550 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE (1992) 86, 550-551
Observations
of subacute
sclerosing
panencephalitis
in South Africa
Barry D. Schoub, Sylvia Johnson and Jo M. McAnemey Nutional Institute for Virology and Department of Virology, University of Witwatersrand, Private BagX4, Sandringham 2131, South Aftica Abstract Analysis of 75 cases of subacute sclerosing panencephalitis (SSPE) reported to the National Institute for Virology, South Africa, in 1984-1990 does not support the role of intensive exposure to measles virus in the pathogenesis of SSPE. The incidence of SSPE per million population was similar in Blacks and Whites, although that of reported measles is up to 10 times greater in Blacks. The age of SSPE follows the distribution of measles cases; thus, significantly more younger SSPE cases were found in Blacks than in Whites. The distribution between males and females was approximately equal. These data suggest SSPE to be a fortuitous complication of measles infection associated with as yet unidentified risk factors rather than a consequence of an excessive dose of infecting virus or immunological immaturity. Introduction Subacute sclerosing panencephalitis (SSPE) is one of the most dreaded complications associated with measles. Widespread immunization and the consequent decline of measles in the developed world has resulted in a corresponding reduction in the incidence of SSPE (BLOCH et al., 1985). However, SSPE remains a disease of significant nrevalence in develouing countries where endemic measles is still responsible fo; providing a major burden of circulatinrr wild-tvne virus (EDITORIAL, 1990). The pathogenesis-of SSPE-, which is characterized by’an insidious onset some 5 to 10 years after measles and a progressive deterioration of neurological function and death in months to years, still remains to be clearly defined. Epidemiological observations from a number of countries have provided some clues regarding factors which may predispose to its development. Earlier observations suggested that racial and genetic factors may play a role in the genesis of SSPE, for example the high prevalence in the ‘coloured’ (mixed race) communitv in the Cane Province of South Africa (MOODIE et al., 1980). The 2 most imnortant renorted enidemioloeical factors in SSPE. the higher incidence in boys and the association with acute measles infection at an earlv age, have been sueaested to be related to intensive expb&k to measles vi& which mav nredisuose to SSPE (AABY et al.. 1984). A further epidemiological feature of‘SSPE has been its over-representation in rural areas, which may be associated with greater exposure to zoonoses or possible arbovirus infecFions whiih may act as triggering mechanisms for SSPE (DETELS et al.. 1973: ENDERS-RUCKLE. 19781. Relatively few studies of SSPE have been carried out in sub-Saharan Africa (EDITORIAL, 1990), where measles is hvnerendemic (GRANT. 1990). in order to examine the importance of intensive kxpos&e to measles virus. Recentlv. examination of 44 cases of SSPE reoorted in 198&1987 to the National Institute for V&ology of South Africa revealed a tendency for an increasing age and equality between males and females in the incidence of the disease (CARMAN & JOHNSON, 1989). In this paper a more detailed examination of the enidemiology of SSPE in South Africa since 1984 is ;esorted. These findings are not consistent with the classical concepts of a male preponderance and early age of measles infection, and question the role of intensive exposure in the genesis of the disease. Patients and Methods The Republic of South Africa is serviced by 7 virology laboratories situated in the main cities and providing diagnostic services for the larger urban hospitals in the country. Diagnostic criteria for SSPE were uniformly applied and conform to those recommended by the CENTERS FOR DISEASE CONTROL (1982), namely a compatible clinical course in addition to supporting laboratory evidence of either detectable measles antibody in cerebrospinal fluid or a characteristic pattern on electroencephalography, or typical histological findings on brain biopsy or necropsy. All positive SSPE cases are re-
ported centrally and recorded at the National Institute for Virology; however, being laboratory-based the clinical and euidemioloaical details which are nrovided are usually sketchy. Results From Tulv 1984 to the end of 1990.75 confirmed cases of SSPEwere reported to the National Institute of Virolonv: 69 from South Africa. 5 from Namibia and one from Botswana. The cases ranged in age from 2 to 29 years (median 11 years); 35 were male and 40 female, a male:female ratio of 1: 1.1. The age distribution of cases for males and females is shown in Fig. 1. Patients aged
14 12 $10 28 I 6 4 2 0
(5
’
6 -10
Fig. 1. Age distribution rica, 19841990.
’
16-20
’
21-25
’
,26
’
of SSPE in male and female patients in South Af-
16 years and older comprised 23% of the total (17 of 75). In this latter group there were 9 males and 8 females, although 3 of the oldest patients (26-29 years) were female. The distribution of cases among Black, White and ‘Coloured’ patients in the various age groups is shown in Fig. 2. Most cases (53, 71%) were seen in Blacks, followed by 16 (21%) in Whites, 5 (7%) in ‘Coloureds’, and 1 in an Asian child. There were significantly more black than white patients in the younger age groups; thus, 29 of the 53 Black patients were under the median age of 11 years2 compared to only 4 of the 16 White patients (PtO.1, x test). Discussion Measles remains a major public health problem in the Black population of South Africa, where the measles incidence as well as the case fatality rate was considerably higher in the Black than in the White population both historically (1980-1983) and recently (1989-1990); see Table. Nevertheless, the mean annual incidence of SSPE in South Africa in 1985-1990 in Blacks of 0.26 per million was actually somewhat lower than the figure for Whites of 0.53 per million (based on population figures
551 30 1 25
20 B E 15 2 10
Age in Years
Fig. 2. Agedistributionof SSPEcasesin Black,Whiteand‘Coloured’patientsin SouthAfrica, 198C1990. Table. fatality
Year 1980 1981 1982 1983 1989 1990
Measles incidence (per 100 000) and measles case rate (per 100) in South Africa”
White 22 (0.10) 8 (0.79) 9 (1.86)
Black 85 (1.64) 72 (1.26) 55 (1.90)
‘Coloured’
Asian
15 (1.49) 9 (1.34)
“Case fatality rates in parentheses. Data from the DEPARTMENT OF NATIONAL HEALTH AND POPULATION DEVELOPMENT, SOUTH AFRICA (1988, 1990).
although in older cases there is a tendency for a higher proportion of female patients (AABY et al., 1984; CARMAN & JOHNSON, 1989). The male preponderance has also been used to support the hypothesis of intensive exposure to measles virus in the pathogenesis of SSPE, as male infants are at relatively greater risk of being exposed to measles in the home., often as secondary cases with an increased dosage of virus (AABY et al., 1984). In our series, other than the oldest 3 cases, which were all female, the sex ratio of SSPE was approximately equal, as has also been reported in a recent publication from South Africa (CARMAN & JOHNSON, 1989). Thus, comparative data for Black and White South African patients do not provide support for the hypothesis that intensive exposure to measles is a risk factor for the development of SSPE. It appears that the development of SSPE may well be independent of the dose of infecting virus during measles and of relative immunosuppression due to immaturity or other causes. SSPE appears rather to be a fortuitous complication in a patient without any obvious predisposing factors, as occurs with other central nervous system complications of measles such as post-infectious demyelinating encephalitis. Acknowledgements We thank the Virology Departments of the Universities of Cape Town, Medunsa, Natal, the Orange Free State, Pretoria and Stellenbosch for supplying the National Institute for Virology with details of SSPE casesin their respective areas. The assistance of Mrs E. M. Venter in the preparation of the manuscript is gratefully acknowledged. We also acknowledge the statistical assistancereceived from Dr J. S. Galpin, Department of Statistics and Actuarial Science, University of the Witwatersrand. References
projected from the 1985 census; DEPARTMENT OF NATIONAL HEALTH AND POPULATION DEVELOPMENT, SOUTH AFRICA, 1987). While there would undoubtedly have been significant under-reporting in the Black population, especially from outlying rural areas, the majority of cases of a disease such as SSPE would still have come to the attention of one of the major hospitals in the country and eventually have been diagnosed at a virology laboratory; even allowing for under-reporting, the incidence appears to be at least similar in Whites and Blacks. The association of SSPE with early measles has also been ascribed to intensive exposure, because of the greater likelihood of secondary cases at a young age with a consequently greater dose of infection and relative increase in viral dose due to immunological immaturity of young infants (AABY et al., 1984). In this series the onset of SSPE occurred at a significantly younger age in the Black than in the White patients. Assuming that the latent period from measles to SSPE is constant between the races, as has been reported for the sexes (AABY et al., 1984), the racial difference in the age of onset of SSPE is consistent with the pattern of the age of measles infection in Blacks and Whites. Thus, in 1987, the notified measles incidence in infants less than 1 year of age was 25 1 per 100 000 in White infants, in contrast to 1592 per 100 000 for Black infants. While in infants 5-9 years of age the corresponding incidences were nearly similar, 266 and 398 resnectivelv (DEPARTMENT OF NATIONAL HEALTH AND ~‘OPLJLA~~~N DEVELOPMENT, SOUTH AFRICA, 1988). Thus, the association of SSPE with measles infection at a young age could well be more a result of the prevalence of infection at a younger age in a particular population rather than being due to measles being a risk factor for SSPE. The male preponderance in SSPE cases has been reported frequently (EDITORIAL, 1990; AABY et al., 1984),
Aaby, Bukh, J., Lisse, I. M. & Smits, A. J. (1984). Risk factors in subacute sclerosing panencephalitis: age- and sex-dependent host reactions or intensive exposure? Reviews of Infectious Diseases, 6,239-250.
Bloch, A. B., Orenstein, W. A., Stetler, H. C., Wassilak, S. G., Amler, R. W., Bart, K. J., Kirby, C. D. & Hinmann, A. R. (1985). Health impact of measles vaccination in the United States.Pediatrics, 76,524-532. Carman, W. F. & Johnson, S. (1989). Subacute sclerosing panenceohalitis in South Africa. Transactions of the Roval Societv of Tiopical Medicine and Hygiene, 83, 117-l 18. d Centers for Disease Control (1982). Current trends: subacute sclerosing panencephalitis surveillance-united States. Morbidig andMortality
Weekly Report, 31,585-588.
Department of National Health and Population Development, South Africa (1987). The 1985 Census. Epidemiological Comments, 14 (l), 38. Department of National Health and Population Development, South Africa (1988). Eight years of measlesnotifications. Eprdemiological Comments,15 (6), l-3 1. Department of National Health and Population Development, South Africa (1990). The six vaccine-preventable diseases. EpidemiologicalComments,17 (lo), l-23. Detels, R., McNew, J., Brody, J. A. & Edgar, A. H. (1973). Further epidemiological studies of subacute sclerosing panencephalitis. Lancet, ii, 11-14. Editorial (1990). SSPEin the developing world. Lancer, ii, 600. Enders-Ruckle, G. (1978). Frequency, serodiagnosis and epidemiological features of subacute sclerosing panencephalitis (SSPE) and epidemiology and vaccination policy for measles in the Federal Republic of Germany (FRG). Developments in Biologicalstandardization,
41, 195-207.
Grant, J. P. (1990). The State of the World’s Children 1990. Oxford: Oxford University Press. Moodie, J. W., MacKenzie, D. J. M. & Kipps, A. (1980). Subacute sclerosing panencephalitis (SSPE) in southern Africa: recent additions to the SSPE registry. South African Medical Journal, 58,964-967.
Received I7 June 1991; revised 29 August 1991; accepted fho$blication I9 August 1991 (unavoidably delayed in
Observations
of subacute
sclerosing
panencephalitis
in South Africa
Barry D. Schoub, Sylvia Johnson and Jo M. McAnemey Nutional Institute for Virology and Department of Virology, University of Witwatersrand, Private BagX4, Sandringham 2131, South Aftica Abstract Analysis of 75 cases of subacute sclerosing panencephalitis (SSPE) reported to the National Institute for Virology, South Africa, in 1984-1990 does not support the role of intensive exposure to measles virus in the pathogenesis of SSPE. The incidence of SSPE per million population was similar in Blacks and Whites, although that of reported measles is up to 10 times greater in Blacks. The age of SSPE follows the distribution of measles cases; thus, significantly more younger SSPE cases were found in Blacks than in Whites. The distribution between males and females was approximately equal. These data suggest SSPE to be a fortuitous complication of measles infection associated with as yet unidentified risk factors rather than a consequence of an excessive dose of infecting virus or immunological immaturity. Introduction Subacute sclerosing panencephalitis (SSPE) is one of the most dreaded complications associated with measles. Widespread immunization and the consequent decline of measles in the developed world has resulted in a corresponding reduction in the incidence of SSPE (BLOCH et al., 1985). However, SSPE remains a disease of significant nrevalence in develouing countries where endemic measles is still responsible fo; providing a major burden of circulatinrr wild-tvne virus (EDITORIAL, 1990). The pathogenesis-of SSPE-, which is characterized by’an insidious onset some 5 to 10 years after measles and a progressive deterioration of neurological function and death in months to years, still remains to be clearly defined. Epidemiological observations from a number of countries have provided some clues regarding factors which may predispose to its development. Earlier observations suggested that racial and genetic factors may play a role in the genesis of SSPE, for example the high prevalence in the ‘coloured’ (mixed race) communitv in the Cane Province of South Africa (MOODIE et al., 1980). The 2 most imnortant renorted enidemioloeical factors in SSPE. the higher incidence in boys and the association with acute measles infection at an earlv age, have been sueaested to be related to intensive expb&k to measles vi& which mav nredisuose to SSPE (AABY et al.. 1984). A further epidemiological feature of‘SSPE has been its over-representation in rural areas, which may be associated with greater exposure to zoonoses or possible arbovirus infecFions whiih may act as triggering mechanisms for SSPE (DETELS et al.. 1973: ENDERS-RUCKLE. 19781. Relatively few studies of SSPE have been carried out in sub-Saharan Africa (EDITORIAL, 1990), where measles is hvnerendemic (GRANT. 1990). in order to examine the importance of intensive kxpos&e to measles virus. Recentlv. examination of 44 cases of SSPE reoorted in 198&1987 to the National Institute for V&ology of South Africa revealed a tendency for an increasing age and equality between males and females in the incidence of the disease (CARMAN & JOHNSON, 1989). In this paper a more detailed examination of the enidemiology of SSPE in South Africa since 1984 is ;esorted. These findings are not consistent with the classical concepts of a male preponderance and early age of measles infection, and question the role of intensive exposure in the genesis of the disease. Patients and Methods The Republic of South Africa is serviced by 7 virology laboratories situated in the main cities and providing diagnostic services for the larger urban hospitals in the country. Diagnostic criteria for SSPE were uniformly applied and conform to those recommended by the CENTERS FOR DISEASE CONTROL (1982), namely a compatible clinical course in addition to supporting laboratory evidence of either detectable measles antibody in cerebrospinal fluid or a characteristic pattern on electroencephalography, or typical histological findings on brain biopsy or necropsy. All positive SSPE cases are re-
ported centrally and recorded at the National Institute for Virology; however, being laboratory-based the clinical and euidemioloaical details which are nrovided are usually sketchy. Results From Tulv 1984 to the end of 1990.75 confirmed cases of SSPEwere reported to the National Institute of Virolonv: 69 from South Africa. 5 from Namibia and one from Botswana. The cases ranged in age from 2 to 29 years (median 11 years); 35 were male and 40 female, a male:female ratio of 1: 1.1. The age distribution of cases for males and females is shown in Fig. 1. Patients aged
14 12 $10 28 I 6 4 2 0
(5
’
6 -10
Fig. 1. Age distribution rica, 19841990.
’
16-20
’
21-25
’
,26
’
of SSPE in male and female patients in South Af-
16 years and older comprised 23% of the total (17 of 75). In this latter group there were 9 males and 8 females, although 3 of the oldest patients (26-29 years) were female. The distribution of cases among Black, White and ‘Coloured’ patients in the various age groups is shown in Fig. 2. Most cases (53, 71%) were seen in Blacks, followed by 16 (21%) in Whites, 5 (7%) in ‘Coloureds’, and 1 in an Asian child. There were significantly more black than white patients in the younger age groups; thus, 29 of the 53 Black patients were under the median age of 11 years2 compared to only 4 of the 16 White patients (PtO.1, x test). Discussion Measles remains a major public health problem in the Black population of South Africa, where the measles incidence as well as the case fatality rate was considerably higher in the Black than in the White population both historically (1980-1983) and recently (1989-1990); see Table. Nevertheless, the mean annual incidence of SSPE in South Africa in 1985-1990 in Blacks of 0.26 per million was actually somewhat lower than the figure for Whites of 0.53 per million (based on population figures
551 30 1 25
20 B E 15 2 10
Age in Years
Fig. 2. Agedistributionof SSPEcasesin Black,Whiteand‘Coloured’patientsin SouthAfrica, 198C1990. Table. fatality
Year 1980 1981 1982 1983 1989 1990
Measles incidence (per 100 000) and measles case rate (per 100) in South Africa”
White 22 (0.10) 8 (0.79) 9 (1.86)
Black 85 (1.64) 72 (1.26) 55 (1.90)
‘Coloured’
Asian
15 (1.49) 9 (1.34)
“Case fatality rates in parentheses. Data from the DEPARTMENT OF NATIONAL HEALTH AND POPULATION DEVELOPMENT, SOUTH AFRICA (1988, 1990).
although in older cases there is a tendency for a higher proportion of female patients (AABY et al., 1984; CARMAN & JOHNSON, 1989). The male preponderance has also been used to support the hypothesis of intensive exposure to measles virus in the pathogenesis of SSPE, as male infants are at relatively greater risk of being exposed to measles in the home., often as secondary cases with an increased dosage of virus (AABY et al., 1984). In our series, other than the oldest 3 cases, which were all female, the sex ratio of SSPE was approximately equal, as has also been reported in a recent publication from South Africa (CARMAN & JOHNSON, 1989). Thus, comparative data for Black and White South African patients do not provide support for the hypothesis that intensive exposure to measles is a risk factor for the development of SSPE. It appears that the development of SSPE may well be independent of the dose of infecting virus during measles and of relative immunosuppression due to immaturity or other causes. SSPE appears rather to be a fortuitous complication in a patient without any obvious predisposing factors, as occurs with other central nervous system complications of measles such as post-infectious demyelinating encephalitis. Acknowledgements We thank the Virology Departments of the Universities of Cape Town, Medunsa, Natal, the Orange Free State, Pretoria and Stellenbosch for supplying the National Institute for Virology with details of SSPE casesin their respective areas. The assistance of Mrs E. M. Venter in the preparation of the manuscript is gratefully acknowledged. We also acknowledge the statistical assistancereceived from Dr J. S. Galpin, Department of Statistics and Actuarial Science, University of the Witwatersrand. References
projected from the 1985 census; DEPARTMENT OF NATIONAL HEALTH AND POPULATION DEVELOPMENT, SOUTH AFRICA, 1987). While there would undoubtedly have been significant under-reporting in the Black population, especially from outlying rural areas, the majority of cases of a disease such as SSPE would still have come to the attention of one of the major hospitals in the country and eventually have been diagnosed at a virology laboratory; even allowing for under-reporting, the incidence appears to be at least similar in Whites and Blacks. The association of SSPE with early measles has also been ascribed to intensive exposure, because of the greater likelihood of secondary cases at a young age with a consequently greater dose of infection and relative increase in viral dose due to immunological immaturity of young infants (AABY et al., 1984). In this series the onset of SSPE occurred at a significantly younger age in the Black than in the White patients. Assuming that the latent period from measles to SSPE is constant between the races, as has been reported for the sexes (AABY et al., 1984), the racial difference in the age of onset of SSPE is consistent with the pattern of the age of measles infection in Blacks and Whites. Thus, in 1987, the notified measles incidence in infants less than 1 year of age was 25 1 per 100 000 in White infants, in contrast to 1592 per 100 000 for Black infants. While in infants 5-9 years of age the corresponding incidences were nearly similar, 266 and 398 resnectivelv (DEPARTMENT OF NATIONAL HEALTH AND ~‘OPLJLA~~~N DEVELOPMENT, SOUTH AFRICA, 1988). Thus, the association of SSPE with measles infection at a young age could well be more a result of the prevalence of infection at a younger age in a particular population rather than being due to measles being a risk factor for SSPE. The male preponderance in SSPE cases has been reported frequently (EDITORIAL, 1990; AABY et al., 1984),
Aaby, Bukh, J., Lisse, I. M. & Smits, A. J. (1984). Risk factors in subacute sclerosing panencephalitis: age- and sex-dependent host reactions or intensive exposure? Reviews of Infectious Diseases, 6,239-250.
Bloch, A. B., Orenstein, W. A., Stetler, H. C., Wassilak, S. G., Amler, R. W., Bart, K. J., Kirby, C. D. & Hinmann, A. R. (1985). Health impact of measles vaccination in the United States.Pediatrics, 76,524-532. Carman, W. F. & Johnson, S. (1989). Subacute sclerosing panenceohalitis in South Africa. Transactions of the Roval Societv of Tiopical Medicine and Hygiene, 83, 117-l 18. d Centers for Disease Control (1982). Current trends: subacute sclerosing panencephalitis surveillance-united States. Morbidig andMortality
Weekly Report, 31,585-588.
Department of National Health and Population Development, South Africa (1987). The 1985 Census. Epidemiological Comments, 14 (l), 38. Department of National Health and Population Development, South Africa (1988). Eight years of measlesnotifications. Eprdemiological Comments,15 (6), l-3 1. Department of National Health and Population Development, South Africa (1990). The six vaccine-preventable diseases. EpidemiologicalComments,17 (lo), l-23. Detels, R., McNew, J., Brody, J. A. & Edgar, A. H. (1973). Further epidemiological studies of subacute sclerosing panencephalitis. Lancet, ii, 11-14. Editorial (1990). SSPEin the developing world. Lancer, ii, 600. Enders-Ruckle, G. (1978). Frequency, serodiagnosis and epidemiological features of subacute sclerosing panencephalitis (SSPE) and epidemiology and vaccination policy for measles in the Federal Republic of Germany (FRG). Developments in Biologicalstandardization,
41, 195-207.
Grant, J. P. (1990). The State of the World’s Children 1990. Oxford: Oxford University Press. Moodie, J. W., MacKenzie, D. J. M. & Kipps, A. (1980). Subacute sclerosing panencephalitis (SSPE) in southern Africa: recent additions to the SSPE registry. South African Medical Journal, 58,964-967.
Received I7 June 1991; revised 29 August 1991; accepted fho$blication I9 August 1991 (unavoidably delayed in
