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Visual loss and cryptococcal meningitis: a reply
TRANSACTIONS
OFTHE
ROYAL
1 Correspondence
(
I
I
SOCIETY
OFTROI’ICALMEDICINE
Malarial drug trials The increasing resistance of Plasmodium falciparum to antimalarial drugs requires a careful approach to ensure that rational national drug policies are developed. Coordinated trials at multiple sites are needed to obtain an overview of resistance patterns within a country or region. It is essential that malaria treatment trials produce comparable results to facilitate this process. The importance of this principle was recently demonstrated by consecutive articles appearing in this journal. Two trials were performed by the same researchers, working in the same hospital but using different methods. In the first trial, Falade et al. (1997: Transactions, 91, 58) compared the efficacies of halofantrine, pyrimethamineisulfadoxine and chloroquine. The inclusion criteria included a minimum l? falciparum parasitaemia of lOOO/ltL and a history of fever within 24 h before presentation. ‘Parasitological cure’ was assessed 7 d after the start of treatment. The parasitaemia was calculated by counting the number of asexual forms per 500 leucocytes and assuming a leucocyte concentration of 8000&L. In contrast, when Sowunmi et al. (1 sj97: Transactions, 91.63) comnared the efficacies of chloroauine and chloro&ine/chl&nheniramine thev used a thieshold narasitae-mia for inclusion of only SOOipL and accepted children with a history of fever within the preceding 48 h. The ‘cure rate’ was assessed at dav 14. Parasitaemias were calculated by counting the number of asexual forms per 1000 leucocytes, or the number of leucocytes per 500 asexual forms, and measuring the leucocyte count. Additionally, there were 3 criteria of treatment failures, though none of these was the same as that in the former study. Estimates of chloroquine efficacy produced by the 2 trials were sianificantlv different (15 cures, 23 failures in the former &id 37 cures, 12 ‘failures in the latter; x2=1 1.56, P
document WHOIMALI96.1077) will greatly facilitate researchers and policy makers involved in the development of rational-national guidelines. D . M. Schellenbern1,2 S. AbdaGal H. Mshindal llfakara Centre for Health Research and Development I? 0. Box 53 Ifakara Tanzania 2Hospital Clinic i Provincial Villarroel 170 08036 Barcelona Spain
AND
HYGIENE
(1997) 91,727-728
727
teroids. Our findings in a prospective study of the ocular manifestations of cryptococcal meningitis in 80 patients with AIDS confirmed the notion that visual loss is lower in immunosuppressed patients than in immunocompetent persons; in our series (Kestelyn et al., 1993: Ameri116, 721) only 9% of can Journal of Ophthalmology, patients experienced visual loss, compared to 52.5% in the series of Seaton and co-workers (Zoc.cit.). In the discussion of our article, not mentioned by Seaton and coworkers, we proposed 3 possible factors to explain the differential rate of visual loss in immunosuppressed and immunocompetent patients who have cryptococcal meningitis. First, cryptococcal meningitis in AIDS patients is often devoid of inflammatory response (Dismukes et al., 1988: Journal of Infectious Diseases, 157, 624). Since the invasion of the optic nerve by the organism may trigger an inflammatory response leading to arachnoiditis and optic nerve compression (Lipson et al., 1984: American Journal of Ophthalmology, 107, 523), the absence of a profound inflammatory response in AIDS patients might explain the lower frequency of visual loss and optic atrophy in these patients. Secondly, the high degree of diagnostic awareness in persons infected with human immunodeficiency virus may lead to a shorter interval between the onset of symptons and the start of effective treatment for cryptococcal meningitis, minimizing the neurological sequelae. Finally, visual loss through optic atrophy was significantly less prevalent in a subgroup of our patients who were treated with oral conazoles alone, as opposed to the group who received amphotericin B or a combination of amphotericin B and conazoles. We interpreted this finding as evidence for a potential toxic effect of amphotericin B on the optic nerve. Whether amphotericin B exerts a direct neurotoxic effect on the optic nerve, as suggested by animal experiments (Racis et al., 1990: Antimicrobial Agents and Chemotherapy, 34, 1360), or whether it has a deleterious effect by increasing the inflammatory response (Herxheimer-like reaction), is unclear. In this context it is interesting to note that, in the patients described by Seaton and co-workers (Zoc.cit.), corticosteroids were prescribed because of the high incidence of febrile reactions to amphotericin B. The way in which patients with cryptococcal infection react to amphotericin B and conazoles may be analogous to that which is observed in onchocerciasis: patients treated with diethylcarbamazine often experienced severe systemic side effects (Mazzotti reaction) and deterioration of optic nerve function, whereas both systemic reactions and visual field deterioration are almost absent in patients treated with ivermectin, the current drug of choice. We were pleased to note that Seaton and co-workers supported our hypothesis that the inflammatory response around the optic nerve is the dominant factor involved in visual loss in patients with cryptococcal meningitis. The potential beneficial role of corticosteroids in lessening visual loss in patients with cryptococcal meningitis is another argument in favour of this view, and the authors should be commended for bringing it to the attention of the medical community. Philippe Kestelyn Department of Ophthalmology University of Gent De Pintelaan 185 9000 Gent, Belgium
Hem-i Taelman
7 May
1997
Visual loss and cryptococcal meningitis We read with great interest the articles by Seaton and co-workers (1997: Transactions, 91, 44 & 50) on visual loss in immunocompetent patients with cryptococcal meningitis and the potential beneficial role of corticos-
Department of Internal Medicine Centre Hospitalier de Kigali B.P. 65.5 Kigali, Rwanda
8 July 1997
Visual loss and cryptococcal meningitis: a reply I am grateful to Drs Kestelyn and Taelman [above] for reiterating their support for the hypothesis of immune-mediated visual loss in patients with cryptococcal meningitis. In our cohort of immunocompetent patients
728
with Cryptococcus neoformans var. gattii meningitis (1997: Transactions, 91, 44), the relationship between amphotericin B and visual loss was not clear. In our study 27/81 (33%) had visual loss before therapy. Of the 14 patients (with complete data) who had normal vision on admission but who subsequently developed visual loss, 8 had papilloedema, a factor which predisposed them to subsequent visual loss. Two of the remaining 6 patients had other cranial nerve palsies before treatment and all had serum cryptococcal antigen titres > 1:1024. These patients may have developed visual loss later in their illness irrespective of treatment with amphotericin B; however, subtle toxic effects on the optic nerve by amphotericin B cannot be excluded. A Mazzotti-type reaction leading to visual loss in treated cryptococcal meningitis is certainly possible, although in our cohort abolishment of febrile reactions due to amnhotericin B with chlorpheniramine did not improve visual outcome.
CORRESPONDENCE
Mortality in patients with var. gattii meningitis also remains unacceptably high and is probably due to the untreated effects of raised intracranial pressure, which may also have an immunological basis in immunocompetent patients (Seaton et al., 1996: Quarterly Journal of Medicine, 89,423). Until there are good data to the contrary, I would recommend adjunct therapy with corticosteroids in most immunocompetent patients with cryptococcal meningitis, including those with normal visual acuity on admission. Prospective, observational studies will be required to determine whether this measure can also limit mortality. R. A. Seaton Infection and Immunodefciency Unit King’s Cross Hospital Clepington Road Dundee, DO3 8EA, UK 19 July 1997
Lokman Hakim et al. Prevalence of Toxocara canis antibody among children with bronchial asthma in Klang Hospital, Malaysia. Transactions, 91, 528. There were two errors in the Table in this paper. The numbers of Malay asthmatic children and of Chinese non-asthmatics should have been 14 and 4, respectively. Eleven of the 19 asthmatic children, and 4 of the 26 non-asthmatics, had anti-Toxocara canis antibody in their sera.
OFTHE
ROYAL
1 Correspondence
(
I
I
SOCIETY
OFTROI’ICALMEDICINE
Malarial drug trials The increasing resistance of Plasmodium falciparum to antimalarial drugs requires a careful approach to ensure that rational national drug policies are developed. Coordinated trials at multiple sites are needed to obtain an overview of resistance patterns within a country or region. It is essential that malaria treatment trials produce comparable results to facilitate this process. The importance of this principle was recently demonstrated by consecutive articles appearing in this journal. Two trials were performed by the same researchers, working in the same hospital but using different methods. In the first trial, Falade et al. (1997: Transactions, 91, 58) compared the efficacies of halofantrine, pyrimethamineisulfadoxine and chloroquine. The inclusion criteria included a minimum l? falciparum parasitaemia of lOOO/ltL and a history of fever within 24 h before presentation. ‘Parasitological cure’ was assessed 7 d after the start of treatment. The parasitaemia was calculated by counting the number of asexual forms per 500 leucocytes and assuming a leucocyte concentration of 8000&L. In contrast, when Sowunmi et al. (1 sj97: Transactions, 91.63) comnared the efficacies of chloroauine and chloro&ine/chl&nheniramine thev used a thieshold narasitae-mia for inclusion of only SOOipL and accepted children with a history of fever within the preceding 48 h. The ‘cure rate’ was assessed at dav 14. Parasitaemias were calculated by counting the number of asexual forms per 1000 leucocytes, or the number of leucocytes per 500 asexual forms, and measuring the leucocyte count. Additionally, there were 3 criteria of treatment failures, though none of these was the same as that in the former study. Estimates of chloroquine efficacy produced by the 2 trials were sianificantlv different (15 cures, 23 failures in the former &id 37 cures, 12 ‘failures in the latter; x2=1 1.56, P
document WHOIMALI96.1077) will greatly facilitate researchers and policy makers involved in the development of rational-national guidelines. D . M. Schellenbern1,2 S. AbdaGal H. Mshindal llfakara Centre for Health Research and Development I? 0. Box 53 Ifakara Tanzania 2Hospital Clinic i Provincial Villarroel 170 08036 Barcelona Spain
AND
HYGIENE
(1997) 91,727-728
727
teroids. Our findings in a prospective study of the ocular manifestations of cryptococcal meningitis in 80 patients with AIDS confirmed the notion that visual loss is lower in immunosuppressed patients than in immunocompetent persons; in our series (Kestelyn et al., 1993: Ameri116, 721) only 9% of can Journal of Ophthalmology, patients experienced visual loss, compared to 52.5% in the series of Seaton and co-workers (Zoc.cit.). In the discussion of our article, not mentioned by Seaton and coworkers, we proposed 3 possible factors to explain the differential rate of visual loss in immunosuppressed and immunocompetent patients who have cryptococcal meningitis. First, cryptococcal meningitis in AIDS patients is often devoid of inflammatory response (Dismukes et al., 1988: Journal of Infectious Diseases, 157, 624). Since the invasion of the optic nerve by the organism may trigger an inflammatory response leading to arachnoiditis and optic nerve compression (Lipson et al., 1984: American Journal of Ophthalmology, 107, 523), the absence of a profound inflammatory response in AIDS patients might explain the lower frequency of visual loss and optic atrophy in these patients. Secondly, the high degree of diagnostic awareness in persons infected with human immunodeficiency virus may lead to a shorter interval between the onset of symptons and the start of effective treatment for cryptococcal meningitis, minimizing the neurological sequelae. Finally, visual loss through optic atrophy was significantly less prevalent in a subgroup of our patients who were treated with oral conazoles alone, as opposed to the group who received amphotericin B or a combination of amphotericin B and conazoles. We interpreted this finding as evidence for a potential toxic effect of amphotericin B on the optic nerve. Whether amphotericin B exerts a direct neurotoxic effect on the optic nerve, as suggested by animal experiments (Racis et al., 1990: Antimicrobial Agents and Chemotherapy, 34, 1360), or whether it has a deleterious effect by increasing the inflammatory response (Herxheimer-like reaction), is unclear. In this context it is interesting to note that, in the patients described by Seaton and co-workers (Zoc.cit.), corticosteroids were prescribed because of the high incidence of febrile reactions to amphotericin B. The way in which patients with cryptococcal infection react to amphotericin B and conazoles may be analogous to that which is observed in onchocerciasis: patients treated with diethylcarbamazine often experienced severe systemic side effects (Mazzotti reaction) and deterioration of optic nerve function, whereas both systemic reactions and visual field deterioration are almost absent in patients treated with ivermectin, the current drug of choice. We were pleased to note that Seaton and co-workers supported our hypothesis that the inflammatory response around the optic nerve is the dominant factor involved in visual loss in patients with cryptococcal meningitis. The potential beneficial role of corticosteroids in lessening visual loss in patients with cryptococcal meningitis is another argument in favour of this view, and the authors should be commended for bringing it to the attention of the medical community. Philippe Kestelyn Department of Ophthalmology University of Gent De Pintelaan 185 9000 Gent, Belgium
Hem-i Taelman
7 May
1997
Visual loss and cryptococcal meningitis We read with great interest the articles by Seaton and co-workers (1997: Transactions, 91, 44 & 50) on visual loss in immunocompetent patients with cryptococcal meningitis and the potential beneficial role of corticos-
Department of Internal Medicine Centre Hospitalier de Kigali B.P. 65.5 Kigali, Rwanda
8 July 1997
Visual loss and cryptococcal meningitis: a reply I am grateful to Drs Kestelyn and Taelman [above] for reiterating their support for the hypothesis of immune-mediated visual loss in patients with cryptococcal meningitis. In our cohort of immunocompetent patients
728
with Cryptococcus neoformans var. gattii meningitis (1997: Transactions, 91, 44), the relationship between amphotericin B and visual loss was not clear. In our study 27/81 (33%) had visual loss before therapy. Of the 14 patients (with complete data) who had normal vision on admission but who subsequently developed visual loss, 8 had papilloedema, a factor which predisposed them to subsequent visual loss. Two of the remaining 6 patients had other cranial nerve palsies before treatment and all had serum cryptococcal antigen titres > 1:1024. These patients may have developed visual loss later in their illness irrespective of treatment with amphotericin B; however, subtle toxic effects on the optic nerve by amphotericin B cannot be excluded. A Mazzotti-type reaction leading to visual loss in treated cryptococcal meningitis is certainly possible, although in our cohort abolishment of febrile reactions due to amnhotericin B with chlorpheniramine did not improve visual outcome.
CORRESPONDENCE
Mortality in patients with var. gattii meningitis also remains unacceptably high and is probably due to the untreated effects of raised intracranial pressure, which may also have an immunological basis in immunocompetent patients (Seaton et al., 1996: Quarterly Journal of Medicine, 89,423). Until there are good data to the contrary, I would recommend adjunct therapy with corticosteroids in most immunocompetent patients with cryptococcal meningitis, including those with normal visual acuity on admission. Prospective, observational studies will be required to determine whether this measure can also limit mortality. R. A. Seaton Infection and Immunodefciency Unit King’s Cross Hospital Clepington Road Dundee, DO3 8EA, UK 19 July 1997
Lokman Hakim et al. Prevalence of Toxocara canis antibody among children with bronchial asthma in Klang Hospital, Malaysia. Transactions, 91, 528. There were two errors in the Table in this paper. The numbers of Malay asthmatic children and of Chinese non-asthmatics should have been 14 and 4, respectively. Eleven of the 19 asthmatic children, and 4 of the 26 non-asthmatics, had anti-Toxocara canis antibody in their sera.