Survival and clinical features in Hispanic amyotrophic ...

Amyotrophic Lateral Sclerosis, 2011; Early Online, 1–7

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Survival and clinical features in Hispanic amyotrophic lateral sclerosis patients

HÉCTOR R. MARTÍNEZ1,2,4, JUAN FRANCISCO MOLINA-LÓPEZ2,3, LEONEL CANTÚ-MARTÍNEZ2,3, MARÍA TERESA GONZÁLEZ-GARZA2, JORGE E. MORENO-CUEVAS2, PATRICIO COURET-ALCARAZ2, SERGIO A. TREVIÑO2,3, YENNY WEBB-VARGAS3, ENRIQUE CARO2, ALFONSO GIL-VALADEZ2, JESÚS SANTOS-GUZMÁN3 & MARTIN HERNANDEZ-TORRE3 1Servicio

de Neurología Hospital San José Tec de Monterrey, 2Servicio de Terapia Celular, CITES Tecnológico de Monterrey, 3School of Biotechnology and Health Tecnologico de Monterrey, and 4Servicio de Neurología Hospital Universitario UANL Monterrey, Mexico

Abstract The demography, survival, and motor phenotypes of amyotrophic lateral sclerosis (ALS) patients have been rarely described in Hispanic countries. The clinical characteristics and survival of a series of Mexican ALS patients are described. Mexican patients with definite ALS were included in a five-year retrospective longitudinal study. Their demographic and clinical features, cumulative survival rates, and independent predictive factors for survival were analysed. Sixty-one definite ALS patients were included. The median follow-up period was 35 months (range 12–108 months). Males were predominant (1.8: 1), the mean age at onset was 47.5 ⫾ 10.5 years, and the median interval from onset to diagnosis was 12 months. Spinal onset occurred in 66% of patients. Upper motor neuron phenotype was predominant in 53% of patients. The overall mean survival from onset was 68.6 months, and from diagnosis was 57.8 months. Longer survival was determined in patients aged ⱕ 40 years (54.7 months) compared with other age groups (p ⫽ 0.006). In conclusion, the clinical heterogeneity, male predominance, and survival rates in our sample are consistent with those of other studies. Patients in this series had a younger age at onset and a clear trend toward longer survival compared with those of other population studies. Key words: Amyotrophic lateral sclerosis, epidemiology, mortality

Introduction Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by rapid deterioration and the selective death of motor neurons in the cerebral cortex, brainstem, and spinal cord (1–3). Its aetiology is unknown. This disorder is sporadic in 95% of cases, whereas 5% have a positive family history of ALS (1–4). European and American studies have reported similar incidences of the disease, ranging from 1.5 to 2.5 cases/100,000 population per year (4). Recent studies have reported a relative stability in the incidence of ALS, with no relevant changes in the clinical or demographic characteristics of Caucasian populations (4–6).

There have been few population-based epidemiological studies of ALS in non-Europeans or nonNorth Americans. One Caribbean study described the ALS mortality rate in an ethnically mixed Cuban population (7). Another South American study described the incidence and prevalence of ALS in the Republic of Uruguay (8). These studies included mixed populations of diverse ethnic origins, which did not strictly correspond to Hispanic ALS patients. A recent systematic review reported a relatively uniform incidence across the white populations of Europe and North America and a lower incidence among Hispanic and African groups (9). The lower incidence and prevalence in these ethnic groups have

Correspondence: H. R. Martinez, Tecnológico de Monterrey, School of Medicine, CITES, 3rd Floor, 3000 Morones Prieto Ave. 64710, Monterrey, N.L. México. Fax: 52 881 8143 0108. E-mail: [email protected] (Received 12 October 2010 ; accepted 19 December 2010 ) ISSN 1748-2968 print/ISSN 1471-180X online © 2011 Informa Healthcare DOI: 10.3109/17482968.2010.550302

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H. R. Martínez et al.

been attributed in part to under-diagnosis, resulting from the socioeconomic status of this group and their poor access to health care. Until now, there has been no population-based study of a well-characterized Hispanic population in a Latin American country. Our objective was to describe the clinical and demographic characteristics of Mexican ALS patients and to determine their survival times.


Material and methods Referred and interested patients with motor neuron diseases were evaluated in the Hospital San Jose Neuroscience Centre between June 2005 and May 2010. Patients who were born and were residing in Mexico and had definite ALS according to the El Escorial criteria (10), were included in a retrospective longitudinal study. In the present series, patients were followed up until death or 15 May 2010. Hospital San Jose Ethics and Research Committee approval was secured for the present study. A trained neurologist with experience in ALS and motor neuron disease conducted the examinations for all diagnoses of ALS, which were based on the well-established El Escorial criteria (10).The patients were evaluated by testing muscle stretch reflexes, pathological reflexes, muscle tone in four limbs, and muscle power and strength, graded according to the Medical Research Council scale (11). The ALS Functional Rating Scale-Revised was used at the initial evaluation and in certain cases during follow-up to assess motor function (12). We considered the date of diagnosis as the point at which ALS was established by the patient’s neurologist. Demographic variables were recorded: sex, age at onset (AO), age at diagnosis, and the time between onset and diagnosis, described as the onsetdiagnosis interval (ODI). Follow-up was until 15 May 2010 or death; in a further detailed analysis survival times were corrected for percutaneous endoscopic gastrostomy (PEG) and non-invasive ventilation (NIV) coded as deceased on the date of the procedure. Normally and non-normally distributed variables were described with means (⫾ SD) and medians (25th and 75th percentile), respectively. Univariate comparisons of the demographic and clinical variables were made with an independent t-test and χ2 test. The median ODI was analysed in each group of patients according to age and site of onset. Differences among these groups were analysed with the Kruskal-Wallis and Mann-Whitney U-tests, respectively. The homogeneity of the proportions of sites of onset according to AO was reviewed with Pearson’s χ2 test. Survival curves were estimated with the Kaplan-Meier method and differences in survival were measured with the log-rank test and the logrank test for trends. The mean survival times from onset and diagnosis were compared according to the clinical features: site of onset (spinal vs. bulbar ALS),

age group (ⱕ40 vs. 41–60 vs. ⱖ60 years), motor neuron involvement (upper motor neuron (UMN) vs. lower motor neuron (LMN) vs. UMN-LMN equally affected) at the time of the physical examination, and median ODI (ⱖ12 months vs. ⬍12 months). We performed a multivariate analysis of the risk of death associated with site of onset, controlling for AO, motor neuron involvement, sex, and ODI, using the Cox proportional hazards model, with proportional hazards tested with the third method described by Grambsch and Therneau (13). All statistical analyses were performed with the SPSS 16.0 software package (SPSS, Chicago, IL, USA). Results The clinical and physical evaluations of 141 ALS patients were made over a five-year period (between June 2005 and May 2010) at the Hospital San Jose Tec de Monterrey. Eighty-five of these patients were Mexicans, 17 South Americans, and 39 from the USA or abroad. Only 61 of the 85 Mexican patients (39 males and 22 females) fulfilled the El Escorial criteria for definite ALS. In the present series, two patients (3.3%) were classified as having hereditary ALS, based on their family histories. Most of the Mexican patients (65%) came from regions with the highest socioeconomic status (6 and 7) and only 13% came from regions with the lowest socioeconomic status (1 and 2; Figure 1). The socioeconomic levels were determined using several indicators: housing infrastructure, quality of house materials, number of occupants per house, house equipment, health, education, and employment. Most patients came from geographic areas with the maximum national life expectancy, 75–76 years or above (14). In Mexico, medical coverage varies by state: 78% of the patients in this study came from geographic regions with one doctor per 575 ⫾ 122 head of population, and only 22% came from regions with one doctor per 1191 ⫾ 270 head of population (15). In the Mexican population, 58.2 million people (53.7%) are served by social security institutions, 2.4 million people (2.2%) by private practice, and the remaining 47.8 million people (44.1%) can access the public health network (16,17). According to the last census report, Mexico has a population of 103 million in 32 states, and this population is served by 957 board-certified neurologists. Nuevo Leon State, which includes the metropolitan area of Monterrey and has a population that exceeds five million, is served by 46 certified neurologists (18). The Mexican race is considered ‘mestizo’, composed of about 35 different ethnic groups from America, Europe, Africa, and Asia. The racial mix differs from region to region. Language proficiency was used as a surrogate index of Amerindian composition: 71.7% of patients came from geographic zones with the fewest indigenous language speakers


Survival and clinical features in Hispanic ALS patients

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Figure 1. Sociodemographic data for ALS patients according to state.

(0.1%–2.3% of the population) and 20% from regions with a higher percentage of indigenous language speakers (4.7%–24.6% of the population) (Figure 2) (19).

The mean ages at onset and diagnosis were 47.5 years ( ⫾ 10.6, 95% CI 44.8–50.24 years) and 48.3 years ( ⫾ 10.6), respectively. Sixty-six per cent of patients (n ⫽ 40) had spinal onset and 34% had

Figure 2. Distributions of ALS patients and people who speak the indian language according to state.

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Table I. Cumulative survival rates since diagnosis (n ⫽ 61). Years 1 2 3 4 5

Survival

95% CI LB

94% 76% 69% 48% 37%

88% 64% 55% 30% 18%

95% CI UB 100% 88% 84% 66% 56%


CI LB: confidence interval lower bound; CI UB: confidence interval upper bound. Determined with Kaplan-Meier point estimation.

bulbar onset (n ⫽ 21). The distribution of ODI was skewed right, with a median value of 12 months (8,16). No significant differences were found in the median ODI between patients with bulbar symptoms at onset and those with spinal symptoms, with median ODIs of 12 months (8,16) and 13 months (9,18), respectively (p ⫽ 0.345). Although the ODI was longer in ALS patients over 61 years of age, the median ODI did not differ significantly among the AO groups: ⱕ 40 years, nine months (7,15); 41–60 years, 12 months (8,16); and ⬎ 60 years, 17 months (13,24; p ⫽ 0.104). During the five years of the study, 20 of the 61 ALS patients died and 14 patients were lost to follow-up. The overall median survival from onset was 63 months (95% CI 49.5–76.5), with a mean value of 68.6 months (95% CI 57.2–79.9), and the median survival from diagnosis was 47 months (95% CI 29.6–64.4), with a mean value of 57.8 (95% CI 44.7–70.4). The mean survival times from onset and diagnosis, corrected for PEG and NIV, were 61.9 months (95% CI 51.4–72.4) and 48.6 months (95% CI 36.5–60.6), respectively. In the present series, the

survival rate was estimated from one to five years after diagnosis (Table I). No significant differences were found in the survival time from onset or diagnosis according to sex, age group, site of onset, motor neuron involvement, or ODI (Table II). Outcome corrected for PEG and NIV showed a longer survival time in individuals aged ⱕ 40 years (54.7 months) compared with the other age groups (41–60 years of age, 38.8 months; ⬎ 60 years of age, 20.2 months; p ⫽ 0.006) (Table III) (Figure 3). When we controlled for AO, motor neuron involvement, sex, and ODI, the differences in survival according to the site of onset were not statistically significant (p ⫽ 0.081, for spinal vs. bulbar RR ⫽ 0.413, 95% CI 0.153–1.113). The median follow-up period for our 61 patients was 35 months (range 12–108 months). All patients (n ⫽ 61) presented with cervical involvement at the time of evaluation, 46% (n ⫽ 28) with dorsal involvement, and 89% (n ⫽ 54) with an affected lumbar spinal cord. Bulbar symptoms were present in 88.5% (n ⫽ 54) of patients at the time of evaluation: 82% (n ⫽ 50) reported that their first bulbar symptoms were related to changes in speech, 3% (n ⫽ 2) identified swallowing difficulty, and 3% (n ⫽ 2) presented with both speech and swallowing problems. A direct physical examination, intended to determine the muscle status of the thenar eminence in at least one hand, demonstrated atrophy in 92% (n ⫽ 56) of patients, hypotonia in 5% (n ⫽ 3), and no remarkable findings in 3% (n ⫽ 2). On physical examination, 53% (n ⫽ 32) of individuals presented with predominantly UMN characteristics, 34% (n ⫽ 21) with LMN predominance, and 13% (n ⫽ 8) with both UMN and LMN involvement. No significant

Table II. Demographic data for Mexican ALS patients. Mean survival time from diagnosis: mo (95% CI LB – CI UB)

Variable

n

Mean survival time from onset: mo (95% CI LB – CI UB)

Total Sample Sex Males Females Age group (years) ⱕ40 41– 60 ⬎60 Site of onset Bulbar Spinal Onset-diagnosis interval (ODI) ⱕ12 mo ∗ ⬎12 mo Predominance UMN LMN UMN-LMN

61

68.6 (57.2 –79.9)

39 (63.9%) 22 (36.1%)

61 (51.2 –70.8) 85.4 (66.7–104.1)

1.04, p ⫽ 0.31

42.0 (34.9 – 49) 75.3 (53.4 – 97.2)

0.77, p ⫽ 0.38

19 (31.1%) 31 (50.8%) 11 (18.03%)

73.7 (58.4 – 89) 59.5 (49.6 – 69.5) 49.9 (36.6 – 63.1)

0.58, p ⫽ 0.45†

63.3 (46.6 –79.9) 42.9(31.9 – 53.8) 25.7 (16.1–35.3)

4.04, p ⫽ 0.09†

21 (34.4%) 40 (65.6%)

51.8 (43.0 – 60.5) 76.2 (61.6 – 90.8)

2.7, p ⫽ 0.1

36.4 (26.3 – 46.6) 66.1 (49.9 – 82.3)

2.95, p ⫽ 0.08

35 (57.4%) 26 (42.6%)

68.1 (52.7– 83.4) 66.6 (53.9 –79.3)

0.29, p ⫽ 0.58

59.0 (42.9 –75.1) 41.0 (30.6 – 51.4)

0.44, p ⫽ 0.5

32 (52.5%) 21 (34.4%) 8 (13.1%)

62.8 (48.6 –77.1) 64.1 (47.7– 80.6) 65.4 (58.0 –72.8)

0.9, p ⫽ 0.63

53.9 (37.2 –70.7) 42.2 (30.8 – 53.5) 50.7 (37.8 – 63.5)

0.44, p ⫽ 0.8

Log rank

Log rank

57.8 (44.7–70.4)

Mo: months; CI LB: confidence interval lower bound; CI UB: confidence interval upper bound; †: trend log rank.

Survival and clinical features in Hispanic ALS patients

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Table III. Demographic data for Mexican ALS patients corrected for PEG and NIV. Mean survival time from diagnosis: mo (95% CI LB – CI UB)

Variable

n

Mean survival time from onset: mo (95% CI LB – CI UB)

Total Sample Sex Males Females Age group (years) ⱕ 40 41– 60 ⬎60 Site of onset Bulbar Spinal Onset-diagnosis interval (ODI) ⱕ12 mo ∗ ⬎12 mo Predominance UMN LMN UMN – LMN

61

61.9 (51.4 –72.4)

39 (63.9%) 22 (36.1%)

55.1 (46.2 – 63.9) 81.9 (62.8 –101.1)

1.44, p ⫽ 0.23

39.1 (32.2 – 46) 72.3 (50.9 – 93.7)

19 (31.1%) 31 (50.8%) 11 (18.03%)

68.9 (53.9 – 84) 54.8 (44.7– 64.9) 37.7 (28.8 – 46.6)

3.22, p ⫽ 0.2

54.7.7 (38.1–71.3) 38.8 (29.1– 48.6) 20.2 (10.9 –29.4)

21 (34.4%) 40 (65.6%)

50.2 (41.1– 59.5) 68.3 (54.2 – 82.3)

1.52, p ⫽ 0.22

36.1 (25.6 – 46.7) 58.1 (42.7–73.4)

1.46, p ⫽ 0.23

35 (57.4%) 26 (42.6%)

56.5 (42.8 –70.2) 63.9 (51–76.8)

1.1, p ⫽ 0.3

47.5 (33.7– 61.4) 38.8 (28.4 – 49.2)

0.59, p ⫽ 0.81

32 (52.5%) 21 (34.4%) 8 (13.1%)

60.1 (45.7–74.5) 58.1 (42.1–74.2) 61.6 (52.3 –70.9)

0.19, p ⫽ 0.91

51.9 (35.7– 68.2) 36.7 (25.2 – 48.2) 46.6 (33.8 – 59.3)

0.17, p ⫽ 0.92

Log rank

Log rank

48.6 (36.5 – 60.6) 1.24, p ⫽ 0.27 10.15, p ⫽ 0.006†

Mo: months; CI LB: confidence interval lower bound; CI UB: confidence interval upper bound; †: trend log rank.

difference was observed when motor neuron predominance (UMN vs. LMN vs. UMN-LMN) was compared across age groups ( ⱕ 40 vs. 41–60 vs. ⬎ 60 years of age; p ⫽ 0.751). With a more detailed analysis, we found that patients with affected upper limbs showed UMN predominance in 53% (n ⫽ 32) of cases, LMN predominance in 42% (n ⫽ 26) of cases, and equal UMN-LMN involvement in 5% (n ⫽ 3) of cases. A similar pattern was observed when the lower limbs were assessed, with predominant UMN involvement in 71% (n ⫽ 43) of patients, LMN in 26% (n ⫽ 16) of patients, and no predominance in 3% (n ⫽ 2) of patients. Discussion ALS is a fatal progressive neurodegenerative disease of unknown aetiology. Its onset is age related, with the highest rate observed between 55 and 75 years (1–3,20). Although information about the frequency of ALS is required if we are to anticipate the need for health resources, the demographic features and motor phenotypes of ALS have been rarely described in Hispanic countries. Only two population-based epidemiological studies of ALS in the Caribbean and South America have been undertaken. These studies included mixed populations of diverse ethnic origins, and their findings were similar to those reported for Caucasian populations (Table IV) (5–8,21–23). The motor phenotypes of ALS are recognized as highly heterogeneous, and are defined by: 1) the site of onset, 2) the relative overlap of UMN and LMN involvement, and 3) the rate of progression (24). In the present series, we observed a high degree of heterogeneity in this disorder. In Mexican ALS patients,

the mean AO was earlier (47.5 ⫾ 10.5 years), the mean survival after onset (68.6 months, 95% CI 57.2–79.9) and diagnosis (57.8 months, 95% CI 44.7–70.4) was longer than that reported in Caucasian series, even after correction for PEG and NIV (Table IV) (5–8,21–23). In Mexico, the life expectancy at birth is 73 and 78 years for males and females, respectively. This is approximately four years less than that reported for the United States and United Kingdom (25,26). Moreover, in Mexico, the population pyramid continues to be broadly based, with only 15.4% of people over the age of 50 years (27). These demographic factors could certainly affect the early AO observed in Mexican patients. Differences in mean survival were observed based on sex, age group, ODI, site of onset, and motor neuron involvement, but these differences were not

Figure 3. Cumulative survival of ALS patients since diagnosis corrected for PEG and NIV by age groups.

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Table IV. Demographic data for ALS patients in other countries.


Country

Incidence males: females

2007 Scotland5

2.68:2.11∗

2007 Ireland6 2009 Cuba7 2008 Uruguay8

2.4:1.7∗ 1.1:1 2.0:1

1976 Israel15

1.9:1

1999 Poland16 1983 Northern Sweden17

1.57:1 1.1:1

2008 Italy18 2010 Mexico

1.6:1 1.8:1

Age of onset (years)

Survival time

65.2, M 67.2, F 66.0 Not reported 58.7, mean 65 –74, M 55 – 64, F 55.4, M 52.4, F 53.2 (51– 60) 60 – 64, M 70 –74, F 65 – 69 combined Not reported 47.5, combined

27.6 mo† 16.4 mo‡ Not reported Not reported

57.6 mo, M∗∗ 67.2 mo, F∗∗ 30.8 mo(ns) 32 mo†

28 mo† 68.6 mo† 57.8 mo‡

Mo: months; ns: not specified. incidence, according to sex. ∗∗Mean estimate from onset, according to paper. †Since onset. ‡Since diagnosis. ∗Peak

statistically significant (Table II). Only after correction for PEG and NIV, significant difference in mean survival was observed based on age groups, where subjects ⱕ 40 years of age had a longer survival time compared with patients between 41 and 60 years of age and ⬎ 60 years of age; this finding is consistent with previous population base studies (28–32). When adjusted for AO, motor neuron involvement, sex, and ODI, the spine as the site of onset tended to be a protective factor (p ⫽ 0.081, RR ⫽ 0.413, 95% CI 0.153–1.113). There was also a trend toward early death after diagnosis in older ALS patients ( ⬎ 60 years of age; p ⫽ 0.09); this finding was significantly different when corrected for PEG and NIV ( ⬎ 60 years of age; p ⫽ 0.006), similar to that reported by Zocolella et al (24). In the present study, older patients had a longer ODI, which could have resulted in a shorter period of survival from diagnosis. However, when survival was analysed based on AO, no statistically significant difference was observed among age groups uncorrected (p ⫽ 0.45) or corrected for PEG and NIV (p ⫽ 0.2). The limitations of this study are related to sample selection and size. Only those subjects who attended the Hospital San Jose Neuroscience Centre were included. All patients were referred from urban centres, so rural populations are not represented in the study. Differences in cultural and economic status could have affected the survival outcomes, with disparities in the patients’ access to medical care. Nevertheless, this study represents the largest investigation undertaken in the last 20 years, and serves to extend our understanding of the sociodemographic aspects of ALS in Latin America.

The subjects evaluated in this study originated from 22 of the 32 states of Mexico. These constitute a considerable territory, but local patients and those from states near the hospital could have been overrepresented. A considerable number of patients were also lost to follow-up (14 of 61 patients), mainly because those subjects did not notify the Hospital Neuroscience Centre of changes in their contact information or addresses. In conclusion, the demographic and clinical features of Mexican patients with definite ALS did not influence their survival. Further studies are required to clarify whether clinical or demographic differences affect Hispanic populations of ALS patients. Declaration of interest: The authors have no interests to disclose. References 1. Mills KR. The natural history of central motor abnormalities in amyotrophic lateral sclerosis. Brain. 2003;126:2558–66. 2. Toft MH, Gredal O, Pakkenberg B. The size distribution of neurons in the motor cortex in amyotrophic lateral sclerosis. J Anat. 2005;207:399–407. 3. Ringel SP, Murphy JR, Alderson MK, Bryan W, England JD, Miller RG, et al. Natural history of amyotrophic lateral sclerosis. Neurology. 1993;43:1316–22. 4. Chio A, Mora G, Calvo A, Mazzini L, Bottacchi E, Mutani R, et al. Epidemiology of ALS in Italy: a 10-year prospective population-based study. Neurology. 2009;72:725–31. 5. Forbes RB, Colville S, Parrat J, Swingler RJ. The incidence of motor neuron disease in Scotland. J Neurol. 2007;254: 866–9. 6. O’Toole O, Traynor BJ, Brennan P, Sheehan C, Frost E, Corr B, et al. Epidemiology and clinical features of amyotrophic lateral sclerosis in Ireland between 1995 and 2004. J Neurol Neurosurg Psychiatry. 2007;79:30–2.


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