68ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:638-643

Konzo: a distinct disease entity with selectiveupper motor neuron damage

T Tylleskar, W P Howlett, H T Rwiza, S-M Aquilonius, E Stalberg, B Linden,A Mandahl, H C Larsen, G R Brubaker, H Rosling

International ChildHealth Unit,Department ofPediatrics, UniversityHospital, Uppsala,SwedenT TylleskarH RoslingKilimanjaro ChristianMedical Center,Moshi, TanzaniaW P HowlettDepartment ofInternal Medicine,Muhimbili MedicalCenter, Dar-es-Salaam, TanzaniaH T RwizaDepartment ofNeurology, UniversityHospital, Uppsala,SwedenS-M AquiloniusDepartment ofClinicalNeurophysiology,University Hospital,Uppsala, SwedenE StalbergDepartment ofRadiology, FalunHospital, Falun,SwedenB lindenDepartment ofOphthalmology,University Hospital,Uppsala, SwedenA MandahlDepartment ofAudiology, UniversityHospital, Uppsala,SwedenH C Larsen

Shirati Hospital,Musoma, MaraRegion, TanzaniaG R BrubakerCorrespondence to:Dr T Tylleskiir,International Child HealthUnit (ICH), Departnent ofPediatrics, UniversityHospital, S-751 85 Uppsala,Sweden.

Received 18 May 1992and in revised form16 October 1992.Accepted 28 October 1992

AbstractTwo Tanzanian patients with konzo wereseverely disabled by a non-progressivespastic paraparesis, since the suddenonset during an epidemic six years ear-lier. At the time of onset they had a highdietary intake of cyanide from exclusiveconsumption of insufficiently processedbitter cassava roots. MRI of brain andspinal cord were normal but motorevoked potentials on magnetic brainstimulation were absent, even in the onlyslightly affected upper limbs. Other neu-rophysiological investigations werelargely normal but the more affectedpatient had central visual field defects.Konzo is a distinct disease entity withselective type upper motor neuron dam-age.

(7 Neurol Neurosurg Psychiary 1993;56:638-643)

Konzo is an upper motor neuron disease,characterised by abrupt onset of a varyingdegree of symmetrical, isolated, and perma-nent but non-progressive spastic paraparesis.It was first described in Zaire in 1938 and isnamed after the local designation in the firstreport.' In the last decade it has beenreported from remote rural areas ofMozambique, Tanzania, and Zaire. The uni-form epidemiological and clinical findingshave identified konzo as a distinct diseaseentity induced by a combined effect of highcyanide and low sulphur intake from exclu-sive consumption of insufficiently processedbitter cassava roots.2 The study of konzo hasformerly been limited to clinical examinationsduring field surveys.

Subjects and methodsTwo male konzo patients aged 25 and 19years were invited to Sweden in October1991. They were diagnosed in 1985 duringan epidemic in Tarime district,"3situated eastof Lake Victoria in the northern part ofTanzania.The study was approved by the ministry of

health of Tanzania and the ethical committeeof Uppsala University. Local civil and healthauthorities informed the patients and theirfamilies about the aim and procedures to beundertaken and obtained written consentfrom the patients to participate. A localhealth worker accompanied the patients toSweden and acted as interpreter.

Histories were taken and neurologicalexaminations were carried out on bothpatients during visits in their homes in May1985 and repeated in 1986, 1988 (WPH),and again in Sweden in 1991 (S-M A).

Magnetic resonance imaging (spin echo) ofthe brain and spinal cord was performed witha Philips T5 MR-scanner (05 Tesla unit)without use of intravenous contrast. Tiweighted, proton density, and T2 weightedimages were obtained in sagittal, coronal, andaxial planes of the brain and in the sagittalplane of the whole spinal cord. Axial protondensity and T2 weighted images over theconus medullaris were also obtained.

Neurophysiological investigations wereperformed with conventional techniquesincluding motor and sensory nerve conduc-tion, small fibre tests such as respiratorydependent heart rate variation,4 thermal per-ception thresholds for warmth and cold andpain threshold for heat and cold; concentricelectromyography (EMG) both at rest, atslight voluntary contraction and during maxi-mal contraction (automatic turn/amplitudeanalysis,5 single fibre EMG, fibre densitymeasurement, jitter analysis, blink reflexes,electroenchephalography (EEG), somatosen-sory evoked potentials (SEP), full field visualevoked potentials (VEP), and brainstemevoked response audiometry (BERA).Transcranial stimulation of the motor cortexwas performed with a magnetic stimulator toelicit motor evoked potentials (MEP).Stimulation was also performed over the C7vertebra. Pure tone audiometry and caloricstimulation of the vestibularis were studied inconventional ways. Electronystagmography(ENG) in a dark room supervised by aninfrared camera was used for the registrationof spontaneous nystagmus, head shake nys-tagmus, positional nystagmus, and gaze nys-tagmus at 300 eye deviation. Smooth pursuitmovements of 600 with a fixed velocity of20°/s 10 movement to the right and 10 to theleft was recorded with ENG and analysed bycomputer for velocity, accuracy, and superim-posed saccades according to standardisedprocedure.6 Voluntary saccades (that is, rapideye movements) of 600 was performed 20times to the right and 20 times to the leftanalysed by computer for start latency, accu-racy, and velocity.6

Conventional ophthalmological investiga-tions included: visual acuity, eye pressure,direct/consensual pupillary reflex, cornealsensitivity, colour vision, dark adaptation,and binocularity. Visual fields were examined

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with Goldmann perimetry. The ocular fundiwere photographed and scrutinised fordefects in the nerve fibre layer.Serum thiocyanate was used as biomarker

for dietary cyanide exposure.2 An extensivebattery of haematological and biochemicalroutine analyses were carried out includinganalyses of blood cells, platelets, haemoglo-bin, serum levels of electrolytes, different pro-teins, enzymes, vitamin B6, B12, thyroidhormones, a plasma electrophoresis, and rou-tine urine tests. Serological testing included:IgM anti-hepatitis A virus, hepatitis B surfaceantigen, anti-hepatitis C virus, antibodies tosyphilis, retroviruses HIV-1 + 2 (EnzygnostAntiHIVi + 2 EIA, Wellcosyme Recom-binant HIV-1 EIA, PCR HIV-1), HTLV-I(Abbot HTLV-I EIA, PCR HTLV-I).Characterisation of lymphocyte subpopula-tions by immunofluorescence and flowcytometry as well as an attempt to isolateHIV-1 and HTLV-I from blood specimenswas performed. Direct microscopy of faeceswas performed for cysts and eggs of intestinalparasites and direct microscopy of blood filmsfor malaria parasites, trypanosomes, andfilaria. ELISA serology for amoeba,echinococcus, filaria, schistosoma, andimmunofluorescence for leishmania, try-panosomes, giardia, and malaria was per-formed. The cerebrospinal fluid was screenedfor syphilis and examined for cells, protein,glucose, and lactate. A protein electrophoresisand an isoelectric focusing was done.

ResultsPATIENT 1This man was born in 1966, the eldest ofthree children. There was no family history ofneurological disorder. He was healthy untilthe 16 March 1985. The night before theonset of his illness he attended a local danceand experienced no difficulties with his legs.Later that night at home on the way to thelatrine he noticed a weakness of the legs. Thefollowing morning the weakness was morepronounced and the legs were trembling onstanding. He also experienced some sensa-tions in the legs, and felt "as if the skin wasnot his". However, he managed to go andwork in the field and when returning forlunch he sat down on a chair to rest. Sincethen he has never been able to walk again.There was a further deterioration during thefirst days with weakness in the arms andslurred speech, but no visual or hearingimpairments. He was confined to bed forapproximately two months after which speechdifficulties cleared and there was a functionalimprovement in his legs and especially in hisarms allowing him to stand with the supportof one person. He did not have any bladderproblems. About one year later, he had anepisode of visual impairment when he wasunable to read a book but this cleared insome weeks. In 1989 he married and the cou-ple have since then had two children. His dis-ability has remained unchanged apart fromthe functional improvements in the first

months. He is able to move around with afour point walking frame and he makes hisliving as a shoe maker.

In the month preceding the onset the fam-ily was almost exclusively eating cassava, theonly crop to survive the drought in 1985. Hisyoungest brother, born in 1973, was similarlybut less severely affected in March 1985.

PATENT 2This man was born in 1972 as the fifth bornin a family of 12 children. There was no fam-ily history of neurological disorder. He washealthy until March 1985 when one night henoticed weakness in both legs while walkingto the latrine. He returned to bed with diffi-culty but in the morning he was unable tostand, and over the next three days the weak-ness increased and he was unable to get outof bed. At this stage he also experienced diffi-culties in speaking, visual disturbances andsome tingling sensations in his legs, and acold feeling in his feet. He also experiencedclumsiness in his hands. He improved oversome weeks and since May 1985 he is able tostand and to walk with the help of two sticks.His hoarseness cleared and his visionimproved.

At the time of onset of the paralysis thediet of the family consisted almost exclusivelyof cassava because of drought. Out of thetotal household of two parents and eight liv-ing children four other siblings aged 6, 11, 12and 14 were similarly affected in March-April1985. The only three to escape the diseasewere the oldest child who was away at aboarding school, the youngest who was stillbreast-feeding, and a four year old boy.

CLINICAL FINDINGS*Figure 1 shows the two patients in October1991, six years after onset. The clinical find-ings from the initial examination in May1985, six weeks after the onset, and theexamination in October 1991 were almostidentical. Both patients were unable to walkunaided because of severe spastic paraparesis.The degree of disability on the expanded dis-ability status scale (EDSS) was rated at 7-0for patient 1 and 6-5 for patient 2. This dis-ability was characterised by extensive motorenvolvement in the legs and a typical toe scis-sors gait on walking. The main abnormalneurological findings were in the legs in bothpatients and were as follows: hypertonia,most obvious in the strongest musclegroups-that is, hip adductors, knee exten-sors and ankle plantar flexors, bilateral sus-tained ankle clonus, loss of power (MRCrange 0/5 ankle dorsi flexors in patient 1 dueto contractures, to 4/5 knee flexors in thesame patient and 3/5 hip flexors to 4 5/5plantar flexors in patient 2), hyperreflexia,

*A 7 minute video tape showing the main neurological find-ings and the magnetic stimulation is available from the author.It is free of charge for colleagues from developing countriesand for others we charge the equivalent of £20 sterling forproduction and postage. Unless otherwise requested we willdistribute a VHS/PAL tape.

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crossed adductor reflexes, and extensor plan-tar responses. Sensation (superficial anddeep) and superficial reflexes were intact. Inthe upper limbs there was an obvious impair-ment of fine repetitive and rapid alternatinghand movements affecting both patients.Patient 2 had a slight (MRC 4-5/5) loss ofpower affecting the extensors at the rightelbow. Otherwise the upper limbs were nor-

mal. The cranial nerves and mental functionwere normal apart from an eye motion abnor-mality and a visual field defect (both pre-sented below). The jaw jerk was absent. Therest of the neurological assessment includingcerebellar, basal ganglia and autonomic func-tion was normal.

MRI AND NEUROPHYSIOLOGYOn MRI no abnormalities were found in themotor cortex, the pyramidal tracts or else-where in the brain, brainstem, or the spinalcord.The main neurophysiological finding was

the complete absence of response at repeatedmagnetic stimulation of the motor cortexusing maximal output of the stimulator atmuscle rest and at various degrees of volun-tary muscle contraction for facilitation; bothin the affected legs and in the only slightlyaffected arms. There was twitching of facialmuscles on magnetic stimulation and normalresponses were obtained from arms upon

Figure (A) Frontal view of the patients showing thetypical toe scissors gait and their usual walking aids.(B) Side view ofpatient 2.

stimulation over the neck at C7 level. Bothpatients showed normal peripheral nerve con-duction, EMG, BERA, and blink reflexes.Respiratory dependent heart rate was alsonormal. In patient 1 the EEG amplitudes ofall frequencies were abnormally low. Therecordings showed nearly no a activity duringwakefulness, drowsiness, hyperventilation, orphotic stimulation. In patient 2 EEG wasnormal but sensory nerve action potentialswere abnormally low and thermal thresholdswere abnormally high. VEP showed asymme-try with longer latency from the right eye butthe absolute values for each eye was withinnormal limits.The pure tone audiometry, electronystag-

mography, and caloric reactions were normal.In the oculomotor test none of the patientshad any eye muscle paralysis but bothpatients had pathological smooth pursuitmovements with regard to velocity and bysuperimposed saccades. The voluntary sac-cades were normal in accuracy and velocitybut the start latency was too slow(288-308 ms) in both patients.

OPHTHALMOLOGYPatient 1 had bilateral central visual fielddefects and a corresponding atrophy of thepapillomacular nerve fibre layer with tempo-ral pallor of the optic discs. His colour vision(blue-yellow discrimination) was borderline.

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Patient 2 had small white spots in the maculalutea, compatible with a chloroquineretinopathy, and a vasculitis with arteriolarsheathing in the nasal part of the left retina.Other ophthalmological examinations werenormal.

LABORATORY INVESTIGATIONSSerum thiocyanate was 532,umol/l for patient1 and 230 pmol/l for patient 2 in May 1985and 62 and 10, umol/ respectively in October1991 (reference value 8-76 umol/1).Other laboratory findings were normal

except in patient 1 (reference values in paren-thesis): white blood cell count 3-2 (4-9 109/1)with 26% polymorphonuclear cells; albumin41 (42-55 g/l); a-amylase 8-0 (1 4-5 pkat/1);plasma Ig G 21L2 (7-0-18-0 g/l), plasma IgM3-62 (0A4-2-75 g/l) but no monoclonalbands were found. Patient 2 had normalvalues except: albumin 36 (42-55 g/l);a-amylase 11 -2 (1-4-5 pukat/l); alkaline phos-phatase 9 4 (0 8-48,ukat/l); AST 0-92 (< 0-6,ukat/l); ALT 0-66 (< 06,ukat/1); LDH 8-5(3-8-6-7,ukat/l), and plasma IgM 3-67(0-4-2.75 g/l).

Both patients were seronegative to HTLV-1, HIV-1, HIV-2, syphilis, and hepatitis in1985 as well as in 1991. No retrovirusescould be isolated from the blood andCD4+/CD8+ lymphocyte ratios were nor-mal.

Microscopy of faeces and blood films werenegative in both patients. ELISA serologieswere negative for amoeba and echinococcusand weakly positive to filaria and schistosomain both patients. Immunofluorescence forleishmania, giardia, and trypanosomes wasweakly positive in both patients but stronglypositive for malaria (1:5120 and 1:81920).

Patient 1 had a traumatic bleed on lumbarpuncture and the collected CSF contained7:2 x 109/l erythrocytes, 24 x 106/1 polymor-phonuclear cells, and 18 x 106/l lympho-cytes. The bleeding also increased the proteincontent to 700 mg/l (150-500 mg/l). CSFalbumin was 198 mg/l (<290 mg/l), and IgG122 mg/l (<33 mg/l). Plasma albumin was 37g/l (35-46 g/l) and IgG 21-2 g/l (7-15 g/l).The albumin ratio (CSF/plasma) was 5-3(<6-5) and IgG index 1-0 (<0 7). Isoelectricfocusing showed no oligoclonal bands.Glucose in CSF/blood was 3-2/5 7 mmol/land CSF lactate was 1-4 mmol/l. Syphilistest was negative.

Patient 2 had normal cerebrospinal fluidwith no erythrocytes or polymorphonuclearcells and 1 x 106/1 lymphocytes. The proteincontent was 240 mg/l, albumin 98 mg/l, andIgG 30 5 mg/l. Plasma albumin was 36 g/land IgG 17-7 g/l (7-15 g/l) and the albuminratio (CSF/plasma) was 2-7 and IgG index0-65. Isoelectric focusing showed no oligo-clonal bands. Glucose in GSF/blood was3.9/5.7 mmol/l and CSF lactate was 1 9mmol/l. Syphilis test was negative.

DiscussionThe clinical findings in both patients were

typical for konzo, that is, a sudden onset of asymmetric, isolated, and non-progressivespastic paraparesis, unchanged over time.The characteristic toe scissors gait, the sym-metrically exaggerated and clonic reflexes inthe lower limbs and the extensor plantarresponses in the absence of sensory or auto-nomic disturbances are all constant findingsin patients with severe konzo.' 7 In the villagesof the two patients, konzo constitute twothirds of all locomotor disabilities3 and thepatients studied belong to the most severelyaffected subjects.A retrovirus aetiology of konzo has been

suspected7 but the two konzo patients studiedwere seronegative to all retroviruses (HTLV-1, HIV-1, and HIV-2), like all other konzopatients tested. 27 Further tests such as PCR,virus isolation, and lymphocyte subpopula-tions showed no sign of retrovirus affection inthe two patients. The distribution of HTLV-Iassociated myelopathy/tropical spastic para-paresis (HAM/TSP) and konzo overlap geo-graphically8 but apart from negative serologykonzo also differs clinically from HAM/TSPby its abrupt onset and non-progressivecourse. Plasma immunoglobulins wereincreased in both patients, as expected insubjects from an environment with high rateof infectious diseases. Patient 1 had a some-what increased IgG index of CSF but nooligoclonal bands could be detected. Suchelevated IgG index are occasionally found innon-inflammatory neurological diseases as anon-specific sign of neurodamage.9 An earlierstudy in Zaire also reported absence of oligo-clonal bands in the CSF of konzo patients.7In conclusion, neither this nor earlier epi-demiological or clinical studies support theinvolvement of an infectious agent in konzo.

At the time of the onset in 1985 bothpatients subsisted on cassava that, because offood shortage, was insufficiently processed.' 3They had high dietary cyanide intakes as sup-ported by very high serum thiocyanate. Highcyanide exposure has been verified at onset inall areas where konzo have been reported.This and other findings strongly indicate atoxiconutritional aetiology in konzo.' 2

Lathyrism is another toxiconutritional dis-ease that is similar to konzo but their geo-graphical distributions do not overlap andthey are attributed to different types ofmonotonous diets. The only clinical differ-ences between the diseases are the occasionalvisual involvement in severe konzo and theoccasional autonomic involvement in lathy-rism."0 A common final pathogenetic mecha-nism has been suggested' but no comparisonof the neurodamage in the two diseases canbe made since similar neuroradiological andneurophysiological examinations are lackingfor lathyrism.The first interesting result of the present

study is the absence of pathological findingson MRI in the two severely handicappedkonzo patients. This is in sharp contrast tothe extensive lesions found on MRI inpatients with multiple sclerosis" (MS) withthe same degree of disability-that is,

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EDSS > 6. The multifocal lesions frequentlyseen on MRI in HAM/TSP12 differ in distrib-ution and are less impressive than thosefound in patients with MS with a similardegree of disability. But in contrast to ournormal findings in the two konzo patients,pathological MRI changes were found in 13out of 14 HAMJTSP"3 patients with a disabil-ity of EDSS > 6. Patients with motor neurondisease'4 have limited lesions along the pyra-midal tract that are related to the severity ofthe disease. The normal MRI in konzo thusindicates a more selective pathogenetic mech-anism than in MS, HAM/TSP, and motorneuron disease.The second interesting result is the

absence of motor evoked potentials on trans-cranial magnetic stimulation of the motorcortex in both konzo patients. Difficulties inexciting the motor cortex electrically or bymagnetic stimulation have been seen inpatients with hyperreflexia, spasticity'5 andextensor plantar responses'6 in relation to theseverity of the upper motor neuron involve-ment.'7 It is therefore not surprising that noresponse could be elicited in the severelyaffected legs but the inexcitability of theupper limbs is surprising since both patientshad a good voluntary control of their arms.Only one study reports some few patientswith motor neuron disease having absentresponses after electrical brain stimulation inmuscles with preserved voluntary control.'8Antiepileptic drug medications have also beenreported to induce a dissociation betweenmagnetic excitability and voluntary control'9although the patients in this study were nottaking any medication.

Frequent involvement of the upper limbsmanifested by weakness and hyperreflexia hasbeen reported at onset of konzo.' This usuallyclears but may persist in the more severelyaffected cases. We have observed a similarpattern in minimally affected lower limbswhere residual disease is manifested by per-sistent hyperreflexia only. In the two patientsstudied the inability to make fine repetitiveand alternating finger and hand movementsin the absence of cerebellar disease is the onlyclinically detectable sign of minimal damageof the corticospinal tracts controlling theupper limbs. The complete inexitability of thearms to cortical stimulation, while supportingthis clinical finding, also suggests that konzomay constitute a rare pattern of corticospinalfailure where a subpopulation of neurons maybe damaged at cortical or corticospinal levelwhile relatively normal muscle power andfunction may be still preserved in the affectedlimbs. This supports the case for a furtherspectrum of minimally detectable or subclini-cal disease among the konzo affected popula-tions. The abnormal findings in eye motionthat is, saccadic eye movements and inabilityto rapidly alternate the fixation, are most eas-ily interpreted as a bulbar analogue to thefindings in the upper limbs.The more severely affected patient in this

study had central visual field defects and acorresponding atrophy of the papillomacular

nerve fibre layer with temporal disc pallor.These findings are characteristic of a"toxic/deficiency optic neuropathy".Y Earlierstudies of konzo have noted reduced visualacuity in severe cases of konzo, especially inthe first weeks following onset.'7 Both theoptic neuropathy found in this study and ear-lier reported findings of reduced visual acuityshow that in severe cases of konzo an opticnerve lesion may add to the isolated damageof corticospinal tracts.

CYANIDE AND THE NERVOUS SYSTEMThe types of neurodamage that has beenattributed to cyanide seem to depend on thedose rate. Firstly it is well known that veryhigh exposure leads to rapid death through aneffect on central neurons. Secondly, the factthat sublethal acute intoxications may resultin. Parkinsonian symptoms following damageto basal ganglia has been shown on MRI insuch patients.2' Thirdly, several years todecades of low dietary cyanide exposure fromcassava has in Nigeria, been associated with asyndrome of slowly progressive ataxia,peripheral neuropathy, and optic atrophy.This syndrome is known as tropical ataxicneuropathy22 and is clinically distinct fromkonzo.The abrupt corticospinal damage in konzo

has been attributed to a fourth pattern ofcyanide exposure, that is, several weeks ofuninterrupted high but sublethal bloodcyanide levels.2 These result from a highdietary cyanide intake in combination withimpaired cyanide to thiocyanate conversiondue to low sulphur intake. This metabolicpattern results from exclusive consumption ofinsufficiently processed bitter cassava rootswithout protein rich supplementary foods.The dietary situation has been identicallyextreme in all five areas of Africa where konzohas been well documented.'2 From the pre-sent study we hypothesise that several weeksof high blood cyanide levels at a certainthreshold, directly or after further metabolicevents, cause an irreversible damage to a hith-erto unidentified structure of some of theupper motor neurons.The effect on CNS of the pattern of

cyanide exposure associated with konzo hasnot been tested in an animal model. Anobservation of hindlimb paralysis in ratsexposed to the combination of a high cyanideand low sulphur, while testing its diabeto-genic effect, is so far the only experimentalsupport for a cyanide aetiology of konzo.2'However, continuous exposure of primates tothe related substance cyanate (OCN) resultedafter six weeks in an abrupt onset of a perma-nent spastic paraparesis identical to konzo.24As only minor histological changes werefound in the corticospinal tracts of thecyanate exposed primates the toxicologicalmechanism may be the same as in konzo. Theproposed toxiconutritional aetiology of konzoshould be possible to confirm in an animalmodel. The inexcitability of motor cortex ontranscranial stimulation may be used toidentify subclinical forms of konzo in such

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models, as well as in future epidemiologicalstudies.

The study would not have been possible without support fromthe Ministry of Health in Tanzania, Dr Festo Kavishe and MrNicolas Mlingi at the Tanzania Food and Nutrition Centre,the regional and local health authorities, Mr Daniel Kumbi,Miss Helena Karlen, and involved staff in different depart-ments at Uppsala University and Falun hospital.We also thank Professors Kjell Bergstrom and Anders

Hemmingsson, Department of Diagnostic Radiology, andProfessor Lars Klareskog, Department of ClinicalImmunology and Transfusion Medicine, University Hospital,Uppsala, Sweden for valuable advice and Dr VasiliosKostulas, Department of Neurology, Huddinge Hospital,Stockholm for performing the isoelectric focusing on the cere-brospinal fluids.The study was supported by SAREC, the Swedish Agency

for Research Cooperation with Developing Countries.

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