NEUROLOGY GRAND ROUNDS

Cyclical Konzo Epidemics and Climate Variability Olusegun Steven A. Oluwole, MBBS, PhD Konzo epidemics have occurred during droughts in the Democratic Republic of Congo (DR Congo) for >70 years, but also in Mozambique, Tanzania, and the Central African Republic. The illness is attributed to exposure to cyanide from cassava foods, on which the population depends almost exclusively during droughts. Production of cassava, a droughtresistant crop, has been shown to correlate with cyclical changes in precipitation in konzo-affected countries. Here we review the epidemiology of konzo as well as models of its pathogenesis. A spectral analysis of precipitation and konzo is performed to determine whether konzo epidemics are cyclical and whether there is spectral coherence. Time series of environmental temperature, precipitation, and konzo show cyclical changes. Periodicities of dominant frequencies in the spectra of precipitation and konzo range from 3 to 6 years in DR Congo. There is coherence of the spectra of precipitation and konzo. The magnitude squared coherence of 0.9 indicates a strong relationship between variability of climate and konzo epidemics. Thus, it appears that low precipitation phases of climate variability reduce the yield of food crops except cassava, upon which the population depends for supply of calories during droughts. Presence of very high concentrations of thiocyanate (SCN2), the major metabolite of cyanide, in the bodily fluids of konzo subjects is a consequence of dietary exposure to cyanide, which follows intake of poorly processed cassava roots. Because cyanogens and minor metabolites of cyanide have not induced konzo-like illnesses, SCN2 remains the most likely neurotoxicant of konzo. Public health control of konzo will require food and water programs during droughts. [Correction added on 26 February 2015, after first online publication: abstract reformatted per journal style] ANN NEUROL 2015;77:371–380

T

he neurological features of konzo are acute or subacute spastic paraparesis or quadriparesis, dysarthria, impaired visual acuity, and nystagmus.1,2 Maximum disability is reached within a day in 90% of cases, and within 3 days in the rest.3 Patients, who are usually previously healthy, develop symptoms on waking in the morning or during prolong walks.2 Although complete recovery and second attacks have been documented,2,4 disabling nonprogressive spastic paraparesis of varying severity is the typical outcome in most subjects.1 Dysarthria and impaired vision, however, improve in >70% of subjects. Comprehensive neuro-ophthalmological assessment of konzo subjects has shown impaired visual acuity in 24%,5 visual field defects in 67%, delayed latency and amplitude of P100 in 48%, and nystagmus in 10%.5 Some neuroophthalmological deficits persist in many subjects. Longitudinal studies indicate, however, that konzo is not a progressive neurological syndrome.2,6 Neuropsychological studies have shown cognitive impairment in 9-year-olds with konzo.7 Magnetic resonance imaging usually shows no structural lesions in the brain and spinal cord,8 but transcranial magnetic stimulation and tib-

ial nerve somatosensory evoked potentials may demonstrate central conduction block.9 Slowing of background electroencephalographic activity in >50% of subjects suggests lesions in the cerebral hemispheres.10 Overall, clinical and neurophysiological data indicate lesions at multiple levels of the neuraxis. In this Neurology Grand Rounds presentation, the epidemiology of konzo and models of its pathogenesis are reviewed. The temporal relationship of konzo to precipitation is analyzed to determine whether konzo epidemics are cyclical and whether there is spectral coherence.

Epidemiology of Konzo Geographical Distribution Konzo remains among the major neurological syndromes in Africa11 >3 decades after it was first described as a hidden endemic problem.12 Konzo was clearly described in the late 1930s in the Kahemba region of the Bandundu district of DR Congo,13 although epidemics of what was probably this syndrome had been recognized in 1928, 1932, and 1937 in the same region.14,15 Epidemics were also documented in 1978 and 1981,16 but more detailed field studies have been done since the mid-

View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24334 Received Jun 26, 2014, and in revised form Nov 30, 2014. Accepted for publication Dec 7, 2014. From the Neurology Unit, College of Medicine, University of Ibadan, Ibadan, Nigeria

C 2015 American Neurological Association V 371

ANNALS

of Neurology

1980s. In 1986, 20 sporadic cases of konzo were identified in the southern Bandundu region of DR Congo.4 The prevalence of konzo ranged from 150 to 280 per 10,000 in 3 ethnic groups in central Bandundu in 1991,3 and was 24 per 10,000 (range 5 2–317) in the Kahemba region, southern Bandundu, in 1996.17 In 2004, the prevalence was found to be 140 per 10,000 in Popokabaka, Bandudu,18 and 6 per 10,000 in 2005 in the South Kivu region of DR Congo.19 Thus, konzo epidemics have occurred in disparate areas of DR Congo for >70 years. The largest epidemic of konzo in the past 40 years, which was called Mantakassa in the local language, occurred in 1981 in Nampula Province, Mozambique, where >1,000 cases were identified.1 Prevalence in surveyed districts ranged from 10 to 340 per 10,000. Konzo epidemics were also documented in 1988 and 1992,20 1998,21 and 2005,22 but sporadic cases occurred annually between epidemics. In northern Tanzania, sporadic and epidemic cases of konzo occurred between 1979 and 1989 in the Tarime district,2,23 and in the early 2000s in the Mtwara and Mbinga districts in southern Tanzania.24 The peak prevalence was 140 per 10,000, which occurred during the epidemic of 1985.23 In the Central African Republic, the prevalence of konzo was 50 per 10,000 in 1994,25 and 10 per 10,000 in 2007.26 Of 469 cases of konzo that were identified in eastern Cameroon between 2005 to 2007, 80% were refugees from the Central African Republic. The occurrence of unexplained myelopathy among rural dwelling Bantu of South Africa, which was described as konzo in 1965, suggests that the geographical distribution of konzo extends deep into southern Africa.27 The description of the myelopathy as "weakness of the lower limbs in previously healthy subjects, which reaches maximum disability in a few days, with absence of sensory symptoms, due to food toxin" is similar to the description of konzo in eastern and central Africa. Thus, the geographical distribution of konzo is chiefly limited to eastern, central, and southern Africa (Fig 1), but detailed epidemiological studies have been done in DR Congo, Mozambique, and Tanzania. Age and Gender Distribution In Mozambique 65% of subjects were 15 years of age, 9% were males and 26% females.1 In Tanzania, a higher proportion of males 20 years of age.23 In Bandundu, DR Congo, there were more males 15 years of age. Konzo and Ataxic Polyneuropathy Konzo has been contrasted with ataxic polyneuropathy,12,28,29 which is endemic in southwest Nigeria,30,31 and in Newala, India,32 but has also occurred in epidemic form in Tanzania and Cuba.33,34 Like konzo, ataxic polyneuropathy is prevalent in communities where cassava foods are consumed frequently and exposure to cyanide is high.35,36 Unlike konzo, however, its onset is insidious, with sensory gait ataxia, sensory polyneuropathy, sensorineural deafness, and optic atrophy. Ataxic polyneuropathy is rare at 18 C.42 Unlike major food crops like rice (Oryza spp), maize (Zea spp), and wheat (Triticum spp), which are Volume 77, No. 3

Oluwole: Climate and Konzo

cyanogenic only during development,43,44 cassava stores cyanogenic glycosides in its edible roots. All cassava cultivars contain 2 cyanogenic glycosides, linamarin45,46 and lotaustralin,45,47 which are present in a ratio of 97:3.45 Production of cassava, a drought-resistant crop, is known to be higher in seasonally dry than in semiarid environments,48 and in relatively poor soil.49 As cassava is an important food crop in the tropics, the presence of cyanogens makes rigorous processing of cassava necessary to reduce the concentration of cyanogens.

blocks that disrupted the food chain were associated with an increase in cases of konzo in Kiwit, Bandundu in 1996.61 Wars in Mozambique,62 DR Congo,19 and Central African Republic,63 which caused critical food insufficiency, have been linked to the occurrence of konzo. Thus, factors that alter food crop production in favor of cassava have been associated with konzo in areas of subsistence farming.

Cassava Processing

Cyanide anions, which are released from ingested linamarin or acetone cyanohydrin, are metabolized to SCN2, but minor metabolites of cyanide include 2iminothiazolidine-4-carboxylic acid, CO2, formate, cyanate, hydrogen cyanide, and cyanocobalamin (see Fig 2).64 Sulfur substrates are required by the enzymes rhodanese and 3-mercaptopyruvate sulfurtransferase, which catalyze metabolism of cyanide to SCN2.64 Field36,65 and experimental studies66,67 show that increased plasma concentrations of cyanide may follow consumption of cassava foods. Intake of 500g of boiled cassava, which contained 105 lmol linamarin and 8 lmol hydrogen cyanide, raised the mean concentrations of urine SCN2 from 5 to 8 lmol/l,66 whereas intake of 150g of gari,67 which contained 128 lmol of cyanide anions, released 13 lmol of cyanide into plasma.

Cassava root is processed to various foods in the tropics, where it is a less expensive source of calories than major food crops like rice, maize, potato, and sorghum. The first stage of processing produces products such as pastes, granules, and flour,50,51 which are storable for weeks or years. Meals are prepared from these products when needed.36 Whereas bitter and sweet cultivars are processed rigorously in Nigerian communities,50 bitter cultivars are processed more rigorously than sweet cultivars in Malawi.52 Types of cassava foods and methods of processing cassava roots vary widely, but the concentrations of cyanogens in the food products are not directly related to the amount of cyanogens in cassava roots.53–55 Cassava flour, the commonest cassava food in konzo-affected communities, is produced using several methods to dry cassava roots before they are milled to flour.56 Water shortage, which has been identified as the major reason for seasonal changes in methods of processing cassava in konzo-affected areas,57 may be the reason why cassava roots are soaked or not soaked in water before sun drying. In Tanzania, the method of soaking cassava roots in water before sun drying, which reduces the concentrations of cyanogens significantly, is practiced during wet seasons and in areas close to rivers,24 whereas sun drying of unsoaked cassava roots, which produces highly cyanogenic flour, is practiced during dry seasons and in areas where there is a shortage of water.21,24 Linamarin, the cyanogen in cassava roots, decomposes to acetone cyanohydrin, which decomposes at pH > 4.0 or temperatures > 30 C to acetone and hydrogen cyanide (Fig 2).58 Soaking of cassava roots in water accelerates disruption of cassava tissues, which promotes enzymatic decomposition of linamarin. Thus, the contribution of variability of climate to the choice of methods for processing cassava in konzo countries59,60 is probably greater than that of cultural practices and culinary preferences. Environmental changes, socioeconomic issues, opening of trade routes,3 military road blockades,61 and wars have been found to disrupt the food chain sufficiently to induce dependency on cassava foods. RoadMarch 2015

Exposure to Cyanide from Cassava Foods and Metabolism of Cyanide

Pathogenesis of Konzo Although abrupt onset and short time to maximal disability are typical of strokes, involvement of multiple levels of the neuraxis at onset excludes strokes as a likely cause of konzo. Its nonprogressive nature makes infectious, immunologic, and neoplastic causes unlikely. The natural histories of acute inflammatory demyelinating syndromes, which can present like konzo at onset, are however not similar to that of konzo. The effects of cassava cyanogens, cyanide, and metabolites of cyanide on neural tissues and animal models have been researched in experimental studies, but none has shown lesions that are consistent with konzo. Models of pathogenesis of konzo are shown in Figure 3. Linamarin, the cyanogen in cassava root, has been shown to be toxic to neural cell culture,68 but lesions that resemble konzo were not induced in rats fed cassava food.69 Acetone cyanohydrin, the product of decomposition of linamarin, induced thalamic lesions in rats,70 but this is not consistent with the neurological features of konzo. There is consensus among konzo researchers that direct neurotoxic effect of cyanide is unlikely to be the cause of konzo,71–74 because the neuropathology of cyanide is largely limited to the basal ganglia.75,76 NaCN 373

ANNALS

of Neurology

FIGURE 2: Cassava Cyanogenesis and Metabolism of Cyanide.

induced seizures in rats on a diet that was deficient in sulfur amino acids, but such effects were not observed in primates on an exclusive cassava diet.77 Cyanate, a minor metabolite of cyanide, depleted glutathione levels in mouse brain,78 and induced motor deficits in rats,77,79 and 2-iminothiazolidine-4-carboxylic acid, another minor metabolite of cyanide, induced lesions in the CA1 region 374

of mice hippocampi.80 Thus, cyanogens, cyanide, and minor metabolites of cyanide have not been shown to be neurotoxicants and likely causes of konzo. SCN2, the major metabolite of cyanide, has been considered by many experts to be the neurotoxicant of konzo,74 but has been less rigorously studied as the causative agent, probably because it is present physiologically Volume 77, No. 3

Oluwole: Climate and Konzo

FIGURE 3: Models of Konzo Pathogenesis.

in many tissues. SCN2, a pseudohalide that has a halflife of 4 days, is handled in biological systems like chloride ions.81 It is, however, more permeant than Cl2 at a variety of chloride channels,82 and has 730 times more affinity than Cl2 in physiological assays.83 Its extracellular distribution falls as the plasma concentration rises,81 perhaps because it is redistributed intracellularly. Br2, a permeant anion that is distributed like Cl2 and SCN2, is known to induce neuronal injury by replacing Cl2.84 Because SCN2 increases the affinity of a-amino-3hydroxy-5-methylisoxazole-4-propionic acid (AMPA) March 2015

receptors for AMPA about 10- to 30-fold and of excitatory postsynaptic potentials by 45%,85 it is a likely candidate to induce the nervous system lesions of konzo. Thus, of the cyanogens, cyanide, and metabolites of cyanide, SCN2 appears the most likely neurotoxicant causing konzo. Nutritional factors, particularly deficiency of sulfurcontaining amino acids, have been considered in the pathogenesis of konzo. Total plasma protein, however, has been found to be similar in konzo cases and family members.2 High blood concentrations of SCN2 in 375

ANNALS

of Neurology

konzo subjects in Mozambique in 1981, 324 vs 288 lmol/l in controls,1 and mean serum SCN2 concentrations of 368 lmol/l in the Tarime district of Tanzania in 1985,2 do not indicate that konzo subjects are deficient in sulfur substrates that are needed to metabolize cyanide to SCN2. Thus, high SCN2 concentrations of >1,000 lmol/l in the urine of konzo subjects86 and high serum SCN2 levels indicate that konzo subjects metabolize cyanide to SCN2 as well as controls. Droughts, High Cassava Production, and Cyclical Konzo Epidemics Konzo epidemics in DR Congo in 1928, 1932, and 1937,14,15 1978 and 1981,16 1988,3 and 200519 occurred during droughts. The konzo epidemics in Tanzania in 1985 occurred during a drought,23 and the epidemics in Mozambique in 1981,1 1988, 1992,20 1998,21 and 200522 were also during droughts. Severe droughts, which reduced food crop production, have been documented in the central, eastern, and southern Africa regions.87,88 Climate change may also have a negative impact on production of maize, rice, beans, sorghum, banana, and potatoes, but the predicted impact on production of cassava ranged from 23.7% to 117.5% and is therefore largely positive.89 Increased production of cassava in the central, eastern, and southern regions of Africa has been linked to environmental warming.90 Increased production of cassava by 13% during low precipitation phases of climate variability90 demonstrates the impact of variability of climate on cassava production. Thus, cassava is an important food security crop in areas of subsistence farming during droughts. The history of konzo epidemics in Bandundu, DR Congo from 1928 to 2005 suggests that the epidemics occur in cycles, which coincide with droughts. Studies of Mozambique from 1981 to 1993, and of Tanzania from 1979 to 1989, also suggest the possibility of cyclical konzo epidemics during droughts. Because changes in precipitation have been shown to correlate with cycles of cassava production,90 it is important to determine whether konzo epidemics also correlate with changes in precipitation.

New Data To test the hypothesis of the relationship of the occurrence of konzo epidemics and changes in precipitation, a time series of annual occurrence of konzo in geographical areas of DR Congo,3,61 Mozambique,20 and Tanzania,23 which had been published earlier, was analyzed. The duration of the data collection was 23 years for DR Congo, 13 years for Mozambique, and 11 years for Tanzania. Precipitation and surface temperature data, 2m above earth surface, for the period of occurrence of 376

konzo for each geographical area were downloaded from the website of the US National Oceanic and Atmospheric Administration (http://www.esrl.noaa.gov/psd/), using the RNCEP package91 of R Statistical Programming and Environment (v3.1.1, 2014, Vienna, Austria).92 The coordinates of the geographical areas where konzo data were generated were used to obtain climate data: latitude 23.78 S to 25.69 S and longitude 15.56 W to 18.90 E for DR Congo, latitude 213.62 S to 216.12 S and longitude 37.27 W to 40.77 E for Mozambique, and latitude 21.13 S to 21.33 S and longitude 33.98 W to 34.18 E for Tanzania. Six-hourly data of precipitation and temperature were aggregated to annual values. The time series were fitted to konzo and climate data. A lag plot was used to detect the presence of cycles in the time series, and an autocorrelation function was used to determine stationarity. Amplitude or frequency filters were not applied to the time series. A Fourier transform was used to convert the series from time to frequency domain. The Mozambique and Tanzania time series were not of sufficient length for valid spectral analysis. Cross power spectral density analysis of precipitation and konzo time series was performed for DR Congo. Magnitude squared coherence was used to determine the strength of correlation of the time series, and a cross spectrum phase plot was used to determine phase shift between time series. Statistical analysis, drawing of chemical structures, and maps were done using packages of R Statistical Programming and Environment (v3.1.1),92 and spectral analysis was done using the signal package of Octave, the open source version of the Matlab numerical computation and programming environment.

New Findings and Discussion The time series of konzo epidemics, precipitation, and environmental temperature, with Loess smoothing, for the 3 countries are shown in Figure 4. The time series of climate and konzo show cyclical changes in DR Congo and Mozambique, but only 1 peak is present in the Tanzania series. These support the historical data of konzo epidemics in DR Congo, but also show that konzo epidemics are cyclical in Mozambique and possibly in Tanzania. Visual inspection of the time series shows that peaks of konzo occur proximate to the troughs of precipitation in the 3 countries (see Fig 4). As all konzo epidemics peaked within 1 year of the troughs of precipitation, there is a strong temporal relationship between low precipitation and konzo epidemics in DR Congo, Mozambique, and Tanzania. Periodicities of dominant frequencies in the spectra of precipitation and konzo range from 3 to 6 years in DR Congo (Fig 5). There is coherence of the spectra of Volume 77, No. 3

Oluwole: Climate and Konzo

FIGURE 4: Konzo and Climate Time Series.

precipitation and konzo at the same frequencies. A cross spectrum phase plot shows that the konzo time series lags the precipitation series. Magnitude squared coherence of 0.9 for the cross spectra of precipitation and konzo indicate strong correlation of cyclical changes in precipitation and konzo epidemics. The findings of spectral analysis of DR Congo show a strong relationship of konzo epidemics to climate variability, and the same findings may have been obtained for Mozambique and Tanzania, if the time series had been longer. Environmental warming overland has been associated with severe droughts in central, eastern, and southern Africa.87,88 Precipitation in konzo-affected areas of central, eastern, and southern Africa has been shown to be lower than in coastal western Africa.90 The impact of low precipitation due to climate change on agriculture has been predicted to be negative for major food crops like beans, maize, millets, sorghum, banana, and potatoes, but largely positive for cassava.89 In konzo-affected areas, 52-year data show cyclical production of cassava, which correlates with changes in precipitation.90 High

production of cassava during periods of low precipitation, when other major food crops fail, can explain the dependence of the population on cassava roots for a supply of calories. Whereas cassava foods with low concentrations of cyanogens are produced during wet seasons, lack of water has been linked to poorly processed cassava during droughts.21,24,57 Average environmental warming of 1.1 C in 52 years90 in konzo-affected areas of central, eastern, and southern Africa is high compared with global average warming of 0.6 C (95% confidence interval 5 0.4–0.8) between 1901 and 2000.87 In this study (see Fig 4), the trend of temperature increased significantly (p < 0.05) between 1974 and 1996 in the Bandundu area of DR Congo. The rise of temperature of 0.5 C in 23 years in this study, however, compares with the rate of warming overland of approximately 0.3 C per decade, but is more than the rate of 0.1 C per decade for the oceans.93 Although climate variability and its relationship with konzo epidemics are evident in this study, it is not possible to infer the effect of environmental warming because of the short duration of the data.

FIGURE 5: Power Spectral Density Plots.

March 2015

377

ANNALS

of Neurology

We propose that the pathogenesis of konzo is induced by events that are initiated by climate variability (see Fig 3). The low precipitation phase of climate variability induces failure of food crops other than cassava. Although this makes cassava a food security crop, lack of water prevents adequate processing of cassava roots to safe food. Exposure to cyanide follows almost exclusive dependence of the population on cassava foods that contain high concentrations of cyanogens. Very high concentrations of SCN2 in bodily fluids result from repeated intake of highly cyanogenic cassava foods and low intake of water. SCN2 modulates excitatory neurotransmission, and its persistent elevation may lead to irreversible neuronal injury. Thus, cyclical konzo epidemics are induced by low precipitation phases of climate variability in areas of subsistence farming in eastern, central, and southern Africa, where the negative effect of climate change on agriculture has been shown to be severe.

of water prevents effective processing of cassava into foods with low concentrations of cyanogens. Very high concentrations of SCN2, the major metabolite of cyanide, are present in increased amounts in the bodily fluids of subjects with konzo. Although the toxicology of linamarin, acetone cyanohydrin, cyanide, and minor metabolites of cyanide like cyanate and 2iminothiazolidine-4-carboxylic acid have not shown lesions consistent with konzo, SCN2 is currently believed to be the most likely neurotoxicant of konzo. Effective public health policy to control konzo epidemics will require food and water programs to eliminate the negative effects of climate variability in areas of subsistence farming where konzo epidemics occur.

Potential Conflicts of Interest Nothing to report.

Public Health Control of Konzo Policies to control konzo epidemics have focused on reduction of exposure to cyanide from foods made from cassava. Cultivation of low-cyanogenic cassava has been proposed, but the success of this may be limited because cyanogenesis in cassava, which varies with altitude and water stress, may change from low to high when a cultivar is planted in a new location,35,94 or during low precipitation. Although development and improvement of methods of processing cassava are attractive strategies to lower cyanogens in cassava products, lack of water during low precipitation will make these strategies difficult to implement, because water is needed to effectively process cassava roots. Although the wetting method,95 a postprocessing modification of cassava flour, has been shown to be effective in reducing exposure to cyanide from cassava foods, there is a need to develop strategies to eliminate the effects of climate variability. Thus, food and water programs are needed during droughts to control konzo epidemics.

References 1.

Ministry of Health Mozambique. Mantakassa: an epidemic of spastic paraparesis associated with chronic cyanide intoxication in a cassava staple area in Mozambique. 1. Epidemiology and clinical and laboratory findings in patients. Bull World Health Organ 1984;62:477–484.

2.

Howlett WP, Brubaker GR, Mlingi N, Rosling H. Konzo, an epidemic upper motor neuron disease studied in Tanzania. Brain 1990;113:223–235.

3.

Tyllesk€ ar T, Banea M, Bikangi N, et al. Epidemiological evidence from Zaire for a dietary etiology of konzo, an upper motor neuron disease. Bull World Health Organ 1991;69:581–589.

4.

Carton H, Kazadi K, Kabeya, et al. Epidemic spastic paraparesis in Bandundu (Zaire). J Neurol Neurosurg Psychiatry 1986;49:620– 627.

5.

Mwanza JC, Tshala-Katumbay D, Kayembe DL, et al. Neuro-ophthalmologic findings in konzo, an upper motor neuron disorder in Africa. Eur J Ophthalmol 2003;13:383–389.

6.

Cliff J, Nicala D. Long-term follow-up of konzo patients. Trans R Soc Trop Med Hyg 1997;91:447–449.

7.

Boivin MJ, Okitundu D, Makila-Mabe Bumoko G, et al. Neuropsychological effects of konzo: a neuromotor disease associated with poorly processed cassava. Pediatrics 2013;131:e1231–e1239.

8.

Tylleskar T, Howlett WP, Rwiza HT, et al. Konzo: a distinct disease entity with selective upper motor neuron damage. J Neurol Neurosurg Psychiatry 1993;56:638–643.

9.

Tshala-Katumbay D, Eeg-Olofsson KE, Kazadi-Kayembe T, et al. Analysis of motor pathway involvement in konzo using transcranial electrical and magnetic stimulation. Muscle Nerve 2002;25:230– 235.

10.

Tshala Katumbay D, Lukusa VM, Eeg-Olofsson KE. EEG findings in Konzo: a spastic para/tetraparesis of acute onset. Clin Electroencephalogr 2000;31:196–200.

11.

Rom an GC. Tropical myelopathies. Handb Clin Neurol 2014;121: 1521–1548.

12.

Roman GC, Spencer PS, Schoenberg BS. Tropical myeloneuropathies: the hidden endemias. Neurology 1985;35:1158–1170.

Conclusions The geographical distribution of konzo epidemics, which have occurred during droughts since the 1920s, is restricted to parts of eastern, central, and southern Africa. Nutritional, infectious, and toxicological mechanisms of causation have been investigated; exposure to cyanide from cassava foods is the most consistent risk factor in all areas where konzo epidemics have occurred. Additional data have shown that konzo epidemics, which are cyclical, correlate strongly with cyclical changes in precipitation. Low yield of food crops during low precipitation phases of climate variability induce dependence of the population on cassava, a drought-resistant crop. Shortage 378

Volume 77, No. 3

Oluwole: Climate and Konzo

13.

Trolli G. Konzo or epidemic spastic paralysis of the Congo. Trop Dis Bull 1939;36:501.

36.

Oluwole OSA. Endemic ataxic polyneuropathy in Nigeria. PhD thesis. Karolinska Institute, Stockholm, Sweden, 2002.

14.

Lucasse C. La “Kitondji,” synonyme le “Konzo,” une paralysie spastique. Ann Soc Belge Med Trop 1952;33:393–401.

37.

15.

Vileu AF. Contribution a la discussion de la paraplegie spastique epidemique du Kwango. Ann Soc Belge Med Trop 1942;22:309–317.

Oluwole OSA, Onabolu AO. High mortality of subjects with endemic ataxic polyneuropathy in Nigeria. Acta Neurol Scand 2004;110:94–99.

38.

16.

WHO. Surveillance of peripheral neuropathies. Wkly Epidemiol Rec 1982;57:213.

Tyllesk€ ar T, Banea M, Bikangi N, et al. Cassava cyanogens and konzo, an upper motoneuron disease found in Africa. Lancet 1992;339:208–211.

17.

Bonmarin I, Nunga M, Perea W. Konzo Outbreak, in the southwest of the Democratic Republic of Congo. J Trop Pediatr 2002; 48:234–238.

39.

Dufour DL. Assessing diet in populations at risk for konzo and neurolathyrism. Food Chem Toxicol 2011;49:655–661.

40.

Allem AC. The origin of Manihot esculenta Crantz (Euphorbiaceae). Genet Resour Crop Ev 1994;41:133–150.

41.

Rogers DJ. Some botanical and ethnological considerations of Manihot esculenta. Econ Bot 1965;19:369–377.

42.

Nassar NAM, Hashimoto DYC, Fernandes SDC. Wild Manihot species: botanical aspects, geographic distribution and economic value. Genet Mol Res 2008;7:16–28.

43.

Jones DA. Why are so many food plants cyanogenic? Phytochemistry 1998;47:155–161.

44.

Montgomery RD. The medical significance of cyanogen in plant foodstuffs. Am J Clin Nutr 1965;17:103–113.

45.

Nartey F. Studies on cassava. Manihot utilissima Pohl-I. Cyanogenesis: the biosynthesis of linamarin and lotaustralin in etiolated seedlings. Phytochemistry 1968;7:1307–1312.

18.

Diasolua Ngudi D, Banea-Mayambu JP, Lambein F, Kolsteren P. Konzo and dietary pattern in cassava-consuming populations of Popokabaka, Democratic Republic of Congo. Food Chem Toxicol 2011;49:613–619.

19.

Chabwine JN, Masheka C, Balol’ebwami Z, et al. Appearance of konzo in South-Kivu, a wartorn area in the Democratic Republic of Congo. Food Chem Toxicol 2011;49:644–649.

20.

Cliff JL. Cassava safety in times of war and drought in Mozambique. Acta Hortic 1994;375:373–378.

21.

Ernesto M, Cardoso AP, Nicala D, et al. Persistent konzo and cyanogen toxicity from cassava in northern Mozambique. Acta Trop 2002;82:357–362.

22.

Cliff J, Muquingue H, Nhassico D, et al. Konzo and continuing cyanide intoxication from cassava in Mozambique. Food Chem Toxicol 2011;49:631–635.

46.

23.

Howlett WP, Brubaker G, Mlingi N, Rosling H. A geographical cluster of konzo in Tanzania. J Trop Geogr Neurol 1992;2:102– 108.

Clapp RC, Bissett FH, Coburn RA, Long L. Cyanogenesis in manioc: linamarin and isolinamarin. Phytochemistry 1966;5:1323–1326.

47.

Mlingi NLV, Nkya S, Tatala SR, et al. Recurrence of konzo in southern Tanzania: rehabilitation and prevention using the wetting method. Food Chem Toxicol 2011;49:673–677.

Du L, Bokanga M, Moller BL, Halkier BA. The biosynthesis of cyanogenic glucosides in roots of cassava. Phytochemistry 1995;39: 323–326.

48.

de Tafur SM, El-Sharkawy MA, Calle F. Photosynthesis and yield performance of cassava in seasonally dry and semiarid environments. Photosynthetica 1997;33:249–257.

49.

El-Sharkawy M. Cassava biology and physiology. Plant Mol Biol 2004;56:481–501.

50.

Oluwole OSA. Cyanogenicity of cassava varieties and risk of exposure to cyanide from cassava food in Nigerian communities. J Sci Food Agric 2008;88:962–969.

51.

Nyirenda DB, Chiwona-Karltun L, Chitundu M, et al. Chemical safety of cassava products in regions adopting cassava production and processing—experience from Southern Africa. Food Chem Toxicol 2011;49:607–612.

24.

25.

Tyllesk€ ar T, L egu e FD, Peterson S, et al. Konzo in the Central African Republic. Neurology 1994;44:959–961.

26.

Mbelesso P, Yogo ML, Yangatimbi E, et al. Outbreak of konzo disease in health region No 2 of the Central African Republic. Rev Neurol (Paris) 2009;165:466–470.

27.

Cosnett JE. Unexplained spastic myelopathy: 41 cases in a nonEuropean hospital. S Afr Med J 1965;39:592–595.

28.

Tyllesk€ ar T. The Causation of Konzo: studies on a paralytic disease in Africa. PhD thesis. Uppsala University, Uppsala, Sweden, 1994.

29.

Oluwole OSA, Onabolu AO, Link H, Rosling A. Persistence of tropical ataxic neuropathy in a Nigerian community. J Neurol Neurosurg Psychiatry 2000;69:96–101.

52.

Mkumbira J, Chiwona-Karltum L, Lagercrantz U. Classification of cassava into ’bitter’ and ’cool’ in Malawi: from farmers’ perception to characterisation by molecular markers. Euphytica 2003;132:7–22.

30.

Money GL, Smith AS. Nutritional spinal ataxia. West Afr Med J 1955;4:117–123.

53.

31.

Osuntokun BO. An ataxic neuropathy in Nigeria: a clinical, biochemical and electrophysiological study. Brain 1968;91:215–248.

Bainbridge Z, Harding S, French L, et al. A study of the role of tissue disruption in the removal of cyanogens during cassava root processing. Food Chem 1998;62:291–297.

54. 32.

Madhusudanan M, Menon MK, Ummer K, Radhakrishnanan K. Clinical and etiological profile of tropical ataxic neuropathy in Kerala, South India. Eur Neurol 2008;60:21–26.

Oluwole OSA, Onabolu AO, Cotgreave IA, et al. Low prevalence of ataxic polyneuropathy in a community with high exposure to cyanide from cassava foods. J Neurol 2002;249:1034–1040.

33.

Plant GT, Dolin PJ, Mohammed AA, Mlingi N. Confirmation that neither cyanide intoxication nor mutations commonly associated with Leber’s hereditary optic atrophy are implicated in Tanzanian epidemic optic atrophy. J Neurol Sci 1997;152:107–108.

55.

Agbor-Egbe T, Lape MI. The effects of processing techniques in reducing cyanogen levels during the production of some Cameroonian cassava foods. J Food Compost Anal 2006;19:354–363.

56.

Banea M, Poulter NH, Rosling H. Shortcuts in cassava processing and risk of dietary cyanide exposure in Zaire. Food Nutr Bull 1992;14:137–143.

57.

Nzwalo H. The role of thiamine deficiency in konzo. J Neurol Sci 2011;302:129–131.

58.

McMahon JM, White WLB, Sayre RT. Cyanogenesis in cassava (Manihot esculenta Crantz). J Exp Bot 1995;46:731–741.

34.

35.

Hedges RD, Hirano M, Tucker K, Caballero B. Epidemic optic and peripheral neuropathy in Cuba: a unique geopolitical public health problem. Surv Ophthalmol 1997;41:341–353. Oluwole OSA, Oludiran AO. Geospatial association of endemicity of ataxic polyneuropathy and highly cyanogenic cassava cultivars. Int J Health Geogr 2013;12:41–48.

March 2015

379

ANNALS

of Neurology

59.

Cardoso AP, Ernesto M, Nicala D, et al. Combination of cassava flour cyanide and urinary thiocyanate measurements of school children in Mozambique. Int J Food Sci Nutr 2004;55:183–190.

60.

Ernesto M, Cardoso AP, Cliff J, Bradbury JH. Cyanogens in cassava flour and roots and urinary thiocyanate concentration in Mozambique. J Food Compost Anal 2000;13:1–12.

61.

Banea M, Tyllesk€ ar T, Rosling H. Konzo and Ebola in Bandundu region of Zaire. Lancet 1997;349:621.

62.

Cliff J, Nicala D, Saute F, et al. Konzo associated with war in Mozambique. Trop Med Int Health 1997;2:1068–1074.

63.

Ciglenecˇki I, Eyema R, Kabanda C, et al. Konzo outbreak among refugees from Central African Republic in Eastern region, Cameroon. Food Chem Toxicol 2011;49:579–582.

64.

Isom GE, Baskin SI. Enzymes involved in cyanided metabolism. In: Guengerich FP, ed. Comprehensive toxicology. Vol 3. Oxford, UK: Pergamon Press, 1998:477–488.

65.

Monekosso GL, Wilson J. Plasma thiocyanate and vitamin B12 in Nigerian patients with degenerative neurological disease. Lancet 1966;1:1062–1064.

66.

Hernandez T, Lundquist P, Oliveira L, et al. Fate in humans of dietary intake of cyanogenic glycosides from roots of sweet cassava consumed in Cuba. Nat Toxins 1995;3:114–117.

67.

Oluwole OSA, Onabolu AO, Sowunmi A. Exposure to cyanide following a meal of cassava food. Toxicol Lett 2002;135:19–23.

68.

Sreeja VG, Nagahara N, Li Q, Minami M. New aspects in pathogenesis of konzo: neural cell damage directly caused by linamarin contained in cassava (Manihot esculent Crantz). Br J Nutr 2003;90: 467–472.

69.

Mathangi DC, Deepa R, Mohan V, et al. Long-term ingestion of cassava (tapioca) does not produce diabetes or pancreatitis in the rat model. Int J Pancreatol 2000;27:203–208.

70.

Soler-Martin C, Riera J, Seoane A, et al. The targets of acetone cyanohydrin neurotoxicity in the rat are not the ones expected in an animal model of konzo. Neurotoxicol Teratol 2010;32:289–294.

71.

Howlett WP, Rosling H. Konzo. In: Chopra JS, Sawhney IMS, eds. Neurology in tropics. New Delhi, India: BI Churchill Livingstone, 1999:93–101.

72.

Rosling H, Tylleskar T. Konzo. In: Shakir RA, Newman PK, Poser CM, eds. Tropical neurology. London, UK: Saunders, 1996:353–364.

73.

Rosling H, Tylleskar T. Cassava. In: Spencer PS, HH Schaumburg HH, eds. Experimental and clinical neurotoxicology. 2nd ed. New York, NY: Oxford, 2000:338–343.

74.

Spencer PS. Food toxins, AMPA receptors, and motor neuron diseases. Drug Metab Rev 1999;31:561–587.

75.

Zaknun JJ, Stieglbauer K, Trenkler J, Aichner F. Cyanide-induced akinetic rigid syndrome: clinical, MRI, FDG-PET, beta-CIT and HMPAO SPECT findings. Parkinsonism Relat Disord 2005;11:125–129.

76.

Sarikaya I, Apaydin H, Topal U, Karaoglan O. Cyanide-induced parkinsonism and F-18 FDG PET/CT findings. Clin Nucl Med 2006;31:363–364.

77.

78.

380

Kimani S, Moterroso V, Morales P, et al. Cross-species and tissue variations in cyanide detoxification rates in rodents and nonhuman primates on protein-restricted diet. Food Chem Toxicol 2014;66:203–209. Tor-Agbidye J, Palmer VS, Spencer PS, et al. Sodium cyanate alters glutathione homeostasis in rodent brain: relationship to

neurodegenerative diseases in protein-deficient malnourished populations in Africa. Brain Res 1999;820:12–19. 79.

Kassa RM, Kasensa NL, Monterroso VH, et al. On the biomarkers and mechanisms of konzo, a distinct upper motor neuron disease associated with food (cassava) cyanogenic exposure. Food Chem Toxicol 2011;49:571–578.

80.

Bitner RS, Kanthasamy A, Isom GE, Yim GKW. Seizures and selective CA-1 hippocampal lesions induced by an excitotoxic cyanide metabolite, 2-Iminothiazolidine-4-carboxylic acid. Neurotoxicology 1995;16:115–122.

81.

Funderburk CF, van Middlesworth L. The effect of thiocyanate concentration on thiocyanate distribution and excretion. Pro Soc Exp Biol Med 1971;4:1249–1252.

82.

Eliasof S, Jahr CE. Retinal glial cell glutamate transporter is coupled to an anionic conductance. Proc Natl Acad Sci U S A 1996;93:4153–4158.

83.

van Dalen CJ, Whitehouse MW, Winterbourn CC, Kettle AJ. Thiocyanate and chloride as competing substrates for myeloperoxidase. Biochem J 1997;327:487–492.

84.

Lugassy D, Nelson L. Case files of the medical toxicology fellowship at the New York City poison control: bromism: forgotten, but not gone. J Med Toxicol 2009;5:151–157.

85.

Arai A, Silberg J, Kessler M, Lynch G. Effect of thiocyanate on AMPA receptor mediated responses in excised patches and hippocampal slices. Neuroscience 1995;66:815–827.

86.

Bumoko GM, Sombo MT, Okitundu LD, et al. Determinants of cognitive performance in children relying on cyanogenic cassava as staple food. Metab Brain Dis 2014;29:359–366.

87.

IPCC. Climate change 2001: the scientific basis. Contribution of working group I to the third assessment report of the Intergovernmental Panel on Climate Change. Cambridge, UK: Cambridge University Press, 2001.

88.

Feng X, Porporato A, Rodriquez-Iturbe I. Changes in rainfall seasonality in the tropics. Nat Climate Change 2013;3:811–815.

89.

Javis A, Ramirez-Villegas J, Campo BVH, Navarro-Racines C. Is cassava the answer to African climate change adaptation? Trop Plant Biol 2012;5:9–29.

90.

Oluwole OSA. Climate Change, Seasonal Changes in Cassava Production and Konzo Epidemics. Int J Global Warming http://www. inderscience.com/info/ingeneral/forthcoming.php?jcode5ijgw.

91.

Kemp MU, van Loon EE, Shamoun-Baranes J, Bouten W. RNCEP: global weather and climate data at your fingertips. R package version 1.0.6. Methods Ecol Evol 2012;3:65–70.

92.

R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2014.

93.

Solomon S, Quin D, Manning M, et al. Climate change 2007: the physical science basis. Contribution of working group II to the fourth assessment report of the Intergovernmental Panel on Climate Change. Cambridge, UK: Cambridge University Press, 2007.

94.

Oluwole OSA, Onabolu AO, Mtunda K, Mlingi N. Characterisation of cassava (Manihot esculenta Crantz) varieties in Nigeria and Tanzania, and farmers’ perception of toxicity of cassava. J Food Compost Anal 2007;20:559–567.

95.

Banea JP, Bradbury JH, Mandombi C, et al. Effectiveness of wetting method for control of konzo and reduction of cyanide poisoning by removal of cyanogens from cassava flour. Food Nutr Bull 2014;35:28–32.

Volume 77, No. 3