Brain Advance Access originally published online on April 15, 2008
Brain 2008 131(5):1402-1407; doi:10.1093/brain/awn069
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Book Review |
‘To sleep, to die’ (with apologies to Hamlet)
Bring Your Medicine if You Like; The One-Eyed Man is King; But Always as Friends. The very titles of the books (Brook, 1966
; Sharwood Smith, 1969; Cox, 2000) are evocative and persuasive; they lead to days long past, to the confidence of an Empire and of its servants, and to costly change in ancient societies. Although the sun has now set on that Empire, its name lives on in the slogans of those for whom its every motive was wrong and for whom its legacy has been doleful. But when the heat of emotion is cooled and the bitter memories of its evident injustices are less sharp, we can today assemble a less hostile picture from the memoirs and chronicles of those who worked as its administrators, agricultural and medical officers, teachers and scientists. What led them to choose work overseas? Was it their family's tradition? Had they failed at home? Were they romantics or uncomfortably seeking a means to prove themselves? There will be many answers, for their stories will reveal much of their writers, still ordinary people, yet pioneers breaking new ground, often as exposed as subalterns in the Somme. Young men had to be responsible far beyond their years and experience, and so they were changed, matured and hardened by the turmoil and contradictions of the cultural front line, from which there was no retreat. There was no glamour in their daily round and common tasks, but the accounts of what they did and how they lived, and died, provide us with an abundant store of fact and of feeling. They did not write narratives as the 19th-century travellers did. While they may have covered some of the same subjects and trodden the same tracks, they wrote as those who were committed to a country and its people, and not merely travelling visitors enraptured by unfamiliar people with unfamiliar ways.
They had tales worth telling and so too has Professor Peter Kennedy, from the University of Glasgow, who has taken up and championed the cause of Sleeping Sickness in Africa with enthusiasm and commitment in The Fatal Sleep. His account is inevitably coloured by the fact that he writes from the standpoint of a valued and respected visitor, a trusted collaborator and colleague, rather than one who has lived for years overseas, as, for example, Professor Brian Greenwood did in his many years of majestic scientific work in West Africa: it is hardly surprising, therefore, that he (Greenwood, 2008) should comment that Kennedy writes with the eye more of the tourist than the resident; his roads have pot holes; much of his Africa is magical. These would not be the comments of those who, like Greenwood, have borne the heat of the day, its hopes and disappointments and its misunderstandings. But Africa still affords rich and enduring friendships, which Kennedy so evidently cherishes through his collaborative work. He is part of that distinguished tradition whereby Glasgow clinicians and scientists did so much for clinical and veterinary medicine in Kenya, not only in trypanosomiasis, but also in the foundation of the University of Nairobi Medical Faculty. In the early 1960s, the then Dean of the Glasgow Faculty of Medicine, Sir Charles Fleming, proposed that a team of Glasgow clinicians should train Kenyan students in Nairobi; the Nairobi Medical Faculty was thus born in 1967 and enjoyed support of resident Glasgow teachers for 6 years.
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Kennedy writes to inform and persuade the lay reader. His interest in Sleeping Sickness arose when Max Murray, his Glasgow colleague in Veterinary Medicine and himself a veteran of work in animal trypanosomiasis in Kenya, heard him lecture on the immunology of a slow virus infection of sheep, visna-maedi, which causes wasting, pneumonia and brain damage; Murray suggested that they could profitably work together. Kennedy was convinced; and 20 years’ subsequent work and the book he has written are the result. He has formed excellent partnerships and is full of justifiable praise for the sophisticated medical and veterinary units in Kenya with which he works and where the disease is studied, monitored and treated. He has chosen to work on one of the great diseases of tropical Africa. Not only is this a true tropical disease, because its vector the tsetse fly is climatically fastidious, but it is also a profound challenge to any African government where the disease is endemic; it is potentially a most significant brake on development, a torpedo to the best rehearsed plans to combat poverty, and a clamp on increased livestock breeding. It is yet another disease in which control may collapse if routine surveillance fails. It can therefore provide a mirror of social and political unrest in Africa.
As I write this review from rural but truly tranquil Ethiopia, where nearly all the patients we have seen are desperately poor, there is bitter internecine killing in its normally peaceful neighbour, Kenya, the focus of Kennedy's affection and endeavour, interest and work; six hundred thousand Kenyans are now classified as IDPs (internally displaced people); tourism may collapse for long enough to damage the economy so that money for basic services will be at risk. If reconciliation is possible and achieved quickly between deeply divided groups, then the country's displaced poor, many in areas at risk for sleeping sickness, may not become its victims. Despite the gloom, there is hope that good sense will indeed prevail; but if it does not, then Kenya will join the sad roll call of Angola, Congo, Sudan and Uganda where civil unrest and war made control of Sleeping Sickness impossible. Common services broke down, endemic disease and notably Sleeping Sickness, became epidemic among the displaced people, and it was not till peace agreements were negotiated, however fragile, that control and treatment could again be established.
The geography of disease in Africa depends so much on the movement of people and on the local ecology. The spread of cholera and of sexually transmitted disease along trade routes are obvious modern examples; the existence of sleeping sickness was first suggested in the fourteenth century by the reports of Caravanners to the Southern Kingdoms of West Africa and later in the Slave Coast of West Africa where ‘a sleepy distemper leading to an untimely death’ was more precisely defined by Thomas Masterman Winterbottom, surgeon to the Sierra Leone Company in Freetown. His name has been given to the sign of palpably enlarged cervical lymph nodes, characteristic of West-African sleeping sickness. Kennedy reproduces Winterbottom's classic description (Winterbottom, 1803):
The Africans are very subject to a species of lethargy which they are much afraid of, as it proves fatal in every instance. The disposition to sleep is so strong, as scarcely to leave a sufficient respite for the taking of food; even the application of a whip, a remedy which has been frequently used, is hardly sufficient to keep the poor wretch awake.... the disease, under every mode of treatment, usually proves fatal within three or four months.Kennedy comments that the spread of sleeping sickness was first documented when camp followers or recruits in Stanley's relief column for Emin Pasha carried the infection with them and introduced it to East and Central Africa, which led to the devastating epidemics of 1898–1900, particularly in the now Democratic Republic of Congo, western Uganda and southern Sudan. This view has been challenged in a study of Sleeping Sickness in the Congo (Lyons, 1992
). Whatever its origin, the result was devastation; in Uganda, village after village fell silent, deserted, empty, so that Felix Oswald (1923), a geologist, was indeed Alone in the Sleeping Sickness Country; what more need be added to a title so full of pathos? It was estimated that over 200 000 people died in the country along the north east shores of Lake Victoria alone, predictable and inevitable when this new infection was introduced to a previously unexposed people (Fig. 1).
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There are two forms of sleeping sickness which is also called Human African Trypanosomiasis (HAT). In East Africa healthy wild animals are the primary host and reservoir and the responsible organism is Trypanosoma brucei rhodesiense, which is transmitted by the bite of the Tsetse fly of the Glossina spp. family. The disease is rapidly fatal but it only accounts for about 10% of cases of sleeping sickness in Africa. In West Africa, the disease is less aggressive so that its clinical course is more protracted, but it is still inevitably fatal, if untreated. Its reservoir is among infected people, and also in pigs, goats and dogs rather than the wild animals of the East-African type; and the organism is Trypanosoma brucei gambiense. The organisms are named after Sir David Bruce, who is just one of the great names in tropical medical research who have helped to define the cause of the disease. It was the devastation in the herds of cattle in 1894 in Zululand, caused by Nagana, a virulent wasting disease, which prompted the Governor of the Province to call on Dr Bruce, as he then was, to bring his formidable skills to the problem of the cattle. Kennedy describes sympathetically how Bruce demonstrated trypanosomes in the blood of diseased cattle, inoculated these protozoan organisms into healthy cattle, and finally established their reservoir in wild animals and their transmission by the bite of the tsetse fly into the domestic cattle.
The next advance and the next great name to be engaged in the study of sleeping sickness was again in response to the devastation caused by the infection, but this time it was the decimation of the Ugandan population by sleeping sickness; the Royal Society responded in 1902 by sending its first Sleeping Sickness Commission, of which Aldo Castellani was the key figure; he was aged 24. His classic paper begins with a gentle understatement (Castellani, 1903); he wrote—
On the 12th November 1902, when examining a specimen of cerebrospinal fluid taken by lumbar puncture during life from a well-marked case of Sleeping Sickness, I was surprised to observe a living Trypanosoma. Since that date I have made as many observations in this direction as possible and the results are to my mind sufficiently surprising to excuse me for presenting this preliminary note.Because he also found streptococci in some late cases, Castellani's results were received with some scepticism in London and so the Royal Society sent its Second Commission, which included Bruce. He was there to help Castellani with his studies, but his going proved to be the seed of dispute. Bruce thought that, until he arrived to help him, Castellani had not truly grasped the significance of the trypanosomes which he had demonstrated in the CSF of patients with sleeping sickness. Kennedy has examined the evidence and is in no doubt that Castellani deserves to be recognised as the one whose discovery was indeed ‘a fundamental landmark in the history of tropical medicine’.
The third great name is Dr Everett Dutton, after whom Borrellia duttoni is named. He had been sent from the recently established Liverpool School of Tropical Medicine to Gambia where, in 1902, he identified a new species of trypanosome in the blood of a European, ill with a fever. He named it Trypanosoma gambiense and thus Dutton identified the organism responsible for the West-African type of sleeping sickness. The final great names were two young physician scientists in the 1970s, at Ahmadu Bello University, Zaria, Nigeria, who reawakened interest in the clinical science of the disease. Brian Greenwood and Hilton Whittle, who later continued their outstanding partnership at the MRC Laboratories in the Gambia, were studying major local infections. Their first laboratory was a converted thatch roofed kitchen and their focus of T. b. gambiense was in the Tiv country around the Benue River. Puzzled at the characteristically very high IgM in the CSF of their patients, they labelled the IgM (Greenwood, 1973) and showed it was derived from another hall-mark of the disease, the morular cells of Mott (1906), plasma cells which Mott had first identified in his work for the Sleeping Sickness Commission in Uganda (Fig. 2). During his studies, Hilton Whittle introduced me to cases of late gambiense infection; one of these was a teenage boy from the Benue valley who was brought to Zaria for treatment; he had been the fat boy of the village, benign and mentally weak, a clinical contrast to the ravages of late disease or the cachexia of the rapidly advancing rhodesiense infection.
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The original reports of the Sleeping Sickness Commissions are absolutely fascinating. The scientific papers, distinctive with just one or two authors, include meticulous notes about individual patients, careful charts of body temperature and heart rate, and photographs of the ecology of the area and thus of the preferred breeding places and habitats of the tsetse fly. To add to the delight of reading such classic reports, the original coloured lithographs of the trypanosomes are beautifully drawn, accurately coloured and printed on heavy paper (Fig. 3).
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Studies of the fly have shown that there are 31 species of the genus Glossina which are restricted to Africa; in the appropriate but not burdensome detail which characterizes his book, Kennedy describes the three groups, which are broadly based on the habitats where they are found: the fusca group in the forests of Central and West Africa; the palpalis group in riverine and wet habitats and also forested areas throughout Africa; and the morsitans group in the broad savannah. T. b. gambiense is transmitted by G. palpalis, G. fuscides and G. tachinoides while T. b. rhodesiense is transmitted by G. morsitans, G. pallidipes and G. swynnerton. It is not possible to be certain that some species are restricted to transmission of human and some to animal parasites. The climatic demands of the fly account for the distribution of the disease and, when linked to human behaviour, beautifully illustrate that man–fly contact is absolutely fundamental in the genesis of sleeping sickness. In a limited outbreak in the north guinea savannah of Nigeria, Ford, in his splendid book, describes how some hill people migrated to the flat savannah and built their thatched homes near the walled village of settled people, with their traditional clay Hausa houses and their own deep wells (Ford, 1971
). The migrants had to draw water during the dry season from pits in the sand of a dry river bed; the women put their calabashes into pits in the shade of mango trees and waited patiently for them to fill with the clean sand-filtered water. But, as they waited, the tsetse found their optimal temperature, protected by the shade of the trees and abetted by the ideal 40–60% humidity of the water hole. Thus, unusually for a sleeping sickness outbreak, the 10 cases among the migrants were equally divided between women and men, but the settled village had only one case, a man hunter. Animal trypanosomiasis has been known for centuries and was seen by Livingstone in a mare which was wasted and to which he gave an arsenical drug for a week; he reported the case in the British Medical Journal in 1848. The animal got better initially but then relapsed. Kennedy quotes sombre data about the impact of tsetse on cattle husbandry in Africa; he gives two conflicting figures for the area infested with the fly, 7 million and 10 million sq km. If the fly could be eradicated from the 7 million sq km, where only 30 million cattle are being raised now, it could support as many as 120 million cattle. What should a pastoralist do if he suspects that his cattle have become infected? Ideally he will get the animals tested for the presence of trypanosomes, but if he is far from a testing centre, and when his and his family's livelihood depends on healthy animals, he will buy what drugs he can and treat them. Almost inevitably, perhaps, unscrupulous manufacturers have marketed drugs which are not active and, even if he gets efficacious drugs, he may be unable to afford all that the cattle need, so that resistance may follow in one or more of the only three drugs that are available. Here the science of the Glasgow team has shown that such resistance is related to a surface membrane defect in drug resistant T. brucei. The team has also studied the phenomenon of trypanotolerance whereby after infection some herds of cattle do not develop anaemia and persistent parasitaemia. Now if such cattle, genetically armed against the trypanosome, can be crossed with other local breeds, there is hope for the pastoralist and for his cattle, which are so very important in the rural economy of much of Africa. In a hungry poor world, action against the fly is therefore a powerful agent against undernutrition and its associated poverty. It is a crippling shame that such potential bounty for the poor cannot be realized, and that such natural resources should not be used and used for the benefit of the people of Africa where the growth of population is not being matched by sustainable food security. As so often in the medicine of Africa, it is puerile to adopt a limited biomedical approach to the prevalent diseases and to their threat to health and wellbeing, as they are so often closely related to, and thus influence, both human and economic development.
The clinical picture of sleeping sickness is very wide. The rhodesiense infection has greater systemic effects than gambiense infection and Kennedy relates how it may lead, for example, to myocarditis and cardiac failure and to signs in many body systems. After the bite of the fly, trypanosomes enter the lymphatics and become blood borne. They are able to survive and evade the host's immune response because of their ability to vary the antigens on their surface through their variant surface glycoproteins (VSG). When, after a variable period, they are able to cross the blood brain barrier, the encephalitic phase of the infection develops. As Kennedy notes, this phase may resemble the neurological presentations of HIV/AIDS—a bewildering galaxy of symptoms and signs. Then the changes in sleep cycle develop, with associated alterations in personality and behaviour. Sleep phases are reversed so that REM occurs early, rather than late in sleep as normal; the rhythm of nocturnal somnolence is replaced by sleep during daylight hours. Kennedy quotes recent work which may, by analysis of sleep patterns, be useful in early diagnosis. And the definition of early sleeping sickness is crucial: it demands much further work because early treatment, before the trypanosome has entered the CSF, can prevent the feared complication of post-treatment reactive encephalopathy (PTRE). This occurs in 10% of late cases treated with melarsoprol and has a 50% mortality.
This is not a dry academic book, rather it reveals a clinical scientist who delights in his work and who shares his enthusiasm with his readers. His team has begun to unlock the mechanisms of sleeping sickness and of PTRE. The team will doubtless add much more, which could lead to the development of novel drugs to target the parasite, but also to the understanding of the blood brain barrier, through studies of their very successful mouse model.
Although patients with sleeping sickness have been described as non-existent in market terms (Stich, 2004), so that they were formerly ignored by the big pharmaceutical companies, this is no longer so. Kennedy has shown what can be done by those at the front line, notably by Médecins sans Frontières who have worked with WHO to bring the disease and its needs before major donors and the scientific community. The result has been the Drugs for Neglected Diseases initiative (DNDi), which is now the focus for work for public–private partnerships in drug development. This initiative neatly complements the 5-year donation by Sanofi Aventis of drugs needed for treatment of cases in Africa.
This is excellent news for the science of sleeping sickness and for the treatment of those who have the disease, but, as so often in the medicine of Africa, there is a wider and a deeper tension. It is not sufficient that there is a supply of the necessary drugs; there must also be a comprehensive sleeping sickness service, able to identify early cases, give the drugs and monitor their effects. Kennedy enriches us with the science, but a control programme for sleeping sickness depends not only on diagnosis and treatment of patients, and active case finding with control of the vector, but also on sustained surveillance and education of the community, which must therefore be stable and so able to take its part. Science is alone if it is not married to political stability, attended by social stability without movement of people, responsible government and a strong infrastructure in the health service. Where the health service staff are not adequately rewarded, so that they are motivated and feel valued and wanted, all the advances of science will be of scant benefit. The story of countries where sleeping sickness prevails illustrates this cogently; the steady rise from the trough of incidence and prevalence towards the end of the last century makes the previous sentence an understatement. War and disruption, greed for natural resources from within and outside the affected countries, with a lack of international leadership, led to a surge of cases and the crisis of treatment and control which have at last been addressed and largely overcome. But the very countries where the disease prevails are among those which Paul Collier so clearly characterizes in The Bottom Billion (2007) as the least likely to remain stable—having a history of civil war, poor governance, and endowment of rich natural resources, and being landlocked; continued surveillance, therefore, is absolutely fundamental if sleeping sickness is not again to become epidemic.
This review cannot close with fear and foreboding, but with hope, because that is how Kennedy sees his work and its effects on patients with this once dreaded disease. He has also introduced a wider and strategic horizon—North–South partnerships, or links between institutions in Africa and their counterparts in the United Kingdom, through scientific, clinical and field collaboration. Kennedy extols the expertise of the teams and institutes in Kenya who are dedicated to their work in sleeping sickness and to the training of their staff. He shows how their work has been enlarged and complemented when harnessed to the additional laboratory expertise in Glasgow, just as Glasgow has enjoyed rich benefit through the collaboration with Kenya. The benefit has not merely been through the scientific challenge of dissecting the mechanisms of disease caused by trypanosomes in the nervous system, but also through their contribution to health and development in Africa. In such collaborative work, both partners can be winners. If Kennedy's book not only awakens readers to the problems of sleeping sickness but is the catalyst for new partnerships between North and South, it will have succeeded far beyond its original, and in this wider sphere, more limited aim.
THET, 1 Wimpole Street, London W1G 0AE and
London School of Hygiene and Tropical Medicine
References
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Castellani A. Presence of Trypanosoma in sleeping sickness in Royal Society. Rep Sleeping Sickness Commission (1903) 1:3–11.
Collier P. The bottom billion. (2007) Oxford: Oxford University Press.
Cox PSV. Bring your medicine if you like. (2000) Leeds: E Cox.
Ford J. The role of the Trypanosomiases in African ecology: a study of the tsese fly problem. (1971) Oxford: Clarendon Press.
Greenwood B. The sleeping giant. Br Med J (2008) 336:159.
Greenwood BM, Whittle HC. Cerebrospinal-fluid IgM in patients with sleeping-sickness. Lancet (1973) 2:5–7.[Medline]
Lyons M. The colonial disease: a social history of sleeping sickness in northern Zaire 1900-1940. (1992) Cambridge: Cambridge University Press.
Mott FW. Histological observations on sleeping sickness and other trypanosome infections Royal Society. Rep Sleeping Sickness Commission No. VII (1906) 15. (pl 1-XI): 1–45.
Oswald F. Alone in the sleeping sickness country. (1923) London: Kegan Paul Trench Trubner.
Sharwood Smith B. But always as friends: Northern Nigeria and the Cameroons 1921-1957. (1969) London: George Allen and Unwin.
Stich G. African Trypanosomiasis. In: Principles of medicine in Africa.—Parry E, Mabey D, Godfrey R, Gill G, eds. (2004) 3rd. Cambridge: Cambridge University Press. 475–88.
Winterbottom TM. An account of the native Africans in the neighbourhood of Sierra Leone; to which is added, An account of the present state of medicine among them. (1803) London: Hatchard and Mawman.
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