Konzo and Continuing Cyanide Intoxication from Cassava in Mozambique

Food and Chemical Toxicology 49 (2011) 631–635

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Food and Chemical Toxicology

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Konzo and continuing cyanide intoxication from cassava in Mozambique

J. Cliff a,*, H. Muquingue b, D. Nhassico b, H. Nzwalo c, J.H. Bradbury d a Department of Community Health, Faculty of Medicine, Universidade Eduardo Mondlane, Maputo, Mozambique b Department of Physiological Sciences, Faculty of Medicine, Universidade Eduardo Mondlane, Maputo, Mozambique c Hospital Central, Faro, Portugal d School of Botany and Zoology, Australian National University, Canberra, Australia article info abstract

Article history: In Mozambique, epidemics of the cassava-associated paralytic disease, konzo, have been reported in asso- Available online 21 July 2010 ciation with drought or war: over 1100 cases in 1981, over 600 cases in 1992–1993, and over 100 cases in 2005. Smaller epidemics and sporadic cases have also been reported. Keywords: Large epidemics have occurred at times of agricultural crisis, during the cassava harvest, when the pop- Konzo ulation has been dependent on a diet of insufﬁciently processed bitter cassava. Konzo mostly affects Cyanide women of child-bearing age and children over 2 years of age. Cassava When measured, serum or urinary thiocyanate concentrations, indicative of cyanide poisoning, have Mozambique been high in konzo patients during epidemics and in succeeding years. Monitoring of urinary thiocyanate concentrations in schoolchildren in konzo areas has shown persistently high concentrations at the time of the cassava harvest. Inorganic sulphate concentrations have been low during and soon after epidemics. Programmes to prevent konzo have focused on distributing less toxic varieties of cassava and disseminating new processing methods, such as grating and the ﬂour wetting method. Attention should be given to the wider question of agricultural development and food security in the regions of Africa where depen- dence on bitter cassava results in chronic cyanide intoxication and persistent and emerging konzo. Ó 2010 Elsevier Ltd. All rights reserved.

1. Introduction 3. Konzo in Mozambique

Konzo is characterized by the sudden onset of irreversible spas- 3.1. Occurrence and patient characteristics tic paraparesis, associated with prolonged high dietary cyanogenic glucoside consumption and a diet deficient in sulphur amino acids The Ministry of Health (1984) first reported konzo in Mozam- (Howlett et al., 1990; Tylleskär et al., 1993). The cyanogenic gluco- bique in 1981, when a large epidemic of over 1100 cases occurred sides originate from insufficiently processed roots of bitter cassava. in northern Nampula Province. District health authorities also re- Since 1981, poor rural communities in some cassava staple areas of ported cases in neighbouring Chiure in Cabo Delgado Province. Mozambique have suffered from konzo both in epidemic and per- The epidemic was associated with a severe drought. sistent form. Following this larger epidemic, smaller epidemics were reported through the 1980s in the same and other districts of Namp- 2. Material and methods ula (Essers et al., 1992; Cliff, 1994). From 1984 to 1992, war engulfed Nampula, and documentation of the epidemics was This review of konzo in Mozambique draws on the published literature and incomplete. unpublished data, gathered by the authors. Methods used to determine urinary In 1992–1993, a further large epidemic of over 600 cases oc- thiocyanate concentration and ankle clonus in schoolchildren are detailed in the ci- ted papers (Casadei et al., 1990; Cliff et al., 1985, 1999; Ernesto et al., 2002). Vari- curred further south in the province (Cliff et al., 1997). In 1992, ations around the mean were expressed in different ways in the different data sets the disease affected communities displaced by war, and in 1993, and were not always available. Since 1999, we have used a picrate kit to measure those returning home after the war ended. urinary thiocyanate (Haque and Bradbury, 1999) and the total cyanogenic potential New cases of konzo continued to be reported in previously af- in cassava products (Egan et al., 1998; Bradbury et al., 1999). fected areas of Nampula (Ernesto et al., 2002). In 2005, an outbreak of 13 cases occurred in Memba District, associated with drought. * Corresponding author. Address: Faculdade de Medicina, CP 257, Maputo, Mozambique. Tel.: +258 82 321 5640; fax: +258 21 325255. Konzo is now persistent in Nampula, with sporadic cases still being E-mail address: [email protected] (J. Cliff). reported.

produce flour, which is cooked as a stiff porridge. Although the resulting flour has lower total cyanogenic potential, it is still unsafe when the initial concentration in the root is high (Cardoso et al., 2005). Our previous studies have shown average total cyanogenic potential of 40–46 mg HCN equivalents/kg flour (fresh weight) in normal years (Cardoso et al., 1998). In years of low rainfall, the average total cyanogenic potential of cassava flour increases to >100 mg HCN equivalents/kg (fresh weight) (Cardoso et al., 2005), more than 10 times the WHO safe level of 10 mg total HCN/kg (FAO/WHO, 1991). The underlying causes of the konzo epidemics in Mozambique have varied. When due to drought, as in the first large epidemic, the cassava root contains a higher concentration of cyanogenic glu- cosides. Women take short cuts in processing, as they are hungry and do not have time to sun-dry for several weeks. They may shorten the sun-drying time or use the inefficient method of pounding and sun-drying the pieces for 1 day. Because other crops Fig. 1. Districts affected by konzo, Mozambique, 1980–1989 and 2000–2009. fail in drought, communities become more dependent on cassava, as it is often the only crop to survive (Ministry of Health, 1984). In the most recent epidemics in Zambézia and Nampula, both In 2000, konzo emerged in Zambézia Province, further south, drought and commercialization have contributed. In Zambézia, when 10 cases were reported from Ile District. In 2005, an epi- communities sold their cassava to neighbouring drought-stricken demic with over 100 reported cases occurred in a large area in Malawi, and were then caught short when their own crop failed. the central part of the province. The epidemic was associated with Our investigation of these cases showed that many families had drought. Zambézia continues to report sporadic cases. purchased dried roots in local markets. In Nampula, in nine house- Over the 28 years since it was first reported in Mozambique, holds with konzo cases, who had purchased roots or flour, the konzo has extended its geographical range. Fig. 1 shows that konzo mean total cyanogenic potential of the flour was 145 mg HCN has been reported from more districts in the decade 2000–2009 equivalents/kg (fresh weight). When due to war, lack of other foods than in the decade 1980–1989. and shortcuts in processing contributed (Cliff et al., 1997). In all epidemics, the clinical picture has been monotonous, with a presentation of irreversible non-progressive symmetrical spastic paraparesis of acute onset and varying severity. 3.3. Cyanide intoxication in konzo-affected communities Konzo has predominantly affected women of child-bearing age and children over 2 years of age. Multiple cases often occur in the In the first large epidemic in Mozambique, 22 community con- same household and now cases are passing down through trols also had high serum thiocyanate concentrations, with a mean generations. of 288 lmol/l (Ministry of Health, 1984). This is well above the Serum or urinary thiocyanate concentrations have always been mean concentration of 42.5 lmol/l recorded in normal Swedish high in konzo patients at the time of epidemics. In the 1981 epi- non-smokers (Lundquist et al., 1979). demic, the mean serum concentration ± SEM registered in 246 Cyanide intoxication in the community at the time of the cas- specimens was 329 ± 8 lmol/l (Ministry of Health, 1984). In Mur- sava harvest has persisted along the years. Monitoring of urinary rupula in 1982, a mean ± SD of 195 ± 39 lmol/l was registered in thiocyanate concentration in schoolchildren has consistently December, 2 months after the epidemic peak (Essers et al., 1992). shown high levels. Table 1 shows the urinary thiocyanate concentrations in pa- Fig. 2 shows the mean urinary thiocyanate concentrations in tients with konzo in two districts in Nampula Province and two schoolchildren in the village of Miaja (also known as Acordos de sites in Mocuba District in Zambézia Province between 2005 and Lusaka) along the years from June 1982 to October 2003 (Casadei 2006. In 2005, a drought year, all the patients had recently ac- et al., 1990; Cliff et al., 1986, 1999; Ernesto et al., 2002, unpub- quired konzo. In 2006, there was no drought and no new cases lished data). The village had first been chosen for study as it was were found. Nonetheless, the patients still had high concentrations severely affected in the 1981 epidemic with an incidence rate of of urinary thiocyanate. The highest mean ± SEM concentration of 34 cases/1000 (Ministry of Health, 1984). Four cases were detected 479 ± 70 lmol/l was found in 12 patients in Mogincual District in in 1982, when the mean concentration of 1175 lmol/l in Septem- 2006. This district has suffered from persistent konzo since the ber was extremely high, compared to a mean, in normal Swedish war-induced epidemic of 1992–1993. non-smokers, of 43.0 lmol/l (Lundquist et al., 1979). Values peaked again at the time of the cassava harvest the following year, 3.2. Underlying causes of konzo with a high of 673 lmol/l. No new cases were reported, probably because the drought had passed and the community had access Epidemics have mostly occurred during agricultural crises, to other food sources. By 1984, concentrations had fallen to near peaking at the time of the cassava harvest, when the population normal values. has been dependent on a diet of insufficiently processed bitter No measurements were taken for the next 9 years, owing to cassava. war. In July 1993, before the harvest, the geometric mean concen- Cassava is the main staple in these areas and is harvested from tration was 113 lmol/l (Cliff et al., 1999), a concentration still August to October. Bitter cassava, which is high in cyanogenic glu- indicative of cyanide intoxication. When next measured in October coside content, predominates. Communities process the root to 1997, the mean concentration was high at 512 lmol/l. Over the lower the cyanogenic glucoside content using a variety of methods. next 5 years, concentrations fell to 130 lmol/l in October 2003. The bulk of the harvest is processed by sun-drying for several The fall coincided with a decline in cassava consumption due to weeks, but concentrations remain high as it is an inefficient meth- an epidemic of brown streak virus in cassava. No new cases have od. Heap fermentation is also used. The roots are then pounded to been reported in this village since the 1980s. J. Cliff et al. / Food and Chemical Toxicology 49 (2011) 631–635 633

Table 1 Urinary thiocyanate concentration in patients with konzo, October 2005 and 2006.

Location Konzo occurrence Urinary thiocyanate concentration Year Mean ± SEM (lmol/l) Nampula Province Mogincual District (n = 12) Epidemic 1992–1993, persistent 2006 479 ± 70 Memba District (n = 12) Epidemic 1981–1982, 2005 2005 528 ± 137 Memba District (n = 10) Epidemic 1981–1982, 2005 2006 380 ± 98 Zambézia Province, Mocuba District Caiave (n = 27) Epidemic 2005 2005 272 ± 33 Caiave (n = 25) Epidemic 2005 2006 289 ± 27 Sassamange (n = 20) Epidemic 2005 2005 379 ± 71 Sassamange (n = 30) Epidemic 2005 2006 321 ± 23

1400

1200

1000

800

(µmol/l) 600 Thiocyanate 400

200

0 Jun Sep Mar Aug Sep Dec Mar Jul Aug Jul Oct Oct Oct Oct 82 82 83 83 83 83 84 84 84 93 97 99 O2 O3 Month/Year

Fig. 2. Mean urinary thiocyanate concentration in schoolchildren, Miaja, 1982–2003.

Table 2 Urinary thiocyanate concentration in schoolchildren in konzo-affected areas.

Location Konzo occurrence Urinary thiocyanate concentration Year (month) Mean ± SEM (lmol/l) Nampula Province Memba District: Cava (n = 34)a Epidemic 1981–1982, 2005 1999 (October) 339 ± 61 Mogincual District: Mocone, Mujocojo, Terrene A (n = 77)b Epidemic 1992–1993 1993 (July) 207 ± 14 Mogincual District: Mujocojo (n = 30)a Persistent 1999 (October) 225 ± 35 Mogincual District: Mujocojo (n = 31) c Persistent 2001 (July) 301 ± 64 Mogincual District: Namichire (n = 30)a Persistent 1999 (October) 298 ± 31 Mogincual District: Terrene A (n = 23)a Persistent 1999 (October) 384 ± 48 Murrupula District: Naha (n = 28)d Epidemic 1982 1993 (July) 219 (173, 277)e Zambézia Province Ilé District: Niboiac Epidemic 2000 2001 (July) 351

a Ernesto et al. (2002). b Cliff et al. (1997). c Cardoso et al. (2004). d Cliff et al. (1999). e Geometric mean (95% conﬁdence intervals).

Table 2 shows that urinary thiocyanate concentrations have 3.4. Low inorganic sulphate concentration in konzo-affected been high in schoolchildren in other konzo-affected sites, both dur- communities ing and after konzo outbreaks. In 1993, the year of a konzo outbreak in Mogincual District, the concentration of linamarin, the Table 3 shows that mean urinary inorganic sulphate concentra- main cyanogenic glucoside present in cassava, was also measured tions in schoolchildren in konzo-affected areas are low, particularly and was high at 80 ± 9 lmol/l (Cliff et al., 1997). during epidemics. In 1983, the concentrations in the previously 634 J. Cliff et al. / Food and Chemical Toxicology 49 (2011) 631–635

Table 3 Urinary inorganic sulphate concentration in schoolchildren in konzo-affected areas, Nampula Province.

Location Konzo occurrence Urinary inorganic sulphate concentration Year Mean ± SEM (mmol/l) Mean ± SEM (mol/mol creatinine) Memba District: Miajaa (n = 30) Epidemics 1981–1982 1982 3.9d 0.41 ± 0.04 Memba District: Miajaa (n = 31) Epidemics 1981–1982 1983 5.9d 0.73 ± 0.08 Memba District: Miajab (n = 26) Epidemics 1981–1982 1993 7.0 (5.3, 9.3)e Mogincual District: Mocone, Mujocojo, Terrene A c (n = 77) Persistent 1993 4.9 ± 0.4

a Cliff et al. (1985). b Cliff et al. (1999). c Cliff et al. (1997). d Recalculated by authors. e Geometric mean (95% confidence intervals). konzo-affected village of Miaja were compared with control impoverishment of the rural poor, a neglect of food production, schoolchildren in the district capital and Swedish children. Mean and climate change may all increase the likelihood of further cases concentrations ± SEM expressed as mmol/mol creatinine were of konzo. 0.73 ± 0.08, 1.34 ± 0.17 and 1.36 ± 0.10, respectively (Cliff et al., 1985). The mean concentration of total urinary sulphate was mea- Conflict of interest sured in six patients in a small epidemic in 1982 (Essers et al., 1992). The concentration of 0.81 (0.34, SD) was low when com- The authors declare that there are no conflicts of interest. pared to Swedish children (range 1–3.3). The low concentrations shown in Table 3 reflect low sulphur amino acid intake. The detoxification of cyanide in the body by conversion to thiocyanate is Acknowledgments dependent on sulphur-containing amino acids. Decreased intake may impair cyanide detoxification, and at the same time detoxifi- We thank the many people who have helped us collect data cation uses up these amino acids (Cardoso et al., 2004). along the years, in particular the provincial health authorities in Nampula and Zambézia Provinces, and the district health officials 3.5. Subclinical pathology in konzo affected districts. The recent investigation has been funded by the Ministry of Science and Technology, Mozambique, Studies showed that a proportion of schoolchildren (4–22%) in and Kyeema Foundation. konzo-affected communities had ankle clonus, a sign of upper motor neuron damage (Cliff et al., 1986, 1999; Ernesto et al., 2002). In References the first two studies, carried out in 1983 and 1993, there was an association between ankle clonus and urinary thiocyanate Bradbury, J.H., 2006. 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