184
is
diagnostic of thrombocythaemic erythromelalgia. In untreated thrombocythaemic erythromelalgia frequently progresses to painful ischaemic acrocyanosis and frank gangrene. Low-dose aspirin can improve the peripheral ischaemic circulation,3 but Raynaud’s-like symptoms may continue because of the persistence of acrocyanotic microvascular ischaemia. The incurable variant-burning distress in the absence of any detectable underlying disorder-is rare. I have designated this entity "idiopathic or primary erythermalgiaand postulated six criteria for the condition: (1) attacks of local red vasodilatation with increased local heat and burning pain constitute the basic disturbances; (2) bilateral distribution; (3) production and aggravation by exercise and heat; (4) relief always provided by cold, rest, and elevation of the affected extremities; (5) no primary or associated disease; and (6) no response to treatment. In contrast with the asymmetric or unilateral localisation of thrombocythaemic erythromelalgia in toes and fingers occurring in adulthood or old age 2,3 primary erythermalgia arises in childhood or puberty as bilateral, more or less symmetrical, burning distress in the feet, ankles, and lower legs.4 There is relative sparing of the toes and no progression to peripheral ischaemia and gangrene. Secondary erythermalgia, without platelet involvement, has been cases,
described in association with inflammatory and circulatory disturbances such as gout, systemic lupus erythematosus, rheumatoid arthritis, cryoglobulinaemia, and endarteritis obliterans, for example, and also with diabetes, neurological conditions, and treatment with vasoactive drugs. These secondary forms of erythermalgia are not identical to the specific condition of thrombocythaemic erythromelalgia, because prompt and lasting relief of pain by aspirin is lacking. Department of Haematology, Dijkzigt Univeristy Hospital, Erasmus University, 3015 Rotterdam, Netherlands
JAN J. MICHIELS
1. Michiels JJ, Ten Kate FWJ,
Vuzevski VD, Abels J Histopathology of erythomelalgia thrombocythaemia. Histopathology 1984; 8: 669-78. 2. Michiels JJ, Abels J, Steketee J, Van Vliet HHDM, Vuzevski VD. Erythromelalgia caused by platelet mediated artenolar inflammation and thrombosis m thrombocythemia. Ann Intern Med 1985; 102: 466-71. 3. Michiels JJ, Van Joost Th. Erythromelalgia and thrombocythemia: a causal relation. J Am Acad Dermatol 1990; 22: 107-11. 4. Michiels JJ, Van Joost Th, Vuzevski VD. Idiopathic erythermalgia: a congenital disorder. J Am Acad Dermatol 1989; 21: 1128-30. m
Graves’ ophthalmopathy and smoking SIR,-In a case-control study the purpose of the comparison (control) group is to identify factors that occur more (or less) often in the cases and which may increase or reduce the risk of the condition under investigation.1 The control group, difficult though it may be to identify, must therefore consist of an unbiased sample of the base population from which the cases arise. They must not be biased with respect to the exposure of interest. Unfortunately Dr Shine and colleagues (May 26, p 1261) did not clearly state the hypothesis that they intended to test, and one consequence was the selection of three small control groups. The validity of each is debatable and the rationale for amalgamating them for comparison with the case group is not discussed. The control groups may have been seriously biased with respect to smoking because the information was derived from questionnaires, to which there was a poor response. Thus the individuals who contributed smoking information were self-selected responders and thus unlikely to have been representative of the groups from which they were derived.2 In one group the response rate was only 32% and the reported prevalence of current smoking was only 13 %. This group almost certainly provided a biased underestimate of smoking, and the apparently significant association of Graves’ disease with smoking may have arisen simply as a consequence of control group selection bias. We agree with your May 12 editorial that criticism of epidemiological studies should not be based on methodological pedantry. However, the fundamental problems relating to the control groups used by Shine et al mean that their findings must be
viewed with considerable circumspection. The apparent association between smoking and Graves’ ophthalmopathy does merit further examination but this would be best achieved in a study large enough to test a single hypothesis and with attention to complete data collection. The effects of potential confounders such as age and sex might also be taken into account. Department of Public Health Medicine, Leicestershire Health Authority, Leicester LE1 6TP, UK
R. SHUKLA
Department of Community Health, University of Leicester
J. J. KURINCZUK
NE, Day NE. Statistical methods in cancer research: vol I-the analysis of case-control studies. Lyon: International Agency for Research on Cancer, 1980. 2. Seltzer CC, Bosse R, Garvey AJ. Mail response by smoking status. Am J Epidemiol 1974; 100: 453-57 1. Breslow
***This letter has been shown to Dr Shine and Dr Weetman, whose reply follows.-ED. L. SIR,- We thank Dr Shukla and Dr Kurinczuk for their comments. Our hypotheses were that there is an association between Graves’ ophthalmopathy and smoking, and that within the group of patients with Graves’ ophthalmopathy there is an association between the degree of ophthahnopathy and amount of tobacco consumption. Our control groups were all of a similar size to the patient group, with much the same responses in three of the four groups. Although self-selection may lead to bias, the direction and magnitude of the bias might be expected to be similar in all groups. It is often only possible to detect bias after the event, by appropriate statistical analysis. We detected no significant differences between the three control groups either with respect to prevalence (chi-squared 47, 4 DF excluding the Graves’ ophthalmopathy group), or to pack-year history (chi-squared 8-4, 4 DF excluding the Graves’ ophthalmopathy group). We are thus happy with the homogeneity of the control groups, and that the first hypothesis is most probably correct. This hypothesis is further supported by our retrospective analysis of data from case records.’ The second hypothesis is lent support by the association of smoking history with degree of ophthalmopathy (our fig 2). Here, there is no need for a specific control group, since we are making a within-group comparison. The low prevalence of smoking seen in both the Moorfields and Cambridge control groups, might be expected from the high overall ages of our subjects. Our survey was conducted three years after the last general survey reported by the Office of Population Censuses and Surveys. If the trend of the previous fifteen years has continued, we would expect a smaller proportion of the general population to be smokers than in that series. There may, in addition, be regional differences, for which our comparison groups should have controlled. Institute of Ophthalmology, University of London, London EC1V 9AT, UK
BRIAN SHINE TONY WEETMAN
1. Shme B, Edwards
OM, Weetman AP. Graves’ ophthalmopathy and smoking Acta Endocrinologica 1989 121 (suppl 2): 182-84 2. Office of Population Censuses and Surveys Cigarette smoking 1972 to 1986. OPCS Monitor. London: Government Statistical Service, 1988; Feb 9: 1-10.
Schizophrenia and encephalitis lethargica SIR,-My spirits were lifted by Dr Boyle’s letter (April 7, p 853) on prevalence of the sequelae of encephalitis lethargica in the population studied by Kraepelin and Bleuler in their identification of dementia praecox and schizophrenia. During my early apprenticeship in 1949, when I was charged with the care of 400 or 500 chronic patients, there was in every ward a sprinkling of cases labelled "encephalitis lethargica, effects of’. These were distinguishable to me because of parkinsonism, choreoathetosis, or night calls to deal with oculogyric crises. Although I had read one or two good books before starting my apprenticeship, I was not able to distinguish these patients from those labelled "chronic paranoid schizophrenia", except by observing their disorders of movement. I the
185
put this down to my ignorance at that time, which was a few years before the introduction of psychotropic drugs. One of my patients today had a viral encephalitis in 1965. His psychiatric symptoms, unusually, started with the acute illness without remission since. After 25 years, he is just beginning to show a choreiform disorder of movement. Nevertheless, despite a clear history, he is still labelled chronic paranoid schizophrenia by psychiatrist and neurologist alike because he is deluded and hallucinatory. His disorder of movement is attributed to past medication for schizophrenia. The lesson of the encephalitis lethargica epidemic 1916-27 is forgotten. I can assure Dr Boyle that these cases still appear but they are now labelled chronic schizophrenia and tardive dyskinesia, whatever the extrapyramidal signs may be. Encephalitis is clearly recognisable in necropsy material whereas schizophrenia is not. This is not much solace to the encephalitic who has been treated for schizophrenia. It is forgotten that the episode of acute encephalitis may only be remembered as an attack of influenza and the interval between the encephalitis and the neuropsychiatric sequelae can be 30 years or more, although it is more commonly half this period. I agree with your correspondent that the postencephalitic cases with extrapyramidal symptoms are more rarely seen-and when seen are never believed. Box 1000, Ponoka, Alberta T0C 2H0, Canada
R. H. BOARDMAN
Efficacy of pyrimethamine/sulfadoxine in uncomplicated severe falciparum malaria in Kenya SIR,—The management of severe Plasmodiumfalciparum malaria in based on parenteral quinine. However, the toxicity, frequency of administration, and cost of this drug restrict its use and availability. Pyrimethamine/sulfadoxine (’Fansidar’, PSD) is a single dose, long acting, antifolate combination which is much cheaper than quinine and readily available. Both pyrimethamine and sulfadoxine are regarded as slow acting schizonticides, and despite their demonstrated synergism when combined at a dose ratio of 20 sulfadoxine to 1 pyrimethamine,’ are recommended only combined with quinine for the management of severe falciparum malariaThis recommendation seems to be based on experience in South-East Asia where malaria patients are mainly non-immune and where parasite clearance and symptomatic improvement after PSD treatment is slower than with quinine, chloroquine, mefloquine, or artemether.3,4However, this is not the case in Nigeria where response rates are similar to those obtained with chloroquine,s or in Pakistanwhere parasite clearance times averaged 1-25 days. Nor is it so in Kenya, where PSD treatment of non-severe, low parasitaemia (1000 to 50 000 asexual parasites per pl blood) falciparum malaria results in a mean parasite clearance time of about 2-5 days7 which is similar to that for quinine (2-4 days) (Schwartz IK, personal communication). We have therefore prospectively compared PSD and quinine in symptomatic, uncomplicated, high parasitaemia falciparum malaria. 22 outpatients at Magadi Hospital, Rift Valley Province (an area of continuous malaria transmission with pronounced seasonal variation), were recruited if they had slide positive falciparum malaria with parasitaemia of 50000IJll or over, but less than 250 000/µl; non-severe clinical presentation; normal blood glucose and creatinine levels; haemoglobin 7 g/dl or over; no history of hypersensitivity to sulphonamides; and if they gave written informed consent to participate. After examination, patients were randomly assigned to receive either oral quinine sulphate, 10 mg salt/kg, every 8 hours for 15 doses (11patients), or oral eastern Africa is
PATIENT CHARACTERISTICS
Parasitaemia in patients with falciparum malaria treated with PSD (n=11) or quinine (n=11). Mean
no
of
parasites shown (vertical bars=1 SD) by time after start of
treatment.
pyrimethamine 1.25 mg/kg plus sulfadoxine 25 mg/kg as a single dose (11). The patients’ clinical condition, parasitological response, and supervision of quinine dose were reviewed every 8 hours. The initial measurement of blood glucose was repeated if clinically indicated. Mean weight, age, and presenting parasitaemia did not differ between the groups (table); nor did mean defervescence times and mean parasite clearance times. There was no difference between the parasite clearance rates (figure). In 1 patient on PSD, parasites had not cleared by day 7 although the patient was symptom-free. All patients remained normoglycaemic during follow-up. Our small trial in Kenya suggests that PSD may be equivalent to quinine with respect to both the rate of parasite clearance and the rate of clinical recovery in patients with non-severe falciparum malaria. However, in contrast with reports from SE Asia, PSD is not a slow acting schizonticide in East Africa. This geographical dichotomy may reflect differences in both host immunity to malaria and parasite chemosensitivity between widely separated regions. The antifolate antimalarials exert specific activity against late erythrocytic stage parasites, which are precisely the stages found in parasitised red blood cells sequestered in cerebral venules,8 whose metabolic activity is responsible for the essential pathology of severe falciparum malaria.’’ We believe therefore that because of the low frequency of resistance to PSD in East Mrica10 antifolate drugs should be investigated for the treatment of severe falciparum malaria in that region. Malaria Unit, African Medical Research and Education Foundation, Nairobi, Kenya
C. G. NEVILL
Clinical Research Centre, Kenya Medical Research Institute, Nairobi
W. M. WATKINS
1. Bruce-Chwatt LJ. Essential malariology, 2nd ed. London: Heinemann, 1985: 228. 2. World Health Organisation. Advances in malaria chemotherapy. Tech Rep Ser 1984; no 711: 63. 3. World Health Organisation Malaria Action Programme. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1986; 80 (suppl): 22. 4. Pinichpongse S, Doberstyn EB, Cullen JR, Yisunri L, Thongsombun Y, Thimsarn K. An evaluation of five regimens for the outpatient therapy of falciparum malaria m Thailand 1980-81. Bull WHO 1982; 60: 909. 5. Lucas AO, Hendrickse RG, Okubadejo OA, Richards WHG, Neil RA, Kofie BAK. The suppression of malarial parasitaemia by pynmethamine in combination with dapsone or sulphormethoxine. Trans R Soc Trop Med Hyg 1969; 63: 216. 6. Strickland GT, Khaliq AA, Sarwar M, Hassan H, Pervez M, Fox E. Effects of Fansidar on chloroquine-resistant Plasmodium falciparum in Pakistan. Am J Med Hyg 1986; 35: 61. 7. Watkins WM, Brandling-Bennett AD, Nevill CG, et al. Chlorproguanil/dapsone for the treatment of nonsevere falciparum malaria in Kenya: a pilot study. Trans R Soc Trop Med Hyg 1988; 82: 398-403. 8. Phillips RE, Warrell DA. The pathophysiology of severe falciparum malaria. Parasitol Today 1986; 2: 271-82. 9. World Health Organisation Malaria Action Programme. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1986; 80 (suppl): 5-7. 10. Miller KD, Lobel HO, Pappaionou M, Patchen LC, Churchill FC. Failures of combined Fansidar and chloroquine prophylaxis in Amencan travellers to E. Africa J Infect Dis 1986; 154: 689-91.
is
diagnostic of thrombocythaemic erythromelalgia. In untreated thrombocythaemic erythromelalgia frequently progresses to painful ischaemic acrocyanosis and frank gangrene. Low-dose aspirin can improve the peripheral ischaemic circulation,3 but Raynaud’s-like symptoms may continue because of the persistence of acrocyanotic microvascular ischaemia. The incurable variant-burning distress in the absence of any detectable underlying disorder-is rare. I have designated this entity "idiopathic or primary erythermalgiaand postulated six criteria for the condition: (1) attacks of local red vasodilatation with increased local heat and burning pain constitute the basic disturbances; (2) bilateral distribution; (3) production and aggravation by exercise and heat; (4) relief always provided by cold, rest, and elevation of the affected extremities; (5) no primary or associated disease; and (6) no response to treatment. In contrast with the asymmetric or unilateral localisation of thrombocythaemic erythromelalgia in toes and fingers occurring in adulthood or old age 2,3 primary erythermalgia arises in childhood or puberty as bilateral, more or less symmetrical, burning distress in the feet, ankles, and lower legs.4 There is relative sparing of the toes and no progression to peripheral ischaemia and gangrene. Secondary erythermalgia, without platelet involvement, has been cases,
described in association with inflammatory and circulatory disturbances such as gout, systemic lupus erythematosus, rheumatoid arthritis, cryoglobulinaemia, and endarteritis obliterans, for example, and also with diabetes, neurological conditions, and treatment with vasoactive drugs. These secondary forms of erythermalgia are not identical to the specific condition of thrombocythaemic erythromelalgia, because prompt and lasting relief of pain by aspirin is lacking. Department of Haematology, Dijkzigt Univeristy Hospital, Erasmus University, 3015 Rotterdam, Netherlands
JAN J. MICHIELS
1. Michiels JJ, Ten Kate FWJ,
Vuzevski VD, Abels J Histopathology of erythomelalgia thrombocythaemia. Histopathology 1984; 8: 669-78. 2. Michiels JJ, Abels J, Steketee J, Van Vliet HHDM, Vuzevski VD. Erythromelalgia caused by platelet mediated artenolar inflammation and thrombosis m thrombocythemia. Ann Intern Med 1985; 102: 466-71. 3. Michiels JJ, Van Joost Th. Erythromelalgia and thrombocythemia: a causal relation. J Am Acad Dermatol 1990; 22: 107-11. 4. Michiels JJ, Van Joost Th, Vuzevski VD. Idiopathic erythermalgia: a congenital disorder. J Am Acad Dermatol 1989; 21: 1128-30. m
Graves’ ophthalmopathy and smoking SIR,-In a case-control study the purpose of the comparison (control) group is to identify factors that occur more (or less) often in the cases and which may increase or reduce the risk of the condition under investigation.1 The control group, difficult though it may be to identify, must therefore consist of an unbiased sample of the base population from which the cases arise. They must not be biased with respect to the exposure of interest. Unfortunately Dr Shine and colleagues (May 26, p 1261) did not clearly state the hypothesis that they intended to test, and one consequence was the selection of three small control groups. The validity of each is debatable and the rationale for amalgamating them for comparison with the case group is not discussed. The control groups may have been seriously biased with respect to smoking because the information was derived from questionnaires, to which there was a poor response. Thus the individuals who contributed smoking information were self-selected responders and thus unlikely to have been representative of the groups from which they were derived.2 In one group the response rate was only 32% and the reported prevalence of current smoking was only 13 %. This group almost certainly provided a biased underestimate of smoking, and the apparently significant association of Graves’ disease with smoking may have arisen simply as a consequence of control group selection bias. We agree with your May 12 editorial that criticism of epidemiological studies should not be based on methodological pedantry. However, the fundamental problems relating to the control groups used by Shine et al mean that their findings must be
viewed with considerable circumspection. The apparent association between smoking and Graves’ ophthalmopathy does merit further examination but this would be best achieved in a study large enough to test a single hypothesis and with attention to complete data collection. The effects of potential confounders such as age and sex might also be taken into account. Department of Public Health Medicine, Leicestershire Health Authority, Leicester LE1 6TP, UK
R. SHUKLA
Department of Community Health, University of Leicester
J. J. KURINCZUK
NE, Day NE. Statistical methods in cancer research: vol I-the analysis of case-control studies. Lyon: International Agency for Research on Cancer, 1980. 2. Seltzer CC, Bosse R, Garvey AJ. Mail response by smoking status. Am J Epidemiol 1974; 100: 453-57 1. Breslow
***This letter has been shown to Dr Shine and Dr Weetman, whose reply follows.-ED. L. SIR,- We thank Dr Shukla and Dr Kurinczuk for their comments. Our hypotheses were that there is an association between Graves’ ophthalmopathy and smoking, and that within the group of patients with Graves’ ophthalmopathy there is an association between the degree of ophthahnopathy and amount of tobacco consumption. Our control groups were all of a similar size to the patient group, with much the same responses in three of the four groups. Although self-selection may lead to bias, the direction and magnitude of the bias might be expected to be similar in all groups. It is often only possible to detect bias after the event, by appropriate statistical analysis. We detected no significant differences between the three control groups either with respect to prevalence (chi-squared 47, 4 DF excluding the Graves’ ophthalmopathy group), or to pack-year history (chi-squared 8-4, 4 DF excluding the Graves’ ophthalmopathy group). We are thus happy with the homogeneity of the control groups, and that the first hypothesis is most probably correct. This hypothesis is further supported by our retrospective analysis of data from case records.’ The second hypothesis is lent support by the association of smoking history with degree of ophthalmopathy (our fig 2). Here, there is no need for a specific control group, since we are making a within-group comparison. The low prevalence of smoking seen in both the Moorfields and Cambridge control groups, might be expected from the high overall ages of our subjects. Our survey was conducted three years after the last general survey reported by the Office of Population Censuses and Surveys. If the trend of the previous fifteen years has continued, we would expect a smaller proportion of the general population to be smokers than in that series. There may, in addition, be regional differences, for which our comparison groups should have controlled. Institute of Ophthalmology, University of London, London EC1V 9AT, UK
BRIAN SHINE TONY WEETMAN
1. Shme B, Edwards
OM, Weetman AP. Graves’ ophthalmopathy and smoking Acta Endocrinologica 1989 121 (suppl 2): 182-84 2. Office of Population Censuses and Surveys Cigarette smoking 1972 to 1986. OPCS Monitor. London: Government Statistical Service, 1988; Feb 9: 1-10.
Schizophrenia and encephalitis lethargica SIR,-My spirits were lifted by Dr Boyle’s letter (April 7, p 853) on prevalence of the sequelae of encephalitis lethargica in the population studied by Kraepelin and Bleuler in their identification of dementia praecox and schizophrenia. During my early apprenticeship in 1949, when I was charged with the care of 400 or 500 chronic patients, there was in every ward a sprinkling of cases labelled "encephalitis lethargica, effects of’. These were distinguishable to me because of parkinsonism, choreoathetosis, or night calls to deal with oculogyric crises. Although I had read one or two good books before starting my apprenticeship, I was not able to distinguish these patients from those labelled "chronic paranoid schizophrenia", except by observing their disorders of movement. I the
185
put this down to my ignorance at that time, which was a few years before the introduction of psychotropic drugs. One of my patients today had a viral encephalitis in 1965. His psychiatric symptoms, unusually, started with the acute illness without remission since. After 25 years, he is just beginning to show a choreiform disorder of movement. Nevertheless, despite a clear history, he is still labelled chronic paranoid schizophrenia by psychiatrist and neurologist alike because he is deluded and hallucinatory. His disorder of movement is attributed to past medication for schizophrenia. The lesson of the encephalitis lethargica epidemic 1916-27 is forgotten. I can assure Dr Boyle that these cases still appear but they are now labelled chronic schizophrenia and tardive dyskinesia, whatever the extrapyramidal signs may be. Encephalitis is clearly recognisable in necropsy material whereas schizophrenia is not. This is not much solace to the encephalitic who has been treated for schizophrenia. It is forgotten that the episode of acute encephalitis may only be remembered as an attack of influenza and the interval between the encephalitis and the neuropsychiatric sequelae can be 30 years or more, although it is more commonly half this period. I agree with your correspondent that the postencephalitic cases with extrapyramidal symptoms are more rarely seen-and when seen are never believed. Box 1000, Ponoka, Alberta T0C 2H0, Canada
R. H. BOARDMAN
Efficacy of pyrimethamine/sulfadoxine in uncomplicated severe falciparum malaria in Kenya SIR,—The management of severe Plasmodiumfalciparum malaria in based on parenteral quinine. However, the toxicity, frequency of administration, and cost of this drug restrict its use and availability. Pyrimethamine/sulfadoxine (’Fansidar’, PSD) is a single dose, long acting, antifolate combination which is much cheaper than quinine and readily available. Both pyrimethamine and sulfadoxine are regarded as slow acting schizonticides, and despite their demonstrated synergism when combined at a dose ratio of 20 sulfadoxine to 1 pyrimethamine,’ are recommended only combined with quinine for the management of severe falciparum malariaThis recommendation seems to be based on experience in South-East Asia where malaria patients are mainly non-immune and where parasite clearance and symptomatic improvement after PSD treatment is slower than with quinine, chloroquine, mefloquine, or artemether.3,4However, this is not the case in Nigeria where response rates are similar to those obtained with chloroquine,s or in Pakistanwhere parasite clearance times averaged 1-25 days. Nor is it so in Kenya, where PSD treatment of non-severe, low parasitaemia (1000 to 50 000 asexual parasites per pl blood) falciparum malaria results in a mean parasite clearance time of about 2-5 days7 which is similar to that for quinine (2-4 days) (Schwartz IK, personal communication). We have therefore prospectively compared PSD and quinine in symptomatic, uncomplicated, high parasitaemia falciparum malaria. 22 outpatients at Magadi Hospital, Rift Valley Province (an area of continuous malaria transmission with pronounced seasonal variation), were recruited if they had slide positive falciparum malaria with parasitaemia of 50000IJll or over, but less than 250 000/µl; non-severe clinical presentation; normal blood glucose and creatinine levels; haemoglobin 7 g/dl or over; no history of hypersensitivity to sulphonamides; and if they gave written informed consent to participate. After examination, patients were randomly assigned to receive either oral quinine sulphate, 10 mg salt/kg, every 8 hours for 15 doses (11patients), or oral eastern Africa is
PATIENT CHARACTERISTICS
Parasitaemia in patients with falciparum malaria treated with PSD (n=11) or quinine (n=11). Mean
no
of
parasites shown (vertical bars=1 SD) by time after start of
treatment.
pyrimethamine 1.25 mg/kg plus sulfadoxine 25 mg/kg as a single dose (11). The patients’ clinical condition, parasitological response, and supervision of quinine dose were reviewed every 8 hours. The initial measurement of blood glucose was repeated if clinically indicated. Mean weight, age, and presenting parasitaemia did not differ between the groups (table); nor did mean defervescence times and mean parasite clearance times. There was no difference between the parasite clearance rates (figure). In 1 patient on PSD, parasites had not cleared by day 7 although the patient was symptom-free. All patients remained normoglycaemic during follow-up. Our small trial in Kenya suggests that PSD may be equivalent to quinine with respect to both the rate of parasite clearance and the rate of clinical recovery in patients with non-severe falciparum malaria. However, in contrast with reports from SE Asia, PSD is not a slow acting schizonticide in East Africa. This geographical dichotomy may reflect differences in both host immunity to malaria and parasite chemosensitivity between widely separated regions. The antifolate antimalarials exert specific activity against late erythrocytic stage parasites, which are precisely the stages found in parasitised red blood cells sequestered in cerebral venules,8 whose metabolic activity is responsible for the essential pathology of severe falciparum malaria.’’ We believe therefore that because of the low frequency of resistance to PSD in East Mrica10 antifolate drugs should be investigated for the treatment of severe falciparum malaria in that region. Malaria Unit, African Medical Research and Education Foundation, Nairobi, Kenya
C. G. NEVILL
Clinical Research Centre, Kenya Medical Research Institute, Nairobi
W. M. WATKINS
1. Bruce-Chwatt LJ. Essential malariology, 2nd ed. London: Heinemann, 1985: 228. 2. World Health Organisation. Advances in malaria chemotherapy. Tech Rep Ser 1984; no 711: 63. 3. World Health Organisation Malaria Action Programme. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1986; 80 (suppl): 22. 4. Pinichpongse S, Doberstyn EB, Cullen JR, Yisunri L, Thongsombun Y, Thimsarn K. An evaluation of five regimens for the outpatient therapy of falciparum malaria m Thailand 1980-81. Bull WHO 1982; 60: 909. 5. Lucas AO, Hendrickse RG, Okubadejo OA, Richards WHG, Neil RA, Kofie BAK. The suppression of malarial parasitaemia by pynmethamine in combination with dapsone or sulphormethoxine. Trans R Soc Trop Med Hyg 1969; 63: 216. 6. Strickland GT, Khaliq AA, Sarwar M, Hassan H, Pervez M, Fox E. Effects of Fansidar on chloroquine-resistant Plasmodium falciparum in Pakistan. Am J Med Hyg 1986; 35: 61. 7. Watkins WM, Brandling-Bennett AD, Nevill CG, et al. Chlorproguanil/dapsone for the treatment of nonsevere falciparum malaria in Kenya: a pilot study. Trans R Soc Trop Med Hyg 1988; 82: 398-403. 8. Phillips RE, Warrell DA. The pathophysiology of severe falciparum malaria. Parasitol Today 1986; 2: 271-82. 9. World Health Organisation Malaria Action Programme. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1986; 80 (suppl): 5-7. 10. Miller KD, Lobel HO, Pappaionou M, Patchen LC, Churchill FC. Failures of combined Fansidar and chloroquine prophylaxis in Amencan travellers to E. Africa J Infect Dis 1986; 154: 689-91.
