A Wake-Up Call About Sleeping Sickness

Sleeping sickness. For many readers, the words conjure up images of a mysterious and terrifying disease of the jungle and veldt, afflicting intrepid Western explorers and rural native Africans with scant access to medical care. That image is not entirely inaccurate, but this disease is staggeringly widespread and its potential for harm is no longer limited to Africa. Fortunately, it is also only partially true that sleeping sickness remains mysterious. Decades of research, recently accelerated by the first infusions of significant financial support, have begun to lay bare the mechanism by which the disease mounts its attack, including the final wholesale assault on the brain. No vaccine is in view, but new treatments are nearing the clinical stage. If success comes, it will be none too soon for Africa, which is desperately in need of the economic resources still held in check by the threat of sleeping sickness, or for other parts of the world, which are now discovering how easily illnesses can travel across borders and even oceans.

Human African trypanosomiasis—the medical name for sleeping sickness—is a major killer in 36 countries in sub-Saharan Africa.¹ Sixty million people are at risk, and, although difficulties in obtaining an accurate count of new cases makes estimates necessary, about 300,000 people develop the disease annually. It is caused by a single-celled parasite called a trypanosome, which is transmitted by the bite of the tsetse fly. Only a few of the more than 20 species of tsetse fly transmit the disease, but a third of the entire land mass of the continent is held captive by these species of tsetse fly. Farming is impossible or severely affected in these areas because the disease also affects animals, including domestic cattle. A tragedy for the African people in turn deprives the world’s economy of Africa’s huge and largely untapped potential.

By the early 1950s, sleeping sickness was under relatively good control through systematic surveillance of the at-risk population and measures to contain the tsetse flies that transmit the disease to humans. Now, it has reemerged as a major threat to health, with waves of new outbreaks and epidemics. There are many causes for this resurgence. In particular, the spread of warfare across Africa has caused keeping track of cases, as well as controlling them, to break down. Other factors leading to new outbreaks are the emergence of more virulent parasite strains, changes in climate and vegetation, and movements of groups of animals that are carriers of the disease.² For many years, successive governments of many African nations have failed to allocate adequate financial resources to the problem, and, until very recently, Western governments and private institutions had showed little interest.

The Sleep from Which You May Never Awaken

For centuries, sleeping sickness was recognized in Africa as a fatal human disease that affected normal sleep behavior, but its cause was not discovered until the late 1890s and early 1900s. Sir David Bruce, working in Zululand in southern Africa, carried out careful studies in domestic and wild cattle affected by a fatal disease called “nagana.” He concluded that the disease in both types of cattle was caused by a particular protozoan trypanosome (which was named Trypanosoma brucei after him) and that it was transmitted by the bite of the tsetse fly.³ Other pioneers soon identified very similar trypanosomes as the cause of sleeping sickness in humans and discovered that they could infect the central nervous system. A little later, scientists recognized that there were two main forms of the African disease, an East African form caused by the protozoan parasite Trypanosoma brucei rhodesiense and a West African form caused by Trypanosoma brucei gambiense. Both parasites are transmitted by the tsetse fly. Infected wild and domestic animals, especially cattle, are the reservoirs, or carriers, for parasites causing the human disease.

If you have read about the 1916-1927 worldwide pandemic of encephalitis lethargica, you might know that it was another kind of “sleeping sickness” and that, in some cases, it led after many years to a crippling and chronic disease known as post-encephalitic Parkinson’s disease, eloquently described by Oliver Sacks in Awakenings. But human African trypanosomiasis is a different disease and affects the brain in a very different way. Although protozoa are single-celled organisms, the simplicity is deceptive because they can be enormously complex in both structure and cellular machinery. Some, including the one that causes sleeping sickness, are consummate little predators with an uncanny knack of evading the protective immune responses of their hosts.

When an infected fly bites its human victim, the trypanosomes enter and multiply in the bloodstream and soon infect organs such as the spleen, liver, lymph nodes, skin, heart, eyes, and endocrine system. A few of the symptoms and organ malfunctions at this stage are rashes, heart failure, jaundice, and blindness.⁴ Untreated, the disease invariably kills. If the patient is not treated at this early stage, the parasite invades the central nervous system (a process that takes longer in the West African than the East African form of the disease). A vast array of neurologic problems can follow. Early on, there can be psychiatric symptoms such as agitation, lassitude, indifference, irritability, uncontrolled sexual impulses, and violence. Motor system disturbances can include tremors, limb paralysis, muscle twitching, and slurred speech. In addition, many people experience unpleasant and painful sensations in their arms and legs.

The sleep disturbances that give the disease its name are very characteristic. Typically, the unfortunate patient has an uncontrollable desire to sleep at any time, although, paradoxically, he could suffer insomnia at night. Monitoring the sleep and recording the brain waves of such patients with an electroencephalogram reveal characteristic disruptions of normal, healthy sleep-wake patterns. These changes disappear if the patient recovers. Otherwise, in the final stages of the illness, the urge to sleep is continuous, and there are seizures, brain swelling, incontinence, coma, and, ultimately, death.

The only effective treatment for the central nervous system phase of the disease is the arsenic-based drug melarsoprol, which, unlike many medications, is able to cross the protective blood-brain barrier. Unfortunately, in about 10 percent of cases, treatment with this drug leads to a severe brain inflammation, known as post-treatment reactive encephalopathy, or PTRE. As many as 50 percent of patients with PTRE (and therefore 5 percent of sleeping sickness patients with central nervous system involvement) will die despite treatment. These are lamentable figures for any disease.

Out of Africa

My colleagues and I have been investigating the causes and treatment of sleeping sickness in Africa for the past 15 years, but the implications of exotic diseases such as malaria and sleeping sickness are global. Apart from the economic ramifications in both Africa and the rest of the world, these diseases, like SARS (severe acute respiratory syndrome) and West Nile viral infection of the nervous system, can travel outside their own natural territory.

Malaria, of course, is familiar to people in North America and Europe. This familiarity is not only because of its reputation for killing millions of people worldwide, but also because some Western tourists to Africa, distressed by the preventive medication’s side-effects, such as nausea, abdominal pain, and psychiatric symptoms, or unaware of the great dangers of stopping medication, unwisely discontinue their antimalarial tablets and develop the disease weeks after their return home. A few die of its complications. Malaria is also an occupational hazard for soldiers who are deployed in the tropics. A stunning example of this hazard was reported in the Washington Post on Sept 10, 2003. Two hundred American marines who returned from service in Liberia in West Africa developed malaria, and 43 of them were ill enough to be hospitalized. Although none of the soldiers died, two of them developed cerebral malaria, the most dangerous form of the disease and one that has a 20 percent mortality rate. Why so many soldiers developed the disease despite taking appropriate preventive antimalarial tablets is not known for certain, but it seems likely that their blood levels of these preventive drugs were not adequate. A constant threat to travelers to Africa is that malaria parasites will develop resistance to these drugs, but no convincing evidence of resistance is apparent in the case of the soldiers.

Sleeping sickness is more exotic to us than malaria, but that perception could change. Global business and increasing tourism in Africa, together with easier and more accessible air travel, carry a real risk of Western travelers returning home with sleeping sickness. Several cases of Europeans developing this disease have appeared in the medical literature. Travelers from the United States and other Western countries, as well as from Asia, are also vulnerable because their increasing numbers and time in Africa raise the odds of contact with the tsetse fly. Western health care systems are ill prepared for this eventuality, despite warning shots across our bow. In 2000, for example, the medical press gave considerable publicity to the story of a traveler with sleeping sickness, recently back in London from Africa, for whom no treatment could be found at first. Luckily, medical authorities did eventually obtain and administer the required drug, called suramin.

Fortunately, there are signs that the situation could be changing. In that same year, the Bill and Melinda Gates Foundation awarded $15.1 million to an international research consortium with teams in America, Africa, and Europe to seek more effective drug therapies for African sleeping sickness (along with another killer disease in Africa called leishmaniasis). The National Institutes of Health in the United States also provides some funding for research into sleeping sickness, as does the Wellcome Trust research philanthropy in the United Kingdom.

One Man’s African Journey

Some people fall in love with Africa from storybooks, or movies, or a charismatic teacher. This wasn’t the case for me. Growing up in England, I developed a keen interest in biology field work in the sixth form at school (equivalent to the last year of high school in the United States) and, because of the efforts of an enthusiastic biology teacher, became enamored of the study of animal habitats. Later, as a medical student at University College Hospital in London, I had only minimal exposure to infectious diseases—although I vividly recall narrowly failing to win a pathology prize examination through failure to recognize human African trypanosomes on a blood slide. It was only at the tail end of my student career that the door to Africa swung open. Medical students in their final year at University College Hospital customarily took a two- to three-month elective devoted to experiencing medicine in another country, usually in Africa or North America. My best friend and I were eager to do our electives in Africa and fortunate to be accepted for a stint at a mine hospital in Zambia.

At the age of 22, one is very impressionable, and the influence of my two months in Africa was immense. We were stationed in a town called Chililabombwe in Zambia’s copper belt. Our hosts, a former lecturer in anatomy from our London hospital and his wife, treated us like family, and we were warmly welcomed by the close-knit expatriate community, most of whom were connected with the town’s copper mine run by the Anglo-American Company. My friend and I were assigned to the mine’s hospital, a well-equipped facility staffed by seven medical officers, several of them also surgeons. These doctors dealt with an impressive range of ills and soon became exceptionally versatile. The problems they confronted could be devastatingly severe, including acute malnutrition and its consequences in children; incapacitating pneumonia in children and adults; Burkitt’s lymphoma; tuberculosis; malaria; the occasional snake bite; severe trauma occasioned by traffic accidents; mine accidents; burns; crocodile attacks; meningitis; difficult obstetric complications; tropical ulcers; trachoma-produced blindness; polio; and cases of measles—a dangerous condition in this community because of the ever-present possibility of developing a deadly pneumonia.

We also rotated through one-week stints in specialties such as public health, when we sprayed insecticide on stagnant ponds to kill the malaria-bearing mosquitoes, and the hospital’s pathology laboratory and pediatric wards. Despite this rotation, and despite mini-safaris to other regions, I cannot recall encountering a single case of sleeping sickness. We were sad indeed to leave at the end of the two-month elective, and before we left we made an adventurous journey that included the historic town of Livingstone, with its awe-inspiring Victoria Falls, and Nairobi, Kenya, with which I formed an immediate and lasting bond. I was enchanted by Nairobi’s physical beauty—its modern buildings, trees, and beautiful flowers—and the friendliness of its people.

My affair with Africa ultimately would span some 28 years (to date) and 17 separate visits, with the past 15 years spent mainly in Kenya studying sleeping sickness. But after my initial visit I spent 14 years wondering when I would see the continent again. The wondering came to an end in 1988 when, as a recently appointed young professor of neurology at Glasgow University, I came to the attention of the charismatic Max Murray. Murray, then chairman of the Veterinary Medicine Department, had spent 10 years as head of a pathology unit in ILRAD, near Nairobi. ILRAD (now ILRI) was an acronym for the International Laboratory for the Study of Animal Diseases and was, and still is, one of Africa’s most eminent scientific institutions. After a lecture I delivered on slow viruses in sheep, Murray invited me back to his office and spent an hour, complete with slide show, describing to me the extent of the problem of African trypanosomiasis in both humans and animals and the challenges it presented. He had a particular concern with how the trypanosomes produce brain disease.

Murray’s office, like his home, was adorned with African art. It reignited the interest in Africa kindled in me years earlier, and I became hooked for life on the problem of sleeping sickness. Murray and I became the closest of friends and colleagues, united in our passion for Africa and its future. We immediately prepared a grant application to what was then known as the European Economic Community (the forerunner of the modern European Union) to support research on immune mechanisms in a mouse model of PTRE (work I will describe later), and it was funded. We recruited a superb postdoctoral scientist, Chris Hunter, and our small group, which grew to include Frank Jennings, who had developed the mouse model, and Barbara Bradley, a gifted animal technician, began making observations on the disease.

In 1988, I finally returned to Africa with Murray and Jennings to attend an important conference in Nairobi on African trypanosomiasis. The meeting was at KETRI, the Kenyan Trypanosomiasis Research Institute, which is supported by the government, whereas ILRAD was funded by the Consultative Group on International Agricultural Research (CGIAR). On that trip, I encountered Joseph Ndung’u, a highly gifted young scientist who was also completing a doctoral degree in Glasgow with Murray. Within a few years, Ndung’u would become director of KETRI, and our paths in Africa would converge in ways neither of us could have imagined. During this single, week-long visit, I learned much about African trypanosomiasis and began to grasp just how much international scientific talent was involved in this field. I also began to fathom the importance of control of human-tsetse fly contact by measures in the field and met other people who would become important to our work in Kenya.

The Alupe Treatment Center

Learning about a disease from papers and textbooks is always very different from seeing the real thing, in real people, especially in Africa. For me, this learning happened, above all, in the Alupe Treatment Center for human sleeping sickness in the Busia district of Western Kenya. KETRI, which I had visited on my first return to Africa in 1988, had been established by the Kenyan government a decade earlier with the goal of “carrying out research into all aspects that would eventually lead to the effective control of human and animal trypanosomiasis and to effective reclamation of tsetse-infected lands.” In line with this mission, KETRI embraces laboratory, clinical, and epidemiologic research. Although KETRI’s headquarters are in Muguga, about 25 miles west of Nairobi, it has associated field stations, one of which is Alupe. Another, its Nguruman field station, some 60 miles southwest of Nairobi, works on cattle in close association with the local Masai villagers. Its Galana Ranch is in the coastal region.

Originally set up with the help of the U.S. Walter Reed Army Institute, the Alupe field station served as a general hospital for the local population, including the provision of care for people with leprosy, until 1991, when the sleeping sickness unit was inaugurated. A few years later, my longtime friend Ndung’u became director of KETRI, which since then has gone from strength to strength under his leadership, and I have visited Alupe every year since 1999 with Ndung’u as my host and guide. The journey by Land Rover from our base in Kisumu, on the shore of Lake Victoria, to Busia is dangerous and hair raising because of the appalling pot holes in the roads. But once we arrive in Alupe everything changes, and it feels like floating into an oasis of calm. Alupe is only five miles from the border with Uganda and is a major location for sleeping sickness.

During the year of an outbreak of sleeping sickness, Alupe might see up to 100 cases, but in most years it is far fewer. Some patients walk in from across the border after the diagnosis is made, usually by finding the trypanosomes in the blood when it is examined under a microscope. There are also 100 or more cases treated annually in the sleeping sickness unit in LHRI (Livestock Health Research Institute) in Uganda, located a few minutes away from the border, and I recently visited that unit. That year was particularly busy at LHRI because of the increase of newly infected cattle herds. During our 2000 visit to Kenya we also went to the village of Akajonit in Busia where 17 of 460 inhabitants were affected with sleeping sickness, a much higher than average percentage. One of these inhabitants was a child of four, severely brain damaged following CNS sleeping sickness, who walked, talked, and behaved like a child of two.

If patients are treated early in the disease with the drug suramin, then the central nervous system phase can be prevented. Unfortunately, many patients assume that they have malaria or some other infection and get to the hospital only very late in the illness. In fact, antimalarial treatment can temporarily reduce fever from sleeping sickness, so the unsuspecting patient even goes back to work. Also, I was intrigued to note that several patients in the early phase reported suffering from double vision, which struck me as odd because they did not have any overt eye problems, although such symptoms generally indicate involvement of the central nervous system. This anomaly is just one of the kind that you encounter in the field but not in textbooks.

The drug melarsoprol is given promptly when it is clear that the central nervous system is involved, which is usually obvious both from the symptoms and from the presence of the trypanosomes in the cerebrospinal fluid. No facilities for electroencephalography, computed tomography, or magnetic resonance imaging scanning facilities are available at Alupe, so everything is based on interviewing and examining the patient and doing a routine check of blood and cerebrospinal fluid.

Alupe staff members are highly experienced in management of PTRE, the severe brain inflammation that can result from arsenic-based drugs such as melarsoprol. It is treated with steroids to reduce the inflammation and brain swelling, anticonvulsants to control seizures, and general intensive support measures. When—and if—the patient survives, then the weekly courses of melarsoprol are restarted, otherwise death will ensue from progression of the disease. It was of great interest for our team to learn that once PTRE is successfully treated, it is very unusual for the patient to have a further episode of PTRE. This lack of recurrence seems to imply that PTRE could be a reaction to a sudden, massive release of parasite components as trypanosomes are killed by melarsoprol. Presumably, the host’s immune response to brain cells after this sudden influx of parasite antigens within the central nervous system could be a major factor in generating the PTRE. That is a good example of how bedside observations can lead to conceptual insights about a disease. But we really do not know what causes PTRE. Other theories have also been suggested. One theory for which there is some good evidence is that the treatment might not have been sufficiently curative, so residual parasites in the CNS cause the reaction.⁵ Other theories include a direct toxic effect of melarsoprol, some type of complex autoimmune reaction, and immune complexes consisting of bound antibody and antigen that clog important structures within the brain.⁶

The Sleeping Sickness Mouse

We cannot, of course, experiment in people to study the central nervous system stage of sleeping sickness, but fortunately a mouse model of PTRE was developed by Frank Jennings at the Veterinary Parasitology Department at Glasgow University. Since 1988, our sleeping sickness team in Glasgow has used this model to seek possible causes of the central nervous system disease and to devise potential therapies. The essence of the model is quite simple. Mice are infected with a set dose of trypanosomes, after which they develop a chronic infection, with parasites established in their central nervous system within 21 days. A few days after this development, the mice are treated “subcuratively” with berenil, a drug that is used to treat African trypanosomiasis in cattle. The effect of this deliberately incomplete treatment is to get rid of the parasites in the blood but not in the central nervous system and brain, because berenil cannot cross the blood-brain barrier. The result is a severe inflammatory reaction within the brain and its covering, producing encephalitis and meningitis, respectively, that looks remarkably like PTRE in humans. If a second dose of berenil is given after a relapse, then the reaction is even more severe.

We have used the PTRE mouse to make several observations. The first abnormality we see is an early activation of cells called astrocytes, which multiply and increase in size.⁷ Astrocytes, one of the major cell types in the central nervous system, have functions that include involvement in immune responses to infection. Astrocytes secrete cytokines, small molecules that can affect both the proliferation and the properties of cells involved in inflammation. Shortly after observing the activation of the astrocytes, we detected many inflammatory cells, such as lymphocytes and macrophages in the brain, as well as a number of cytokines, some of them, such as tumor necrosis factor-alpha and interleukin-1, known to be produced by astrocytes. This leads us to believe that the astrocyte is central in causing the inflammatory reaction characteristic of PTRE. Some cytokines we see are also known to be pro-inflammatory, which means that they enhance inflammation, but other cytokines in infected mice and humans could be counter-inflammatory. We are collaborating with Jeremy Sternberg at Aberdeen University and Martin Odiit at LHRI in Uganda to investigate that possibility, as well.

Next, we have sought to reduce the degree of astrocyte activation and inflammation in the mouse, using various drugs such as the immunosuppressant drug azathioprine, which is given to patients who have immune-mediated diseases and can prevent this inflammatory reaction (but cannot improve it once it has started).⁸ By contrast, results with the drug eflornithine (also known as DFMO), which is an enzyme inhibitor, are dramatic. When DFMO is given to the mice in their drinking water, not only is the severe experimental PTRE completely prevented, but we also see vast improvement in already established cases of PTRE.⁹

Working with Susan Leeman at Boston University, we treated mice that had PTRE with an antagonist to the neuropeptide called substance P. We tried this because substance P is known to be involved in immune responses, in addition to its role as a neurotransmitter in pain pathways. We found a moderate but significant reduction in the degree of inflammation and astrocyte activation.¹⁰ This showed that substance P also plays a key role in producing the inflammatory reaction in the brain, although we think the mechanism is probably complex.

The results achieved with DFMO were not a total surprise to us. In the 1980s, it had been shown to be an effective treatment for West African trypanosomiasis.¹¹ Despite this, for a variety of financial and political reasons, it became an orphan drug in 1990—meaning the disease it treated affected only a relatively small number of people and so it was not worth funding. This totally unsatisfactory situation was at least temporarily rectified by the remarkable efforts of Médecins Sans Frontières, working together with the World Health Organization and the drug companies Aventis Pharma and Bristol-Myers. Several million doses of DFMO have now been made available for patients with sleeping sickness. Unfortunately, DFMO is not as effective in East African sleeping sickness, although Ndung’u tells me that it can sometimes be tried in cases of resistance to melarsoprol treatment, which unfortunately can occur in both types of disease.

Finally, other work, both in the mouse model and African patients, has suggested that better use of existing drugs could be promising. This could mean trying different treatment regimens of individual drugs or of novel combinations of two or more current drugs.¹²

But Are We Winning the Race?

Because involvement of the brain and central nervous system in sleeping sickness is a delayed result of infection, more effective treatment at the early stage will be pivotal in conquering the brain disease. We urgently need an effective oral anti-trypanosomal drug that can be taken when symptoms first appear. We also need better treatment for the central nervous system disease when it occurs, because the side effects of melarsoprol are unacceptably severe. New combinations of existing drugs, including more widespread use of DFMO, is an avenue well worth exploring. Vaccine development is not realistic at present, both because of the ability of the trypanosome to change its structure rapidly enough to evade the host immune response and for financial reasons.

If sleeping sickness is ever to be controlled in Africa, the challenge must be tackled on many fronts. For example, the careful, accurate monitoring of new human and animal cases as they develop is essential, so case surveillance must continue even at times of war and political-social upheaval. Related to this is the need to improve diagnostic tests for the disease. Extensive monitoring and treatment of infected animals is not feasible in the wild but might well be possible in domestic herds. A key strategy in controlling the disease in humans is to reduce dramatically the level of human-tsetse fly contact. A battery of methods for doing this, such as tsetse fly traps impregnated with insecticide, is currently in operation, but all these measures, too, must be much improved. Without vastly increased financial investment by Western countries, progress will be very slow. At the same time, however, solutions must be socially and economically acceptable to the people of Africa.

Sleeping sickness has been called the Cinderella disease12 because it has so long been overlooked, attracting far less attention than it merits and in contrast to diseases that are less effective killers. This situation is beginning to change, but whether enough will happen in time—for Africa and for an ever-smaller globe—only time will tell. Midnight is fast approaching.