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Lymphology 43 (2010) 168-177
PODOCONIOSIS, NON-FILARIAL ELEPHANTIASIS, AND LYMPHOLOGY
G. Davey
Brighton & Sussex Medical School, University of Sussex, Falmer, Brighton, United Kingdom
ABSTRACT HISTORY
Several recent reviews of podoconiosis From the time of the Roman Empire, already exist in journals and on public access travelers recorded anecdotes about people websites. After briefly covering the historical with progressive swelling of the feet. A more and epidemiological background, this detailed reference to ‘swollen legs’ appears in narrative review will therefore attempt the Tibetan translations of a fourth century explicitly to link podoconiosis with revelation originally recorded in Sanskrit as lymphology, examining gaps in what is known the second book of rGyud-bzhi (the ‘four of pathogenesis and identifying the areas of tantras’). However, it was not until c.905 research in which input from lymphologists is that the Persian physician Rhazes first most required. Finally, prevention and distinguished elephantiasis ‘of the Greeks’ treatment will be described and the need for (lepromatous leprosy) from that ‘of the operational research to optimize community- Arabs’ (most probably non-filarial based interventions outlined. elephantiasis) (1). In the 1770s, the adventurer James Bruce Keywords: podoconiosis, elephantiasis, gave a graphic description of the elephan- lymphedema, soil tiasis he saw in Gondar, northern Ethiopia: “The chief seat of this disease is from the Podoconiosis is a type of lower limb bending of the knee downwards to the ankle; tropical elephantiasis distinct from lymphatic the leg is swelled to a great degree, becoming filariasis (LF). It is a geographically localized one size from bottom to top, and gathered disease, clinically distinguished from LF into circular wrinkles.... from between these through being an ascending and usually circular divisions a great quantity of lymph bilateral lymphedema. It is highly prevalent constantly oozes. It should seem that the in focal areas, hence its alternative title, black colour of the skin, the thickness of the endemic non-filarial elephantiasis. Podoconi- leg, its shapeless form and the rough osis (endemic non- filarial elephantiasis) has tubercules or excrescences, very like those been recognized as a specific disease entity seen upon the elephant, gave the name to for over one thousand years and is this disease...” widespread in tropical Africa, Central Bruce obtained permission from the America and north India, yet it remains a emperor, Ras Mikhail, to treat a sufferer, neglected and under-researched condition using a range of regimes and medications, (Fig. 1). but beyond assuaging the patient’s thirst with
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Fig. 1. Advanced, asymmetrical podoconiosis in a female patient from northern Ethiopia. a constant supply of whey, no treatment among Guatemalan patients with elephan- (including hemlock, mercury and tar-water) tiasis, Robles inferred that the disease (which appeared effective (2). he called ‘pseudo-lepra’) was associated with Through the eighteenth and nineteenth walking barefoot (1). He described the centuries, the pathogenesis of elephantiasis ecological niche and the disease process in was gradually elucidated through Hendy’s detail, noting the lifelong nature of the study of the lymphatic system in affected disease, but his enquiry was not continued in people. Wucherer (in Brazil), Lewis (in South America. India), Manson and Bancroft all recognized Progress in recognizing the international the role of filarial parasites in elephantiasis, distribution of non-filarial elephantiasis came and for a time it was concluded that all as Cohen suggested the use of the term elephantiasis was filarial. Towards the end of ‘idiopathic lymphedema’ in place of the local the nineteenth century, the discrepancy terms ‘verrucosis lymphatica’ in Kenya and between distribution of elephantiasis and ‘mossy foot’ in Ethiopia (3). The location of distribution of filaria in North Africa, central the next set of investigations into non-filarial America and Europe prompted revision of elephantiasis was western Ethiopia, where this theory. Central to current research has in the 1960s, Oomen described a type of been the identification of podoconiosis as a elephantiasis caused neither by onchocerciasis type of elephantiasis distinct from filarial nor filariasis (4). He noted that most cases disease. This distinction was first clearly were found between 1000m and 2000m, made in 1938, when on the basis of repeated but was unable to fully resolve questions negative tests for bacteria and microfilaria about etiology.
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Fig. 2. Global distribution of podoconiosis. (Adapted from WHO website)
Price extended Oomen’s epidemiological Central American highlands in Mexico and studies (5,6), and described the etiology (7), Guatemala south to Ecuador and Brazil in pathology (8,9), and natural history (10) of South America (19,20). Further east, on the non-filarial elephantiasis in Ethiopia, north coast of South America in Suriname establishing the term podoconiosis (from the and French Guiana, the distinction between Greek for foot: podos, and dust: konos) (11), filarial and non-filarial elephantiasis has not which has gained widespread acceptance. been confirmed. Although filarial elephantiasis predominates in India, podoconiosis has been EPIDEMIOLOGY reported from north-west India, Sri Lanka and Indonesia (Fig. 2). Geographical Distribution Price holds that podoconiosis was previously common in North Africa (Algeria, Podoconiosis is found in highland areas Tunisia, Morocco and the Canary Islands) of tropical Africa, Central America and and Europe (France, Ireland and Scotland) north-west India. Areas of high prevalence but is no longer found in these areas since have been documented in Uganda (12), use of footwear has become standard (19). Tanzania (13), Kenya (14), Rwanda, Burundi, Sudan and Ethiopia (15), and in Equatorial Prevalence Guinea (16), Cameroon (17), the islands of Bioko, Sao Tome & Principe (18) and the Prevalence estimates have been made in Cape Verde islands. Ethiopia and, recently, in Cameroon. Early The condition has been reported in the estimations of prevalence using counts of
Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 171 attendees at fifty-six markets ranged from goldmine workers, and weavers who sit at a 0.42 to 3.73% (4), and further investigation ground level loom. in Wollamo zone, southern Ethiopia demon- strated prevalence of 5.38% across five Geology and Climate markets. In the village of Ocholo, located at 2000m altitude in the mountains west of An association between podoconiosis and Lake Abaya, southern Ethiopia, elephantiasis exposure to the local soil was suspected by was present in 5.1% of long-term residents Robles in Guatemala at the end of the (21), while in two resettlement schemes in nineteenth century. However, it was not until Ilubabor, western Ethiopia, 9.1% of long-term Price superimposed maps of disease residents were affected, and 5.2% of people occurrence onto geological surveys that resettled some 7-8 years previously (22). More persuasive evidence of a link with red clays recent population-based surveys in northwest derived from volcanic activity was provided (23), southern (24) and western Ethiopia (15,25). The climatic factors necessary for (personal communication), and northwestern producing irritant clays appear to be high Cameroon (17), have documented prevalence altitude (between 1000 and 2500m above sea of 6%, 5.4%, 2.8% and 8.1%, respectively. level) and seasonal rainfall (over 1000mm annually). These conditions contribute to the Age, Gender and Occupation steady disintegration of volcanic ash and the reconstitution of the mineral components into Early reports based on clinic attendees silicate clays. Comparison of soil from an cannot be relied upon to derive an accurate endemic area with that from outside the area sex ratio. Price found a male: female ratio of revealed high levels of beryllium and zirco- 1:1.4 in market studies, which he attributed nium (both known to induce granulomata) to greater use of footwear by men (7). Genene (26), but the role of these elements is not Mengistu documented a male: female ratio of yet established. 1:4.2 in a survey in Ocholo, but many men of Although the earlier literature on working age were absent from the community podoconiosis suggested quartz to be a causal at the time (21). By contrast, Kloos noted agent, it is possible that kaolinite/smectite or higher prevalence among men in three of four smectite clay particles are etiologically resettlement communities in Keffa Region involved. Military surgeons in the United (22). In a single village in Pawe, Hailu Birrie States of America first recognized the found a male: female ratio of 1:1.4 among biologically active properties of sterile soil in sufferers (23). The most recent community- the 1970s. Early research identified clay based study recorded a gender ratio among particles (<2µm diameter) as more powerful podoconiosis sufferers (1:0.98) that was not than sand (2µm Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 172 (29). Particle size has been shown to be more by the remote locations of most podoconiosis important than surface reactivity in causing communities. cytotoxicity through apoptosis and necrosis (30). Ongoing studies comparing soils Clinical Pathology from endemic and non-endemic areas aim to characterize the mineral trigger. The pathology and natural history are described in a range of articles (3,10,32). Pathology and Pathogenesis Podoconiosis is characterized by a prodromal phase before elephantiasis sets in. Early The pathogenesis of podoconiosis is not symptoms commonly include itching of the yet fully elucidated. At present, most evidence skin of the forefoot and a burning sensation suggests an important role for mineral in the foot and lower leg. Early changes that particles on a background of genetic suscep- may be observed are splaying of the forefoot, tibility, but the possible role of other co- plantar edema with lymph ooze, increased factors (for example chronic infection or skin markings, hyperkeratosis with the micronutrient deficiencies) has not been formation of moss-like papillomata, and explored. Colloid-sized particles of elements ‘block’ (rigid) toes. The ‘mossy’ changes common in irritant clays (aluminum, silicon, predominate in a slipper pattern around the magnesium and iron) have been demonstrated heel and border of the foot, reflecting the in the lower limb lymph node macrophages distribution of underlying superficial of both patients and non-patients living lymphatics (Fig. 3). barefoot on the clays (9). Electron microscopy Later, the swelling may be soft and shows local macrophage phagosomes to fluid (‘water-bag’ type); or hard and fibrotic contain particles of stacked kaolinite (‘leathery’ type), often associated with (Al2Si2O5(OH)4). multiple hard skin nodules (19), or Price describes changes in the dermis, intermediate with both sets of features. Acute afferent lymphatics and lymph nodes of episodes (acute adenolymphangitis, ALA) affected individuals. The primary lymphatics occur on average 5 times per year, and become dilated and surrounded by lympho- patients become pyrexial with a warm, cytes, while edema and disorganized collagen painful limb, necessitating on average 4.5 production occurs. This fibrosis affects the days off work each episode (personal commu- afferent lymphatics, narrowing and nication). These episodes appear to be related eventually obliterating their lumen. If fibrosis to progression to the hard, fibrotic leg. predominates, both dermis and subdermis become bound to underlying deep fascia by Genetics collagen fibers, eventually destroying sweat and sebaceous glands and hair follicles. If Among many families, exposure to edema predominates, afferent vessel walls irritant soil is more or less uniform, yet not become rigid and dilated, provoking valvular all family members will develop podoconiosis dysfunction (8). No animal model has yet during their lifetime. Recent studies in a been developed for podoconiosis, but experi- southern Ethiopian population demonstrate ments have shown that silica suspension the contribution of both genetic and injected into rabbit lymphatics can provoke environmental factors to the pathogenesis of intense macrophage proliferation followed by podoconiosis. The estimated heritability was lymphatic fibrosis and blockage (31). Further 63%, with sibling recurrence risk estimated as histopathology and imaging studies using 5.1. The ‘best-fitting’ genetic model was an modern methods will be vitally important to autosomal co-dominant major gene with age understanding pathogenesis but are limited and footwear as significant covariates (33). Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 173 Fig. 3. ‘Slipper’ pattern mossy changes. A genome-wide association study has shown meetings, churches and mosques, and barred significant association between podoconiosis from marriage with unaffected individuals and single nucleotide polymorphisms (SNPs) (35). Price reports one podoconiosis sufferer in or near the HLA-DQB1, HLA-DQA1 and as having remarked that ‘it would be better HLA-DRB1 genes (personal communication). to have leprosy,’ since stigma surrounding leprosy has diminished as a consequence of ECONOMIC AND SOCIAL effective medicine and health care services CONSEQUENCES (6). The belief that there is no effective Economic Consequences medical treatment may act as a barrier to accessing health care. A comparative cross-sectional study was Understanding of and attitudes towards performed in 2005 to calculate the economic podoconiosis in local communities has been burden in a zone endemic for podoconiosis. investigated in Ethiopia and Cameroon. In Total productivity loss for a patient amounted Cameroon, most (77.8%) respondents knew to 45% of total working days per year, and in a descriptive local term for the condition, and a zone of 1.5 million people, the total overall 81.4% recognized the disease when prompted annual cost of podoconiosis was calculated with a photograph (17). These findings to exceed US$ 16 million per year (34). are consistent with those in a community Projected to the whole of Ethiopia, the direct endemic for podoconiosis in southern and productivity costs would amount to at Ethiopia (36). Almost all (91.6%) adult least US$ 208 million per year. respondents in this study knew local terms for podoconiosis, and 93.5% recognized the Social Stigma and Access to Health Care disease when shown a photograph. Both studies demonstrated stigmatizing Social stigma against people with attitudes towards disease in endemic podoconiosis is rife, patients being excluded communities – in Cameroon only 7.2% from school, denied participation in local thought that healthy community members Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 174 would consider marrying a person with a method by which their treatment efforts lymphedema (17), in Ethiopia 53.9% would can be measured. not eat with a person with podoconiosis (36). Such attitudes may be linked to relatively low Assessment of Disease: Cardiff Dermatology levels of awareness of treatment: only 32% Life Quality Index of the Cameroonians interviewed and 41.4% of Ethiopians were aware that treatment was The Dermatology Life Quality Index available. More worryingly, more than half (DLQI) was developed to measure quality of of the Ethiopian health professionals life by investigators in Cardiff in 1994 (41). interviewed thought podoconiosis was an Investigators in Ethiopia had the DLQI infectious disease, and all held at least one translated and back translated twice stigmatizing attitude towards podoconiosis according to the authors’ instructions, and patients (37). assessed feasibility of use, internal The potential harm that may be done to consistency and concurrent validity among patients through research that identifies them podoconiosis patients in southern Ethiopia as having podoconiosis is very real for such a (42). The DLQI was easy to administer, thoroughly stigmatizing disease. Strategies to taking approximately 4 minutes per patient. minimize the consequences of research on The overall value of Cronbach’s alpha was podoconiosis stigma have been investigated 0.90, indicating high internal reliability. and may be used by other groups planning Concurrent validity was assessed through research in podoconiosis (38). comparison of patients at first visit to the treatment outreach clinic with those who CLINICAL ASPECTS had been treated for at least three months (median scores 13 and 3, respectively, Assessment of Disease: Staging System p<0.001). The investigators concluded that the Amharic DLQI was another useful tool Investigators in Ethiopia developed a in assessing podoconiosis patients at staging system with the aims of enabling presentation, and in evaluating physical and disease burden to be measured and social interventions. interventions to be assessed (39). Initial attempts to validate the Dreyer system (a Differential Diagnosis seven-step system for staging filarial elephantiasis) (40) indicated that this existing The conditions podoconiosis must most system did not transfer adequately to often be distinguished from are filarial and podoconiosis. A new system was developed leprotic lymphedema, endemic Kaposi’s through a series of iterative field tests. This sarcoma and chronic recurrent erysipelas. system is designed to be used by community Clinical features of podoconiosis that help workers with little health training, has five distinguish it from filarial elephantiasis stages, and is based on the proximal spread include the foot being the site of first of swelling, knobs and bumps. The stage is symptoms (rather than elsewhere in the leg) recorded together with presence or absence and bilateral but asymmetric swelling usually of mossy changes (M+ or M-) and the greatest confined to the lower leg (compared to the below-knee circumference. The repeatability predominantly unilateral swelling extending and validity of the staging system were above the knee in filariasis). Groin involve- assessed and showed good inter-observer ment in podoconiosis is extremely rare. A agreement and repeatability. The staging recent study using both midnight thick film system has, anecdotally, been adopted with examination and BinaxTM antigen cards has enthusiasm by patients who are grateful for confirmed that in a podoconiosis-endemic Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 175 area, community workers’ diagnoses are non-agricultural occupation are also effective highly predictive of podoconiosis (43). but may not be feasible for the patient. Podoconiosis may be distinguished from leprosy lymphedema by the preservation of Tertiary Prevention sensation in the toes and forefoot, the lack of trophic ulcers, thickened nerves or hand Tertiary prevention (the management involvement. of those with advanced elephantiasis) encompasses secondary prevention measures, PREVENTION AND TREATMENT elevation and compression of the affected leg, and, in selected cases, removal of prominent Primary Prevention nodules. For elevation to be successful, at least 18 hours with the legs at or above the Evidence suggests that primary level of the heart are needed each day. prevention should consist of avoidance of Previously, Charles’ operation (removal of prolonged contact between the skin and skin, subcutaneous tissue, and deep fascia to irritant soils. This may be achieved by use of lay the muscles and tendons bare, followed robust footwear or covering of floor surfaces by grafting of healthy skin), or a variant, in areas of irritant soil. An Ethiopian national was used (3,19), but long-term results are non-government organization, the Mossy disappointing. Follow-up of patients suggests Foot Prevention and Treatment Association that those unable to scrupulously avoid (MFTPA), trains treated patients to make contact with soil experience recurrent low-cost durable leather boots and shoes for swelling which is more painful than the their communities in an attempt at primary original disease because of scarring. Social prevention. In addition, new partnership with rehabilitation is vital and includes training TOMS Shoes (a US-based business whose treated patients in skills that enable them to founding principle is to give away a pair of generate income without contact with irritant shoes to a child in need for every pair sold) soil. Successful training in shoemaking, has allowed the distribution of nearly 100,000 bicycle repair, hairdressing and beauty care, pairs of shoes through podoconiosis electronics and carpentry has been given prevention programs in Ethiopia since 2009. to several hundred treated patients by the Operational research to measure the effect of MFTPA in southern Ethiopia. this prevention campaign is much needed. International Health Aspects Secondary Prevention Worldwide, very few public or private Secondary prevention (prevention of the sector organizations offer treatment to people progression of early symptoms and signs to with podoconiosis. This is the result of a overt elephantiasis) takes the form of training lack of evidence-based treatment options in foot hygiene (washing daily with soap and compounded by patchy acknowledgment that water, using antiseptics and ointment), and the disease even exists. In southern Ethiopia, use of socks and shoes. Compression a local non-government organization, the bandaging is highly effective in reducing the Mossy Foot Treatment & Prevention Associ- size of the soft type of swelling, but bandages ation (MFTPA), has pioneered prevention are often difficult for patients to afford. and treatment using a low-tech community- Progression can be completely averted if these based intervention. The program was measures are strictly adhered to, but compli- recently evaluated (45) against a model ance must be life-long (44). Relocation from devised for control of chronic diseases in low- an area of irritant soil (10) or adoption of a income settings, the WHO Innovative Care Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 176 for Chronic Disease Framework, ICCC (46). area (Kapchorwa District) of Uganda. Acta. The evaluation describes the structure and Trop. 78 (2001), 171-176. aims of the program and identifies areas of 13. de Lalla, F, P Zanoni, Q Lunetta, et al: Endemic non-filarial elephantiasis in Iringa the program that require strengthening. District, Tanzania: A study of 30 patients. Podoconiosis currently lacks an Trans. R. Soc. Trop. Med. Hyg. 82 (1988), international advocacy body and, therefore, 895-897. lacks profile and voice at international level. 14. Crivelli, P: Non-filarial elephantiasis in Nyambene range: A geochemical disease. The WHO Department for Control of East. Afr. Med. J. 63 (1986), 191-194. Neglected Tropical Diseases has indicated 15. Price, EW, D Bailey: Environmental factors willingness to include podoconiosis in its in the etiology of endemic elephantiasis of the remit by the close of 2010. lower legs in tropical Africa. Trop. Geog. Med. 36 (1984), 1-5. 16. Corachan, M, JM Tura, E Campo, et al: REFERENCES Podoconiosis in Aequatorial Guinea. Report of two cases from different geological environments. Trop. Geog. Med. 40 (1988), 1. Price, EW: The elephantiasis story. Trop. Dis. 359-364. Bull. 81 (1984), R1-R12. 17. Wanji, S, N Tendongfor, M Esum, et al: 2. Pankhurst, R: An Introduction to the Medical Elephantiasis of non-filarial origin History of Ethiopia, first ed, Red Sea Press (podoconiosis) in the highlands of north- Inc., Trenton, NJ, 1990. western Cameroon. Ann. Trop. Med. 3. Cohen, LB: Idiopathic lymphoedema of Parasitol. 102 (2008), 1-12. Ethiopia and Kenya. East. Afr. Med. J. 37 18. Ruiz, L, E Campo, M Corachan: (1960), 53-74. Elephantiasis in Sao Tome and Principe. 4. Oomen, AP: Studies on elephantiasis of the Acta. Trop. 57 (1994), 29-34. legs in Ethiopia. Trop. Geog. Med. 21 (1969), 19. Price, EW: Podoconiosis: Non-filarial 236-253. Elephantiasis. Oxford Medical Publications, 5. Price, EW: Non-filarial elephantiasis of the Oxford, 1990. lower legs in Ethiopia. Trop. Geog. Med. 25 20. Tada, MS, PD Marsden: Probable (1973), 23-27. podoconiosis in Brasilia. Rev Soc Bras. Med. 6. Price, EW: Endemic elephantiasis of the lower Trop. 26 (1993), 255. legs in Ethiopia, an epidemiological survey. 21. Mengistu, G, DP Humber, M Ersumo, et al: Ethiop. Med. J. 12 (1974), 77-90. High prevalence of elephantiasis in Ocholo, 7. Price, EW: The relationship between endemic south-west Ethiopia. Ethiop. Med. J. 25 elephantiasis of the lower legs and the local (1987), 203-207. soils and climate. A study in Wollamo 22. Kloos, H, A Bedri Kello, A Addus: Podoconi- District, Southern Ethiopia. Trop. Geog. Med. osis (endemic non-filarial elephantiasis) in 26 (1974), 225-230. two resettlement schemes in western Ethiopia. 8. Price, EW: The site of lymphatic blockage in Trop. Doct. 22 (1992), 109-112. endemic (non-filarial) elephantiasis of the 23. Birrie, H, F Balcha, L Jemaneh: Elephantiasis lower legs. J. Trop. Med. Hyg. 80 (1977), in Pawe settlement area: Podoconiosis or 230-237. bancroftian filariasis? Ethiop. Med. J. 35 9. Price, EW, WJ Henderson: The elemental (1997), 245-250. content of lymphatic tissues in barefooted 24. Desta, K, M Ashine, G Davey: Prevalence of people in Ethiopia, with reference to endemic podoconiosis (endemic non-filarial elephantiasis of the lower legs. Trans. R. Soc. elephantiasis) in Wolaitta, Southern Ethiopia. Trop. Med. Hyg. 72 (1978), 132-136. Trop. Doct. 32 (2003), 217-220. 10. Price, EW: Endemic elephantiasis: Early signs 25. Price, EW: The association of endemic and symptoms, and control. Ethiop. Med. J. elephantiasis of the lower legs in East Africa 21 (1983), 243-253. with soil derived from volcanic rocks. Trans. 11. Price, EW: Non-filarial elephantiasis – R. Soc. Trop. Med. Hyg. 70 (1976), 288-295. confirmed as a geochemical disease and 26. Frommel, D, B Ayranci, HR Pfeifer, et al: renamed podoconiosis. Ethiop. Med. J. 26 Podoconiosis in the Ethiopian Rift Valley. (1988), 151-153. Role of beryllium and zirconium. Trop. Geog. 12. Onapa, AW, PE Simonsen, EM Pedersen: Med. 45 (1993), 165-167. Non-filarial elephantiasis in the Mt Elgon 27. Rodeheaver, G, D Pettry, V Turnbull, et al: Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY. 177 Identification of the wound infection- informed consent for genetic research on potentiating factors in soil. Am. J. Surg. 128 podoconiosis: A qualitative study. BMC Med. (1974), 8-14. Ethics10 (2009), 13. 28. Donaldson, K, V Stone, CL Tran, et al: 39. Tekola, F, Z Ayele, D HaileMariam, et al: Nanotoxicology. Occ. Environ. Med. 61 Development and testing of a de novo staging (2004), 727-728. system for podoconiosis. Trop. Med. Int. 29. Donaldson, K, V Stone, A Clouter, et al: Health 13 (2008), 1277-83. Ultrafine particles. Occ. Environ. Med. 58 40. Dreyer, G, D Addiss, P Dreyer, et al: Basic (2001), 211-216. Lymphedema Management, first ed, Hollis 30. Fröhlich, E, C Samberger, T Kueznik, et al: Publishing Co. New Hampshire, US, 2002. Cytotoxicity of nanoparticles independent 41. Findlay, AY, GK Khan: Dermatology Life from oxidative stress. J. Toxicol. Sci. 43 Quality Index (DLQI)–A simple practical (2009), 363-375. measure for routine clinical use. Clin. Exp. 31. Fyfe, NCM, EW Price: The effects of silica on Derm. 19 (1994), 210-216. lymph nodes and vessels – A possible 42. Henok, L, G Davey: Validation of the mechanism in the pathogenesis of non-filarial Dermatology Life Quality Index among endemic elephantiasis. Trans. R. Soc. Trop. podoconiosis patients in southern Ethiopia. Med. Hyg. 79 (1985), 645-651. Br. J. Derm. 159 (2008), 903-6. 32. Price, EW: Pre-elephantiasic stage of endemic 43. Desta, K, M Ashine, G Davey: Predictive nonfilarial elephantiasis of lower legs: value of clinical assessment of patients with “Podoconiosis”. Trop. Doct. 14 (1984), podoconiosis in an endemic community 115-119. setting. Trans. R. Soc. Trop. Med. Hyg. 101 33. Davey, G, E GebreHanna, A Adeyemo, et al: (2007), 621-623. Podoconiosis: A tropical model for gene- 44. Sikorski, C, M Ashine, Z Zeleke, et al: environment interactions? Trans. R. Soc. Effectiveness of a simple foot hygiene Trop. Med. Hyg. 101 (2007), 91-96. treatment package in podoconiosis 34. Tekola, F, D HaileMariam, G Davey: management in southern Ethiopia. PLoS Economic costs of endemic non-filarial NTD 4 (2010), e902. elephantiasis in Wolaita Zone, Ethiopia. 45. Davey, G, E Burridge: Community-based care Trop. Med. Int. Health 11 (2006), 1136-1144. of a neglected tropical disease: The Mossy 35. GebreHanna, E: The social burden of Foot Treatment and Prevention Association. podoconiosis and familial occurrence in its PLoS NTD 3 (2009), e424. development. MPH Thesis, Addis Ababa 46. WHO: Health Care for Chronic Conditions University, 2005. Team. Innovative Care for Chronic 36. Yakob, B, K Deribe, G Davey: High levels of Conditions: Building Blocks for Action, 2002. misconceptions and stigma in a community highly endemic for podoconiosis in southern Ethiopia. Trans. R. Soc. Trop. Med. Hyg. 102 Dr. Gail Davey (2008), 39-44. 37. Yakob, B, K Deribe, G Davey: Health Reader in Global Health professionals’ attitudes and misconceptions Brighton & Sussex Medical School regarding podoconiosis: Potential impact on University of Sussex, Falmer integration of care in southern Ethiopia. Brighton BN1 9PS Trans. R. Soc. Trop. Med. Hyg, 104 (2009), Email: [email protected] 42-47. 38. Tekola, F, S Bull, B Farsides, et al: Impact of Tel: +44-1273-877662 social stigma on the process of obtaining Fax: +44-1273-877886 Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY.