Working together to eliminate , konzo and tropical ataxic neuropathy (TAN).

Cassava Cyanide Diseases Network

Issue Number 12, December 2008

and konzo if both disorders occurred Contents 2,5 Differential diagnosis of in the same population. konzo from other tropical Konzo and TAN have been Differential diagnosis of diseases: a review attributed to dietary cyanide konzo from other tropical exposure from consumption of diseases: a review ...... 1 Konzo with its upper motor neurone insufficiently processed manifestations can be confused with roots, but rates of exposure differ in 7 other diseases and differential both diseases. In contrast to konzo, Comparison of cassava flour diagnosis is important. Using the TAN is a progressive disorder with and gari ...... 2 WHO criteria, konzo by its spastic slow onset that mainly affects older paraparesis can easily be adults. Furthermore, konzo involves distinguished from causes of flaccid damage to upper motor neurones Outbreak of konzo disease in such as poliomyelitis, without sensory involvement, health region No. 2 of the leprosy or trauma.1 The commonest whereas TAN is mainly caused by damage of sensory neurons in the ...... 3 neurological diseases to be considered in its differential spinal cord resulting in ataxia. TAN diagnoses include , rarely progresses to inability to walk, Endomyocardial fibrosis: Tropical Ataxic Neuropathy (TAN) whereas walking difficulties are the primary symptom of konzo and a cause still unknown ...... 4 and Tropical Spastic Paraparesis/ HTL V-I Associated Myelopathy high proportion of the konzo- (TSP/HAM) (see Table 1). affected subjects are unable to walk. About half of the TAN cases have Konzo is clinically very similar to optic atrophy which is rare among konzo cases. About one in five TAN CCDN Coordinator: neurolathyrism but differs from TAN 2-5 cases has exaggerated reflexes, a Dr. J. Howard Bradbury and TSP/HAM. The socio- Botany and Zoology, School of Biology, economic conditions of konzo and sign that occurs in all konzo 1,2 Australian National University neurolathyrism patients are very cases. Canberra ACT 0200, Australia similar as well. Both diseases can Phone: +61-2-6125 0775 be considered a sign of poverty, TSP/HAM is clinically possible to E-mail: [email protected] monotonous unbalanced diet and distinguish from both konzo and illiteracy.6 Neurolathyrism only neurolathyrism, although the clinical Coordinating Group: differs from konzo with the features of TSP/HAM include typical Julie Cliff, Ian Denton, Humberto somewhat higher age of onset, signs that are similar to both Muquingue, Arnaldo Cumbana, Dulce diseases such as weakness in the Nhassico predominance of males among the affected, sphincter involvement in legs, hyperflexia, clonus and extensor plantar responses. Country Contacts: some cases and the absence of 2 TSP/HAM is characterised by a Cameroon: E.E Agbor; cranial nerve involvement. There is no geographical overlap between chronic progressive spastic D.R. Congo: D.D. Ngudi; the consumption of grass pea seed paraparesis with sphincter India: Bala Nambisan and K.T. Shenoy; and cassava roots and therefore disturbances, urinary incontinence Indonesia: A.Hidayat; there is no geographical overlap of and impotence. There is mild to no : Anabela Zacarias; the two diseases. Combination of sensory loss and absence of spinal cord compression. Most but not all Nigeria: M.N.Adindu and P.N.Okafor grass pea and cassava in the diet could even amplify the risk. It would cases of TSP/HAM are seropositive 3,4,8,9 be difficult to make a differential for HTLV-1. Website: diagnosis between neurolathyrism www.anu.edu.au/BoZo/CCDN Table 1:Characteristic features of four tropical myeloneuropathies (Tylleskär et al, 1994b) Konzo Tropical ataxic Neurolathyrism HTLV-I associated neuropathy myelopathy Geographical area Africa Africa Asia/ Africa Worldwide Occurrence Epidemic and endemic epidemic and endemic endemic endemic Highest prevalence 3 % 3 % 3 % 0.1 % Familial clustering yes yes yes yes Type of onset acute slow acute slow Course permanent progressive permanent progressive High incidence age group < 40 > 40 < 40 > 40 Main neurological findings: Gait abnormality Spastic paraparesis Ataxia Spastic paraparesis Spastic paraparesis Peripheral neuropathy no yes no common Sphincter involvement no no rare yes Optic atrophy rare yes no no Deafness no common no no Etiology Attributed to weeks of A t t r i b u t e d t o Caused by months of Caused by chronic high cyanide exposure prolonged, varying high grass pea HTLV-I infection from cassava cyanide exposure (Lathyrus sativus) from cassava consumption

References Comparison of cassava flour has a slightly sour taste because of and gari the lactic acid present. 1 Howlett WP (1994). Konzo: A new human disease entity. Acta Horticulturae 375, 323-329. Total cyanide content. The sun Cassava flour is the major stable 2 Tylleskär T, Ruiza HT, Banea M, Howlett WP, drying of peeled cassava roots does product made from cassava roots in Aquilonius S-M, Persson L-Å, Rosling H (1994). not allow the enzyme linamarase to Similarities between konzo and lathyrism suggest Eastern, Southern and Central Africa, come into intimate contact with a common pathogenetic mechanism. In The whereas gari is the main stable linamarin, as occurs during gari grass pea and lathyrism.; Abegaz B. M., product made from cassava roots Haimanot R. T., Palmer, V. S., and Spencer, P. production, and hence linamarin is which is used in West Africa and also S., Eds.; Proceedings of the Second International only partially broken down in the flour, Lathyrus/ lathyrism Conference in Ethiopia; Third in southern Mozambique. World Medical Research Foundation: New York, which is found to contain linamarin at USA,; pp 26-32. average levels of 45 ppm.3 During a P r o c e s s i n g . Table A gives a 3 Cliff J, Nicala D (1997). Long term follow-up of drought the cassava plant produces comparison of the preparation of these konzo patients. Transactions of the Royal Society greatly increased amounts of of Tropical Medicine and hygiene, 91, 447 – 449. two products.1 Sun drying of cassava linamarin4 and the total cyanide 4 Zaninovic V (2001). Similarities between roots is a very simple method that content of flour increases 2-4 fold to Tropical Spastic Paraparesis (TSP) and requires no mechanised equipment neurolathyrism. Lathyrus Lathyrism Newsletter, 2, >100 ppm.5 The World Health and is carried out by women at home. 11– 14. Organisation (WHO) safe level for total 5 By comparison gari is normally Lambein,F.,Defoort,B.,Kuo,Y-H, (2004). Konzo cyanide in cassava flour is 10 ppm.6 or neurolathyrism. Is there a difference? CCDN produced in a factory using a Levels of total cyanide in gari (present News No 3, 2-3. mechanical grinder to grate the peeled 6 as acetone cyanohydrin) range from 0- Getahun H, Lambein F, Vanhoorne M, Van Der cassava roots, a press for dewatering Stuyft (2002).Pattern and associated factors of 40 ppm with mean values of 15-20 and the roasting process is done by the neurolathyrism epidemic in Ethiopia. Tropical ppm.5 Medicine and International Health, 7, 118 – 124. women. 7 Howlett WP, Brubaker GR, Mlingi N, Rosling H Cassava flour in water is neutral (pH Availability of cyanogens in the (1990). Konzo an upper motor neurone disease about 6.5), whereas gari in water is body. Acetone cyanohydrin is studied in Tanzania. Brain, 113, 223 – 235. acidic (pH 4.1), due to lactic acid 8 completely decomposed to cyanide Tylleskär T (1994). The causation of konzo. fermentation that occurs during Studies on a paralytic disease in Africa. Acta under the alkaline conditions present prolonged processing of the wet Universitatis Upsaliensis. Comprehensive in the human gut, whereas linamarin is Summaries of Uppsala Dissertations from the cassava mash. The long processing stable under these conditions and Faculty of Medicine 413, 67 pp. allows the enzyme linamarase to 9 only about 50% is absorbed in the Cassab J, Penalva-de-Oliveira AC (2000). The hydrolyse linamarin completely to pathogenesis of tropical spastic parparasesis/ body.7 Thus the total cyanide acetone cyanohydrin, which is human T-cell leukemia type I-associated absorbed by the body from cassava myelopathy. Brazilian Journal of Medical and unstable above pH 5,2 and most of it flour under non-drought conditions is Biological Research, 33, 1395 – 1401. breaks down spontaneously to about 22.5 ppm and from gari about acetone and hydrogen cyanide (HCN) 15-20 ppm Delphin D. Ngudi & Fernand Lambein gas which partly escapes to the air. Ghent University, Belgium. The remainder of the HCN and nearly Methods to reduce cyanide. The [email protected]; all the acetone cyanohydrin is total cyanide content of cassava flour [email protected] removed in the roasting process, but is reduced 3-6 fold by mixing it with some remains in the final gari, which water, spreading it in a thin layer on a 2 CCDN News basket and leaving in the shade for comsumption of cyanide from gari at 4Bokanga M, Ekanayake IJ, Dixon AGO & Porto MCM, (1994) Acta Hort., 375, 131-139. five hours. This allows linamarase sub-lethal levels. TAN has also been 5 Cardoso AP, Mirione E, Ernesto M, Massaza F, present to hydrolyse linamarin to reported from a wide range of other Cliff J, Haque MR, & Bradbury JH, (2005) J. Food acetone cyanohydrin which breaks cassava-growing countries including Comp. Anal. 18, 451-460. 6 down spontaneously at pH 6.5 with Tanzania, West Indies and southern FAO/WHO, 1991. Joint FAO/WHO Food 8-10 10,14 Standards Programme. Codex Alimentarius liberation of HCN gas. The method India. Commission XII, Supp. 4, FAO, Rome, Italy. was checked out in northern 7 Carlsson L, Mlingi N, Juma A, Ronquist G & Mozambique and found to be very The key to the removal of these Rosling H, (1999) Food Chem. Tech. 37, acceptable to rural women. cyanide-induced diseases is a 307-312. 8 Unfortunately over the 2-3 years since considerable reduction in the cyanide Bradbury JH. (2006) J Foood Comp Anal. 19, 388-393. its discovery there has been very little intake from cassava. The universal 9 Cumbana A, Mirione E, Cliff J, & Bradbury JH. use of the wetting method in flour introduction of the wetting method (2007) Food Chem 101, 894-897. 10 processing areas. Acetone would reduce cyanide intake from Nhassico D, Muquingue H, Cliff J, Cumbana A & Bradbury JH. (2008) J Sci Food Agric 88, 2043- cyanohydrin in gari is stable at pH 4.1 cassava flour and could remove konzo 2049. and does not breakdown at ambient altogether. Clearly it is also important 11 Ngudi DD & Lambein F. (2008) CCDN News temperatures8 or in the sun. to develop methods to reduce the No 12,(this issue), P 1-2. 12 cyanide content of gari, that may also Ernesto M, Cardoso AP, Nicala D, Mirione E, Massaza F, Cliff J, Haque MR, & Bradbury JH. Konzo and tropical ataxic lead to a reduction of the incidence of (2002) Acta Trop. 82, 357-362. neuropathy (TAN). Konzo occurs TAN. 13 Oluwole OSA, Onabolu AO, Link H, & Rosling under conditions of high cyanide H. (2000), J Neurol Neurosurg Psychiatry 69, 96- 101. intake over a relatively short period References 14 Madhusudanan M, Menon MK, Ummer K, & 10,11 due to drought or to war. However Radhakrishnanan K (2008) Eur Neurol. 60(1), 21- konzo is endemic (persistent) in 1Adindu, M N, CCDN News No 8, Dec. 2006, P 1 26. see CCDN News No 11, June 2008, P 3. certain locations in Nampula Province 2White, WLB, Mc Mahon, JM & Sayre, RT (1994) J Howard Bradbury of Mozambique.12 TAN is also Acta Hort., 375, 69-77. 3 [email protected] 13 Cardoso AP, Ernesto M, Cliff J, Egan SV, & persistent in Nigeria and this is Bradbury JH, (1998) Int.J. Food Sci. Nutr. 49, 93- probably due to long term 99.

Table A Gari Cassava flour Where used West Africa & southern Mozambique Eastern, southern & central Africa Method of Production Peeled root is grated & the mash Peeled root sun dried for ca 7 days then fermented for 2-3 days in a hessian bag, pounded to a powder & sieved. In heap dewatered, sieved & heated in a metal fermentation peeled roots are heaped up in dish with stirring to remove cyanogens the shade for ca 4 days & then sun dried. PH of product ca 4.1 due to lactic fermentation neutral, about 6.5 Major cyanogen present acetone cyanohydrin linamarin Total cyanide content in ppm range 0-40 ppm mean 15-20 ppm mean 45 ppm rising to >100 ppm in a drought year Availability of cyanogens 100% about 50% Simple method to remove cyanogens Wetting method does not work because Wetting method. Mix flour with water & leave pH is too low in thin layer in shade for 5 hours. Total cyanide content reduced 3-6 fold

Outbreak of konzo disease in health region No. 2 in the Central acuity (65.4%). The predominant health region No. 2 of the African Republic. METHOD: A neurological signs were lower limb descriptive cross-sectional study was paresis (90.0%) and hyperesthesia Central African Republic conducted among patients collected (66.7%). CONCLUSION: Konzo is a during a one-month period (July 16 to serious public health problem in this Rev Neurol (Paris). 2008 Dec 9. [Epub August 16, 2007) of active surveillance region of the Central African Republic. ahead of print] for acute flaccid . RESULTS: A prevention program should be set- [Article in French] Eighty-one cases of konzo were up. identified during the study period, Mbelesso P, Yogo ML, Yangatimbi E, Paul- INTRODUCTION: Konzo is a representing a prevalence of 10 per Sénékian VD, Nali NM, Preux PM. neuromyelopathy characterized by 100,000. Mean age of patients was permanent spastic paraparesis, linked 10.7+/-7.7 years. Children and women Service de neurologie, hôpital de l'Amitié, to a subacute poisoning by cyanide were most affected. The main warning Bangui, République centrafricaine. found in cassava. The purpose of the signs were fatigability (97.6%), tremor study is to describe the (88.9%), walking difficulty (100.0%), epidemiological aspects of konzo in dysarthria (67.9%) and a loss of visual CCDN News 3 Endomyocardial fibrosis: Although cassava has never been cassava diet on Cercopithecus aethiops hearts excluded as a possible cause, there and its possible role in the aetiology and cause still unknown. pathogenesis of endomyocardial fibrosis in man. are many other stronger candidates: East Afr Med J 73: S11–S16. A recent review article concluded that But despite investigation into these Julie Cliff the cause of endomyocardial fibrosis causes, nobody has come up with a Faculdade de Medecina, 1 (EMF) is still a mystery . EMF is a definite conclusion. The search Universidade Eduardo Mondlane severe chronic heart disease in which continues. Maputo, Mozambique the inner layer of the heart becomes [email protected] References fibrous and thickens. Most patients 1 CCDN News is the Newsletter of the Cassava Cyanide Bukhman G, Ziegler J, Parry E (2008) Diseases Network (CCDN). The CCDN is a free, present with advanced heart failure. Endomyocardial fibrosis: still a mystery after 60 worldwide network commenced in June 2001, which is The outlook is poor, with a high y e a r s . P L o S N e g l e c t e d T r o p i c a l working towards the elimination of konzo, TAN and other incidence of sudden death. Diseases2(2):e97doi:10.1371/journal.pntd.00000 cassava cyanide diseases. 97 CCDN News will consider for publication short articles and 2Mocumbi AO, Ferreira MB, Sidi D, Yacoub M M letters (1-3 pages A 4 double spaced) written in English The disease is common in some Because CCDN News is a newsletter, full-size original tropical areas, with estimates that (2008) A population study of endomyocardial papers or reviews cannot be considered for publication. around 10 million people are affected.2 fibrosis in a rural area of Mozambique. New Material published in CCDN News may be freely England Journal of Medicine 359:43-49. reproduced, but please always indicate that it comes from Most cases have been reported from 3Mocumbi AO, Yacoub S, Yacoub M (2008). CCDN News. Please send all correspondence to the Neglected tropical cardiomyopathies: II. CCDN Coordinator, Dr J Howard Bradbury, Botany and Uganda, Ivory Coast, Nigeria and Zoology, School of Biology, Australian National University, 3 Endomycoardial fibrosis. Heart 94: 384-90. India. . EMF is usually limited to Canberra, ACT 0200, Australia. 4Rutakingirwa M, Ziegler JL, Newton R, Freers J specific geographical areas. Most (1999) Poverty and eosinophilia are risk factors studies are based in clinics; a recent for endomyocardial fibrosis (EMF) in Uganda. Posters (in several languages) community-based study in a known Trop Med Int Health 4: 229–235. explaining how to reduce the poison in 5Sezi CL (1996) Effect of protein deficient cassava flour can be found at high prevalence area in Mozambique www.anu.edu.au/BoZo/CCDN gave an estimated prevalence of 19.8%.2 The disease is commoner in children and young adolescents, but also occurs in adults. Male preponderance has been described in Kerala and Nigeria, and female preponderance in Brazil and Uganda.3 In the Mozambican community-based study,2 the prevalence rate (28.1%) was highest in 10-19 years old and the male prevalence rate (23.0%) was higher than female (17.5%). Only 22.7% of cases had symptoms. Many causes have been suggested including worm infestation, malaria, genetic susceptibility, cerium or thorium in monazite deposits in the soil, and prolonged ingestion of cassava associated with a low protein diet. No single cause explains EMF in all the areas where it has been reported.3 Regarding cassava as a possible cause, a case-control study in Uganda showed an association between the disease and markers of poverty, including a cassava-based diet.4 Experiments by Sezi5 found that monkeys fed on a cassava-based diet developed heart lesions, while those fed on a banana diet did not. The review authors state that “despite the known role of cyanogens from improperly processed cassava in konzo, an upper-motor neuron disease reported from Central and East Africa, cardiac manifestations have not had a part in these outbreaks”. As far as we know, no-one has s e a r c h e d t h o r o u g h l y f o r endomyocardial fibrosis in populations affected by konzo. 4 CCDN News