260 PRACTICAL NEUROLOGY REVIEW Sleeping sickness Pract Neurol: first published as on 1 October 2005. Downloaded from http://pn.bmj.com/ on September 28, 2021 by guest. Protected copyright. – human African trypanosomiasis © 2005 Blackwell Publishing Ltd OCTOBER 2005 261 Peter G. E. Kennedy Burton Professor of Neurology, Head of University Department of Neurology, Division of Clinical Neurosciences, University of Glasgow, Institute of Neurological Sciences, Glasgow, UK; E-mail: [email protected] Practical Neurology, 2005, 5, 260–267 Pract Neurol: first published as on 1 October 2005. Downloaded from INTRODUCTION 1996). Infected animals, usually wild and domestic cattle, are the One of the great advantages of working with veterinary col- reservoirs for the parasites causing HAT leagues is the insight they often bring to the pathogenesis of human disease through their studies of natural animal diseases EPIDEMIOLOGY and animal models. In 1988 Professor Max Murray of the Univer- The global importance of HAT is not generally well known, but it sity of Glasgow Veterinary School introduced me to the problem is in fact considerable. Indeed, we coined the term ‘Cinderella dis- of African trypanosomiasis in animals, its close relationship to ease’ to highlight the relative lack of research interest and funding its human counterpart that is known as sleeping sickness, and for HAT despite the fact that it is a major threat to human health, the unsolved problems of neurological involvement in that con- and invariably fatal if untreated (Kennedy et al. 2002). dition. We have now been investigating the neuropathogenesis The disease occurs in 36 countries in sub-Saharan Africa, and of human African trypanosomiasis (HAT) in the laboratory and about 60 million people are at risk of developing it world wide the African fi eld for the last 16 years (Fig. 1). Neurologists will (WHO 1986). The incidence is diffi cult to determine precisely, realize of course that HAT is not to be confused with the other but a likely fi gure is at least 300 000 cases annually, and probably ‘sleeping sickness’ known as encephalitis lethargica, famous for more. About one-third of the entire African land mass is infested the pandemic during the fi rst quarter of the 20th century, and with the tsetse fl y, which makes farming in these areas impos- which still occurs sporadically. While the cause of the latter dis- sible. ease has yet to be discovered (although many suspect a virus as There are two types of HAT – West African sleeping sickness the culprit), the cause of HAT has been known for over a century. caused by Trypanosoma brucei (T.b) gambiense, and East Afri- In 1899, Sir David Bruce identifi ed a protozoan parasite known can sleeping sickness caused by T.b.rhodesiense. The geographi- as Trypanosoma brucei as the cause of the disease in cattle in Zu- cal distribution differs considerably (Fig. 2). The tempo of the http://pn.bmj.com/ luland. The trypanosome is transmitted by the bite of the tsetse two forms of the disease is different too. Rhodesiense infection fl y of the Glossina species. Within 10 years of that discovery, the is acute with early CNS involvement 3–4 weeks after the ini- trypanosomes causing human disease in Africa were identifi ed tial bite, with death in weeks to months, whereas gambiense is with the seminal descriptions of trypanosomes in the blood and slower with later involvement of the CNS and a chronic course cerebrospinal fl uid (CSF) by Aldo Castellani in 1903 (Williams of months to years until death (Atouguia & Kennedy 2000). on September 28, 2021 by guest. Protected copyright. Figure 1 The author and his colleague Dr Joseph Sulo at the Alupe Figure 2 The distribution of the two types of human African Sleeping Sickness Treatment Centre in the Busia district of North- trypanosomiasis (reproduced with permission from Atouguia & western Kenya. Kennedy 2000). © 2005 Blackwell Publishing Ltd 262 PRACTICAL NEUROLOGY The incidence and mortality from HAT have meal’. They are transmitted to the human host varied considerably over the last 100 years. The through biting (Fig. 3). About 5–15 days after disease was nearly brought under control in the the bite, a painful circumscribed primary skin 1950s, and had almost disappeared by 1962, lesion known as a trypanosomal chancre usually but since then the incidence and mortality have develops following which the parasites spread Pract Neurol: first published as on 1 October 2005. Downloaded from steadily increased. There are many possible rea- through the bloodstream to the lymph nodes sons for this increase, and the periodic epidem- and other organs such as spleen, liver, heart, ics and very localized outbreaks in various parts endocrine system and eye (Duggan & Hutch- of Africa. A prominent factor for the periodic ington 1966; Atouguia & Kennedy 2000). Un- re-emergences has been a breakdown of disease treated, the parasites then cross the blood–brain surveillance, especially during wars when public barrier and invade the CNS. Without treatment health systems become disrupted, even though an infected individual will invariably die. during these periods one might expect less re- A critical feature of the trypanosomes is their porting of the disease. Other factors have also remarkable ability to undergo antigenic vari- played a part including changes in host suscep- ation and thereby to constantly evade the im- tibility, changes in parasite virulence and drug mune response of the host resulting in waves of resistance, variations in climate and vegetation, parasitaemia (parasites in the blood). The mo- and geographical changes in animal reservoirs lecular basis of this phenomenon is essentially (Kuzoe 1993). due to a constant variable surface glycoprotein (VSG) gene switching process, which causes SUMMARY OF THE RELEVANT rapid changes of the VSGs distributed over the PARASITE BIOLOGY surface of the parasite, making it impossible to For a detailed account of the general and mo- develop an effective vaccine (Barry 1997; Donel- lecular biology of HAT the reader is referred son 2002). to our recent reviews (Atouguia & Kennedy 2000; Kennedy 2004). In brief, after the tsetse CLINICAL FEATURES fl y feeds from an infected animal, the trypano- There are two stages – the early or haemolym- http://pn.bmj.com/ somes undergo a complex series of structural phatic stage, and the late or encephalitic stage. and biochemical changes in the fl y’s midgut. The range of systemic features that may be seen Once the parasites reach the fl y’s salivary glands in the early stage is summarized in Table 1. The they are infective, about 21 days after the ‘blood fi rst symptoms, which are more non-specifi c on September 28, 2021 by guest. Protected copyright. Figure 3 Tsetse fl y biting a human arm. © 2005 Blackwell Publishing Ltd OCTOBER 2005 263 Table 1 Non-neurological features of human African tis and facial oedema in addition to the primary trypanosomiasis (modifi ed from Atouguia & Kennedy chancre also occur. Cardiac involvement may be (2000) with permission) indicated by tachycardia and a variety of cardiac abnormalities. A range of endocrine disturbanc- Pract Neurol: first published as on 1 October 2005. Downloaded from Systemic features es has also been described (Atouguia & Kennedy Fever 2000). Eye involvement such as iritis, keratitis Debility and conjunctivitis is well recognized (Atouguia & Headache Kennedy 2000). Other visual disturbances occur Facial oedema due to CNS involvement (see below). Anaemia (mainly haemolytic) The late stage features of HAT can be conven- Lymph node enlargement iently grouped into psychiatric, sleep disorders, Skin motor, sensory, abnormal refl exes and ophthal- Rash mic. As can be seen from Table 2, a wide range of Chancre psychiatric symptoms, some of them quite non- Pruritis specifi c, have been described and early symp- Gastro-intestinal features toms may be subtle making the diagnosis very Hepatic dysfunction and hepatomegaly diffi cult. The CNS symptoms usually emerge Splenomegaly within a few weeks of infection in rhodesiense Heart disease but over the course of several months Early tachycardia Myocarditis Table 2 Neurolgical features of human African Congestive cardiac failure trypanosomiasis (modifi ed, with permission, from Pericarditis Atouguia & Kennedy (2000)) Endocrine dysfunction Menstrual disorders, sterility and abortion Psychiatric and mental disturbances Premature still births Lassitude and indifference http://pn.bmj.com/ Loss of skin hair Anxiety and irritability Loss of libido and impotence Mania and agitation Gynaeacomastia Violent and suicidal behaviour Testicular atrophy and orchitis Uncontrolled sexual impulses Eye Hallucinations and delirium Iritis Sleep disturbances on September 28, 2021 by guest. Protected copyright. Iridocyclitis Daytime somnolence Keratitis Nocturnal insomnia Conjunctivitis Uncontrollable urges to sleep Choroidal atrophy Motor disturbances Pyramidal signs Extrapyramidal – abnormal movements and such as malaise, fever and fatigue (Apted 1970), The patient may tremors occur 7–21 days after the initial bite in rhode- Muscle fasciculation siense infection, and usually some weeks longer feel relatively Slurred speech than that in gambiense infection (J. Atouguia, Cerebellar ataxia personal communication). Episodes of fever, and well between Neuritis and polyneuritis also generalized lymphadenopathy, are typical Sensory disturbances and the fever may be associated with headache, these febrile Pruritis rigors and vomiting. The patient may feel rela- Paraesthaesia, hyperaesthesia, anaesthesia tively well between these febrile episodes, which episodes, which Abnormal refl exes not surprisingly are often misdiagnosed as ma- Pout refl ex laria. Splenomegaly and liver dysfunction may not surprisingly Palmo-mental refl ex be apparent and a variety of skin symptoms may Visual involvement occur such as rashes. In particular, an evanescent, are often Double vision circinate and macular skin rash has been de- Optic neuritis scribed over the trunk, shoulders and thighs and misdiagnosed as Optic atrophy is thought to be a specifi c early sign in European Papilloedema patients (Duggan & Hutchington 1966).