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Nodding syndrome, other forms of epilepsy, and the Nakalanga syndrome most likely directly or indirectly caused by Onchocerca volvulus
JNS-14865; No of Pages 2 Journal of the Neurological Sciences xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Nodding syndrome, other forms of epilepsy, and the Nakalanga syndrome most likely directly or indirectly caused by Onchocerca volvulus Keywords: Nodding syndrome Onchocerciasis Epilepsy
Dear Editor Based on a case-control study performed in Uganda (n = 50 agematched pairs), PS Spencer and colleagues report univariate associations between nodding syndrome (NS) and a reported history of measles, body weight, and nutritional intake (specifically with respect to use of maize, moldy maize, and eating emergency food supplies) before the onset of nodding [1]. From these associations, the authors make a case that NS is a post-measles disorder potentially triggered by high levels of malnutrition occurring at a time of civil war in Northern Uganda. We provide comments concerning the study methodology and authors' interpretation of the results and propose that the body of evidence continues to support Onchocerca volvulus (Ov) as the aetiology for NS. With the ~8 year difference between nodding onset and the time of the study, the risk for introduction of recall bias is high when using a standardized questionnaire about food intake so many years before. Moreover, NS has become a politicised issue in Uganda whereby caregivers of persons with NS have attributed the cause of NS to the Ugandan government or international organisations [2]. It is not surprising, then, that caregivers more often reported that their children with NS had eaten moldy maize and emergency food supplies from the World Health Programme. Regarding the association between a reported history of measles and NS, although the relationship is statistically significant [odds ratio (OR): 6.00; 95% confidence interval (CI): 1.03–113, p = 0.047)], the very wide CI implies that there is little precision around the OR point estimate. While the authors do not provide absolute numbers of exposed and unexposed patients, a 2009 study from Kitgum reported that 23.5% (12/ 50) of NS cases and 6.1% (3/49) of non-NS controls had a reported history of measles [3]. In this study, the association between measles and NS was not found to be statistically significant after being adjusted for age (OR 3.3; CI 0.8–13.6). Notably, the majority of cases developed NS without a history of measles. Also, the authors do not provide details about what proportion of NS cases fits the case definitions for suspect, probable, or confirmed cases. Since a measles infection may lead to encephalitis followed by symptomatic epileptic seizures, the few participants with a reported history of measles may have been misclassified as NS suspect cases. The main argument against measles infection as the cause of NS is that there have been many measles epidemics in the world that were
never followed by an NS or epilepsy epidemic. In contrast, we believe that the existing data more strongly support the claim that Ov is the etiologic agent for NS. While it has only been reported to occur in Uganda, South Sudan and Tanzania, NS' localisation to only those countries is attributable to the fact that the first proposal of a case definition for “confirmed NS” did not occur until 2012, during a WHO coordinated meeting in Kampala, Uganda. Before 2012, NS-like clinical manifestations have been reported in many onchocerciasis hyper-endemic regions, including in South America and many other regions in Africa and particularly in places before onchocerciasis control measures had been implemented [4,5]. A closely related condition, the Nakalanga syndrome, is characterized by stunted growth, absence of external signs of sexual development, mental retardation, and very often epilepsy [6]; several of these manifestations are also part of the WHO definition of NS [7]. Nearly all reported cases with Nakalanga syndrome were found to have onchocerciasis [6]. The argument that Ov DNA was never isolated from cerebrospinal fluid (CSF) in patients with NS certainly should be taken into account. However, past use of ivermectin may have been responsible for this absence. In 1938, before the use of ivermectin, Ov microfilariae in CSF were described by Casis Sacre in Mexican Ov-infested patients with NS- and Nakalanga-like clinical manifestations [8]. Dead and live microfilariae were also found in 1959 by Mazzotti in the CSF of Mexican patients treated with diethylcarbamazepine for onchocerciasis and in 1976, Duke et al. observed microfilariae in the CSF of heavily infected patients from Cameroon [9]. The argument that the “peaks of head nodding onset in April and June do not correlate with human biting activity of blackflies” is not relevant. Indeed, the onset of NS is less likely to be related to the biting time of the blackfly and more likely dependent on the production of microfilariae by the adult female worm and whether or not the person is treated with ivermectin. NS and other forms of onchocerciasis-associated epilepsy, most likely appear when a certain level of microfilaria infestation is reached [5]. As is it may take 20 years of Ov infestation before a person becomes blind, it may also take several years for NS to develop [5]. Thus, the absence of Ov infection in a small percentage of NS cases in Uganda (5% without Ov antibodies) can be explained in several ways [3]. First, none of the Ov diagnostic tests is 100% sensitive. Second, even a combination of tests may not detect past Ov exposure if ivermectin to treat onchocerciasis had been used. Third, an emerging explanation for the absence of Ov DNA in the CSF may be that NS is caused by the occurrence of an autoimmune response induced by the Ov infection [10]. Epidemics of NS, other forms of epilepsy, and Nakalanga syndrome all seem to disappear with improved onchocerciasis control which ultimately strengthens the case for Ov being the aetiologic pathogen [5]. On the other hand, the proposed measles aetiology of NS does not explain why NS seems to only occur in onchocerciasis-endemic regions. In conclusion, NS, other forms of epilepsy, and the Nakalanga syndrome are most likely clinical manifestations of onchocerciasis. The pathophysiological mechanism explaining how the Ov infestation is able to cause these conditions remains to be determined.
http://dx.doi.org/10.1016/j.jns.2016.10.008 0022-510X/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: R. Colebunders, et al., Nodding syndrome, other forms of epilepsy, and the Nakalanga syndrome most likely directly or indirectly caused by Onchocerca volvulus, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2016.10.008
2
Letter to the Editor
Acknowledgements Robert Colebunders has received an ERC grant (No. 671055) for work mentioned in this letter. References [1] P.S. Spencer, R. Mazumder, V.S. Palmer, et al., Environmental, dietary and case-control study of nodding syndrome in Uganda: a post-measles brain disorder triggered by malnutrition? J. Neurol. Sci. 369 (2016) 191–203. [2] K. Buchmann, ‘You sit in fear’: understanding perceptions of nodding syndrome in post-conflict northern Uganda, Glob. Health Action 7 (2014) 25069. [3] J.L. Foltz, I. Makumbi, J.J. Sejvar, et al., An epidemiologic investigation of potential risk factors for nodding syndrome in Kitgum District, Uganda, PLoS One 8 (6) (2013), e66419. [4] B.O. Duke, Onchocerciasis, epilepsy and hyposexual dwarfism, Trans. R. Soc. Trop. Med. Hyg. 92 (2) (1998) 236. [5] R. Colebunders, A. Hendy, M. van Oijen, Nodding syndrome in onchocerciasis endemic areas, Trends Parasitol. 32 (8) (2016) 581–583. [6] A.B. Rapert, R.G. Ladkin, Endemic dwarfism in Uganda, East Afr. Med. J. 27 (1950) 339–359. [7] World Health Organisation, International Scientific Meeting on Nodding Syndrome, Kampala, Uganda, http://www.who.int/neglected_diseases/diseases/Nodding_ syndrom_Kampala_Report_2012.pdf 2012. [8] S.G. Casis, El Sindrome Epileptico y sus reaciones con Onchocercosis, Bol. Salub. Hig. 1 (1938) 11–31. [9] B.O. Duke, J. Vincelette, P.J. Moore, Microfilariae in the cerebrospinal fluid, and neurological complications, during treatment of onchocerciasis with diethylcarbamazine, Tropenmed. Parasitol. 27 (2) (1976) 123–132.
[10] R. Idro, B. Opar, J. Wamala, et al., is nodding syndrome an Onchocerca volvulus-induced neuroinflammatory disorder? Uganda's story of research in understanding the disease, Int. J. Infect. Dis. 45 (2016) 112–117.
R. Colebunders P. Suykerbuyk Global Health Institute, University of Antwerp, Antwerp, Belgium S.T. Jacob Division of Allergy and Infectious Diseases, University of Washington, Seattle, United States M. van Oijen Global Health Institute, University of Antwerp, Antwerp, Belgium Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands Corresponding author at: Global Health Institute, University of Antwerp, Antwerp, Belgium. E-mail address: [email protected] 27 September 2016 Available online xxxx
Please cite this article as: R. Colebunders, et al., Nodding syndrome, other forms of epilepsy, and the Nakalanga syndrome most likely directly or indirectly caused by Onchocerca volvulus, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2016.10.008
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Nodding syndrome, other forms of epilepsy, and the Nakalanga syndrome most likely directly or indirectly caused by Onchocerca volvulus Keywords: Nodding syndrome Onchocerciasis Epilepsy
Dear Editor Based on a case-control study performed in Uganda (n = 50 agematched pairs), PS Spencer and colleagues report univariate associations between nodding syndrome (NS) and a reported history of measles, body weight, and nutritional intake (specifically with respect to use of maize, moldy maize, and eating emergency food supplies) before the onset of nodding [1]. From these associations, the authors make a case that NS is a post-measles disorder potentially triggered by high levels of malnutrition occurring at a time of civil war in Northern Uganda. We provide comments concerning the study methodology and authors' interpretation of the results and propose that the body of evidence continues to support Onchocerca volvulus (Ov) as the aetiology for NS. With the ~8 year difference between nodding onset and the time of the study, the risk for introduction of recall bias is high when using a standardized questionnaire about food intake so many years before. Moreover, NS has become a politicised issue in Uganda whereby caregivers of persons with NS have attributed the cause of NS to the Ugandan government or international organisations [2]. It is not surprising, then, that caregivers more often reported that their children with NS had eaten moldy maize and emergency food supplies from the World Health Programme. Regarding the association between a reported history of measles and NS, although the relationship is statistically significant [odds ratio (OR): 6.00; 95% confidence interval (CI): 1.03–113, p = 0.047)], the very wide CI implies that there is little precision around the OR point estimate. While the authors do not provide absolute numbers of exposed and unexposed patients, a 2009 study from Kitgum reported that 23.5% (12/ 50) of NS cases and 6.1% (3/49) of non-NS controls had a reported history of measles [3]. In this study, the association between measles and NS was not found to be statistically significant after being adjusted for age (OR 3.3; CI 0.8–13.6). Notably, the majority of cases developed NS without a history of measles. Also, the authors do not provide details about what proportion of NS cases fits the case definitions for suspect, probable, or confirmed cases. Since a measles infection may lead to encephalitis followed by symptomatic epileptic seizures, the few participants with a reported history of measles may have been misclassified as NS suspect cases. The main argument against measles infection as the cause of NS is that there have been many measles epidemics in the world that were
never followed by an NS or epilepsy epidemic. In contrast, we believe that the existing data more strongly support the claim that Ov is the etiologic agent for NS. While it has only been reported to occur in Uganda, South Sudan and Tanzania, NS' localisation to only those countries is attributable to the fact that the first proposal of a case definition for “confirmed NS” did not occur until 2012, during a WHO coordinated meeting in Kampala, Uganda. Before 2012, NS-like clinical manifestations have been reported in many onchocerciasis hyper-endemic regions, including in South America and many other regions in Africa and particularly in places before onchocerciasis control measures had been implemented [4,5]. A closely related condition, the Nakalanga syndrome, is characterized by stunted growth, absence of external signs of sexual development, mental retardation, and very often epilepsy [6]; several of these manifestations are also part of the WHO definition of NS [7]. Nearly all reported cases with Nakalanga syndrome were found to have onchocerciasis [6]. The argument that Ov DNA was never isolated from cerebrospinal fluid (CSF) in patients with NS certainly should be taken into account. However, past use of ivermectin may have been responsible for this absence. In 1938, before the use of ivermectin, Ov microfilariae in CSF were described by Casis Sacre in Mexican Ov-infested patients with NS- and Nakalanga-like clinical manifestations [8]. Dead and live microfilariae were also found in 1959 by Mazzotti in the CSF of Mexican patients treated with diethylcarbamazepine for onchocerciasis and in 1976, Duke et al. observed microfilariae in the CSF of heavily infected patients from Cameroon [9]. The argument that the “peaks of head nodding onset in April and June do not correlate with human biting activity of blackflies” is not relevant. Indeed, the onset of NS is less likely to be related to the biting time of the blackfly and more likely dependent on the production of microfilariae by the adult female worm and whether or not the person is treated with ivermectin. NS and other forms of onchocerciasis-associated epilepsy, most likely appear when a certain level of microfilaria infestation is reached [5]. As is it may take 20 years of Ov infestation before a person becomes blind, it may also take several years for NS to develop [5]. Thus, the absence of Ov infection in a small percentage of NS cases in Uganda (5% without Ov antibodies) can be explained in several ways [3]. First, none of the Ov diagnostic tests is 100% sensitive. Second, even a combination of tests may not detect past Ov exposure if ivermectin to treat onchocerciasis had been used. Third, an emerging explanation for the absence of Ov DNA in the CSF may be that NS is caused by the occurrence of an autoimmune response induced by the Ov infection [10]. Epidemics of NS, other forms of epilepsy, and Nakalanga syndrome all seem to disappear with improved onchocerciasis control which ultimately strengthens the case for Ov being the aetiologic pathogen [5]. On the other hand, the proposed measles aetiology of NS does not explain why NS seems to only occur in onchocerciasis-endemic regions. In conclusion, NS, other forms of epilepsy, and the Nakalanga syndrome are most likely clinical manifestations of onchocerciasis. The pathophysiological mechanism explaining how the Ov infestation is able to cause these conditions remains to be determined.
http://dx.doi.org/10.1016/j.jns.2016.10.008 0022-510X/© 2016 Elsevier B.V. All rights reserved.
Please cite this article as: R. Colebunders, et al., Nodding syndrome, other forms of epilepsy, and the Nakalanga syndrome most likely directly or indirectly caused by Onchocerca volvulus, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2016.10.008
2
Letter to the Editor
Acknowledgements Robert Colebunders has received an ERC grant (No. 671055) for work mentioned in this letter. References [1] P.S. Spencer, R. Mazumder, V.S. Palmer, et al., Environmental, dietary and case-control study of nodding syndrome in Uganda: a post-measles brain disorder triggered by malnutrition? J. Neurol. Sci. 369 (2016) 191–203. [2] K. Buchmann, ‘You sit in fear’: understanding perceptions of nodding syndrome in post-conflict northern Uganda, Glob. Health Action 7 (2014) 25069. [3] J.L. Foltz, I. Makumbi, J.J. Sejvar, et al., An epidemiologic investigation of potential risk factors for nodding syndrome in Kitgum District, Uganda, PLoS One 8 (6) (2013), e66419. [4] B.O. Duke, Onchocerciasis, epilepsy and hyposexual dwarfism, Trans. R. Soc. Trop. Med. Hyg. 92 (2) (1998) 236. [5] R. Colebunders, A. Hendy, M. van Oijen, Nodding syndrome in onchocerciasis endemic areas, Trends Parasitol. 32 (8) (2016) 581–583. [6] A.B. Rapert, R.G. Ladkin, Endemic dwarfism in Uganda, East Afr. Med. J. 27 (1950) 339–359. [7] World Health Organisation, International Scientific Meeting on Nodding Syndrome, Kampala, Uganda, http://www.who.int/neglected_diseases/diseases/Nodding_ syndrom_Kampala_Report_2012.pdf 2012. [8] S.G. Casis, El Sindrome Epileptico y sus reaciones con Onchocercosis, Bol. Salub. Hig. 1 (1938) 11–31. [9] B.O. Duke, J. Vincelette, P.J. Moore, Microfilariae in the cerebrospinal fluid, and neurological complications, during treatment of onchocerciasis with diethylcarbamazine, Tropenmed. Parasitol. 27 (2) (1976) 123–132.
[10] R. Idro, B. Opar, J. Wamala, et al., is nodding syndrome an Onchocerca volvulus-induced neuroinflammatory disorder? Uganda's story of research in understanding the disease, Int. J. Infect. Dis. 45 (2016) 112–117.
R. Colebunders P. Suykerbuyk Global Health Institute, University of Antwerp, Antwerp, Belgium S.T. Jacob Division of Allergy and Infectious Diseases, University of Washington, Seattle, United States M. van Oijen Global Health Institute, University of Antwerp, Antwerp, Belgium Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands Corresponding author at: Global Health Institute, University of Antwerp, Antwerp, Belgium. E-mail address: [email protected] 27 September 2016 Available online xxxx
Please cite this article as: R. Colebunders, et al., Nodding syndrome, other forms of epilepsy, and the Nakalanga syndrome most likely directly or indirectly caused by Onchocerca volvulus, J Neurol Sci (2016), http://dx.doi.org/10.1016/j.jns.2016.10.008