Keywords : Africa, Clinical trials, Ethics

A recent article in the New England Journal of Medecine, entitled “A new Colonialism ? Conducting Clinical Trials in India” (3) denounces a new government policy there that amounts to opening the door to various abuses in clinical trials. Criticism from a number of quarters has been voiced against some clinical tests conducted by Western pharmaceutical companies in countries of the developing world. Up to the 1990s, such trials were performed in the developed world, on people drawn from their population. Today, however, about a quarter of such research is conducted in the third world, and the trend is accelerating. The Washington Post even speaks of a “human body hunt”. Scandalous, isn’t it ? Looks like “another instance of the poor being abused by the rich”! Thinking further, however, isn’t responsibility shared for this state of affairs ? Are not the countries in the South who have signed such research agreements guilty of failing to exercise due caution or even of complicity in actions that potentially violate the laws ?

Under a project to develop a preventive treatment for AIDS, an NGO, Family Health International (FHI) and Gilead Laboratories have been conducting tests on prostitutes in Douala, Cameroon. Both organizations are accused of using these women as “guinea-pigs”, and disregarding their rights, and the project has given rise to legitimate controversy. The prostitutes were given a tablet of tenofovir (Viread*) to test its possible effectiveness in preventing contamination by the HIV. No medical treatment was given to those of the women who were already infected with AIDS. Local administrative officials have proclaimed their good faith in the matter, arguing “the need to distinguish and avoid mixing up ethical and humanitarian aspects” (4). Properly speaking, such an incomprehensible and irresponsible position is dumbfounding !

The same study is currently conducted in Ghana (Tema), in Botswana, and in Malawi.

Cambodia is a small country ; a poor country among the poorest in the world, bled to its knees by a domestic genocide in which a quarter of the population was herded off to mass graves ; a country still torn apart by political battling over power, but it said “no” to this operation which some African countries have agreed to establish. How can we explain that Cameroon, Ghana, Botswana and Malawi have agreed so easily to this operation ? Did the prestige and label of the Bill and Melinda Gates Foundation facilitate acceptance ? The Indian decision may be related to India’s adoption of an unbridled so-called “market” economy free of social and political controls, a version of “economic liberalism” propounded by the Chicago School of economics whose flaws have been pointed out by the Nobel prize-winner in economic science J. Stiglitz (5) ; it appears that the same recipe, perceived as a cure-all, is being applied in Africa.

However, the example set by Cambodia sweeps away the underlying financial-cum-economic arguments. Lack of information, the shortage of technical capabilities among African medical practitioners are very likely to have been contributing factors to the establishment of such a research station and especially acceptance of its mode of operation. Given the persistent identity problems in Africa, a lack of self-confidence may also be considered as a possible cause. African governments, no doubt, are partly to blame, but the responsibility of the African scientific elite cannot be swept under the carpet either. How are we to explain, otherwise, that 60 % of 260 “research papers”, according to a researcher who is a member of the Ethics Committee of Cameroon, are “pirates” (unauthorized) ?? (4) Is this due to lack of precautions, to corruption or to social inhibitions ?

JP Chippaux, a researcher at Institut de Recherche pour le Développement (IRD), is the author of « The Practice of Clinical Trials in Africa », a book (2) in which he defines, as follows, a number of ethical criteria for conducting clinical research :
– Social or scientific value (a measure of operational efficiency);
– scientific validity;
– selection of research subjects (including a pertinent choice of sample population and the protection of vulnerable or exploitable groups);
– a good risk-to-benefit ratio;
– independent evaluations (including an evaluation of possible conflicts of interest)
– respect for the research subjects (right to withdraw from the research at any time without incurring penalties-ensuring the confidentiality of data-subject security-communication of results to participants).

African traditional societies, based on a customary hierarchical system of communal kinship and government or guidance by elders has imploded as a result of the unavoidable and forcible intrusion of the modern world. The traditional fabric of society can no longer be a backbone for resistance. In this context, as societies are speedily being transformed, roles are redistributed in a disorderly fashion and on a commercial, even mercantile, basis, which is by nature unstable and opportunistic. The means used to get to the top of the social ladder ignore ethical rules. Money, even filthy money, is dominant. The participants in the macabre dance around dying people are no doubt short-sighted politicians, guided by what a political analyst, JF Bayart (1), has perceptively called their “stomach”. But they are not alone. For cases such as medical trials show other participants and social groups. Among these the elite, made up of scientific and other leaders who, too often, have given up the fight. Let us remind ourselves that the end, however worthy, does not justify the means.

The responsibility of members of the scientific and intellectual elite is to remain constantly attentive, looking not only into the distance but also at their doorstep to detect, alert, point out the potential dangers facing the larger Community. This is especially necessary in the field of medicine.

Mots clés : Afrique, Essais cliniques, Ethique

Un article paru récemment dans le New England Journal of Medecine, « A New Colonialism? – Conducting Clinical Trials in India » dénonce la nouvelle politique adoptée par le gouvernement sur les essais cliniques pratiqués en Inde, ouvrant la porte ouverte à tous les excès (3). Plusieurs voix se sont élevées contre les essais cliniques réalisés par l’industrie pharmaceutique du Nord en direction des populations du Sud en relevant le cynisme des instigateurs. Jusqu’aux années 1990, les pays du Nord conduisaient ces tests sur leurs populations. Actuellement, les contraintes administratives, commerciales et éthiques sont telles que le mouvement de « délocalisations » des essais croît de manière exponentielle. Un quart des tests pharmaceutiques est effectué dans le Tiers Monde et le mouvement s’accélère. Le « Washington Post » décrit « une chasse au corps humain » Quel scandale ! Les pauvres sont de nouveau abusés par les riches !! Mais à bien y réfléchir, la responsabilité n’est-elle pas partagée ? Les pays du Sud qui ont accepté ce type de contrat ne sont-ils pas coupables de légèreté, voire de complicité, avec ces actes potentiellement criminels ?

L’essai d’un traitement préventif contre le sida mené sur des prostituées à Douala (Cameroun) depuis mai 2004 par l’ONG américaine Family Health International (FHI) et les laboratoires Gilead a suscité une polémique légitime. Il s’agissait d’administrer à ces prostituées un comprimé de tenofovir (Viread*) afin de vérifier son éventuelle efficacité dans la prévention contre la contamination par le VIH. La prise en charge thérapeutique de ces femmes, véritables cobayes, contaminées au cours de l’essai n’était pas assurée. Les autorités administratives ont clamé leur bonne foi en avançant qu’« il faut éviter l’amalgame et séparer les questions éthiques des questions humanitaires. » Ce propos incompréhensible et irresponsable laisse pantois !

La même étude est menée actuellement au Ghana (Tema), au Botswana et au Malawi.

Le Cambodge. Un « petit » pays. Pays pauvre parmi les plus pauvres de la planète, saigné par un autogénocide ayant emporté dans des fosses communes un quart de sa population, déchiré de manière permanente par des combats politiques de conquête de pouvoir a dit non à l’étude accepté par des pays africains. Comment expliquer que le Cameroun, le Ghana, le Botswana, le Malawi aient cédé avec une telle facilité ? Le label de la Fondation de Bill et Melinda Gates y est peut-être pour quelque chose. Le choix d’une économie libérale débridée, dite de « marché » sans entrave socio-politique promue par l’Ecole de Chicago et dénoncée avec justesse par le prix Nobel d’économie, J. STIGLITZ ( 5 ) peut expliquer le choix de l’Inde et il en sera de même pour l’Afrique car la recette de la « libéralisation » économique est imposée comme étant la panacée.

L’exemple du Cambodge balaie l’argument financier. Le manque d’information, de formation du monde médical africain a très vraisemblablement contribué à la mise en place de cet essai. Mais il y a également le manque de confiance en soi, lié à la récurrente problématique identitaire africaine qui mène de facto à une capitulation. Il y a certes une responsabilité des gouvernements africains, mais la responsabilité de l’élite africaine scientifique ne peut être exclue. Comment expliquer que sur près de 260 « travaux de recherche», selon un chercheur membre du Comité d’éthique du Cameroun, 60 % de ces tests sont « pirates » !! ( 4 ) Défaut de vigilance ? Manque de courage ? Corruption ? Inhibition identitaire ? Un peu de tout cela.

JP CHIPPAUX, chercheur à l’Institut de Recherche pour le Développement (IRD) dans son ouvrage « La pratique des essais cliniques en Afrique » définis ainsi les critères éthiques de la recherche clinique ( 2 ) :
– valeur sociale ou scientifique (mesure de l’efficacité d’une intervention) ;
– validité scientifique ;
– sélection des sujets (avec choix de population pertinent et une protection des populations vulnérables ou exploitables) ;
– rapports risque/ bénéfique favorable ;
– évaluation indépendante (et notamment évaluation des conflits d’intérêts) ;
– consentement informé ;
– respect des sujets (avec possibilité de retrait à tout moment sans pénalité, confidentialité des informations, sécurité des sujets, communication des résultats aux participants).

L’explosion de la société traditionnelle africaine, bâtie autour d’une hiérarchie coutumière mêlant à la fois communautarisme et gérontocratie, fait les frais de l’inéluctable intrusion par effraction de la modernité en s’offrant comme un ventre mou. Le positionnement dans une société se construisant avec célérité, redistribue dans le désordre les rôles, sur une base mercantile dont on connaît la labilité et l’opportunisme. Les moyens pour accéder en haut de l’échelle sociale ne répondent à aucune règle éthique. La fin ne justifie pas les moyens. Il faut s’approprier des biens matériels de manière gloutonne. Le lucre étant élu roi. Les acteurs du ballet macabre autour d’une population agonisante sont certes les politiciens à courte vue, guidées « par le ventre » bien décrit par le politologue avisé, JF BAYART ( 1 ). Mais l’exemple des essais thérapeutiques dévoile d’autres corps sociaux comme acteurs. En particulier, les élites qui démissionnent.

La responsabilité de l’élite est d’être en permanence en éveil, de scruter autant l’horizon que le pas-de-porte afin de déceler, d’alerter, de dénoncer les potentiels dangers qui peuvent ébranler la Cité surtout lorsque cette responsabilité concerne le domaine médical.

ABSTRACT

Background

Symptomatic peripheral neuropathy in a diabetic patient may be associated with the presence of other foot complications, which may otherwise be overlooked.

Objective

We conducted this study to determine the prevalence of symptomatic peripheral neuropathy among diabetic patients attending the diabetes outpatient clinic of our hospital as well as document the presence of other foot complications/problems in patients with symptomatic peripheral neuropathy.

Methods

A cross-sectional survey of foot complications was conducted over a 6-month period in diabetic patients symptomatic for peripheral neuropathy and compared with age/sex matched diabetics without peripheral neuropathy and apparently healthy individuals.

Results

Of 322 diabetic patients studied, 64(19%) had symptomatic peripheral neuropathy. The most frequent symptoms of peripheral neuropathy were numbness or tingling sensation in (65.6%), cramps, aches and fatigue (14.1%) respectively, and burning sensation (10.9%). Dry skin, hyperpigmentation, corns and callosities, cracked skin
and fungal infections were the most frequent lesions seen in diabetic patients symptomatic for peripheral neuropathy. These lesions occurred more frequently in them than in patients without neuropathy and healthy subjects. While (34.7%) symptomatic patients had foot ulcers, none was recorded in the asymptomatic or healthy population.

Conclusion

Foot complications other than foot ulcers may occur in diabetic patients with symptomatic peripheral neuropathy. Awareness of these skin and foot lesions and their sequelae with prompt initiation of measures to limit disability may prevent limb losses/foot deformities and should be emphasised. Proper education on foot care and frequent limb inspection can never be over emphasised. Moreover, these foot lesions may also serve as markers for the presence as well as severity of peripheral neuropathy.

RESUME

Introduction

Les neuropathies diabétiques symptomatiques s’accompagnent de complications au niveau des pieds qui risquent d’être négligées.

But

Le but de l’étude est de déterminer la prévalence des neuropathies périphériques ainsi que les complications au niveau des pieds chez des diabétiques suivis dans notre département, en ambulatoire.

Méthode

Une étude transversale a été menée pendant six mois chez des diabétiques atteints d’une neuropathie périphérique symptomatique et des individus apparemment sains.

Résultats

Sur les 322 patients étudiés, 64 (19%) présentaient une neuropathie périphérique symptomatique. Les symptômes les plus souvent rencontrés sont : les engourdissements ou picotements (65,6%), les crampes, des douleurs continues, une fatigabilité (14,1%) et une impression de brûlure (10,9%). Une peau sèche et craquelée, une hyperpigmentation, des callosities ainsi que des signes de mycoses étaient les lésions les plus souvent observées chez les patients diabétiques ayant une neuropathie périphérique. Aucun ulcère n’a été noté chez les individus sains contrairement à la population diabétique ( 34,7%).

Conclusion

L’attention est portée sur la nécessité de surveiller et de diagnostiquer au plus tôt les lésions cutanées chez les patients diabétiques. Par ailleurs, les lésions cutanées sont l’expression de la sévérité de la neuropathie périphérique sous-jacente, chez ce type de patients.

Keywords : Diabetes mellitus, foot complications, peripheral neuropathy, Afrique, diabete, complications, neuropathie peripherique, pied diabetique

INTRODUCTION

Peripheral neuropathy, which commonly manifests as loss of sensation in the feet is an important factor in the pathogenesis of foot ulcers. There is a complex inter play between this abnormality and a number of other contributing factors such as peripheral vascular disease, altered foot pressure, limited joint mobility, glycaemic control, ethnicity and cardiovascular parameters.(1,13,15) Some published data suggest that in addition to foot ulcers, some other foot lesions may be associated with the presence of peripheral neuropathy in diabetics .(6,13)

We have therefore conducted this study to determine the prevalence of symptomatic peripheral neuropathy among diabetic patients attending the diabetes outpatient clinic of the Obafemi Awolowo University Teaching Hospital Complex (OAUTHC), Ile-Ife, Nigeria as well as document the presence of other foot complications/problems in patients with symptomatic peripheral neuropathy.

METHODS

All patients who attended the diabetes clinic of the OAUTHC, Ile Ife between July and December 2000 were recruited into the study. A comprehensive history was taken from each patient followed by a thorough physical examination. The history included data on demography, type and duration of diabetes, symptoms associated with peripheral neuropathy, use of footwear, alcohol and cigarette use, occupation, and literacy level.

Physical examination included objective evaluation for signs of peripheral neuropathy, peripheral vascular disease, and the presence of other foot lesions/complications. Symptoms and signs of peripheral neuropathy were assessed using the scoring system proposed by Young et al(15) (Appendix). Scores of 3 or more implied the presence of peripheral neuropathy. The presence of other foot lesions were also determined in age-sex matched diabetics who were not symptomatic for peripheral neuropathy as well as apparently healthy controls recruited from hospital staff and members of public. The frequency of such complications was then compared across the three groups. Peripheral vascular disease was defined by an ankle/arm blood pressure ratio greater than 0.9.
Data are presented as mean (SD) and percentages as appropriate.

RESULTS

During the six-month study period 322 diabetic patients were seen. 64(19%) had symptomatic peripheral neuropathy and are further described (Table 1). There were equal number of males and females, their ages ranged between 36 -80 years, mean 58.1 ± 8.1 years. 56 (87.5%) were non-insulin dependent diabetics, 2(3.1%) were insulin dependent while 6(9.4%) were non-insulin dependent now requiring insulin. The mean duration of disease was 8.41 ± 7.1 years, range 2 to 29 years. The type of out door footwear used by patients varied from covered shoes 8 (12.5%), flat heeled slippers 50 (78.1%), to both slippers and covered shoes 16 (25%). No one walked outdoors without footwear though 10 patients admitted to not using footwear a times when indoor. None of the patients smoked nor took alcohol.

The most frequent symptoms of peripheral neuropathy were numbness or tingling sensation in (65.6%), cramps, aches and fatigue (14.1%) respectively, and burning sensation (10.9%). 27(42.19%) patients had moderate and severe neuropathy symptoms scores respectively, while 8(12.5%) were mild. Neuropathy sign scores were mild in 36 (56.3%) patients; moderate 26(40.6%), and severe in none. 2(3.1%) had no severity score. The commonest signs elicited were impaired vibration sense in 39(60.9%) and loss of ankle reflex in 33 (51.7%). Peripheral vascular disease was present in 3 (4.7%) patients.

Table 2 compares foot lesions seen in patients with and without symptomatic peripheral neuropathy and apparently healthy non-diabetic subjects. Dry skin, hyperpigmentation, corns and callosities, cracked skin and fungal infections were the most frequent lesions seen in diabetic patients symptomatic for peripheral neuropathy. These lesions occurred more frequently in them than in patients without neuropathy and healthy subjects. While 3 (4.7%) symptomatic patients had foot ulcers, none was recorded in the asymptomatic or healthy population.

DISCUSSION

This study assessed foot problems associated with peripheral neuropathy. The prevalence rate of symptomatic peripheral neuropathy was 19%. The commonest symptoms/signs of peripheral neuropathy numbness, cramps and burning sensation in the feet, impaired vibration sense and loss of ankle jerk.
Our PN prevalence rate of 19% is lower than those reported from previous studies.(4-7,9,12) This difference may be accounted for by variations in methodology, diagnostic criteria and intrinsic differences in the study populations. Qualitative sensory tests and/or electrophysiological studies, if employed, may have detected the presence of PN in our apparently asymptomatic patients. Our data, like in previous studies show that numbness, burning feet and posterior column tract signs with a depressed ankle jerk remain the commonest presenting features of peripheral neuropathy. It should be noted however that the severity of some of these features are influenced a great deal by shoe wearing habits. Many rural Nigerians still walk barefoot. Osuntokun(10) had observed attenuation of the plantar response in apparently healthy rural Africans who walk without their shoes on. He had attributed this to the thickening of the soles observed in these individuals as well as possible subclinical malnutrition.

Patients with symptomatic peripheral neuropathy also presented with a myriad of additional foot/skin lesions such as dry skin, callosity, fungal infection, paronychia, hyperpigmentation, yellow nails, cracked skin, ulcers, corns etc. Dry skin, paronychia (both bacteria and candida), corns and hallux valgus were commoner in symptomatic patients than in the asymptomatic or healthy population. Similar foot/skin problems have been previously described among European diabetic patients(2) and in indigenous Tanzanians.(14) All forms of peripheral neuropathy including autonomic, sensory and motor neuropathy each contribute to skin lesions in the diabetic foot. Autonomic neuropathy can be associated with both absence of sweating as well as compensatory over sweating and perspiration in other areas.(8) Dry skin, resulting from absence of sweating, predisposes to puritus a known presenting symptom of diabetes. Dry skin also cracks easily especially when scratched (pruritus) encouraging bacterial invasion and superimposed bacterial infections. Use of emollient in these patients prevents dry skin and itching. Fungal infections are often associated with poor glyceamic control, which is itself a risk factor for peripheral neuropathy.(11) Hyperhydrosis of autonomic neuropathy make the feet conducive for fungal infections in the diabetic as fungi thrives best in moist areas. Sesori-motor neuropathy, which may result in imbalance of internal musculature and poor standing posture coupled with ill-fitting shoes can cause callosities and neuropathic ulcers.(3)
Foot complications other than foot ulcers may occur in diabetic patients with symptomatic peripheral neuropathy. Awareness of these skin and foot lesions and their sequelae with prompt initiation of measures to limit disability may prevent limb losses/foot deformities and should be emphasised. Proper education on foot care and frequent limb inspection can never be over emphasised. Moreover, these foot lesions may also serve as markers for the presence as well as severity of peripheral neuropathy.

TABLE I: CLINICAL CHARACTERISTICS OF STUDY PATIENTS (mean ± SD)

TABLE II: FREQUENCY OF FOOT LESIONS IN SYMPTOMATIC PATIENTS, ASYMPTOMATIC PATIENTS AND HEALTHY SUBJECTS.

APPENDIX

1 – Assessment Of symptoms of P Neuropathy

• Description of symptoms:
  Fatigue(1pt), cramps(1pt) or aches (1pt),
  Burning (2pt), Numbness (2pt) or Tingling (2pt),
• Site of discomfort :
  Calf muscles (1pt),
  Feet or soles (2pt)
• Time of worst symptoms:
  Day (0pt),
  Night (2pt)
  Both Day and Night (1pt)
• Night time insomnia for symptoms :
  No (0pt),
  Yes (1pt)
• Factors that alleviate symptoms:
  Standing (1pt),
  Walking (2pt)

2 – Assessment of signs of P Neuropathy

• Pain, temperature and vibration
  If impaired or absent (1pt)
• Ankle reflex
  If only present with reinforcement (1pt),
  If absent (2pt)

3 – Assessment of peripheral vascular diseases
Peripheral vascular diseases is defined by an ankle / arm blood pressure ratio <0.9 (1 - 1.4 in normal subjects)

RESUME

Objectif

Les données épidémiologiques sur la migraine, chez les Malgaches, sont rares ou discordantes. D’où l’intérêt de cette enquête de prévalence en population générale.

Méthodes

L’étude a été menée dans le « Grand Antananarivo », du 1er Juin 2001 au 31 Décembre 2001. Ont été incluses, les personnes des deux sexes, âgées de plus de 14 ans, ayant présenté au cours des 12 mois précédant l’enquête, des céphalées récidivantes.

Résultats

Sur les 496 personnes interviewées, 96 ont souffert de migraine, donnant le taux de prévalence brut de 19 % (96/496) et spécifique de 26,8 % (76/284) chez la femme versus 9,4 % (20/212) chez l’homme. Seuls 35 % des malades ont consulté un médecin, et 28% reçu des soins appropriés. La population migraineuse était plus jeune (p <0,01). Les statuts de femme (p <0,0001) ou de divorcé (p <0.05), le style de vie urbain (p <0,005), mais pas le bas niveau d'instruction (p >0,1), ou la grande taille familiale (p >0,1) étaient associées à la maladie.

Résultat

Du fait de sa fréquence élevée, la migraine pose à Madagascar, un problème de santé publique.

SUMMARY

Background

Epidemiological data on migraine are rare or discrepant in the malagasy medical literature.

Objective

This general population survey, carried out in the “Grand Antananarivo” from June 1st 2001 to December 31st 2001, is intended to supply this deficiency.

Methods

People of both sexes more than 14 years old, having suffered from recurrent headaches during the 12 months preceding the study, were included.

Results

Ninety six (96) out of the 496 persons submitted to the interview have suffered from migraine, giving the crude prevalence rate of 19 %, and specific rates of 26.8 % for women versus 9.4 % for men. Only 35 % of sufferers have consulted a doctor, and no more than 28 % received an appropriate treatment.
Migraineurs were younger (p <0.01). The disease was associated with female status (p <0.0001), divorce (p <0.05) and urban lifestyle (p <0.005), but neither with lower instruction (p >0.1), nor with the big family size (p >0.1).

Conclusion

Migraine set a public health problem because of its high prevalence.

Mots clés : Afrique, Epidémiologie, Migraine, Madagascar, Africa, Epidemiology, Migraine, Malagasy

INTRODUCTION

Douze à quinze pour cent de la population occidentale souffrent de migraine (5,7,9). L’Africain noir et l’Asiatique, des deux sexes, seraient moins touchés par la maladie (12,19). Les malgaches, qui partagent les deux origines raciales, devraient être aussi épargnés.
Or, les données épidémiologiques disponibles sont discordantes : une étude faite dans un centre de soins primaires d’Antananarivo, la capitale de Madagascar, rapporte une faible prévalence (16), alors que la migraine représente le deuxième motif de consultation neurologique à Mahajanga, une ville côtière (1). D’où la décision de mener cette enquête pour décrire la situation, en population générale.

POPULATION D’ETUDE – METHODES

L’enquête a été menée sur la population du « Grand Antananarivo » (14) , qui comprend le Renivohitra (capitale), de type urbain et les fivondronana (préfectures) d’Ambohidratrimo, d’Antananarivo avaradrano et atsimondrano, de type rural.
Ces fivondronana sont subdivisés en firaisana (communes rurales ou arrondissements, pour la capitale) eux mêmes formés de fokontany (quartiers), .
Les échantillons ont été tirés au hasard parmi les personnes des deux sexes, > 14 ans résidentes des habitats privés issus des fokontany.
Trois arrondissements la capitale sur les six, et un parmi les 3 fivondronana périphériques, ont été tirés au hasard .
Au cours de l’étape suivante, on procédait au tirage, également aléatoire du ¼ des communes rurales constitutives de ce fivondronana .
On recensait ensuite tous les fokontany des arrondissements urbains et des communes rurales, et on y repérait, avec un procédé également aléatoire, les habitats privés où l’on désirait prendre la personne à enquêter.
La taille globale de l’échantillon a été calculée, en tenant compte de la prévalence attendue de la maladie (15%), de la précision souhaitée (3%) et du risque alpha (0,05).
Le nombre de personnes tirées par firaisana était fonction du nombre de ses habitants.
L’enquête, qui s’est déroulée du 1erJuin 2001 au 31 Décembre 2001, a été menée par deux étudiants en médecine en fin de cursus, préalablement formés à l’enquête porte à porte (18).
Le questionnaire comportait des renseignements sur l’état civil de la personne interrogée (sexe, âge, niveau d’instruction, statut matrimonial, taille de sa famille, hérédité céphalalgique, style de vie urbain ou rural) et sur les caractéristiques de la céphalée.
Ont été inclus, comme cas de migraine, les personnes ayant souffert de céphalées récidivantes, au cours des douze mois précédant l’enquête.
Une fois dépistés, ces cas étaient authentifiés par un neurologue entraîné dans le domaine de la migrainologie, et utilisant les critères de l’International Headache Society (4).
Les différentes comparaisons ont été faites avec le test du X².

RESULTATS

Les 1er, 2ème et 6èmearrondissements de la capitale (type urbain) et 6 des 24 firaisana du fivondronana d’Antananarivo atsimondrano (représentant du pattern rural), ont été tirés au hasard
L’effectif total de l’échantillon était fixé à 500 personnes.
Le nombre de dossiers complet, à la fin de l’enquête était de 496.
Cent quarante trois (143) cas de migraine ont été dépistés dont 96 authentifiés par le neurologue, ce qui donne les taux de prévalence brut de 19 % (96/496) et spécifique de 26,8 % (76/284) pour les femmes vs 9,4 % (20/212) pour les hommes.
Les personnes migraineuses étaient plus jeunes (29 ±12 ans) que les non migraineuses (33 ±14,6 ans) [p <0,01] mais, à part le sexe (surreprésentativité féminine), le style de vie (atteinte plus prononcée de la population urbaine) et le statut matrimonial (taux plus élevé chez les personnes divorcées), les autres caractéristiques socio-démographiques (niveau d'instruction, grande taille familiale) n'étaient pas discriminantes ( tableau 1). Parmi les personnes souffrantes, 35 % seulement (34/96) ont consulté un médecin et 28 % seulement ont pu suivre régulièrement le traitement préventif. Les caractéristiques de la maladie sont rapportées sur le tableau 2. DISCUSSION

Bien que notre échantillon ne soit pas représentatif de l’ensemble des malgaches, la prévalence de la migraine, dans notre population, paraît plus élevée que celles, rapportées chez le Caucasien [x 1,4] (5,7,9,11), chez le Noir africain [x 3,5] (12) et chez le Chinois [x 27,5] (19).
Certaines enquêtes occidentales ont toutefois rapporté des taux aussi élevés (13,17).
Dans notre étude, il s’agit de migraine « active », celle qui nécessite vraiment une intervention médicale (8 ).
Du fait du double lien qu’elles entretiennent (3), la prévalence élevée de la migraine concorde avec celle de la dépression, retrouvée dans une étude récente (2).
Bien que le handicap provoqué par la maladie soit reconnu (17,18), le taux de recours médical est faible (35 %), et peu de patients reçoivent une prise en charge correcte (28%).
Ce seraient plutôt l’insuffisance d’informations et l’ancrage populaire aux pratiques traditionnelles qui favorisent la sous médicalisation des patients, mais non leur niveau d’instruction global (similaire à celui des non migraineux) [tableau 1].
De ce fait, les centres de soins primaires sont peu fréquentés (étude de Tehindrazanarivelo & coll)[16], tandis que les cas sévères ou survenant chez les per- sonnes suffisamment occidentalisées, sont concentrés dans les services spécialisés (1).
Les médecins généralistes eux mêmes, qui interviennent en première ligne, sont peu familiarisés avec la maladie, d’où les errances diagnostiques, déroutantes pour les malades: carences calcique ou magnésienne, troubles oculaires, hypothétiques sinusites (1).
Globalement, les caractéristiques de la maladie et des malades (prédominance féminine, âge plus jeune par rapport aux non migraineux, hérédité) sont superposables à celles rapportées dans la littérature (tableaux 1 et 2).
Les effets défavorables de certains styles de vie (stress urbain), des déboires matrimoniaux (effet négatif du divorce) nécessitent une confirmation par des études plus appropriées.
Contrairement à ce qui se passe chez leurs lointains ancêtres (l’africain et l’asiatique), les malgaches semblent avoir une propension à faire la migraine.
Les facteurs génétiques, à eux seuls, n’arrivent pas à expliquer cette différence : la culture et l’environnement jouent certainement un rôle qu’il faudrait identifier par des études plus approfondies.

CONCLUSION

Bien que non représentatifs de l’ensemble des malgaches, les résultats de cette enquête
confirment la forte prévalence de la migraine, déjà évoqués par une étude clinique antérieure (1).
Cette maladie pose, par conséquent, un problème de santé publique qui devient une priorité, si l’on tient compte du nombre de malades échappant au circuit thérapeutique, alors que l’on dispose de médicaments efficaces et de coût accessible. (6,15).
L’idéal serait d’entreprendre des études plus exhaustives et de plus grande envergure, dans d’autres régions de l’île, mais leur organisation, coûteuse, s’avère impossible dans le contexte économique actuel.
Il serait plus judicieux de mettre d’emblée en place un programme national de lutte, intégrant la sensibilisation et la formation des professionnels de santé, l’information du public et l’approvisionnement du marché en médicaments efficaces (génériques).
L’Organisation Mondiale de la Santé, qui a classé la migraine parmi les quatre affections les plus handicapantes [ avec la psychose, la tétraplégie et la démence] (10), et les Sociétés savantes peuvent fournir l’appui technique et scientifique, voire financier pour accompagner un tel programme.

TABLE 1 – Caractéristiques des patients migraineux.

* Les migraineux sont plus jeunes que les non migraineux (p <0,01)
**La migraine était plus fréquente chez la femme (p <0,0001)
Hérédité: 1/3 des migraineux (32/96) avaient une hérédité familiale directe pour la maladie

Style de vie: la migraine était plus fréquente en milieu urbain (p <0,005)
Situation matrimoniale: il y avait plus de divorcés dans la population migraineuse (p <0,05)
Pas de différence entre migraineux et les non migraineux pour les items suivants : bas niveau d’instruction (p >0,1), grande famille (>6 personnes) [p >0,1].

TABLE 2 – Caractéristiques des accès migraineux.

ABSTRACT

Background

Epilepsy is particularly highly prevalent in developing African countries and has been associated with cognitive disturbances, but more importantly is the contribution of the anti-epileptic drugs (AEDs).

Objective

This study aimed at comparing the effects of AEDs on the cognitive functions of Nigerian epileptic patients.

Methods

This is a prospective study of 55 consecutive patients with epilepsy, aged 14 years and above, over a two year period (October 2000 to October 2002), recruited from the Neurology Clinic of the University Teaching Hospital, Benin City, Nigeria. Anti-epileptic treatment with either carbamazepine (19 patients), phenytoin (18 patients), or phenobarbitone (18 patients) which was randomly assigned constituted the interventional measure.
Cognitive testing, using the Iron Psychology (FePsy) a computerized neuro-psychological test battery, measured the visual and auditory reaction times, the continuous performance test and the recognition memory test to assess the mental speed, attention and memory respectively.

Results

The effect of the individual drug on cognitive performance revealed significant impairment of mental speed (p<0.001) with the exemption of improved performance with phenytoin on auditory reaction time (p>0.05). Carbamazepine did not significantly affect the verbal (Words section) memory scores (p>0.05) implying better performance in tasks of verbal memory (p<0.05). All the three anti-epileptic drugs strongly reduced the attention abilities of the patients (p<0.001). Patients on phenobarbitone had the worst scores in both the verbal and non-verbal memory tasks. Conclusion
The results of this study will be useful in the rationale selection of anti-epileptic drugs with the objective of minimizing, as much as possible, their cognitive side effects.

RESUME

Introduction

La prévalence de l’épilepsie est élevée en Afrique de même que les troubles cognitifs associés à l’utilisation des antiépileptiques (AEDs).

But

Le but de l’étude est de comparer les effets des AEDs sur les fonctions cognitives d’une population épileptique nigériane.

Methodes

L’étude prospective, randomizée, concerne 55 patients épileptiques âgés de 14 ans et plus, étudiés sur une période de 2 ans (octobre 2000 à octobre 2002) et recrutés dans le service de neurologie du CHU de Benin City. Le traitement était soit la carbamazépine, (19 patients) soit la phénitoïne (18 patients), soit du phénobarbital (18 patients)
Les tests cognitifs utilisant le Iron Psychology (FePsy), tests psychologiques, ont mesuré les temps de réaction auditif et visuels, les tests de performance de la mémoire mentale, de l’attention et de la mémoire.

Resultats

Chacun des médicaments a entrainé une perturbation de la vivacité mentale (p < 0.001) à l'exception d'une amélioration du temps de réaction auditive avec la phénitoïne (p > 0.05). La carbamazepine n’a pas affecté de manière significative la mémoire verbale (mots) (p > 0.05). Tous les autres antiépileptiques ont réduit les capacités d’attention des patients ( p < 0.001) Les patients sous phénobabital ont eu les plus mauvais scores. Conclusion
Les résultats de cette étude aideront à une utilistion rationnelle des anti-épileptiques afin d’éviter les effets cognitifs.

Keywords : Africa, Anti-epileptic drugs, Epilepsy, Memory, Mental speed, Nigeria, Afrique, Antiépileptiques, Epilepsie, Mémoire. Nigéria, Tests psychologiques

INTRODUCTION

Epilepsy is the second most common disorder of the central nervous system, affecting 1% of the human population (5). It is particularly highly prevalent in developing African countries (10,12). Epilepsy has been associated with cognitive disturbances, but more importantly is the contribution of the anti-epileptic drugs (AEDs).
Anti-epileptic drugs (AEDs) have adverse effects on cognitive functions such as attention, memory and psychomotor speed. There is evidence that drug-induced cognitive impairment has great impact on critical daily life function of patients with epilepsy (3,7). The cognitive effects of AEDs are of special concern because they are iatrogenically induced (3).
Comparative studies of AEDs in developed countries have shown that while carbamazepine had minimal side effects, phenytoin and phenobarbitone have less favorable cognitive side effects with impairments of mental speed, memory and attention (4,13,14). These latter two drugs are however the most widely used in developing countries, because of good efficacy, broad spectrum of activity and low cost (11).
There is little information available in the literature on the effect of AEDs on the cognitive functions of African epileptic patients. This study was aimed at comparing the effects of the commonly used AEDs on the cognitive performances of Nigerian patients with epilepsy. The results of such a study will be useful in the rational selection of anti-epileptic drugs and in the educational and vocational counseling of patients. Moreover, this study provides another opportunity to gain more information about the older AEDs, i.e phenobarbitone and phenytoin.

SUBJECTS AND METHODS

Patient’s Selection

All the patients that presented with recurrent afebrile seizures in the outpatient neurology clinic of the University Teaching Hospital Benin City, Nigeria between October 2000 and October 2002 were recruited i.e. a total of 147 patients.

A total of 55 consecutive patients aged 14 years and above, satisfied the inclusion criteria. Patients with psychiatric illness, mental sub-normality and those with progressive neurological disorders were excluded from the study. An EEG was not required for diagnosis, as epilepsy is a clinical diagnosis. These patients have not been on AED prior to presentation.

Patient’s Demographic Data

All patients completed questionnaires designed to obtain demographic information on the age, sex, level of education, age at onset of seizures, frequency of seizures and type of seizures.

The seizure types were classified clinically, based on the International League against Epilepsy (ILAE) classification of 1981 (6). The patients comprised 35 men and 20 women, with a mean age of 29.8 (+/- 12.47) years. Seventeen patients had primary education, 26 had secondary education and 12 had post- secondary education. Forty-five patients had primary or secondary generalized seizures while 10 had partial seizures. Laboratory investigations done on the patients included:

(a)Liver function tests (b) Urea and electrolytes (c) Blood sugar estimations and (d) if indicated, lumbar puncture for cerebrospinal analysis.

Patients and Drug Therapy

Patients and Drug Therapy

After initial diagnoses, the patients were randomly assigned to anti-epileptic medications, with nineteen (19) patients receiving carbamazepine (CBZ), eighteen (18) receiving phenobarbitone (PB) and eighteen (18) phenytoin (PHT).

The treatment was chosen at random.

(A) Carbamazepine group

The median dosage for these patients was 600 mg per day (range 400-1200 mg) with a modal seizure frequency of 3-4 attacks per month, and mean duration of seizures of 6.5 years.

(B) Phenytoin group

The median dosage was 300 mg per day (range 200-300 mg) with a modal seizure frequency of 2 attacks per month, and mean duration of seizures of 5.5 years.

(C) Phenobarbitone group

The median dosage was 120 mg per day (range 60-180mg) with a modal seizure frequency of 3-4 attacks per month and a mean duration of 7.5 years.

There was no significant difference in the three groups of patients at recruitment in terms of seizure variables or demographic data. (Refer Table 1)
The patients’ cognitive performances were assessed after three months of AED therapy, following the initial pre-medication assessment at recruitment. AEDs were available freely to all patients in the study. At the initial visit each patient was given a health talk on AED compliance and was well motivated to take AEDs because of the stigma locally attached to epilepsy.
There were no facilities for AED serum level estimations in our hospital where the study was conducted.

Cognitive Testing

The administration of tests was done with the FePsy computerized neuropsychological test battery (1, 3, 8, 9). Test presentation and response registration were controlled by a microcomputer, but one of the authors (O.O) was always present to adjust instructions to the individual performance level of the patients. The cognitive assessment was not blind as the author (O.O) was aware of the patients’ drug status. However, this did not affect result of neuropsychological testing as it is computer-controlled, and the evaluation of performance is not dependent on the author, but on the testees’ cognitive abilities.
(A)Short-term Memory was assessed using the Recognition Memory test (RMT). The test involves the use of study items which consist of 3 or 4 figures (for the visual, non-verbal memory test) and 4 or 6 words (for the verbal memory test) which are presented simultaneously.

The task is divided into a study phase in which the material to be remembered is presented and a test phase in which recognition is tested. A delay of two seconds is allowed between study phase and the test phase. In the test phase, the figures or words are presented again and the target item has to be recognized. Patients with primary school education were tested using 3 figures and 4 words, while those with secondary and post-secondary education were tested using 4 figures and 6 words. The results were calculated as percentage of correct responses. The evaluation of the recognition task was performed in the context of the short-term memory function (8).
(B)Psychomotor Speed was assessed by the Simple Reaction Time. In the auditory version the testee was asked to react as quickly as possible to sound stimuli of 800 hertz generated by the computer. For the visual version, the testee reacts as quickly as possible to a white square in the middle of the computer screen. In both versions the inter-stimulus interval is randomly varied form 2.5 to 4 seconds. The evaluation of the results was done within the context of speed of information processing and alertness functions (8).

(C)Attention was assessed using the Continous Performance Test, which involves the display of a string of eight characters, either ‘XXXXXXXX’ or ‘XAXXXXXX’. The stimuli are presented during a short (200 msec) period. The testee has to respond (by pressing a key on the keyboard) to the appearance of a character ‘A’ at a random position in the stimulus string. The results are computed by the FePsy software, according to a signal detection model (8).

Statistical Analysis

The patients were divided into three categories based on the type of AEDs received. The data from each cognitive task was separately submitted to a one-way analysis of co-variance with cognitive performance as the dependent variable and AED medication as the independent variable. Significance level was set at 5%.
Data comparing performances pre- and post- medication were tested using the Student’s ‘t’ test with level of significance set at p< 0.05. RESULTS

Reaction Times (Mental speed)

The comparison of the data on the cognitive performances of the patients pre- and post medication revealed statistically significant adverse effect on the mental speed, with phenobarbitone group having the worst scores ( p< 0.001 ). On the other hand, phenytoin had a favorable effect on the auditory reaction time (p> 0.05). Refer Tables 11b and 11c. But when the effects of all the three AEDs were compared, there was no statistically significant difference between the three drug groups in both auditory and visual reaction times. Refer Table 111.

Memory

The carbamazepine group performed better than those on phenytoin and phenobarbitone in tasks of both verbal Words and visual, non-verbal memory Figures but only the difference in verbal memory performance reached statistical significance (p < 0.05). Refer Table 111. The effect of carbamazepine on verbal and visual memory was also favorable when the three AEDs were compared post medication (p>0.05) refer table 11a. Patients on phenobarbitone had the worst scores in both verbal and non-verbal memory tasks. Refer Table 111.

Attention

All the three drug groups showed significant worse performances in attention when the pre- and post- medication Continuous Performance test scores d’ were compared (p< 0.05) without significant difference in their response bias(p>0.05). But the scores reflected better perceptual sensitivity and sustained attention in patients on phenytoin and carbamazepine compared to those on phenobarbitone; though these differences did not reach statistical significance. Refer Table 111.

DISCUSSION

This study was aimed at assessing the effects of phenobarbitone, phenytoin and carbamazepine on cognitive function in newly diagnosed Nigerians with epilepsy. The patients were randomly assigned to one of the three AEDs and their cognitive function assessed by computer at recruitment and three months after commencement of medications. The computer-based test battery has been shown to be highly sensitive in detecting cognitive dysfunction in patients with epilepsy (8, 9). This setting is unique as similar studies have not been carried out in Africans with epilepsy.

The study showed significant deterioration in cognitive performances with all the three drugs when their scores before and after medication were compared, with the only exemption being the improved performance in the auditory reaction time in patients on phenytoin and significant improvement in verbal memory scores in the carbamazepine group.

However, there were no significant differences in auditory and visual reaction times between the three AEDs. Although on the whole, reaction times were longer for the patients on phenobarbitone. Patients on carbamazepine performed significantly better in verbal memory tasks, and also had a trend towards better performances in non-verbal memory. Patients on phenobarbitone had the worst performance in the tests of sustained attention, though there was no difference in the response bias of the three groups of patients. This implies that this observation is not due to chance.

Our study reconfirms in Africans the observations in the literature that carbamazepine has a relatively favorable cognitive profile compared to phenytoin and phenobarbitone (1, 2, 4, 13, 14). Though it would have been desirable to correlate the cognitive performances with serum levels of these drugs, this facility was not available in our center.

CONCLUSION

Our study has confirmed the presence of cognitive impairments in epilepsy prior to administration of, and the worsening of these by, antiepileptic medications commonly used in Nigeria and other African countries. There is significant deterioration in attention abilities, mental speed and memory performance. However, carbamazepine appears to have a more favorable profile than phenytoin and phenobarbitone.

Coping with day-to-day activities demands unimpaired cognitive abilities including memory, attention and psychomotor speed. For instance, the learning process requires sustained attention and intact memory. Although costs and the relative unavailability of health care systems will not allow the ideal selection of AEDs in all circumstances, the results of this study suggests the need for careful follow up of African patients on AEDs, especially phenobarbitone, in other to minimize cognitive side effects and to maximize quality of life.
There is need for simple tests of cognitive function that can screen patients with epilepsy and determine the need for more sophisticated tests of cognitive function, such as computerized test used in this study.

TABLE 1 – Descriptive details of the patients

TABLE 2 – The Effect of AEDs on Mean Cognitive Performances – [pre- and post-medication]

TABLE 2a – Carbamazepine Group ( n = 19)

TABLE 2b – Phenytoin Group ( n = 18)

TABLE 2c – Phenobarbitone Group ( n = 18)

TABLE 3 – The Effect of Anti-Epileptic Drugs on Mean Cognitive Performances