immediately before the onset of PMNS. The median time from parasite clearance to onset of the PMNS-defining neurological symptoms was 96 h (95% CI 66 to 351, range 6 h to 60 days). In the 15 patients whose GCS fell below 15 during their episode of malaria the median time between recovery of the GCS to 15 and the onset of PMNS was 192 h (95% CI 52 to 389, range 24–1128). At the time of onset of PMNS residual manifestations of the malaria infection were evident in 12 (55%) patients; 10 were anaemic, six were still jaundiced, and six still had abnormal renal function (plasma creatinine >265 mol/L). Seven patients still had splenomegaly, and two had hepatomegaly. In those patients with residual abnormal renal function the median plasma creatinine was 610 mol/L (range 309–1129), though none had any systemic signs or symptoms of uraemia or evident disturbance of electrolyte balance. Similarly those patients who were still jaundiced had no signs or symptoms of acute liver failure. Relation of PMNS to preceding mefloquine treatment Overall 17 patients (77%) were treated at some stage in the illness with mefloquine, 10 (46%) with quinine, 13 (59%) with a qinghaosu derivative (artesunate seven and artemether six), and four (18%) with pyrimethamine/sulphadoxine. The median time from the end of antimalarial treatment to the onset of PMNS was 78 h (95% CI 31 to 180, range 11–1344). The relation between drug use and development of PMNS overall can be estimated only imprecisely because the details of previous treatment in the 18 124 malaria patients admitted to the hospitals who were not known to have developed PMNS are incomplete. Following severe malaria PMNS developed in 16 of 412 known mefloquine recipients compared with 4 of 764 patients who did not receive mefloquine (relative risk 7·4, 95% CI 2·5 to 22) and in one of 1012 patients who were prescribed mefloquine in uncomplicated malaria (relative risk following severe malaria 39·3, 5·2 to 295). This indicates synergy between the drug and disease severity in inducing PMNS (p=0·0009). All patients who were known to have received mefloquine had detectable plasma levels, whereas mefloquine was not detected in the plasma of the five patients without a history of mefloquine treatment. There was no relation between plasma mefloquine concentrations and any particular neuropsychiatric symptom. 11 patients with PMNS had 919
THE LANCET
been enrolled in the prospective comparison of intramuscular artemether and intramuscular quinine in severe falciparum malaria.12 A total of 516 cases were enrolled in this comparison during the study period, giving an incidence for PMNS following severe malaria of 21·3 per 1000 (exact 95% CI 10·7 to 37·8 per 1000), a similar value to the incidence estimate for the whole study period. In the first randomisation, five of the PMNS patients received quinine and six artemether. In the second randomisation, 10 of 228 patients who received mefloquine developed PMNS compared with only one of 210 patients who were randomised to receive quinine and sulphadoxine-pyrimethamine; relative risk 9·2 (95% CI 1·2 to 71), p=0·012. Thus 4·4% (95% CI 2·1 to 7·9) of patients with severe malaria who subsequently received mefloquine developed PMNS. Overall 17 out of 22 PMNS patients (77%) had received mefloquine. The median time from taking the mefloquine to onset of PMNS was 84 h (95% CI 32 to 246, range 0·5–1200). There was no significant difference between patients treated with mefloquine and those treated with other antimalarials in the time from parasite clearance or from the end of treatment to the onset of PMNS, or in the nature or duration of PMNS. A logistic regression analysis of data from the 516 severe malaria patients in the artemether/quinine trial12 did not identify any clinical features of the malaria infection or drug treatment other than mefloquine which predisposed to the development of PMNS. The significant association between mefloquine treatment and subsequent PMNS was found to be robust and not explicable by co-segregation of any other variable; odds ratio 9·4 (95% CI 1·2 to 76).
Discussion Although the manifestations of post-malaria neurological syndrome in this series are diverse, there are several common features. These include a negative blood smear at the onset of neurological or neuropsychiatric symptoms, recent recovery from P falciparum malaria with a preceding severe rather than moderate or mild infection, and complete recovery from PMNS without specific treatment within ten days. PMNS was associated strongly with mefloquine treatment, although this did not account for all cases or any particular clinical presentation. No specific predisposing factors other than mefloquine treatment and the severity of the falciparum malaria were identified. It is possible that the pathology of PMNS is linked directly to the neuropathological processes which are common in severe falciparum malaria. The brain is a favoured site of parasitised erythrocyte sequestration.2 In several necropsy series the findings of parasitised red blood cells blocking brain capillaries have not been limited to patients who died of the cerebral form of severe malaria (refs 19 and 20, and G Turner, personal communication). Falciparum malaria is associated specifically with convulsions even in uncomplicated malaria,21 so sequestration of parasitised erythrocytes in the brain may well occur in all patients with falciparum malaria. However, structural lesions such as infarcts or haemorrhages are difficult to reconcile with the extent of central nervous system dysfunction in PMNS, and its rapid resolution. An immune basis for this syndrome is possible; immunological mechanisms have been implicated also in 920
the pathogenesis of the delayed post-malaria cerebellar syndrome, which would be included in our broad definition of PMNS.22 Over half of the PMNS patients were febrile but they had no other evidence of infection. At lumbar puncture most patients had a slightly raised CSF protein and some had a CSF lymphocyte pleocytosis. Further immunopathological studies are needed to substantiate this hypothesis. Co-infection with a virus capable of causing encephalitis is another possible explanation for PMNS, though we found no laboratory evidence of Japanese B virus infection (the most common cause of encephalitis in this region) or herpes simplex infection, and recovery was usually rapid. Dengue is very common in southern Vietnam during the rainy (malaria) season, but this seldom causes encephalitis. Dengue virus IgM antibody was found in the serum, but not the CSF, of two PMNS patients but this was judged coincidental. Although metabolic abnormalities are well known to cause confusion and neurological dysfunction, we found no evidence for such causation except possibly in the patient with hypoglycaemia. The strong association between treatment with mefloquine and the development of PMNS suggests a role for mefloquine in the aetiology of this syndrome in most cases. Acute self-limiting neuropsychiatric reactions to mefloquine have been well described in the context of both malaria prophylaxis and treatment.23 The data from this study indicate synergistic neurotoxicity between the drug and disease, which increases with the severity of the infection. This interpretation is supported by observations from the western border of Thailand8 where eight neuropsychiatric reactions were reported in a series of 13 950 supervised mefloquine treatments for acute uncomplicated falciparum malaria, giving an incidence of 0·57 per 1000 mefloquine treated patients (exact 95% CI 0·25 to 11·3). This figure is comparable with the approximate PMNS incidence of 0·1% following uncomplicated falciparum malaria in the present series. It is about ten times higher than the estimated incidence in healthy individuals receiving mefloquine prophylaxis (1 in 15 000) but it is 31 times lower (95% CI 13·9 to 70) than the incidence of 17·8 (exact 95% CI 10·8 to 27·7) per 1000 following severe malaria in the present series. However, mefloquine is not the only risk factor for PMNS since five patients in the present series had definitely not received the drug. Because a proportion of the patients had already been discharged from hospital after recovery from malaria, is it possible that prejudice in the community against mefloquine led to differential reporting and a spurious association between malaria and mefloquine? This is highly unlikely, since in Vietnam at the time of this study mefloquine was not widely available and public awareness of any potential sideeffects would have been very low. The importance of mefloquine in the aetiology of PMNS was confirmed by the observations from the randomised controlled trial. All patients who developed PMNS in this trial did so while still in hospital (and the patients randomised to mefloquine were not observed in hospital for any longer than those randomised to quinine). This study indicated a relative risk of 9·2 of developing PMNS if mefloquine was used following severe malaria, and an absolute risk of approximately 5%. This risk is unacceptable, and where an effective alternative drug is available
Vol 348 • October 5, 1996
THE LANCET
mefloquine should not be used after treatment of severe malaria.
9 10 11
We thank the directors and staff of the Centre for Tropical Diseases (CTD) and Dong Nai Paediatric Centre for their support and in particular Tran Thi Hong Chau, Pham Phu Loc, Ha Vinh, Tom Solomon, and Cao Xuan Thanh Phuong for their invaluable help. We are also grateful to the doctors and nurses on the severe malaria ward and the paediatric intensive care unit at the CTD. Special thanks go to Dinh Xuan Sinh, Nguyen The Dung, Nguyen Minh Duong, Bui Minh Cuong, Nguyen Van Vinh Chau, Nguyen Thi Giac, and David Vaughan, Department of Virology, US AFRIMS component, Bangkok, Thailand. This study was funded by the Wellcome Trust of Great Britain.
12
13 14 15 16
References 1 2 3 4
5
6
7 8
Roman GC. Cerebral malaria: the unsolved riddle. J Neurol Sci 1991; 101: 1–6. White NJ, Ho M. The pathophysiology of malaria. Adv Parasitol 1992; 31: 83–172. Brewster D, Kwiatkowski D, White NJ. Neurological sequelae of cerebral malaria in children. Lancet 1990; 336: 1039–43. Warrell D, Looareesuwan S, Warrell M, et al. Dexamethasone proves deleterious in cerebral malaria: a double-blind trial in 100 comatose patients. N Engl J Med 1982; 306: 313–19. White NJ, Miller K, Marsh K, Berry C, Turner RC, Williamson DH, Brown J. Hypoglycaemia in African children with severe malaria. Lancet 1987; i: 708–11. Weinke T, Trautmann M, Held T, et al. Neuropsychiatric side effects after the use of mefloquine. Am J Trop Med Hyg 1991; 45: 86–91. Rouveix B, Bricaire F, Michon C, Franssen G, Le Bras J. Mefloquine and an acute brain syndrome. Ann Intern Med 1989; 110: 577–78. Luxemburger C, Nosten F, ter Kuile F, Frejacques L, Chongsuphajaisiddhi T, White NJ. Mefloquine for multidrugresistant malaria. Lancet 1991; 338: 1268.
Vol 348 • October 5, 1996
17 18
19
20
21
22
23
Speich R, Haller A. Central anticholinergic syndrome with the antimalarial drug mefloquine. N Engl J Med 1994; 331: 57–58. Sowunmi A. Psychosis after cerebral malaria in children. J Natl Med Assoc 1993; 85: 695–96. Silva HJD. Delayed cerebellar ataxia following falciparum malaria: lack of evidence for antibody mediation. Trans R Soc Trop Med Hyg 1992; 86: 608. Hien TT, Day NPJ, Phu NH, et al. A controlled trial of quinine or artemether in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996; 335: 76–83. Burke DS, Lorsumrudee W, Leake CJ, et al. Fatal outcome in Japanese encephalitis. Am J Trop Med Hyg 1985; 34: 1203–09. Powell KF, Anderson NE, Frith RW, Croxon MC. Non-invasive diagnosis of Herpes simplex encephalitis. Lancet 1991; 335: 357. Miettinen OS. Estimation of relative risk from individually matched series. Biometrics 1970; 26: 75–86. Mood A, Graybill F. Introduction to the theory of statistics. 2nd ed. New York: McGraw-Hill, 1963. Hosmer D, Lemeshow S. Applied logistic regression. New York: Wiley, 1989. World Health Organization. Control of tropical diseases. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990; 84 (suppl 2): 1–65. Pongponratn E, Riganti M, Punpoowong B, Aikawa M. Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. Am J Trop Med Hyg 1991; 44: 168–75. Macpherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria: a quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol 1985; 119: 385–401. Wattanagoon Y, Srivilairit S, Looareesuwan S, White NJ. Convulsions in childhood malaria. Trans R Soc Trop Med Hyg 1994; 88: 426–28. de Silva H, Hoang P, Silva ND, Jewell D, Peiris J. Immune activation during cerebellar dysfunction following Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 1992; 86: 129–31. Phillips-Howard P, ter Kuile F. CNS adverse events associated with antimalarial agents, fact or fiction? Drug Safety 1995; 12: 370–83.
921