4738-Eisen-18 6/16/06 5:58 PM Page 361 Handbook of Clinical Neurology, Vol. 82 (3rd series) Motor Neuron Disorders and Related Diseases A.A. Eisen, P.J. Shaw, Editors © 2007 Elsevier B.V. All rights reserved Chapter 18 Toxic disorders of the upper motor neuron system D. DESIRE TSHALA-KATUMBAY* AND PETER S. SPENCER Center for Research on Occupational and Environmental Toxicology and Department of Neurology, School of Medicine, Oregon Health and Science University, Portland, Oregon, USA 18.1. Introduction 18.2. Epidemiology Dysfunction of the motor system has been associated 18.2.1. Historical background with dietary dependence on food plants with neurotoxic potential, notably the grass pea (chickling pea) and cas- Lathyrism has affected humans and animal populations sava (manioc), in various and geographically distinct since antiquity. The disease was known to ancient regions of the world. Reliance on grass pea (Lathyrus Hindus, to Hippocrates (460–377 BC), Pliny the Elder sativus or related neurotoxic species) or on insufficiently (23–79 AD), Pedanius Dioskurides (50 AD) and Galen processed bitter cassava (Manihot esculenta Crantz) as (130–210 AD) (Desparanches, 1829; Hippocrates, staples, the latter in association with malnutrition, has 1846; Proust, 1883; Hubert, 1886; Schuchardt, 1887; resulted in epidemics of (neuro)lathyrism and konzo Spirtoff, 1903). Lathyrism affects populations reliant (neurocassavism), respectively; these are clinically on food products derived from neurotoxic species of the similar self-limiting neurodegenerative disorders con- Lathyrus genus, member of the Fabacae family, most fined to the upper motor neuron system. Studies of out- commonly Lathyrus sativus (grass pea) (Stockman, breaks of lathyrism and konzo have suggested 1917; Selye, 1957; Dwivedi and Prasad, 1964; Rao et al., individual susceptibility to the toxic effects of these 1969; Kislev, 1985). Sale of flour prepared from plants varies with subject age, gender, nutritional status L. sativus was banned by George, Duke of Württemberg and motor activity, as well as the toxin content of grass (1671) because of its ‘paralysing effects on the legs’ pea (lathyrism) or cassava (konzo), methods of food (Schuchardt, 1887). Years later (1873), the disease was preparation and duration of consumption. The common referred to as latirismo (‘lathyrismus’) (Cantani, 1873). clinical picture is a spastic paraparesis or, in the poten- Since the 17th century, outbreaks of lathyrism have been tially more severe cassava-associated disorder, a tetra- reported on the Indian sub-continent (Bangladesh, India, paresis. Electrophysiological studies reveal prominent Pakistan), in Europe (France, Italy, Germany, Romania, pyramidal dysfunction in both lathyrism and konzo; Spain, Ukraine), Afghanistan, China and North Africa neuropathological data are sparse or lacking, respec- (Algeria, Ethiopia and Eritrea) (Desparanches, 1829; tively. Molecular mechanisms of these remarkably sim- Proust, 1883; Grandjean, 1885; Stockman, 1917, 1929; ilar neurotoxic disorders have yet to be understood. Selye, 1957; Barrow et al., 1974; Gebre-AB et al., 1978; Though there is no effective treatment for these persist- Mannan, 1985; Kaul et al., 1989; Tekle-Haimanot et al., ently disabling conditions, lathyrism and konzo can 1990; Spencer, 1994; Getahun et al., 1999) (Figs. 18.1 both be prevented by modifying food preparation or and 18.2(A)). changing diet. Konzo (Fig. 18.2(B)), a lathyrism-like handicapping disorder, was first documented by Tessitore (1936) in the south-western region (Bandundu province) of Zaïre, the former ‘Belgian Congo’, presently the Democratic Republic of Congo (DRC) (Trolli, 1938). Despite the *Correspondence to: Desire Tshala-Katumbay, MD, PhD, Center for Research on Occupational and Environmental existence of striking clinical similarities between lath- Toxicology, Oregon Health & Science University, 3181 yrism and konzo, outbreaks of these two diseases occur SW Sam Jackson Park Road, L606, Portland, OR 97239, in two distinct, non-overlapping geographical areas of USA. E-mail: [email protected], Tel: +1-503-494-0999, the globe (Fig. 18.1). Whereas lathyrism has occurred Fax: +1-503-494-6831. among populations that cultivate the grass pea, outbreaks 4738-Eisen-18 6/16/06 5:58 PM Page 362 362 D. D. TSHALA-KATUMBAY AND P. S. SPENCER Fig. 18.1. World map depicting zones where lathyrism has been reported (dark gray) and those affected by konzo (light gray). of konzo have been reported mainly in sub-Saharan known whether konzo has also occurred during ancient Africa among those who subsist on cassava as staple times and/or among the Indians from the Amazonian food (Rosling and Tylleskär, 2000). Cassava is a member forests who cultivate cassava (Lathrap, 1970). of the Euphorbiaceae family (DeBower, 1975). The plant Available literature indicates the disease was known was cultivated in tropical America for approximately to the local populations (Yaka) of the Bandundu 5000 years before it was exported into Africa around province in the DRC in the late 1800s. The Yaka named the 1600s by Portuguese traders to feed slaves (Jones, the disease ‘konzo’, which means ‘tied legs’ in kiyaka, 1959; DeBower, 1975; Allem, 1994; Olsen and Schaal, the local spoken language (Trolli, 1938; van den Abeele 1999). Today, it is used worldwide and constitutes the and Vandenput, 1956; van der Beken, 1993). This des- prime source of dietary calories for over 500 million ignation was a good description of the ‘cross-legged gait’ people in the tropics and subtropics (Cock, 1982). It is not of affected subjects. Since the 19th century, outbreaks of Fig. 18.2. (A) Young Bangladeshi male affected by lathyrism (courtesy of Third World Medical Research Foundation). (B) Young Congolese male affected by konzo (photograph by Thorkild Tylleskär, by permission). 4738-Eisen-18 6/16/06 5:58 PM Page 363 TOXIC DISORDERS OF THE UPPER MOTOR NEURON SYSTEM 363 konzo have occurred in many others countries of the outbreaks of characteristic neurologic disease (Spencer, sub-Saharan Africa including Mozambique (where it is 1994; Rosling and Tylleskär, 2000). called mantakassa), Tanzania, Central African During World War II, outbreaks of lathyrism Republic, Cameroon, Angola and Uganda (Fig. 18.1) occurred among a group of Rumanian Jews interred in (Ministry of Health Mozambique, 1984a,b; Cliff et al., a German hard-labor camp in the Ukraine and among 1985; Rosling, 1989; Tylleskär et al., 1991, 1994; Howlett Germans held in a French prisoner-of-war camp. The et al., 1992; Banea et al., 1993; Davis and Howarth, causative chain of lathyrism is best illustrated in the 1993; Mlingi et al., 1993; Lantum, 1998; Bonmarin, outbreak that occurred in the Ukrainian town of 2002; Rosling and Tylleskär, 2000; Tshala-Katumbay Wapniarka (Kessler, 1947; Cohn and Streifler, 1981a,b). et al., 2001a). On September 16, 1942, 1200 Rumanian Jewish males were put on a diet of 400 g grass pea daily cooked in 18.2.2. Role of environmental and salt water and 200 g of bread. Three months later, there contextual factors was a monophasic outbreak of lathyrism involving 800 inmates. Ukrainian and Russian inmates who had sur- Epidemics of lathyrism and konzo usually appear when vived prior to the arrival of the Rumanians on a diet of adverse environmental conditions result in heavy dietary 200 g per day grass pea remained free of disease for reliance on the grass pea (Figs. 18.3(A, B)) or on cassava 3–6 months, but developed lathyrism when their intake (Figs. 18.3(C, D)), respectively (Spencer, 1999). Both was doubled with the arrival of the latter. Those previ- the grass pea and cassava are annual high-yielding crops ously incarcerated were affected earlier and in a greater with relative resistance to harsh environmental condi- proportion than prisoners brought (in relatively good tions such as drought, insect attacks and/or pests. Grass health) from their homes. The outbreak of lathyrism pea has a high protein content (with most of the essential among Wapniarka inmates was documented by Kessler, amino acids well represented) while cassava is a rich a physician and prisoner who himself developed mild source of carbohydrate (Gopalan and Balasubramanian, lathyrism. He identified the disease and its cause, and 1963; Roy and Roa, 1978; Cock, 1982). Food products persuaded the guards to change the diet. Consumption derived from these two plants usually make a major of the grass pea was subsequently stopped at the end component of the diet among populations in areas of 1942 and no new cases were thereafter reported endemic for either lathyrism (grass pea) or konzo (cas- (Kessler, 1947). sava). However, adverse environmental conditions, Other illustrative examples include outbreaks of such as extreme weather leading to flood or drought, lathyrism on the Indian sub-continent and in Ethiopia. pestilence or war, have forced populations to rely almost In India, the disease historically has been mainly con- exclusively on food products made from these two fined to Uttar Pradesh, Madhya Pradesh (where Acton drought-resistant crops; this situation has often led to identified the presence of 60,000 cases) and Bihar Fig. 18.3. Two drought-resistant plants associ- ated with neurological disease. The grass pea plant (A) and seeds (B) that are grown in areas affected by lathyrism. (C) Cassava roots and plant (D) are cultivated in areas affected by konzo. 4738-Eisen-18 6/16/06 5:58 PM Page 364 364 D. D. TSHALA-KATUMBAY AND P. S. SPENCER (Acton, 1922; Dwivedi, 1989). In these settings, lath- Because poverty and war appear to be linked to the yrism has occurred mostly among small land-holders occurrence of konzo, it is not surprising the disease and farmers who cultivate grass pea. In Bangladesh, a persists in the DRC and neighboring countries, includ- large producer and consumer of the grass pea, espe- ing Angola, Uganda and Central African Republic, all cially in the northwest of the country, the prevalence theaters of armed conflict. rates of lathyrism have fluctuated in proportion to the production and consumption of the grass pea.