Multiple Sclerosis and Related Disorders (2013) 2, 80–89

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journal homepage: www.elsevier.com/locate/msard

REVIEW

Multiple sclerosis in Colombia and other Latin American Countries Jaime Toroa,b,c,d,n, Sim´ on Ca rdenasd, Carlos Fernando Mart´ıneza,c,  Urrutiab, Camilo D´ıazd Julian a

´n Santa Fe de Bogota , Calle 119 No. 7-75, Bogota , Colombia Department of Neurology, Hospital Universitario—Fundaci o School of Medicine, Universidad de Los Andes, Carrera 1 No. 18 A-12, Bogota , Colombia c School of Medicine, Universidad El Bosque, Carrera 7B Bis No. 132-11, Bogota , Colombia d ´n Santa Fe de Bogota , Avenida 9 No. 117-20 Multiple Sclerosis Investigation Group, Hospital Universitario—Fundaci o Oficina 409, Colombia b

Received 10 August 2012; received in revised form 30 August 2012; accepted 5 September 2012

KEYWORDS

Abstract

Latin America; Colombia; Multiple sclerosis; Health policy; Prevalence; Review

The spectrum of multiple sclerosis (MS) in Latin America is characterized by geographic and racial/ genetic particularities. In this review we describe major studies of MS epidemiology, genetics, and clinical presentation in Latin America, with a focus on Colombia. We also consider the influence of national health care systems on the treatment of MS in Latin American patients. Epidemiologic studies indicate that the regional incidence of MS in Latin America is more complex than once thought, and broadly consistent with the geographical (latitudinal) distribution of MS in other parts of the world. Low prevalence of MS is considered to be o5/100.000 inhabitants and high prevalence 430/100,000. Colombia is considered a low-risk region for MS, as are other countries located near the equator, such as Panama and Ecuador. By contrast, Latin American countries located farther from the equator are medium or high-risk regions. National health care systems generally cover MS treatment, although bureaucratic problems sometimes interfere with delivery of high-cost medications and access to diagnostic tests, particularly in rural areas. The population of Colombia is racially diverse and genetically heterogeneous, making it difficult to study genetic associations within a complex disease such as MS. The clinical spectrum of MS in Latin America is similar to that of Europe or North America. & 2012 Published by Elsevier B.V.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Health care system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

n

 Corresponding author. Asociaci´ on Medica de Los Andes, Avenida 9 No. 117-20 Oficina 409, Bogota , Colombia. Tel.: +57 1 2150169; fax: +57 1 2150205. E-mail address: [email protected] (J. Toro). 2211-0348/$ - see front matter & 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.msard.2012.09.001

Multiple sclerosis in Colombia and other Latin American Countries 3. Epidemiology. . 4. Genetics . . . . 5. Clinical course . Conflict of Interest References . . . . .

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Introduction

The literature review presented in this paper is based on a search of MEDLINE and the Literatura Latino-Americana y del Caribe en Ciencias de la Salud (LILACS) database for all published articles on multiple sclerosis (MS) in Latin America. Among Latin American countries, Colombia is considered to have a particularly low prevalence of multiple sclerosis (MS). According to Kurtzke (1975), the regional prevalence of MS can be categorized according to disease frequency: low (o5 cases per 100,000 inhabitants), medium (5–30 cases per 100,000 inhabitants), and high (430 cases per 100,000 inhabitants). Bogota , the capital of Colombia, is located at a mean altitude of 2640 m above sea level, has an area of 1587 km2, and is located at geographic coordinates 4135N 74104W. The temperature of the city varies between 8 1C and 16 1C yearround, unlike the temperature of Argentina, Uruguay, Chile, or Brazil, which varies by season. Bogota has approximately 8,000,000 inhabitants and its population increases annually at a rate of 2.4%. The population of modern-day Colombia is genetically diverse and includes people with Native American, European, and African origins. There is no significant immigration to Bogota from European countries. It is likely that the low prevalence of MS in Colombia (Toro et al., 2007; Sanchez et al., 2000) and other Latin American countries as compared to other parts of the world, is related to genetic and environmental differences between European/North American/Asian/ African and Latin American populations. Access to advanced imaging and medical care may also contribute to the observed differences in disease prevalence among some Latin American countries. Before the advent of modern techniques for the study of genetic contributions to disease, it was proposed that differences in sunlight exposure may contribute to the geographic (latitude-based) distribution of MS. In Tasmania a case–control study showed that higher sun exposure during childhood and early adolescence is associated with a lower risk of MS (van der Mei et al., 2003). More recently, the geographic distribution has been attributed to genetic differences among populations, and growing evidence suggests that vitamin D insufficiency may account for the latitudinal gradient of MS (Munger et al., 2006; Beretich et al., 2009). The disease seems unlikely to result from a single causative event; instead, MS seems to develop in genetically susceptible populations as a result of environmental exposures like sunlight, which might influence levels of vitamin D. On the other hand a lower risk of MS could potentially be explained by direct protective effect of ultraviolet B radiation (UVB), independent of vitamin D synthesis (Lucas and Ponsonby, 2006). In 1993, health care reform resulted in an expansion of health insurance coverage to 70% of the population of

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Bogota (as compared to 27% previously), including the poor, formal and informal employees, and their families. Since then, health care organizations have been required to cover modern diagnostic tests and treatments for patients with MS. These changes offer a unique opportunity to estimate the prevalence of MS in Colombia more accurately than was possible previously.

2.

Health care system

The Political Constitution and Constitutional Court of Colombia enshrine a fundamental right to health care, which can be upheld judicially through a constitutional protection writ called tutela (Constituci´ on Pol´ıtica de Colombia (1991); Corte Constitucional de Colombia (2008)). Thus, every Colombian has the right to a basic health benefits package, the Plan Obligatorio de Salud (POS), which is provided under a national insurance program and administered by either public or private Health Promoting Entities (EPSs; the local equivalent of health maintenance organizations). Although the POS covers an array of services, including some high-cost diagnostic and medical procedures for both acute and chronic conditions, patients can request types of care not included in the POS by means of the tutela when their health is threatened demonstrably by a lack of such care. Furthermore in Colombia and many Latin American countries, families are closely involved in the long-term care of patients with MS. Health insurance expansion through the POS has resulted in increased risk protection, usage of traditionally under-utilized preventative services, and reduced out-of-pocket expenses for health care services (Castan ˜o et al., 2002). This system has given most MS patients access to high-cost diagnostic procedures, such as visual evoked potential (VEP) tests and magnetic resonance imaging (MRI) scans, irrespective of income (CRES, 2011). Therefore, up to 80.4% of MS patients in Colombia have received at least one MRI scan (Toro et al., 2007). Individual patients can request excluded interventions by means of the tutela, thus Colombian MS patients do have access to a mechanism by which they can, in principle, secure state-ofthe-art care. The most effective health care policies for the management of MS at a population level remain to be established. Differences in policy among Latin American countries and in the rest of the world highlight this lack of consensus. For example, in Brazil, clinical guidelines establish which types of care are covered by the national health care system (Brazilian Ministry of Health, 2010). In Chile, MS is included as a disease category covered through the national health care program, Acceso Universal conGarantias Explicitas (AUGE), as of 2010 (Chilean Ministry of Health, 2010a, b). Clinical guidelines of the Chilean Ministry of Health offer treatment options and diagnostic procedures (Chilean Ministry of Health, 2010a, b). In Uruguay, the National Resource Fund (FNR) ensures financing of

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Table 1 Approach to the diagnosis and treatment of Multiple Sclerosis in Latin America.

Table 1 (continued )

Country

Patients with PPMS subtype are excluded from coverage Venezuela IFNb, GA, other In 2006 approximately medications affecting 87% of all MS patients were receiving free disease progression integral treatment through the Venezuelan Institute of Social Security Therapies for disease complications (e.g. botulinum toxin for spasticity) Argentina IFNb Bureaucratic inefficiencies frequently delay access to treatment

Coverage

Colombia MRI scans VEP tests

CSF tests

Brazil

Chile

Uruguay

Comments Important administrative barriers to access that limit the benefits to patients Treatment with IFNb, natalizumab, GA or mitoxantrone is not covered

Inpatient treatment with IV steroids for flares Physical therapy MRI scans VEP tests CSF tests IV methylprednisolone for flares IFNb or GA (first line) Natalizumab (second line) Yearly follow-up MRI Treatment offered for patients with RRMS scan and SPMS with VEP tests relapses CSF tests IFNb-1 A, IFNb-1B, GA (first line) Mitoxantrone, IVIG, azathioprine (second line) Hospitalizations for: diagnostic purposes, treatment of exacerbations with IV methylprednisolone, treatment of disease complications Psychological support, treatment and rehabilitation for fatigue, spasticity, ataxia, tremor, urinary and GI tract dysfunction, pain, emotional liability IFNb, GA Treatment offered only to patients meeting detailed inclusion and exclusion criteria regarding age, comorbidities, quality of life, and prognosis

Country

Coverage

Comments

CSF, cerebrospinal fluid; IFNg, interferon beta; IVIG, intravenous immunoglobulin; GA, glatiramer acetate; GI, gastrointestinal; MRI, magnetic resonance imagining; PPMS, primary-progressive multiple sclerosis; RRMS, relapsingremitting multiple sclerosis; SPMS, secondary-progressive multiple sclerosis; VEP, visual evoked potentials.

treatment only for patients with a reasonable life expectancy as a result of adequate response to therapy. To qualify for treatment, patients must provide documentation that the center requesting coverage is capable of providing integral, multidisciplinary treatment including psychosocial support and rehabilitation therapy. This documentation must be provided anew each month to secure funding for the following month’s treatment (National Resource Fund, 2008). In Venezuela, all citizens have a right to health care including high-cost medications and treatments (Venezuelan Institute for Social Security, 2009). In Argentina, the Special Programs Administration (APE) covers treatment with IFNb only for patients with RRMS or for SPMS with relapses (Special Programs Administration, 2004). By law, health insurance agencies are obligated to fund this therapy for all eligible patients (Instituto de Estudios sobre Pol´ıticas de Salud, 2011) (see Table 1 for a summary of diagnosis and management of MS in Latin America). Recently fingolimod has been introduced in several countries of Latin America (Argentina, Brazil, Chile, Colombia, Guatemala, Mexico, Panama, Peru and Venezuela). The most common problem in MS treatment in Colombia and elsewhere in Latin America is the intermittent use of IFNb due to problems with bureaucracy and medication delivery by the Health Care System. It is well-known that intermittent use of this medication, as is common in Colombia and Latin America, is associated with no benefit in terms of relapsing of the disease (Tan et al., 2011). Another issue that one must consider in Latin America regarding treatment of MS is the physician–industry relationship through educational activities, meetings and seminars which create an unconscious social expectation of reciprocity that could influence many of the doctors prescribing

Multiple sclerosis in Colombia and other Latin American Countries behavior. However, relationships between physicians and industry can have some positive effects on patients care. In Latin America there is an average of one neurologist per 202,000 inhabitants (WFN, 2001). A recent survey of 855 neurologists in nine out of 20 Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, Panama , Per´ u, Uruguay and Venezuela) found that 94% reported sufficient patient access to MRI scans, 82% reported adequate patient access to VEP tests, and only 45% reported access to CSF oligoclonal band detection tests, in their home countries. Although most respondents indicated that their first-line treatment of choice is GA or IFNb, only 64% reported that generic versions of these drugs are approved for use in their home countries, and all agreed that health care systems need to improve coverage offered at a population level (Carra et al., 2011). These experiences are by no means confined to the developing world. In England and Wales, treatment with IFNb and GA was not initially recommended by the National Institute for Clinical Excellence (NICE) due to unacceptably low levels of cost-effectiveness (National Institute for Health and Clinical Excellence, 2002), but subsequently were included via a special and controversial risk-sharing plan designed to lower costs. These treatment options are also offered in Australia and New Zealand (Raftery, 2008), but there is ongoing debate about the soundness of these policies (McCabe, 2010).

3.

Epidemiology

The geographical distribution of MS is very heterogeneous and has been studied and discussed widely. It is well established that MS prevalence has a latitudinal gradient; that is, that MS prevalence grows as one moves farther from the equator. Colombia is in a low-risk region because of its localization on the equator (Kurtzke, 1975). In this section we discuss the epidemiology of MS in Colombia vs. other South American countries, particularly neighboring countries near the equator. Colombia lies in the northwest region of South America, bordered on the north by the Caribbean Sea and on the west by the Pacific Ocean, and extending south and east to the Amazon basin and the Orinoco basin, respectively. It is crossed by the north end of the Andes range, which splits into three smaller ranges (east, central, and west). The country is divided in five regions that vary in climate and altitude: the Andean, Pacific, Amazon, Caribbean, and Oriental regions. Most of the urban population is in the Andean region. There are only two studies published on prevalence of MS in Colombia. Sa nchez and colleagues used the capture– recapture method to estimate MS prevalence on December 30, 1997, in the provinces of Santander (located on the oriental range) and Antioquia, Risaralda, and Caldas (located on the central range), all of which are at similar altitudes and have similar climates. The prevalence for these regions was estimated between 1.48 and 4.98 per 100,000.(Sanchez et al., 2000). These four regions equaled 26% of the total Colombian population at that time. We estimated MS prevalence on December 31, 2002, in Bogota to be 4.41 per 100.000 approximately. At that time Bogota was 15% of the total Colombian population (Toro et al.,

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2007). All the cases noted by Sa nchez et al. fulfilled the Poser criteria for MS (Poser et al., 1983). All the cases that we registered fulfilled the McDonald criteria for MS (McDonald et al., 2001). The results of both studies indicate that MS is rare in Colombia, and that Colombia can be classified as a low-risk region for MS according to the criteria of Kurtzke (1975) . It is important to note that the regions that were studied are the most populous of Colombia. Within these regions lie the two most important and populous Colombian cities, Bogota and Medell´ın. The population of Bogota may be representative of the entire Colombian population because of the internal migration from all over the country. However, the prevalence of MS in the other regions of the country, including rural areas, has not been studied. These findings are consistent with the view that the tropics are a low-prevalence region for MS (Kurtzke, 1975; Pugliatti et al., 2002). They are also in agreement with the low estimated prevalence of MS in neighboring countries. In Mexico, the prevalence of MS in the city of San Pedro Garza Garc´ıa (located in the northeast, along the USA border with the state of Texas) is estimated to be 30 per 100,000 inhabitants (De la Maza Flores and Arrambide Garc´ıa, 2006). In Mexico City the prevalence was 1.6 per 100.000 on January 1, 1968 (Alter and Olivares, 1970). In the French West Indies (i.e. the islands of Martinique and Guadeloupe) a crude MS prevalence of 14.8 per 100,000 was calculated on December 31, 1999 (Cabre et al., 2005). A study performed in 2007 in the city of Lima (Per´ u) provided a prevalence of 7.64 per 100,000 (Vizcarra Escobar et al., 2009). Another study in Uruguay reported an MS prevalence of 30 per 100,000 (Oehninger et al., 1998). In Chile a prevalence of 5.69 per 100,000 was reported recently (Melcon et al., 2012). As of July 2005, the prevalence of MS in Panama was estimated to be 5.24 cases per 100,000 inhabitants (Gracia et al., 2009). In Quito, the capital of Ecuador, the prevalence of MS was estimated to be 5.05 cases per 100,000 in 2006. In two other major Ecuadorian cities, Cuenca and Guayaquil, the prevalence rates for MS was of 0.75 cases per 100,000 and 2.26 cases per 100,000, respectively (Abad et al., 2010). Some studies of sub-Saharian Africa and southern Asia, which are at the same latitude as Colombia, indicate a similarly low prevalence of MS (Kurtzke, 1975; Pugliatti et al., 2002; Kioy, 2001). By contrast, MS is more prevalent in South American countries located farther from the equator, especially Brazil and Argentina. MS prevalence in Sa~ o Paulo was estimated by Callegaro et al. (2001) to be 15.0 cases per 100,000 inhabitants for 1997. They noted a 3-fold increase in MS prevalence over a 7-year period following their initial estimate (Callegaro et al., 1992), but it is reasonable to assume that this discrepancy reflects diagnostic difficulties in the first study as opposed to a real increase in prevalence. Similar estimates were obtained in the cities of Londrina and Arapongas (Kaimen-Maciel et al., 2004), which lie approximately 600 km to the west of Sa~ o Paulo. Reports for MS prevalence in other Brazilian cities have been published: Cuiaba 15 per 100,000 (Melcon et al., 2012), Belo Horizonte 18.1 per 100,000 (Lana-Peixoto et al., 2012), Botucatu 17 per 100,000 (Rocha et al., 2002), Santos 15.5 per 100,000 (Fragoso and Peres, 2007), Rio de Janeiro 5 per 100,000 (Alvarenga et al., 2000) and Recife 1.36 per

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Figure 1 Prevalence of multiple sclerosis (MS) among Latin American countries and Colombian cities.

100,000 (Ferreira et al., 2004). In Argentina prevalence estimates range from 13.4 to 21.5 cases per 100,000 inhabitants, depending on the city surveyed, indicating that the entire country is a medium-risk region (Cristiano et al., 2009; Melcon et al., 2008). As expected because of latitudinal gradient, the incidence of MS was higher in the southern cone, as shown by Cristiano et al. (2010), who estimated disease incidence of 1.76 cases per 100,000 inhabitants per year, and by D´ıaz et al. (2012) who found an incidence of 0.90 cases per 100,000 inhabitants per year in Chile. These findings are both higher than those found in Panama by Gracia et al. (2009). However, a study performed in the French West Indies after return migration of the population, calculated a crude mean annual MS incidence of 1.4 per 100,000 inhabitants, for the period between July 1, 1997, and June 30, 2002. The French West Indies comprise two islands, Martinique and Guadeloupe, both situated in the Caribbean basin at latitudes between 14130 N and 161N. Martinique showed a higher incidence (two per 100,000) than Guadeloupe (0.7 per 100,000) (Cabre et al., 2005). It is worth noting that these findings support the hypothesis of certain environmental factors serving as triggers for the development of MS. Collectively, these studies confirm the oft-described latitudinal gradient of MS frequency in South America. This is clear in the comparison of findings from southern countries such as Argentina, Chile, and Brazil with countries on the equator. The gradient could be taken support the hypothesized role of ultraviolet radiation and vitamin D levels in MS pathogenesis (Ascherio, 2010), but further studies on this topic are needed. However, the populations of the two regions (southern vs. equatorial South America) have different genetic backgrounds stemming from different waves of immigration, particularly from European countries other

than Spain (mainly Italy and Germany), which took place in the second half of the 19th century and the early decades of the 20th century (Sa nchez-Albornoz et al., 1968). This issue will be discussed in Section 4 The latitudinal gradient of MS frequency is not as clear within countries as it is between countries. However, this could be due to factors unrelated to MS risk or etiology such as internal migration, access to health care services for diagnosis or treatment, and disability-related issues. The only study to provide evidence for a latitudinal gradient within a country found that MS incidence in the Magallanes region of Chile (the southernmost region of the country) is almost four times that of the country as a whole (D´ıaz et al., 2012). Although there have been some reports which show that the prevalence of MS among persons born in regions with higher altitude to be greater than those born in lower regions (Cernacek et al., 1971) this is not the case in Latin America. Furthermore a study published by Norman et al. (1983) shows that altitude does not affect the risk of MS when adjusted for latitude of birth place. The frequency of MS in other regions of South America is unknown. Definitive prevalence studies are needed in countries such as Paraguay, Bolivia, and Venezuela, and in secondary cities and rural regions of most South American countries. Figure 1 summarizes the different MS prevalences among some Latin American countries and highlights the MS prevalence for several Colombian cities.

4.

Genetics

MS is believed to develop in genetically susceptible people when triggered by an environmental factor. The genetics of

Multiple sclerosis in Colombia and other Latin American Countries MS have been studied intensively in many high-prevalence countries, but not in Latin America. The Colombian population is genetically heterogeneous, with Native American, European, and African (primarily subSaharan) origins. Colombia was the first South American region conquered by the Spanish in the 15th century (Sa nchezAlbornoz et al., 1968). Prior to that Colombia was inhabited by native populations with a relatively homogeneous genetic background. The maternal lineage of the modern Amerindian populations in Colombia is distributed equally among the major Amerindian mitochondrial haplogroups A, B, and C, with a low frequency of haplogroup D. However, this distribution is disrupted by the Andes, which divide the Amerindian population in two, one resembling the central and North American populations to the north and west of the range, and the other resembling South American populations to the south and east of the range (Keyeux et al., 2002; Melton et al., 2007). The genetic background of the indigenous population was blurred by the arrival of the Spanish conquerors, which also brought African slaves. The three populations have shared the region since then, and there has been significant mixing among them. The most common is the admixture of Caucasian men and native women, called mestizos (Sa nchez-Albornoz et al., 1968). Modern admixed populations, such as Mestizos, Mulattos (from the admixture of Caucasian men and African women), and Afro-Colombians, share their ancestry with Native American and Sub-Saharan African populations (Salas et al., 2008; Rodas et al., 2003). Because the Colombian population is so genetically heterogeneous, it is difficult to study genetic associations with complex diseases such as MS. Mesa and colleagues studied autosomal, Y chromosomal, and mitochondrial DNA markers of different populations in Colombia, including native tribes (Mesa et al., 2000). They found that mating occurred predominantly between male conquerors and female natives. A similar finding was reported by CarvajalCarmona (Carvajal-Carmona et al., 2000), who showed that a specific Colombian population living in the province of Antioquia has been genetically isolated throughout the history of the country and has an important contribution from Jewish populations. This is the only population in Colombia in which the genetics of MS have been studied. Sa nchez also studied the association of MS with human leukocyte antigen (HLA)–DQ alleles in a sample of 32 MS patients from Antioquia (Sa nchez et al., 2000). They found a significant protective association with the HLA-DQ3 allele. Palacio studied linkage disequilibrium of the 6p chromosome using STR microsatellites (Palacio et al., 2002). They found an association between MS and certain polymorphisms of the microsatellite loci D6S276 and D6S273, suggesting that the region 6p21.3–21.4, which contains HLA and tumor necrosis factor (TNF) genes, is associated with MS in this population. More recently, Rojas conducted a case–control study in which 65 patients were matched with 184 healthy controls (Rojas et al., 2010). They typed HLA-DRB1 alleles and found a significant association between MS and alleles HLA-DRB1n0103 and HLADRB1n15. Interestingly, they found a protective association with the alleles HLA-DRB1n0301 (OR: 0.512; CI: 0.29–0.906) and HLA-DRB1n0703 (OR: 0.264; CI: 0.079–0.883). Because these three studies were restricted to MS patients from Antioquia, their findings might not be representative of the entire population of Colombia.

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Importantly, Rojas et al. (2010) did not find an association between MS frequency and HLA-DRB1n1501, which is the allele most consistently associated with MS worldwide (Schmidt et al., 2007; Hafler et al., 2007; Esposito et al., 2010), including Latin American countries such as Mexico (Ala ez et al., 2005) and Brazil (Alves-Leon et al., 2007; Kaimen-Maciel et al., 2009). Likewise, in Bogota we found no association of the HLA DRB1n15 allele with MS. However, a significant protective association with the HLA DRB1n14 allele was noted (unpublished data). Brum and colleagues also found a protective effect of HLA DRB1n14 in their analyses of a mixed population as well as white and mulatto populations independently (Brum et al., 2007). Collectively, these findings may indicate that the Native American genetic background of the South American population carries protective alleles that are at least partly responsible for the low prevalence of MS in the tropical countries of South America. However, this protective association has been found in Caucasian populations as well, leaving this issue unresolved (Barcellos et al., 2006; Dyment et al., 2005). The association of MS with HLA alleles other than DRB1n01 is yet to be clearly defined. Alves-Leon et al. (2007) showed that black and white populations are genetically independent and that genetic associations with MS in the two populations are different. This racial difference has not been studied in Colombia, most likely because black MS patients are very scarce in Colombia. In fact, none of the three published Colombian studies reported the proportion of black patients in their populations, and we have no knowledge of any black MS patients in Bogota .

5.

Clinical course

Traditionally, MS has been described as a chronic medical condition predominantly affecting Caucasian people in developed countries. Nevertheless, recent studies in countries outside of high-prevalence regions suggest that MS is not as uncommon in Latin America and other low-frequency zones as once thought. An increasing number of studies have appeared since the 1990s, most of them coming from Brazil. In a retrospective study in Rio de Janeiro, 122 MS patients were identified since 1978 (Alves-Leon et al., 2008). They described the most common symptoms and clinical features seen in their populations and compared their observations with those of other Brazilian studies. The majority of the patients were female (70%) and Caucasian (67%). There were pyramidal symptoms in 42.4% of the patients, sensory loss in 14.1% of the patients, and brainstem dysfunction in 12% of the patients. Interestingly, visual symptoms (6.2%) were not as common as in other studies (Alves-Leon et al., 2008). Table 2 describes the clinical features of MS patients in studies done in Latin America. Few studies have examined the clinical spectrum of MS in Colombia. Sa nchez et al. (2001), analyzed 65 Caucasian patients with definite MS, described the frequency of clinical manifestations in this population, and compared them with another series from temperate zones. Most patients (69.2%) had RRMS; the remainder (31.8%) had chronic-progressive MS (CPMS). As many as 60% of patients reported only one symptom before MS was diagnosed. The frequency of motor disturbances was 35.7%, while optic neuritis was seen in 46.4%

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Table 2

Studies of multiple sclerosis in Latin America.

Authors and country

Number of patients

Clinical subtypes

Arruda et al. (2001) (Brazil) Alves-Leon et al. (2008) (Brazil) Vizcarra-Escobar et al. (2005) (Peru) Herna ndez-Valero et al. (2004) (Cuba) Tilbery et al. (1995) (Brazil) Toro et al. (2007) (Colombia)

200

91% RRMS, 8% PPMS, 1% SPMS

122 55 50 214 224

Symptoms at disease onset

Brainstem/cerebellar 63%, sensory 53%, motor 49.5%, optic neuritis 39.5% 69.6% RRMS, 13.1% PPMS, 17.2% SPMS Brainstem/cerebellar 8%, sensory 23%, motor 24%, visual 14% 49.1% RRMS, 20% PPMS, 12.7% SPMS, Sensory 33%, motor 35%, optic neuritis 36% 12.7% PRMS 5.5% CIS 74% RRMS, 12% PPMS, 14% SPMS Brainstem/cerebellar 42%, sensory 44%, motor 44%, visual 52% 82% RRMS, 18% PPMS Brainstem/cerebellar 32%, sensory 27%, motor 47%, visual 27% 75.7% RRMS, 3% PPMS, 6.4% SPMS, N/A 1.3% PRMS, 10% UN

RRMS, relapsing/remitting multiple sclerosis; PPMS, primary progressive multiple sclerosis; SPMS, secondary progressive multiple sclerosis; PRMS, progressive relapsing multiple sclerosis; CIS, clinically isolated syndrome; UN, unclassified.

of the population. Of particular interest was the analysis of the patient’s extended pedigree, which failed to identify relatives affected by MS or a similar disease (Sa nchez et al., 2001). This finding contrasts with that of a European study in which MS incidence was increased among relatives of afflicted people (Sadovnick et al., 1988). In general, the clinical spectrum of MS in Latin America is similar to that in high-prevalence regions. Visual, brainstem, motor, and sensory domains are involved most commonly. The relative frequencies may vary, even within a country, but there is no evidence that might suggest any systematic difference in the clinical presentation of MS in Latin America vs. high-prevalence regions (Alves-Leon et al., 2008; Finkelstein A et al., 2009). Besides clinical symptoms, other characteristics have been studied, such as clinical subtypes, progression, and demographic factors. The most frequent type of MS is RRMS, similar to Europe or the United States. PPMS is usually seen in 10% to 15% of most series worldwide; however, almost all of these series are from the United States, Europe or Australasia. PPMS is different from RRMS in several ways. PPMS tends to affect older people and has a male-to-female ratio of 1:1. The majority of PPMS patients develop motor disturbances related to spinal cord involvement, with a high progression rate (Bashir et al., 1999). The frequency of PPMS reported in Latin American countries varies between 8 and 18% in Brazil (Arruda et al., 2001), is 20% in Peru (Vizcarra-Escobar et al., 2005) and is 8% in Western Cuba (Hernandez-Valero et al., 2004). In Colombia, although no studies specifically address this question, it is important to note that in Bogota , the proportion of patients with PPMS was only 3% among a population of 296 cases (Toro et al., 2007). This could suggest a differential incidence of PPMS in different populations, but this finding must be confirmed in future investigations. In a Brazilian study examining the progression of MS, Ferreira Vasconcelos et al. (2010) described differences in disease progression and disability in PPMS patients of different ethnicities. They found that the progression of MS was particularly rapid and severe in Brazilian patients of African origin, consistent with findings of American and

European studies of patients of African descent (Jeannin et al.,2007), suggesting that race may play a greater role than environment in the progression of MS (Ferreira Vasconcelos et al., 2010). There is not enough information available to compare the clinical presentation of MS patients in Latin America with the rest of the world in terms of male-to-female ratio, age of onset, or secondaryprogressive forms (Vasconcelos et al., 2006). A few studies have described CSF characteristics of MS patients in Latin America and other parts of the world. The proportion of patients with positive oligoclonal bands in Latin American studies(Puccioni-Sohler et al., 1999) is quite similar to that seen in studies in high-prevalence zones (Bourahoui et al., 2004). There are no important regional differences in other CSF findings (Puccioni-Sohler et al., 1999; Ferreira Vasconcelos et al., 2008). A differential diagnosis that one must consider is HTLV-1associated myelopathy/tropical spastic paraparesis (HAM/ TSP). This insidious inflammatory chronic myelopathy is caused by the Human T Cell Lymphotropic Virus Type 1 (HTLV-1). It is usually progressive and can mimic a primary progressive multiple sclerosis (PPMS) (Keegan, 2011). HTLV-1 is a retrovirus that can be transmitted sexually, by sharing contaminated needles, blood transfusions and through breast feeding from mother to child (Goncalves et al., 2010). The highest prevalence rate for HTLV-1 includes south western Japan, several sub-Saharan African countries, Central and South America and some areas of Iran and Melanesia (Carneiro-Proietti et al., 2006). All 13 South American countries have reported the presence of HTLV-1, but the prevalence varies greatly from less than 0.1–5%. The highest proportion of infection among the general population (1–5%) has been reported in Brazil, Colombia and Per´ u. On the other hand, HTLV-1 appears to be uncommon in central and southern Argentina and in Venezuela. HTLV-1 is seen more frequently in tropical, developing areas, in African-American population such as individuals in the state of Bahia in Brazil, French Guiana, Guyana, Suriname, the Pacific coast of Colombia (Tumaco city) (Arango et al., 1988; Roma n and Roma n, 1988; Zaninovic et al., 1988) and Peru (Chincha province) (Carneiro-Proietti et al., 2002, 2006;

Multiple sclerosis in Colombia and other Latin American Countries Gotuzzo et al., 2000). Unfortunately neither pregnant women nor blood donors are routinely screened for HTLV1 in Colombia. It has been suggested that approximately 0.2–5% of HTLV1 carriers develop HAM/TSP. In general, the onset of HAM/ TSP is in the fourth to fifth decade of life (Carneiro-Proietti et al., 2006; Gotuzzo et al., 2000; Proietti et al., 2005). HAM/TSP is clinically characterized by spastic paraparesis and gait disturbance, frequently associated with sensory and bladder dysfunction. The myelopathy is usually thoracic with the MRI showing spinal cord atrophy and non-enhancing T2 lesions. The diagnosis is based on the clinical and radiologic findings and the presence of Western blot confirmed HTLV-1-specific antibodies in the serum and CSF (Engstrom, 2011; Gotuzzo et al.,2000; Keegan, 2011; Wingerchuk, 2012). Up to now, no treatment for HAM/TSP has proven to be effective consistently and in the long term. Neuromyelitis optica (NMO) is another differential diagnosis that one must consider. Although in HAM/TSP there have been some case reports in which patients develop optic neuritis, this is extremely unusual (Komaba et al., 1996; Yoshida et al., 1998). There are only two reports published of prevalence of NMO in Latin America and the Caribbean. In Cuba a study showed a prevalence of 0.52/ 100,000 inhabitants and an annual incidence of 0.053/ 100,000 (Cabrera-Gomez et al., 2009). In the French West Indies the prevalence of NMO was of 4.2/100,000 inhabitants and the mean annual incidence for the period July 2002 to June 2007 was 0.2/100,000 (Cabre et al., 2009). In Colombia and many countries of South America reference laboratories are used for measurements of anti NMO antibodies. The growing literature on the regional prevalence of MS contributes to our understanding of the clinical profile and evolution of MS in Latin American countries, particularly when considering that there are different prevalence zones within Latin America itself.

Conflict of Interest The authors have nothing to declare.

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