Konzo From Poverty, Cassava, and Cyanogen Intake to Toxico-Nutritional Neurological Disease

Konzo From Poverty, Cassava, and Cyanogen Intake to Toxico-Nutritional Neurological Disease Konzo:FromPoverty,Cassava,andCyanogenIntaketo Toxico-NutritionalNeurologicalDisease Hipo?litoNzwalo1*,JulieCliff2 1FaroCentralHospital,Faro,Portugal,2DepartmentofCommunityHealth,FacultyofMedicine,UniversidadeEduardoMondlane,Maputo,Mozambique Lessonsfromthepreviousoutbreaksindicatethatthenumberof Abstract: Konzo is a distinct neurological entity with peopleaffectedbykonzoisunderestimated.Unofficialreportspoint selective upper motor neuron damage, characterized by toanalarmingnumberof100,000casesintheDRCin2000[21]. an abrupt onset of an irreversible, non-progressive, and Examples from the past confirm that the disease can be easily symmetricalspasticpara/tetraparesis.Despiteitsseverity, overlooked. In the 1986 Zaire (now DRC) epidemic, the actual konzo remains a neglected disease. The disease is numberofcaseswasestimatedtobeatleasttwiceasmanyasthose associatedwithhighdietarycyanogenconsumptionfrom reported[22].InMozambique,in1981,duringaseveredrought, insufficientlyprocessedrootsofbittercassavacombined anoutbreakofmorethan1,000casesofkonzooccurred,andwas withaprotein-deficientdiet.Epidemicsoccurwhenthese disease,locallynamed‘‘Mantakassa’’,wasrestrictedtotheremotest to 1993, outbreaks in poor rural areas in Africa contrib- associated with an almost exclusively cassava-based diet. The areasoftheisolatednorthernprovinceofNampula.Theextentof uted tomorethan 3,700 cases of konzo.The numberof conditionscoincideattimesofseverefoodshortage.Up theepidemicwasonlyrevealedafteranextensive2-monthactive affected people is underestimated. From unofficial re- case detection exercise [23]. Nonetheless, cases were missed, and ports, the number of cases was estimated to be at least furtherresearchcarriedoutbytheauthorsfoundthattheepidemic 100,000in2000,incontrasttothe6,788casesreportedup extendedbeyonditspreviouslyreportedboundaries[14]. to2009frompublishedpapers. Cultural and religious aspects may also play a role in underreporting, particularly in sporadic cases of konzo. In the Congo,‘‘konzo’’wasthenameofafetishusedwithtrapstocatch Introduction wildanimalsbyweakeningtheirlegsandpreventingtheirescape.In man,theappearanceofkonzowasinterpretedasakindofdivine Konzo is a distinct neurological entity with selective upper punishmentorsorcerycausedbyimproperlyusingthefetish[6]. motor neuron damage, characterized by an abrupt onset of an Sporadiccasesofkonzocanbemisdiagnosedifhealthcarestaff irreversible, non-progressive, and symmetrical spastic para/ are not trained to recognize the symptoms. In 1981, in tetraparesis[1–8]. Mozambique, the disease was initially considered to be of viral Thediseaseisassociatedwithprolongedhighdietarycyanogen origin[23].IntheDRC,acommunity-basedsurveyrevealedthat consumption from insufficiently processed roots of bitter cassava casesofacuteparaparesisinitiallyattributedtopoliomyelitiswere combinedwithaprotein-deficientdietlowinsulphuraminoacids infactcasesofkonzointhecontextofanoutbreak[17]. (SAAs)[1–8]. Thepossibilityofaninfectiousagentwasconsideredintheearly Since its first description by the Italian doctor Trolli eight reportedepidemics,particularlyHTLV-I-associatedmyelopathy/ decades ago in the former Belgian Congo (now the Democratic tropical spastic paraparesis (HAM/TSP). Cerebrospinal fluid Republic of Congo [DRC]), epidemics have been reported from studies were, however, normal, and serology for the retroviruses many cassava-consuming areas in rural Africa. Up to 1993, the (HIV or HTLV-1) implicated in progressive spastic myelopathy totalofreportedcaseswasapproximately3,700to4,000[9–11]. wasnegative[2,8,23–25]. Konzo remains a health problem in Africa. Since 1993, the Inaneraofclimatetransformationandcontinuedinsecurity,it diseasehasextendedbeyonditsfirstreportedboundaries[12],and is important to keep in mind the possibility of new epidemics of thereportednumberofkonzocaseshasalmostdoubled,reaching konzo in vulnerable areas, particularly in Africa. We therefore atotalof6,788(Table1,Figure1). reviewthedisease,fromaetiologytoclinicalevolution. Outbreaks in past decades in Cameroon [12], Mozambique [13,14], Tanzania [15], the Central African Republic [16], and the DRC [17,18] often received insignificant attention from the Citation:NzwaloH,CliffJ(2011)Konzo:FromPoverty,Cassava,andCyanogen IntaketoToxico-NutritionalNeurologicalDisease.PLoSNeglTropDis5(6):e1051. media and local health authorities despite the clinical severity of doi:10.1371/journal.pntd.0001051 konzo.Asintheearlierreportedoutbreaks,povertyinassociation Editor: Simon Brooker, London School of Hygiene & Tropical Medicine, United withagriculturalcrisesprovokedbydroughtorwarwasaconstant Kingdom feature. Those affected belonged to the poorest segments of the PublishedJune28,2011 mostremoteruralareasofAfrica,perpetuatingthesilencearound Copyright: ß 2011 Nzwalo, Cliff. This is an open-access article distributed thedisease. under the terms of the Creative Commons Attribution License, which permits Cassava is also an important source of food in the tropics unrestricted use, distribution, and reproduction in any medium, provided the outside of Africa [19], and, although remote, the possibility of originalauthorandsourcearecredited. konzo occurring in these areas should be considered. Another Funding:Theauthorsdidnotreceiveanyfundingandtherearenocommercial disease associated with chronic cassava consumption, tropical associations that might pose or create a conflict of interest with information presentedinthissubmittedmanuscript. ataxic neuropathy (TAN), has been described recently in India [20]. The same socioeconomic factors implicated in konzo were CompetingInterests:Theauthorshavedeclaredthatnocompeting interests exist. present, and in some cases, patients had clinical features compatiblewithkonzo. *E-mail:nzwalo@gmail.com www.plosntds.org 1 June2011 | Volume 5 | Issue 6 | e1051 considerably less than that for other crops, and this is a major KeyLearningPoints reason for its promotion and increasing use in HIV/AIDS- KonzoisaneurologicalentityfoundinAfricacharacter- affected communities [32]. N ized by an abrupt onset of an irreversible, non- Cassava is drought tolerant, grows on poor soils without progressive, and symmetrical spastic para/tetraparesis. fertilizer where no other staple can be cultivated, and generates Itaffectsthepoorestpeoplefromtheremotestareasin acceptable yields even on depleted and marginal lands. Its roots thecontinent. may be kept in the soil for extended time periods, securing a Poverty is the main risk factor, and commercialization, carbohydrate source in years of agricultural crisis in poor N drought,orwarsaretheusualprecipitators. communities, and bridging the seasonal food gap during the hungryanddryseasonwhenothercropsusuallyfail[31,33]. The number of cases is probably underestimated; the N It is no surprise that in times of agricultural crisis, cassava disease continues to be reported and is expanding to newareasofthecontinent. becomesthedominant,andsometimestheonly,sourceoffood. The epidemics are associated with prolonged high N dietary cyanogen consumption from insufficiently pro- CassavaandCyanogenConsumption Many species of plants liberate hydrogen cyanide from cessedrootsofbittercassavacombinedwithaprotein- deficientdietlowinsulphuraminoacids. cyanogenicglycosides(CGs),aphenomenoncalledcyanogenesis, as a defense mechanism against animals and marauding insects [34,35].Cassavaisbyfarthemostimportanthumanfoodsource Methods thatusescyanideasadefensemechanism[35]. RootsandleavesofcassavaofallvarietiescontainCGs,mainly We aimed to provide a non-systematic review of konzo, using aslinamarin,butalsoaslotaustralin,indifferentconcentrationsin published and unpublished sources. For published literature, we theircellularvacuoles[34,36]. firstsearchedtheMedlinedatabaseusingthesearchterms‘‘konzo Cyanogenesis is initiated in cassava when the plant tissue is andcassava’’,‘‘konzoandcyanogen’’,‘‘konzoandcyanide’’,and damaged. Linamarase, a cell wall enzyme, is necessary for ‘‘spasticparaparesisandcassava’’.Thissearchyielded52articles. production of acetone cyanohydrin (AC) from the hydrolysis of We then searched the Agricola database using the search term linamarin (Figure 2). AC in cassava flour is unstable and can konzo,andobtained15articles.Wereviewedallthesepublished decompose to acetone and hydrogen cyanide spontaneously at articles, three PhD theses on konzo, and a further 25 articles pH.5.0 or at elevated temperatures (above 35uC), or enzymat- identifiedbyreferencereview. icallyduetotheactionofhydroxynitrilelyase[34–37].Ingari,a commonly consumed cassava product, AC is quite stable at FromPovertytoCyanogenIntoxication pH4.2at50uC,andevenat100uCitisonlyslowlyremoved,and canonlyberemovedifpHisraisedtoaround5[38]. MonotonousDietBasedonCassava The concentration of CGs depends on both genetic and Cassava (Manihot esculenta Crantz) is a perennial 1–3 meter environmental factors. Water stress increases CG concentration, high tropical shrub. The leaves have a high content of protein and agro-ecological differences can influence the cyanogenic andvitamins, andnormally theyareconsumed after processing, potentialofthesamecassavacultivar[39,40]. which removes cyanogens. The major harvested organ is the CGsincassavacanbereducedbyappropriateprocessingofthe root. The roots have a high content of carbohydrate and also plant material prior to consumption. Processing also improves small amounts of some vitamins and minerals. Their protein palatability and increases shelf life, as the root suffers rapid post content is low and deficient in SAAs such as cystine and harvestdeteriorationifpreservedinthefreshstateformorethana methionine [26–28]. few days [41,42]. The final product may be flour (tapioca) or From 1965 to 2000, cassava cultivation in Africa showed an granules(gari). extraordinary increase, from 35 million to 90 million tons, at Highdietarycyanogenexposureoccurswhenhighcyanogenic least partly in response to declining soil fertility and increased cassavaandinsufficientcassavaprocessingarecombined,usually cost of inorganic fertilizers. For countries such as DRC, inacontextoffoodshortage. Tanzania, and northern Mozambique, cassava is the most In konzo-affected areas, insufficient cassava processing is important cropforthelargest proportion offarming households attributed toshort cuts in the established methods and is related [29–31].Theamountoflabourrequiredforcassavacultivationis to food shortage due to drought, crop failure, and sometimes commercialization of cassava [9]. Water stress may also increase the CG concentration in cassava to a level where the traditional Table1.Totalnumberofkonzocasesreportedupto2009. processing methods can no longer avoid high retention of cyanogens[43,44]. Cassavarootsareprocessedbyavarietyofmethods,depending Country Priorto1975 1975–1993 1994–2009 Total on factors such as traditional preferences, time taken, and the DemocraticRebublicof 1,237 919 1,303 3,459 availability of water and technology. Common methods used in Congo Africaincludesoaking,sundrying,heapfermentation,andgrating Mozambique 2,123 281 2404 plusroasting[30,42].Mechanicaldisruptionofplantcellsduring Tanzania 121 238 359 these processes allows a cyanogenesis reaction (Figure 2) to 16 81 97 proceed,andthusCGsareeliminatedindifferentdegrees. CentralAfricanRepublic Anew,feasible,andsimplemethod,the‘‘wettingmethod’’,may Cameroon 469 469 beusedforcassavaflour,anddecreasessubstantiallythecyanide 2,372 6,788 Total 1,237 3,179 content [45]. This method has been successfully tested and accepted in rural communities in Mozambique and Tanzania, Adaptedfrom[9]. doi:10.1371/journal.pntd.0001051.t001 where water is in short supply and sun drying and heap www.plosntds.org 2 June2011 | Volume 5 | Issue 6 | e1051 Figure1.CountriesinAfricawherekonzohasbeenreported. doi:10.1371/journal.pntd.0001051.g001 fermentation are common processing methods [46–48]. In the Theneurotoxicmechanismisnotyetclarifiedandtheexistent DRC,wheresoakingistheprevalentmethod[3],atrialrecently neuropathological or imaging studies have not revealed any showed that the wetting method was acceptable, but the final particular abnormality [4,5,49]. Neurophysiological studies in resultsarestilltobeevaluated[48]. konzopointtoinvolvementofeitherthecorticomotorneuronsor High cyanogen consumption is an endpoint of preventable thedescendingmotorpathways[5,49]. factorsactinginsequenceorsynergisticallyinthepre-pathogenic Althoughseveralcompoundshavebeenproposedascandidates phaseofkonzo(Figure3). for the neurotoxic agent in konzo, few experimental studies involving those candidates have been reported. Table 2 summa- rizes the results of the principal experimental studies that have CyanogenToxicityandKonzo The association between the occurrence of konzo and high been carried out to date. The closest human model for konzo consumptionofimproperlyprocessedcassavahasbeendescribed. comesfromprimateexperiments[55].Thesehaveshownthatthe clinical and pathological findings in the central nervous system In all major epidemics the appearance of konzo has been secondarytocyanateexposurearecompatiblewithkonzo. associated with a sustained and sub-lethal intake of cassava high Cyanide, a mitochondrial oxidative phosphorylation blocker in CG concentration in combination with a low SAA intake [1–8,12–18]. [56], is the first described candidate for neurotoxicity in konzo Figure2.Thecyanogenesisreaction. doi:10.1371/journal.pntd.0001051.g002 www.plosntds.org 3 June2011 | Volume 5 | Issue 6 | e1051 [1–8]. There is an association at individual level between high bloodcyanideandkonzo[4,57]. Cyanidecomesfromtheconversionoflinamarin,butwedonot knowwherethishappensmost.Processingcausessomeconversion toAC,whichprobablydecomposestocyanideinthehighpHof thegut[7,9]. Cyanide is also absorbed through skin or the respiratory tract andisrapidlydistributedthroughoutthebody.Highestlevelsare typicallyfoundintheliver,lungs,blood,andbrain[58]. Rhodanese is the enzyme responsible for most cyanide detoxification, transforming it to thiocyanate, which is subse- quentlyexcretedintheurine.Theenzymeislocatedinalltissues, but mainly in the liver. This process requires sulphur donors, providedfromdietarySAAs,whicharedeficientincassavaroots [58,59]. The capture of cyanide with the iron in the erythrocytic haemoglobintoformmethaemoglobinisanimportanttemporary measure to keep the cyanide under control. Other mechanisms, such as capture with hydroxycobalamin (vitamin B12a) to yield cyanocobalamin (vitaminB12), provideno practicalcontribution toreducingitstoxiceffects[58,59]. The evidence for the association between konzo and cyanide comes essentially from ecological studies and no similar neuro- damage secondary to exposure from other cyanide sources is known [57,59]. These limitations need to be taken into account whenconsideringcyanidetoxicityasacauseofkonzo. The presence of high concentrations of unmetabolized lina- marin in urine in individuals from konzo-affected communities comparedwithcontrols,andthepotentialoflinamarintoinduce neuronal lesions in experiments, support the possibility of linamarinasacauseofkonzo[7,50,51]. AC,ametaboliteoflinamarin(Figure 2),ispresent incassava flour consumed in association with konzo. As it is labile, its concentration decreases with time during storage. When an agricultural crisis results in food shortage, cassava may be consumed without previous storage, increasing exposure to AC. In experimentson rats,this metabolite causedselective neuronal degenerationindifferentbrainareas,includingnon-corticalareas. Evenconsideringtheobviouslimitationsofananimalmodel,this Figure3.Frompovertytocyanogenintoxication. findingsuggestsapossiblecontributionofthismetabolitetokonzo doi:10.1371/journal.pntd.0001051.g003 neurotoxicity and could help explain the additional non-motor Table2.Experimentsshowingcyanogenneurotoxicity. Subjects/Animals Exposure RelevantNeurotoxicFindings MotorChangesandSimilaritiestoKonzo Neuralphaeochromocytoma Linamarin(acute) Directlinamarin-inducedlesionneural None cellculture[50] culture RatsonlowSAAdiet[51] Linamarin(chronic) Structuralandfunctionalproteomic Non-motorsymptoms;hindlimbtremorscanoccur modificationsinthespinalcord transientlyatonsetofkonzo RatsonlowSAAdiet[51] Cyanate(chronic) Structuralandfunctionalproteomic Motorweakness,gaitabnormalitiesresemblingfindings modificationsinthespinalcord inkonzo Rats[52] Cyanate(Acute) Glutathionedepletionbyinhibitionof None glutathionereductaseactivityinthebrain RatsonlowSAAdiet[53] Acetonecyanohydrin Structuralbrainlesionsinnonmotorareas None (chronic) Goats[54] Cyanate(chronic) Structurallesionsatdifferentlevelsofthe None nervoussystem(includingventralhornof thespinalcordandbrainstem) Rhesusmonkeys[55] Cyanate(chronic) Structurallesionsatdifferentlevelsofthe Suddenonsetofirreversiblespasticquadriparesis nervoussystem(Betzcellsinthemotor resemblingkonzo,inassociationwithgeneralsigns cortex,basalganglia,andanteriorhorncells) (wasting,anorexia) SAA,sulphuraminoacid. doi:10.1371/journal.pntd.0001051.t002 www.plosntds.org 4 June2011 | Volume 5 | Issue 6 | e1051 neurological findings in konzo patients. Undernutrition favored theappearanceofdiseaseinthismodel[53]. The possibility of neurotoxicity by nitriles such as AC is attractive, as in theory it could unify the pathogenesis of konzo withtwootherfamiliarandsimilartoxico-nutritionalneurological diseases:lathyrism,anon-progressivebilateralsymmetricparapa- resisassociatedwithconsumptionofgrasspea(Lathyrussativus ),and TAN, which has been associated with cassava consumption for many years. In theory, different nitriles present in cassava and grasspeacouldcausedifferentdirectneurotoxicpatternsand/or differentdiseases[60]. Excitotoxic damage related to glutathione deficiency in konzo andlathyrismisalsounderdebate[61].SAAssuchasmethionine are essential for the synthesis of brain glutathione, which is the most abundant intracellular antioxidant and an important agent Figure 4. Children with konzo in a rural area of Mozambique for detoxification of xenobiotics [62]. The absence of the (facesblurred). doi:10.1371/journal.pntd.0001051.g004 cytoprotectiveglutathione,secondarytodeficiencyofSAA,would expose the brain to cyanogen neurotoxicity in konzo. Oxidative stress can be induced by exercise, and levels of glutathione distribution ismore likely tobe explainedby common exposure, thangeneticsusceptibility. transiently decrease during physical activity [63,64]. As konzo ofteninstallsduringorafterexercise,itcouldbeaconsequenceof an exacerbation of a chronic state of neuron glutathione TheClinicalExpressionofKonzo deficiency. Acute intoxication symptoms due to cyanide include tachy- Recently, thiamine deficiency, due to the use of thiamine pnoea, tachycardia, dizziness, headache, abdominal pain, vomit- sulphur for cyanide detoxification, was proposed as a possible ing, diarrhea, mental confusion, and convulsions, generally 4–6 causeofkonzo[65].Althoughperipheralneuropathyissometimes hours after ingestion of meals containing cassava [58,71–73]. reported in konzo epidemics, the absence of other typical Thesesymptomsaresometimesreportedduringkonzoepidemics manifestations of thiamine deficiency, such as Wernicke enceph- and in acute poisoning cases are attributed to cassava consump- alopathy,Korsakoffsyndrome,orwetberiberi,doesnotfavorthis tion,butwithoutanyrecognizablemotorsequelae[71–73]. hypothesis[66,67]. The hallmark of konzo is difficulty in walking, and often the Traditionally, thiocyanate is considered to be an innocuous affectedpersonwalkswiththehelpofsticks(Figure4). productofcyanidedetoxification,butsomeauthorshaveproposed Usually, in less than a week, an acute and non-progressive thatitmayhaveanaetiologicalroleinkonzo[59]. symmetric spastic paraparesis becomes installed. The disease sometimes starts during or after manual work or a long walk. FromIndividualSusceptibilitytotheClinical Although it starts abruptly, konzo follows the consumption of a ExpressionofKonzo SusceptibilitytoKonzo Peoplearenotuniformlyaffectedbykonzo.Childrenabovethe age of 3 years and women in the fertile age group are more affectedthanadultmales[1–8]. Many possible reasons can explain these differences. Adult malesaremoreprivilegedintermsoffindingandeatingadditional sourcesoffood.Womenandtheiraccompanyingchildrenmaybe moreexposedtocassavacyanidebecausetheyeatthetoxicfresh roots,andmayhaveadditionalexposurefromcyanideinhalation duringpreparationorstorage. Pregnancyandbreast-feedingareadditionalnutritionalstresses that could predispose women to the toxic effects of cassava [9]. Biological differences, as in other neurological diseases, could affectsusceptibilitytocyanogens[68]. Breast-feeding children do not get konzo [1–8]. Studies have shown that the mammary gland barrier reduces thiocyanate passagefrommaternalserumtomilk[69,70].Welackinformation about the presence in breast milk of the other candidates for neurotoxicity under the magnitude of exposure that occurs in konzo, and with the associated nutritional deficiency. Breast-fed childrenare, however,unlikely tobedirectly exposedtomost of thepotentiallytoxiccompounds,asthemilkhasbeenprocessedin thebodyofthemother. Familialclusteringofcasesofkonzoisfoundineveryreported Figure 5. Different degrees of severity of konzo in children outbreak. Such clustering does not discriminate between genetic from Democratic Republic of Congo (faces blurred). Image susceptibility and environmental factors such as socioeconomic Credit:ThorkildTylleskar. doi:10.1371/journal.pntd.0001051.g005 status andfoodintake.Inthecaseofkonzo,theageandgender www.plosntds.org 5 June2011 | Volume 5 | Issue 6 | e1051 nystagmus, pseudobulbar dysarthria, and hypoacusia are seen in somecases[6,9,23,75,76]. Signsofuppermotordamage,intheformofspasticityresultingin exaggeratedreflexes,ankleclonus,andextensorplantarreflexesare clinicalmarkersintheabsenceofparaparesis.Studieshaveshown that the rate of ankle clonusis highin apparently healthy school childrenfromaffectedareas2yearsaftertheepidemics[77]. Dependingonitsseverity,konzoisdividedintothreecategories: mildwhenindividualsareabletowalkwithoutsupport,moderate whenindividualsneedoneortwostickstowalk,andseverewhen theaffectedpersonisunabletowalk(Figure5)[10]. Using a comprehensive definition of disease, konzo should include the complete spectrum of clinical manifestations, ranging from ‘‘minor’’ isolated signs such as clonus to severe forms with tetraparesis(Figure6).Thecasedefinitionofkonzorecommended by the World Health Organization (WHO) is based on the combination of visible spastic abnormalities in walking, a history of sudden onset in a formerly healthy person, and bilaterally exaggeratedkneeoranklejerkswithoutsignsofdiseaseofthespine [10].Byusingthesecriteria,peoplewithclonusandmildspasticity, butwithoutvisibledifficultyinwalking,arenotconsideredtohave konzo. However, because these minor signs are present in apparentlyhealthypeople[77],andtheyareonlyrecognizableif neurological examination is performed, case detection and comparisonbetweencaseserieswouldbedifficulttocarryout. Ongeneralexamination,noconsistentabnormalityisfoundin konzo,butsignsofmalnutrition,anaemia,andsplenomegalymay bepresent[76]. Secondattackshavebeenreportedinaround10%ofpatients. Contractures are a commonly developing complication over the yearsinmoreseverecaseswithoutphysiotherapy,andpainfulcalf musclespasmmaybeamajorchronicsymptom[9,74,78]. There is no proven treatment for konzo. WHO recommends dietarydiversificationandimmediatetreatmentwithhighdosesof multivitamins,particularlyvitaminB,inordertoavoidincreased neurodamageduetoconcurrentvitamindeficiency[10]. Figure 6. From individual susceptibility to the spectrum of Thereisalackofconsistentstudiesassessingexcessmortalityin konzo. konzo, but in Tanzania and DRC, increased death rates were doi:10.1371/journal.pntd.0001051.g006 reported[2,21]. monotonousdietbasedoncassavawithhighcyanidecontentfor ConclusionandFutureDirections severalweeks[6–10]. Transient non-motor symptoms such as paraesthesiae in the Taking Africa as a whole, konzo may not be a major public lowerlimbs,cramping,painortremblinginthelegs,andlowback health problem, but for affected communities, the disease is a pain can precede or accompany the paraparesis of konzo, and major burden. Increasing cassava production, declining produc- disappearinweeks[2,8–10]. tionofotherfoods,globalwarming,morefrequentdroughts,wars, Upper limb involvement in konzo varies from impairment of and population displacement have set the scene for konzo to finemotorfunctionaccompanyingspasticparaparesis,toaspastic persist. Early recognition of konzo and active case detection is tetraparesis, preventing autonomous ambulation [8,9,74]. Addi- tional neurological findings such as optic neuropathy, rotatory important to reveal the real extension of any konzo outbreak. 5KeyPapersintheField CliffJ,LundquistP,Ma?rtenssonJ,RoslingH,So?rboB(1985)Associationofhighcyanideandlowsulphurintakeincassava- N inducedspasticparaparesis.Lancet326:1211–1213. Tylleska?rT,BaneaM,BikangiN,CookeRD,PoulterNH,RoslingH(1992)Cassavacyanogensandkonzo,anuppermotoneuron N diseasefoundinAfrica.Lancet15:339–440. Tylleska?rT,HowlettPW,AquiloniusSM,Sta?lbergE,RoslingH,etal.(1993)Konzo:adistinctdiseaseentitywithselectiveupper N motorneurondamage.JNeurolNeurosurgPsychiatry56:638–643. Tshala-KatumbayD,Eeg-OlofssonK,Kazadi-KayembeT,Tylleska?r T,Fa?llmar P(2002)Analysisofmotorpathwayinvolvement N inkonzousingtranscranialelectricalandmagneticstimulation.MuscleNerve25:230–235. NhassicoD,MuquingueH,CliffJ,CumbanaA,BradburyJH(2008)RisingAfricancassavaproduction,diseasesduetohigh N cyanideintakeandcontrolmeasures.JSciFoodAgric88:2043–2049. www.plosntds.org 6 June2011 | Volume 5 | Issue 6 | e1051 Local authorities should promptly initiate interventions to avoid Furtherresearchisneededontheimpactofglobalwarmingon furthercases. cassava production and cyanogen content. At a local level, determination of the acceptability on a wider scale of efficient Immediate interventions to prevent konzo in affected areas, processing methods is needed. Finally, the pathophysiology of such as providing food and vitamins, and promotion and konzostillneedstobeelucidated. disseminationofmethodssuchasthewettingmethodtodetoxify cassavaflourinsomeaffectedareas,areessential. Inalong-termperspective,otherinterventionsincludeimprov- SupportingInformation ing food diversity and intake through more investment and AlternativeLanguageAbstractS1 Translationoftheabstract support to rural agriculture. Introduction of new low cyanide intoPortuguesebytheauthors. cassava varieties that are also high yielding and disease resistant Found at: doi:10.1371/journal.pntd.0001051.s001 (0.03 MB mayalsobeconsidered. DOC) References 1. Cliff J, Lundquist P, Ma?rtensson J, Rosling H, So?rbo B (1985) Association of antibodiesto HTLV-I,HIV,or HIVgag-encoded proteins.JAcquirImmune high cyanide and low sulphur intake in cassava-induced spastic paraparesis. DeficSyndrHumRetrovirol12:317. Lancet326:1211–1213. 26. MollerBL,SeiglerDS(1999)Plantaminoacids:biochemistryandbiotechnol- ogy.SinghBK,ed.pp563–609. 2. Howlett WP, Brubaker GR, Mlingi N, Rosling H (1990) Konzo, an epidemic 27. uppermotorneurondiseasestudiedinTanzania.Brain113:223–235. 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