Diagnosis of central nervous system (CNS) involvement in sleeping sickness is crucial in order to give an appropriate treatment regimen. Neurological symptoms occur late, therefore field diagnosis is based on white blood cell count, total protein concentration and presence of trypanosomes in cerebrospinal fluid (CSF). More sensitive and specific parameters are now available. Blood-CSF barrier (B-CSFB) dysfunction, intrathecal total and specific immunoglobulin synthesis were evaluated in 95 patients with and without obvious meningoencephalitis, and compared to field criteria.B-CSFB dysfunction is a rather late event in the course of CNS involvement and correlates with the presence of trypanosomes, neurological signs and intrathecal polyspecific and specific immune response. IgM intrathecal response and particularly IgM antibody index are early markers of CNS invasion. We showed that 29% of patients with CSF abnormalities but without trypanosome detection in the field had no neuro-immunological response. In contrast, patients with normal CSF according to field diagnosis showed an intrathecal immune response in 31% of the cases.Field diagnosis can therefore fail to determine neurological involvement but can also provide false positive results. Improved criteria including B-CSFB dysfunction and IgM detection are needed in order to provide an adapted treatment regimen.

Although nearly one-fifth of the Angolan population is at risk of becoming infected with trypanosomiasis, only 6% currently have access to surveillance and treatment because of the war and its resultant destruction of the country's infrastructure. The paper outlines the history of human African trypanosomiasis (HAT) control activities in Angola and sums up what measures need to be taken to re-establish them.

Journal Article Central nervous system involvement in African trypanosomiasis: presence of anti-galactocerebroside antibodies in patients' cerebrospinal fluid Get access S. Bisser, S. Bisser ∗ 1Institut d'Epidémiologie Neurologique et de Neurologie Tropicale, Faculté de Médecine, 2 rue du Docteur Raymond Marcland, 87025 Limoges Cedex, France ∗Author for correspondence: phone +33 555 435 821, fax +33 555 435 821. ient@unilim.fr Search for other works by this author on: Oxford Academic PubMed Google Scholar Z. Ayed, Z. Ayed 1Institut d'Epidémiologie Neurologique et de Neurologie Tropicale, Faculté de Médecine, 2 rue du Docteur Raymond Marcland, 87025 Limoges Cedex, France Search for other works by this author on: Oxford Academic PubMed Google Scholar B. Bouteille, B. Bouteille 1Institut d'Epidémiologie Neurologique et de Neurologie Tropicale, Faculté de Médecine, 2 rue du Docteur Raymond Marcland, 87025 Limoges Cedex, France3Service de Parasitologie, Faculté de Médecine, 2 rue du Docteur Raymond Marcland, 87025 Limoges Cedex, France Search for other works by this author on: Oxford Academic PubMed Google Scholar A. Stanghellini, A. Stanghellini 4Ambassade de France en Angola, C.P. 707, Luanda, Angola Search for other works by this author on: Oxford Academic PubMed Google Scholar J.C. Breton, J.C. Breton 1Institut d'Epidémiologie Neurologique et de Neurologie Tropicale, Faculté de Médecine, 2 rue du Docteur Raymond Marcland, 87025 Limoges Cedex, France Search for other works by this author on: Oxford Academic PubMed Google Scholar M. Dumas, M. Dumas 1Institut d'Epidémiologie Neurologique et de Neurologie Tropicale, Faculté de Médecine, 2 rue du Docteur Raymond Marcland, 87025 Limoges Cedex, France Search for other works by this author on: Oxford Academic PubMed Google Scholar M.O. Jauberteau M.O. Jauberteau 1Institut d'Epidémiologie Neurologique et de Neurologie Tropicale, Faculté de Médecine, 2 rue du Docteur Raymond Marcland, 87025 Limoges Cedex, France2Service d'Immunologie Faculté de Médecine, 2 rue du Docteur Raymond Marcland, 87025 Limoges Cedex, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Transactions of The Royal Society of Tropical Medicine and Hygiene, Volume 94, Issue 2, March-April 2000, Pages 225–226, https://doi.org/10.1016/S0035-9203(00)90285-2 Published: 01 April 2000 Article history Received: 06 August 1999 Revision received: 08 November 1999 Accepted: 10 December 1999 Published: 01 April 2000

The stage of human African trypanosomiasis (HAT) is important to define precisely as far as it is directly related to the type of treatment used. The beginning of the neurological involvement is dif ficult to find out because there is no known specific clinical or biological sign. This study is trying to look for a precise marker and has been realized in Congo. 70 subjects with parasitologically confir med HAT and 70 controls are included. The stage of HAT is determined according to the classical definition on the field using the cerebrospinal fluid (CSF) cell count : less than 5 cells/μl for the first stage (P1), more than 5 cells/μl for the second stage (P2). The blood analysis has included : glucose, urea, creatinine, sodium, potassium, calcium, chloride, phosphorus, uric acid, total bilirubin, uncon jugated bilirubin, total cholesterol, triglycerides, total proteins, aspartate aminotransferase, alanine aminotransferase, creatinine phosphokinase, alkaline phosphatase, gamma-glutamyltransferase, immunoglobulins M and G, C3c fraction of complement, transferrin, seromucoid α1, haptoglobin and albumin. In CSF we have analyzed IgM, IgG, protein levels and the bloodbrain barrier (BBB) impairment. The comparison between the subjects and their controls, the subjects in P1 and in P2, the CSF cell count and the other CSF alterations show the interest of the IgM level in CSF and the BBB impairment to identify subjects in P2. However there is a low gradation in the biological dis turbances and not a precise threshold point. Nevertheless it seems reasonable to raise the CSF cell count level to 20 cells/μl to define the beginning of the nervous involvement.

In human African trypanosomiasis (sleeping sickness), sleep and wake episodes are sporadically distributed throughout the day and the night. Plasma melatonin, sleep-wakefulness and rectal temperature rhythms were studied in 9 Congolese patients suffering from sleeping sickness compared to 6 healthy controls submitted to the same light/dark regime. The circadian distribution of the sleep-wake cycle was disturbed in relation to the severity of the disease. As controls, patients maintained a very distinct plasma melatonin nyctohemeral rhythm which displayed a significant phase advance (1:08 ± 0:43 and 2:34 ± 0:31 mean ± SD, in patients and controls respectively; p < 0.01, U test), as well as a persistent rectal temperature rhythm (mesor 36.67 ± 0.29 and 36.74 ± 0.13°C, amplitude 0.29 ± 0.16 and 0.32 ± 0.13°C, acrophase 13:53 ± 2:47 and 15:32 ± 0:36 for patients and controls respectively). No alteration of these rhythms was observed after treatment. In African controls we observed plasma melatonin characteristics similar to those of European controls, especially for the onset and the duration of the secretion and the stability of the rhythm, despite a different light/dark regime. The dissociation observed between the 3 rhythms (melatonin, temperature and sleep-wake cycle) is discussed, taking into consideration a functional compartmentalization of the suprachiasmatic nuclei or more likely a disruption of the neural pathway between the circadian clock and structures involved in the regulation of the sleep-wake cycle, related to the activity of compounds released by the parasites or host cells.

The stage of human African trypanosomiasis (HAT) is important to define precisely as far as it is directly related to the type of treatment used. The beginning of the neurological involvement is difficult to find out because there is no known specific clinical or biological sign. This study is trying to look for a precise marker and has been realized in Congo. 70 subjects with parasitologically confirmed HAT and 70 controls are included. The stage of HAT is determined according to the classical definition on the field using the cerebrospinal fluid (CSF) cell count: less than 5 cells/microliters for the first stage (P1), more than 5 cells/microliters for the second stage (P2). The blood analysis has included: glucose, urea, creatinine, sodium, potassium, calcium, chloride, phosphorus, uric acid, total bilirubin, unconjugated bilirubin, total cholesterol, triglycerides, total proteins, aspartate aminotransferase, alanine aminotransferase, creatinine phosphokinase, alkaline phosphatase, gamma-glutamyltransferase, immunoglobulins M and G, C3c fraction of complement, transferrin, seromucoid alpha 1, haptoglobin and albumin. In CSF we have analyzed IgM, IgG, protein levels and the bloodbrain barrier (BBB) impairment. The comparison between the subjects and their controls, the subjects in P1 and in P2, the CSF cell count and the other CSF alterations show the interest of the IgM level in CSF and the BBB impairment to identify subjects in P2. However there is a low gradation in the biological disturbances and not a precise threshold point. Nevertheless it seems reasonable to raise the CSF cell count level to 20 cells/microliters to define the beginning of the nervous involvement.

In human African trypanosomiasis (sleeping sickness), sleep and wake episodes are sporadically distributed throughout the day and the night. To determine whether these sleep disturbances affect the 24-h hormone profiles and the normal relationships between hormone pulsatility and sleep stages, polygraphic sleep recordings and concomitant hormone profiles were obtained in 6 African patients with sleeping sickness and in 5 healthy African subjects selected from Abidjan on the Ivory Coast. Polysomnographic recordings were continuous, and blood was taken every 10 min throughout the 24-h period. Plasma was analyzed for cortisol, prolactin, and plasma renin activity (PRA). The 24-h rhythm of cortisol, considered to be an endogenous circadian rhythm, was attenuated in all of the patients except one. However, as in normal subjects, slow wave sleep (SWS) remained associated with the declining phases of the cortisol secretory episodes. Prolactin and PRA profiles, which are strongly influenced by the sleep-wake cycle, did not manifest the nocturnal increase normally associated with the sleep period; instead, they reflected a sporadic distribution of the sleep and wake episodes throughout the 24-h period. In patients with sleeping sickness as in normal subjects, rapid eye movement (REM) sleep began during the descending phases of prolactin pulses. In both groups, PRA reflected the sleep stage distribution with non REM (NREM) sleep occurring during the ascending phases and REM sleep during the descending phases of the PRA oscillations. However, in sleeping sickness patients, the marked sleep fragmentation often did not allow sufficient time for PRA to increase significantly, as is normally the case in subjects with regular NREM-REM sleep cycles. These results demonstrate that, together with the disruption of the sleep-wake cycle, there are profound differences in the temporal organization of the 24-h hormone profiles in humans with African trypanosomiasis. However, the relationship between hormonal pulses and specific sleep stages persists, indicating the existence of a robust link between hormonal release and the internal sleep structure.

An exonic BalI polymorphism and an intronic MspI polymorphism of the dopamine D3 gene were genotyped in 101 Caucasians from the Alsace and in 56 people from the Congo. This is the first study of the BalI polymorphism in sub-Saharan Africa and the first population study of the MspI site. BalI allele 1 was rare in the Congo (0.12) whereas it is the most frequent allele in all studies in Europe and Asia. MspI allele 1 was also significantly less frequent in the Congolese (0.24) than in Caucasians (0.52). D3 gene alleles show different frequencies in sub-Saharan Africa and may be useful for population studies.

We studied plasma melatonin profiles by radioimmunoassay in nine patients suffering from human african trypanosomiasis and six healthy controls matched according to the age and the photoperiodic conditions. The circadian periodicity of the sleep-wake cycle was disturbed proportionally to the degree of severity of the disease. On the contrary, the patients' plasma melatonin profile was similar to the controls' one. These results suggest that, beside the master clock generating the main circadian rhythms (sleep-wake, melatonin and core temperature rhythms), an additional regulating system of the melatonin rhythm could be involved.

In order to determine whether sleep disturbances would affect the hormonal patterns and the normal relationships between hormone pulses and sleep stages, the 24-hour profiles of cortisol, prolactin and plasma renin activity (PRA) were analysed in 6 sleeping sickness patients studied at Brazzaville and in 5 healthy African controls studied in Abidjan. Polysomnographic recordings were done continuously and blood was taken every 10 minutes throughout the 24-hour period. Plasma was analyzed for cortisol, prolactin and PRA. The circadian rhythm of cortisol, considered as an example of an endogenous rhythm was attenuated in all the patients but one, but as in normal subjects, slow wave sleep (SWS) remained associated with the declining phases of the secretory episodes. Prolactin and PRA profiles, which are strongly influenced by the sleep-wake cycle did not show the increase normally associated with long sleep periods and reflected the spreading of sleep and wakefulness throughout the 24-hour period. However, rapid-eye movement (REM) sleep began in sleeping sickness patients, as in normal subjects, during the descending phases of prolactin pulses. In both groups, PRA reflected the sleep stage distribution with non rapid-eye movement (NREM) sleep occurring during the ascending phases and REM sleep during the descending phases of the oscillations. However, in sleeping sickness patients, the marked sleep fragmentation often did not allow sufficient time for PRA to increase significantly, as observed with regular NREM-REM sleep cycles. These results demonstrate that, together with the disruption of the sleep-wake cycle, there are profound differences in the temporal organization of the 24 hour hormone profiles in human African trypanosomiasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Last century, patients with human African trypanosomiasis were described as sleepy by day and restless by night, and physicians referred to this condition as sleeping sickness. Such a description could have evoked a disturbance of circadian rhythms. However, it is only in 1989 that the first 24-hour recording was performed by our team in Niamey (Niger) in a patient with sleeping sickness. The patient was a Niger-born farm worker who had contracted the disease near Gagnoa (Côte d'Ivoire). Polysomnographic recordings (electroencephalogram, EEG, electrooculogram, electromyogram, electrocardiogram, buccal and nasal airflow, and chest respiratory movements) showed a disappearance of the circadian distribution of sleep and wakefulness, which tended to occur evenly throughout day and night, with a sleep-wake alternation of approximately 80 minutes. Two investigations were conducted thereafter. The first one was done at Daloa (Côte d'Ivoire) in 8 patients who were recorded during two 24-hour periods, with and without hourly blood samples; the second at Brazzaville (Congo) in 10 patients recorded for 24 hours before and after treatment with melarsoprol. All patients were at the stage of early meningoencephalitis. At Daloa, polysomnographic recordings were taken on two 8-channel EEG machines (Alvar Minihuit, and T3-ECEM), as well as on a portable Oxford Medilog 9000 system from the same electrodes. Sleep and wake structure was altered in the most severely sick patient, the EEG trace being loaded with slow waves. Stages 1 and 2, and stages 3 and 4 could not be distinguished from one another. In the other patients, all sleep stages were easily scored. No difference was seen between recordings, regarding blood collection.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied plasma melatonin profiles by radioimmunoassay in nine patients suffering from human african trypanosomiasis and six healthy controls matched according to the age and the photoperiodic conditions. The circadian periodicity of the sleep-wake cycle was disturbed proportionally to the degree of severity of the disease. On the contrary, the patients' plasma melatonin profile was similar to the controls' one. These results suggest that, beside the master clock generating the main circadian rhythms (sleep-wake, melatonin and core temperature rhythms), an additional regulating system of the melatonin rhythm could be involved.

The authors highlight the major target for the prevention of human african trypanosomiasis (HAT) i.e. decrease of parasites reservoir. For this purpose, they state that it is necessary to detect HAT patients, to treat them, and to break down the contact between human and vectors. Then, they review the environmental factors that could be involved in the HAT outbreak. A political direction would strengthen the HAT prevention by the increase of resources attributable to the disease. But, choice of priorities is based on technical criteria which are not in favour of HAT. Many difficult situations, occurring at the borders of concerned states, are restricting factors for a global and co-ordinated prevention. Moreover, internal political disturbances and local conflicts lead to a mismanagement of health care departments. These conflicts lead also to a migratory flow of populations; thereafter, the individuals have no access to medical structure. Beside the economical and political factors, some others have a great importance: human behavior, estimation of risk by the authorities, psychological perception of the disease by the population. The part of these different factors must be perfectly identified to avoid any disturbance in the actions of HAT prevention. The least failure leads to a quick increase of parasites transmission, and the NAT control has to start all over again.

The pathogenesis of the central nervous system (CNS) damage in human african trypanosomiasis (HAT) is unknown. In view of an immunological mechanism, as in another trypanosomiasis, Chagas' disease, the causative agent of which is Trypanosoma cruzi, we have searched autoantibodies directed against glycosphingolipids of CNS. Detection and characterization of autoantibodies were performed by ELISA and detection after thin-layer chromatography of glycolipids with sera of an experimental model of HAT in sheep and sera of patients suffering of HAT from Côte d'Ivoire and Congo. The predominant reactivity of these sera, was characterized with galactocerebrosides, the major glycolipids of the myelin. Autoantibodies were detected in 42.8% and 25% of patients' sera, respectively from Côte d'Ivoire and Congo. The proportion of these antibodies increased dramatically to 72% in sera of patients with neurological symptoms. Anti-galactocerebroside antibodies were also found in CSF of 24.4% of Congolense patients. The pathogenic significance of these anti-galactocerebroside antibodies remains to be determined. They may constitute a predicative marker for the neurological improvement in HAT.

Last century, patients with human African trypanosomiasis were described as sleepy by day and restless by night, and physicians refered to this condition as sleeping sickness. Such a description could have evoked a disturbance of circadian rhythms. However, it is only in 1989 that the first 24-hour recording was performed by our team in Niamey (Niger) in a patient with sleeping sickness. The patient was a Niger-born farm worker who had contracted the disease near Gagnoa (Cote d'lvoire). Polysomnographic recordings (electroencephalogram, EEG, electrooculogram, electromyogram, electrocardiogram, buccal and nasal airflow, and chest respiratory movements) showed a disappearance of the circadian distribution of sleep and wakefulness, which fended to occur evenly throughout day and night, with a sleep-wake alternation of approximately 80 minutes. Two investigations were conducted thereafter. The first one was done at Daloa (Cote d'lvoire) in 8 patients who were recorded during two 24-hour periods, with and without hourly blood samples the second at Brazzaville (Congo) in 10 patients recorded for 24 hours before and after treatment with melarsoprol. Aii patients were at the stage of early meningoencephalitis. At Daloa, polysomnographic recordings were taken on two 8-channel EEG machines (Alvar Minihuit, and T3-ECEM), as well as on a portable Oxford Medilog 9000 system from the same electrodes. Sleep and wake structure was altered in the most severely sick patient, the EEG trace being loaded with slow waves. Stages 1 and 2, and stages 3 and 4 could not be distinguished from one another. In the other patients, all sleep stages were easily scored. No difference was seen between recordings, regarding blood collection. All patients presented a marked disturbance in the circadian organisation of their sleep-wake cycle, this alteration being proportional to the severity of the disease. A 17-year-old patient presented a 90-minute periodic occurrence of REM sleep throughout the nychthemeron. These results were confirmed in another 10 patients recorded at Brazzaville, using 2 Alvar Minidix and two portable Oxford Medilog 9000 II systems, with continuous blood withdrawal. wrist actimetry was also taken. In parallel with the major circadian disturbance in the sleep-wake cycle observed in the most severely sick patients, wrist actimetry proved to be unable to distinguish between rest and activity episodes. These circadian disturbances were improved after the first melarsoprol treatment. The alteration of the circadian rhythmicity of sleep and wakefulness was not found in 6 healthy volunteers recorded in the same experimental conditions with an intravenous catheter to collect blood every 10 minutes. In conclusion, at the stage of meningoencephalitis, human African trypanosomiasis, sleeping sickness, represents a dysregulation of the circadian rhythm of the sleep-wake cycle, rather than a hypersomnia, which may be related to a functional and reversible alteration of the circadian body clock.