Blood-cerebrospinal fluid barrier and intrathecal immunoglobulins compared to field diagnosis of central nervous system involvement in sleeping sickness.

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.

The situation of sleeping sickness in Angola: a calamity.

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.

[African human trypanosomiasis. Therapeutic strategies]. / La trypanosomose humaine africaine. Stratégie thérapeutique de lutte.

Although therapeutic strategies for trypanosomiasis appear to be straightforward, their application in the field raises a number of questions which are successively examined below. After a quick reminder of the available drugs, we discuss: Criteria for eligibility: problems of beginning treatment for immunological suspects and determination of the development phase. Present-day problems: availability of drugs; side effects; therapeutic failures. While efforts should be continued to make existing drugs available, it is important that fundamental research be carried out to enhance their utilisation as well as to develop new active molecules.

Plasma melatonin rhythm is maintained in human African trypanosomiasis.

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 degrees C, amplitude 0.29 +/- 0.16 and 0.32 +/- 0.13 degrees 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.

Effect of melarsoprol treatment on circulating IL-10 and TNF-alpha levels in human African trypanosomiasis.

The pathogenesis of human African trypanosomiasis (HAT) has been the object of considerable research interest but has remained incompletely understood. The importance of cytokines in the pathophysiology of this protozoan infection is now widely recognized, but the full spectrum of cytokines involved has yet to be determined. In the present investigation we compared the plasma concentrations of TNF-alpha and IL-10 in normal African controls and patients suffering from advanced meningocephalic (late-stage) Trypanosomiasis brucei (T.b.) gambiense infections, before and after treatment with the arsenical trypanocide melarsoprol. We found that patients with late-stage T. b. gambiense exhibit chronically elevated circulating levels of both of these cytokines, and that these levels quickly decline following melarsoprol treatment. These findings confirm that TNF-alpha is involved in the immunopathogenesis of late-stage African trypanosomiasis and suggest that IL-10 may also play an important regulatory role in this disease.

[Contribution of biochemical tests in the diagnosis of the nervous phase of human African trypanosomiasis]. / Apport des examens biochimiques dans le diagnostic de la phase nerveuse de la trypanosomose humaine africaine.

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.

Disruption of endocrine rhythms in sleeping sickness with preserved relationship between hormonal pulsatility and the REM-NREM sleep cycles.

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.

BalI and MspI polymorphisms of the dopamine D3 receptor gene in African Blacks and Caucasians.

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.

[First case of multiforme granuloma in Congo]. / Premier cas congolais de granulome multiforme.

We report a case of multiform granuloma observed in a young woman of 28 years from Brazzaville, Congo. Extended lesions on the arms, back, face, legs and feet appeared over one month. They consisted of slightly squamous erythemato-oedematous plaques, with polycyclical margins and raised papular borders. The diagnosis was made histologically and recovery was spontaneous over a period of two months. We discuss clinical and histopathological aspects, which can sometimes lead to confusion with Hansen's disease.

[Drug sensitivity of Plasmodium falciparum in vivo and in vitro in Brazzaville (Congo)]. / Chimiosensibilité in vivo et in vitro de Plasmodium falciparum à Brazzaville (Congo).

Various projects were launched in 1993 to monitor the chemosensitivity of Plasmodium falciparum in Congo. Resistance of 34 strains in Brazzaville to chloroquine, quinine and mefloquine and of 35 to halofantrine was investigated in an in vitro survey using an isotopic micro test. The resistance rates were 61.8, 14.7, 3.0 and 0.0% respectively. Thus, the chemoresistance which first appeared in 1990 is confirmed and is stable in the population. This finding was further confirmed by a parallel in vitro analysis of sensitivity to chloroquine in Brazzaville. A chloroquine monitoring network is now being established throughout the country based on simplified WHO tests of 100 asymptomatic schoolchildren conducted every six months. The first results in 1993, from three Southern regions indicate that parasites are found in 20 to 60% of cases seven days after a standard 3 day treatment with 25 mg/kg, according to the region. The results of in vitro and in vivo tests are very variable. Indeed, the value of such results for these tests for national monitoring is questionable: a more reliable system of identifying true therapeutic failures would be better suited.

[The detection of anti-galactocerebroside autoantibodies in human African trypanosomiasis]. / Détection d'autoanticorps anti-galactocérébrosides au cours de la trypanosomose humaine africaine.

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.

[The distribution of sleep and wakefulness in human African trypanosomiasis]. / Distribution du sommeil et de la veille dans la trypanosomose humaine africaine.

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)

[The nyctohemeral rhythm of melatonin is preserved in human African trypanosomiasis]. / Le rythme nycthéméral de la mélatonine (MLT) est conservé dans la trypanosomose humaine africaine.

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.

[Maintenance of the relation between the pulsed secretion of hormones and the internal sleep structure in human African trypanosomiasis]. / Maintien des relations entre la sécrétion pulsatile des hormones et la structure interne du sommeil dans la trypanosomiase humaine africaine.

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)

[Epidemiological aspects of human African trypanosomiasis in south Chad]. / Aspects épidémiologiques de la trypanosomiase humaine africaine dans le sud du Tchad.

The authors are recording results of a clinical, parasitological and immunological sample survey about african human trypanosomiasis in the South Chad where old focus has been reexplored. In 1988 the situation ever remains as a problem in some areas (Tapol, Ranga) where high prevalence rates are found again.

[Trypanosomiasis caused by T. b. gambiense: methods of control]. / La trypanosomiase a T. b. gambiense: méthodes de lutte.

This paper reviews the different ways currently available for screening sleeping sickness. These ways are then integrated and discussed by the author in proposing different strategic and methodologic solutions after emphasizing the role of each of the technical stages. Altogether, there isn't one standard solution but adaptations around a main plan, according to contexts and having regard to efficiency and profitability. At all events, success depends on political will, community participation and the motivation and good training of the personnel.

[Technics of detection and diagnosis of African trypanosomiasis in humans]. / Techniques de dépistage et de diagnostic de la trypanosomose humaine africaine.

The authors review the most recent and sophisticated laboratory techniques for screening and diagnosis of human african trypanosomiasis. Immunological screening: indirect immunofluorescence, card agglutination test. Parasitological diagnosis: hematocrit centrifuge technique, miniature anion exchange/centrifugation, cerebrospinal fluid centrifugation. For each of these techniques, the authors deal successively with principle and method, interest, possible applications.

[Epidemic of yellow fever in the southeastern region of Upper Volta (October-December, 1983). Epidemiological study. Preliminary results]. / L'épidémie de fièvre jaune du sud-est de la Haute-Volta (octobre-décembre 1983). Etude épidémiologique. Résultats préliminaires.

An epidemic of yellow fever raged during the last three months of 1983 in South East of Upper Volta. It spread on about ten thousand square kilometers, in a bushy savanna area, affecting only populations living in contact with forest galleries, belonging especially to the peul ethnical group. The transmission of the virus was effected by sylvatic vectors, essentially Aedes furcifer. Serological tests showed that about 50 % of the population living in contact with forest galleries was affected, that is to say 15.000 to 17.500 people. The average death rate on the whole area was 4 % (800 to 1.700 deaths); the lethality rate was estimated between 6 and 10 % of affected people. On the whole, 54 strains of yellow fever virus were isolated from human blood samples, and 26 strains from batches of mosquitoes. We called this epidemic "intermediate sylvatic epidemic". The epidemic quickly decreased in the sylvatic area, owing to climatic conditions. A mass campaign of vaccinations prevented it from spreading to near urban centres. On this particular case, the thermostability on field of the vaccine 17D provided by the Institute Pasteur of Dakar was proved to be effective.