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Keywords:

  • amyotrophic lateral sclerosis;
  • cardiovascular risk factors/diseases;
  • dementia;
  • depression

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information

Background and purpose

Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive paralysis of striated muscles due to the loss of upper and lower motor neurons. The disease leads to death within 2–5 years, mainly due to respiratory failure. The pathogenesis of ALS is still unexplained for the most part. In this study, we aimed to determine the prevalence of different cardiovascular, metabolic, and neuropsychiatric comorbidities in a large ALS cohort and to evaluate their influence on the disease course.

Methods

A cohort of 514 patients with ALS of our ALS outpatient clinic was investigated retrospectively with reference to known prognostic factors and comorbidities. The prevalence of concomitant diseases was compared with the data from the German general population. Uni- and multivariate survival analyses were performed using the Cox proportional hazards model and Kaplan–Meier analysis.

Results

The prevalence of cardiovascular diseases and cardiovascular risk factors was significantly lower in patients with ALS compared to the German general population, whilst the prevalence of dementia, parkinsonism, and depressive symptoms was significantly higher in the ALS cohort. None of the investigated comorbidities had an influence on the disease course or on the survival of patients.

Conclusions

Persons with cardiovascular diseases or risk factors seem to be at lower risk of ALS. Although these diseases are apparently somehow protective regarding ALS susceptibility, their presence did not modify disease progression and survival in patients with ALS. Our study further confirms the well-known continuum between ALS and dementia. It also suggests a link with other neurodegenerative diseases such as Parkinson's disease.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterized by the loss of upper and lower motor neurons. This leads to impairment of motor function at spinal and bulbar level and ultimately causes death within 2–5 years due to respiratory failure.

Patients with ALS present with different phenotypes and histories, so that distinct etiologies have been proposed. ALS is increasingly recognized to be not only a disorder of the motor system but to involve also non-motor areas of the brain and even to affect whole-body physiology [1].

For several comorbidities, for example, cardiovascular, metabolic, and neuropsychiatric diseases, both differences in prevalence between patients with ALS and the general population and a specific impact of these disorders on ALS progression have been described [2-8]. It is an often reported observation that patients with ALS prior to disease onset are slim, physically fit, and without cardiovascular risk factors [4, 5]. It has been controversially debated whether metabolic alterations, in particular regarding lipid metabolism, are associated with ALS and whether hypercholesterolemia (HC)/hyperlipidemia slows disease progression [6, 7, 9]. A wide range of behavioral abnormalities, ranging from subtle frontal executive dysfunction to manifest frontotemporal dementia (FTD), can occur in patients with ALS, and recent genetic and neuropathologic evidence (mutations in the genes coding for TDP-43 and FUS/TLS as well as the most recently identified hexanucleotide repeat expansion in C9orf72; detection of neuronal cytoplasmic TDP-43-positive aggregates in post-mortem tissue in both ALS and FTD) confirms the link between ALS and FTD [2, 10, 11]. The rate of depression in patients with ALS is, most commonly, estimated to lie between 24% and 28% [12, 13].

Our study assesses the frequency of comorbidities such as cardiovascular diseases and risk factors as well as neuropsychiatric disorders and their impact on survival and disease progression in patients with ALS.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information

We retrospectively analyzed a cohort of 514 patients with ALS from our ALS outpatient database (covering a period of 15 years). Patient consent forms have been received from all patients, and no further approval was needed according to the local regulations.

All patients had met the revised El Escorial criteria for probable or definite ALS within the observation period. The initial evaluation in our ALS clinic routinely includes the medical history, current medication, and the time of disease onset as well as the body region of the first symptoms. Amyotrophic Lateral Sclerosis Functional Rating Scale revised (ALSFRS_R) score, progression of symptoms as well as newly developed comorbidities or additional medications are recorded at each visit. The ALSFRS_R score ratio, which means the deterioration of the score per month, is used for the estimation of disease progression [14].

The prevalence of comorbidities in our ALS cohort was compared with the data of the German general population in different age groups (sources: Robert Koch institute, German society of Alzheimer's disease, German society of epileptology, competence network Parkinson's disease, and publications cited in accordant text passages). These sources provided the prevalence data for the distinct comorbidities/risk factors of the general population, subdivided in slightly different age groups. Therefore, patients of our cohort were divided according to age groups for each comorbidity, respectively. Significant differences of prevalence of the several comorbidities between the general population and age-matched patients with ALS were identified by non-parametric two-sided 95% Clopper Pearson confidence intervals which were compared to the respective prevalence in the general population as a fixed value.

Survival analysis was performed using Cox regression, and the differences in survival were measured by hazard ratios (HR) with corresponding 95% confidence intervals. First, univariate Cox regressions were conducted with only one independent factor in each regression. To adjust for known factors that influence the survival in ALS, we also performed multivariate regressions: a basic model with the prognostic factors ‘age at diagnosis’, ‘region of onset’, and ‘time from first symptom to diagnosis’ was used, in which each comorbidity was included separately (Table 1A). Kaplan–Meier survival plots were used to illustrate parts of the results.

Table 1. Effect of basic prognostic factors and comorbidities on survival (A) and progression (B) in univariate and multivariate analyses
 Univariate analysisMultivariate analysis (adjusted for age, bulbar onset and time to diagnosis = basic model)
P HR [95%-CI] P HR [95%-CI]
(A)
Basics
Gender (f/m)0.161.16 [0.94, 1.42]  
Age at diagnosis (years) <0.001 1.03 [1.02, 1.04]  
Bulbar onset (bulbar/spinal) <0.001 1.49 [1.19, 1.86]  
Time from first symptom to diagnosis (month) <0.001 0.989 [0.980, 0.998]  
Comorbidities
Hypertension 0.001 1.41 [1.14, 1.75]0.311.13 [0.90, 1.41]
Cardiac arrhythmia0.700.94 [0.67, 1.31]0.460.88 [0.63, 1.24]
Coronary heart disease (CHD) 0.035 1.44 [1.03, 2.03]0.161.28 [0.91, 1.82]
Myocardial infarction (MI) 0.032 1.53 [1.04, 2.24]0.241.27 [0.85, 1.87]
Diabetes mellitus (DM)0.391.18 [0.81, 1.70]0.601.11 [0.76, 1.60]
Hypercholesterolemia (HC)0.391.11 [0.87, 1.43]0.691.05 [0.82, 1.36]
Depressive symptoms0.870.98 [0.78, 1.24]0.640.95 [0.75, 1.19]
Dementia0.531.14 [0.76, 1.71]0.211.31 [0.87, 1.97]
Parkinson0.170.59 [0.28, 1.26]0.170.58 [0.27, 1.25]
Epilepsy 0.047 0.25 [0.06, 0.98] 0.045 0.24 [0.06, 0.97]
  P Mean ratio [95%-CI] P Mean ratio [95%-CI]
  1. Significant P-values are given in bold

(B)
Basics
Gender (f/m)0.370.90 [0.74, 1.12]  
Age at diagnosis (years) 0.015 1.01 [1.00, 1.02]  
Bulbar onset (bulbar/spinal) 0.012 1.34 [1.07, 1.68]  
Time from first symptom to diagnosis (month) <0.001 0.99 [0.98, 0.99]  
Comorbidities
Hypertension0.711.04 [0.84, 1.31]0.730.96 [0.76, 1.21]
Cardiac arrhythmia0.490.89 [0.64, 1.23]0.390.87 [0.63, 1.20]
CHD0.581.12 [0.76, 1.62]0.561.12 [0.76, 1.65]
MI0.231.28 [0.85, 1.92]0.351.21 [0.81, 1.80]
DM0.501.14 [0.77, 1.68]0.711.07 [0.74, 1.57]
HC0.201.19 [0.91, 1.54]0.331.14 [0.88, 1.46]
Depressive symptoms0.150.84 [0.66, 1.07]0.360.90 [0.70, 1.14]
Dementia0.580.89 [0.58, 1.36]0.751.07 [0.70, 1.63]
Parkinson 0.03 0.41 [0.19, 0.90] 0.04 0.46 [0.22, 0.98]
Epilepsy0.220.61 [0.28, 1.34]0.290.66 [0.31, 1.40]

The primary population for survival analysis (Kaplan–Meier survival plots, multivariate regression) consisted of all patients with at least two visits and an observation time over at least 6 months (n = 488). Survival times were calculated as the time from diagnosis to death (n = 360), tracheostomy (n = 6), or censoring (n = 122). Patients were censored at the last recorded time point of contact (visit or phone call) when they were lost to follow up (n = 58), had died of another cause than ALS (n = 12), or were still alive at the time of analysis (n = 52). For sensitivity analyses, calculations were also made with survival time defined as the time from symptom onset to death, tracheostomy, or censoring.

To estimate the influence of a specific comorbidity on the course of disease, linear regression analysis was carried out, using the logarithmic ALSFRS_R score ratio as the dependent variable and the respective comorbidity as the predictor variable. Similar to the survival analysis, all comorbidities were assessed as additional independent covariates in the aforementioned basic model to adjust for known prognostic factors. Differences in ALSFRS_R score ratio are measured as mean ratio with corresponding 95% confidence intervals (Table 1B).

Statistical analyses were performed using SPSS 19.0 (SPSS, Chicago, IL, USA). R 2.14.1 was used for prevalence bar plots with Clopper Pearson intervals. Because multiple tests were performed without correction of the type one error, P-values are exploratory and P-values < 0.05 are considered to be statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information

Characterization of the population

We analyzed the data from 514 patients with ALS, 288 (56%) male and 226 (44%) female patients (gender ratio 1.3:1). The mean age at diagnosis was 58.8 years. Three-hundred and seventy patients (72%) had a spinal onset, and 144 patients (28%) had developed bulbar symptoms first. Elder patients and women more often suffered from bulbar onset than younger and male patients (supplementary Table S1).

The median survival time was 42 months from onset of symptoms and 28 months from time of diagnosis. The survival and the course of disease were significantly affected by several already known prognostic factors: advanced age at disease onset, bulbar onset, and a short time between symptom onset and diagnosis were associated with a shorter survival (Table 1A and B). Female patients with ALS had a slightly increased risk, but the gender differences were not significant.

Figure 1a shows the overall prevalence of comorbidities in our ALS patient cohort. In the following, the prevalence of the individual comorbidities was compared to the prevalence in the total German general population and their influence on survival and disease progression of ALS was assessed.

image

Figure 1. Prevalence (in percent) of comorbidities in our ALS patient cohort (n = 514) in descending order (a) and comparison of prevalence rates of arterial hypertension (b), cardiac arrhythmia (c) and myocardial infarction (d), diabetes mellitus (e), hypercholesterolemia (f), depressive symptoms (g), and dementia (h) in our ALS patient cohort and the German general population. Patients with ALS suffered considerably less often from cardiovascular and metabolic disorders (b–f) and more often from neuropsychiatric disorders (g, h) compared with the general population. Significant differences are highlighted by asterisks (*P < 0.05, **P < 0.01, ***P < 0.001).

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Lower prevalence of cardiovascular diseases and metabolic disorders in patients with ALS

Arterial hypertension (HT) was the most frequent comorbidity in our ALS cohort: nearly one-third (31.5%) of the ALS population suffered from HT. The prevalence of this comorbidity was significantly lower in patients with ALS compared to the general population (Fig. 1b). Univariate analysis of all patients resulted in significantly longer survival in patients without HT (Table 1A, Fig. 2a). However, the distribution of the known confounding factors age and region of onset was irregular between patients with and without hypertension. Thus, adjustment for confounding factors in the multivariate Cox model resulted in a HR of only 1.13 (P = 0.31). Therefore, HT turned out not to be a significant prognostic factor per se, which is shown in a Kaplan–Meier analysis stratified according to the confounding factors (Table 1A, Fig. 2b).

image

Figure 2. Survival of amyotrophic lateral sclerosis (ALS) patients with and without hypertension (HT) or hypercholesterolemia (HC) Kaplan–Meier survival diagram for all ALS patients with and without arterial HT showed a significantly longer survival of ALS patients without HT (log-rank P = 0.001, median survival with HT 21 months, without HT 31 months) (a). But patients with HT differed significantly from patients without this comorbidity, especially in age, and after stratification of the groups according to the well-characterized basic prognostic factors (Table 1), the difference in survival was not significant anymore (log-rank P = 0.124) (b). The presence of HC had no influence on survival (log-rank P = 0.386) (c), when analyzed in the whole cohort. The patient groups with and without HC differed significantly in the region of onset (bulbar versus spinal onset), which is a prognostic factor. A stratified analysis (only patients with spinal onset) showed no significant difference in survival (log-rank P = 0.357) (d). Censored patients are marked with +.

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The overall prevalence of cardiac arrhythmia was 9.7% in our ALS cohort. Although the prevalence increased with age, cardiac arrhythmia was significantly less frequent in patients with ALS compared with the general population in the age groups between 50 and 64 years and above (Fig. 1c). The presence of cardiac arrhythmia had no influence on survival, neither in the univariate analysis nor within the multivariate analysis considering known prognostic factors (basic model, Table 1a).

In our cohort, 8.6% of patients with ALS suffered from coronary heart disease (CHD), and 6.4% had a history of myocardial infarction (MI). In Fig. 1d, it is visible that MI was less frequent in patients with ALS compared with the general population (Fig. 1d). A history of both CHD and MI was associated with shorter survival when analyzed by univariate analysis. Using multivariate analysis, we found a smaller, statistically non-significant HR for CHD and MI, which were therefore not significant prognostic factors per se (Table 1A).

In our cohort, 7.2% of our patients with ALS suffered from diabetes mellitus (DM). The prevalence of DM increases with age both in the general population and in the patients with ALS. Nevertheless, in all age groups, the prevalence of DM was lower in patients with ALS. This difference was significant in the age group above 65 years (Fig. 1e). The presence of DM had no influence on survival neither in the univariate regression nor following adjustment for the above-mentioned prognostic factors (Table 1A).

Hypercholesterolemia was reported by 17.9% of patients with ALS. Compared with the German general population, the prevalence of HC was significantly lower in patients with ALS in all age groups above 40 years (Fig. 1f). In patients with bulbar onset, HC was significantly more frequent (23.6%) than in patients with spinal onset (15.7%) (P < 0.05, χ2 test). Univariate analysis revealed no influence of HC on survival. After adjustment for disease onset and the other covariates of the basic model, HC still had no influence on survival (Table 1A), which is shown in separate Kaplan–Meier survival curves for all patients (Fig. 2c) and patients with spinal onset (Fig. 2d).

Regression analysis using the ALSFRS_R score ratio as dependent variable showed no significant influence of any cardiovascular or metabolic disease on disease progression [all P-values > 0.3 for cardiovascular and metabolic covariates by multivariate analysis (basic model, Table 1B)].

Higher prevalence of neuropsychiatric diseases in patients with ALS

In almost a quarter (22.8%) of patients with ALS, depressive symptoms (e.g., sadness, listlessness, insomnia) were reported by patients themselves or their relatives, or were apparent in the patient's history. This frequency was significantly higher than in the general population (Fig. 1g). No significant difference in survival between ALS patients with and without symptoms of depression could be detected (Table 1A).

The prevalence of apparent dementia (detectable at the clinical examination without further neuropsychological testing) in our whole cohort was 5.8% without significant differences between bulbar- and spinal-onset patients. In the general population, the prevalence of dementia in people younger than 65 years is very low (0.1%) and increases with advancing age. Patients with ALS of our cohort had a significantly higher prevalence of dementia at a younger age (<65–69 years) (Fig. 1h).

Symptoms of Parkinson's disease were observed in 1.8% of our patients with ALS. As the prevalence in the general population is indicated as 0.1–0.2%, parkinsonian syndromes seem to occur more frequently in patients with ALS. This difference was, similar to our observations regarding dementia, mainly caused by a higher prevalence of Parkinson symptoms in younger patients with ALS. The presence of symptoms of dementia or Parkinson's disease had no influence on survival time (Table 1A).

Of our patients with ALS, 1.6% suffered from epilepsy. Compared with the general population (0.45–1%) [15], the rate of patients with epilepsy was slightly higher in patients with ALS. The survival time of ALS patients with epilepsy was significantly longer compared with ALS patients without this comorbidity (Table 1A).

Regression analysis using the ALSFRS_R score ratio as dependent variable showed no significant influence of any neuropsychiatric disease on the course of disease, except for Parkinson's disease with a mean ratio of 0.46 (P = 0.03), which means a slower progression in ALS patients with concomitant symptoms of Parkinson's disease (Table 1B).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information

The composition of our patient cohort regarding gender ratio, age, and region of onset was similar to the results of previous epidemiological studies [16-18]. The prognostic relevance of the factors age at disease onset, region of onset, and time from first symptoms to diagnosis has been previously described [19, 20] and was confirmed in our study.

Cardiovascular diseases and metabolic disorders

Lower frequencies of HT, cardiac arrhythmia, MI, DM and HC were seen in patients with ALS compared with the German general population. These findings are in accordance with previous studies that have also shown lower prevalence rates of HT, CHD, and low-density lipoprotein/high-density lipoprotein ratio in ALS [4, 5, 21]. Regarding DM, higher or equal frequencies of impaired glucose tolerance in ALS have previously been described [3, 7]. Two studies found a higher frequency of hyperlipidemia in patients with ALS as opposed to the significantly decreased prevalence in our cohort. A protective effect of dyslipidemia has also been discussed in these studies; however, other prognostic factors (age, region of onset, etc.) were not taken into account, or multivariate analysis was negative in these studies [6, 7]. Others could not confirm an association between hyperlipidemia and increased survival [9, 22]. In our analysis, neither HC nor any other cardiovascular or metabolic comorbidity had a significant impact on the survival of patients with ALS once we had included other confounding factors into the multivariate analysis.

It has been discussed that lower lipid levels in patients with ALS occur as a result of lower forced vital capacity (FVC) and poor nutrition [4, 9]. Our observation of a significantly increased percentage of bulbar onset in the patient group with HC argues against poor nutrition and increased respiratory effort as a main cause for lower rate of dyslipidemia. Therefore, we rather consider hypermetabolism and increased resting energy expenditure, which is common in patients with ALS [1, 23], as main reason for the lower rate of HC in patients with ALS. This is in line with the data from the ALS mouse model where hypolipidemia can already be measured in the pre-symptomatic stage [24].

We also found a significantly lower prevalence of cardiac arrhythmia in our ALS cohort compared with the general population. Involvement of the autonomous nervous system in ALS and subsequent risk of bradycardia and sudden cardiac arrest has been controversially debated: several studies have postulated an imbalance between the sympathetic and parasympathetic nervous system and reduced sympathetic activities due to neuronal loss in the intermediolateral nucleus in patients with ALS [25, 26], whereas in other clinical studies no involvement of the autonomic nervous system in ALS was found [27, 28]. The lower prevalence of cardiac arrhythmia in our ALS population could also be caused by the lower frequency of the risk factors for cardiac arrhythmia (e.g., hypertension) and does not prove the absence of autonomic dysfunction.

Reasons for the lower rates of cardiovascular diseases/risk factors in general remain unclear. Physical activity as a risk factor for ALS and possible protective effects of medication in cardiovascular diseases (e.g., antiplatelet agents or statins) have been suggested [5]. Genetic disposition for cardiovascular and metabolic disorders may simultaneously be associated with decreased susceptibility to pathogenic mechanisms in ALS. ALS-associated metabolic alterations are possibly present already in pre-symptomatic disease stages and may prevent the occurrence of cardiovascular disorders. After all, it is also possible that some patients with cardiovascular diseases die before they could develop ALS or that patients die of ALS before they could develop a cardiovascular disease, and hence, their prevalence is lower in patients with ALS. However, it is noteworthy that this prevalence ratio cannot be detected in other age-related neurodegenerative diseases: in Alzheimer's disease (AD), on the contrary, the presence of cardiovascular risk factors is associated with a higher risk of AD [4, 29].

Neuropsychiatric diseases

Almost a quarter (22.8%) of patients with ALS in our population was afflicted with depressive symptoms, which is comparable to the prevalence of depression in patients with ALS most often described in the literature [12, 13, 30]. Thus, depressive symptoms were significantly more frequent in our ALS cohort compared with the general population. The presence of signs of depression had no influence on the survival time, implicating that there was no increased mortality due to suicide. Six of our patients with signs of depression had committed suicide, which corresponds to a suicide rate of 5.1% of patients with ALS suffering from depressive symptoms. Regarding the whole ALS cohort, suicide rate was still 1.17%, which was considerably higher than in the general population (0.012%, WHO data). However, the suicide rate within ALS patients with depressive symptoms was lower than it has been reported for patients with depression in general (6.7–15%) [31, 32]. These results are in favor of the assumption that depression in patients with ALS is most often not severe and not progressive with increasing disability [12, 13, 33].

The prevalence of dementia was significantly higher in middle-aged patients with ALS of our cohort than in the general population. This is in line with recent findings that dementia is more frequent in ALS than previously assumed and that there is a neuropathological link between ALS and frontotemporal dementia in the form of TDP-43 aggregates [34]. With 5.8%, the prevalence of dementia in our cohort was still low compared to the data from the literature, where the frequency of dementia and cognitive deficits in patients with ALS ranges between 15% and 50% [2, 10]. This is probably caused by the fact that the majority of our patients had not undergone neuropsychological testing and that less apparent cognitive/behavioral abnormalities were therefore not recorded.

The frequency of symptoms of Parkinson's disease in our ALS cohort (1,8%) was significantly higher than in the general population. A combination of ALS and parkinsonism is known from the ALS–parkinsonism–dementia complex of Guam and Kii, but has also been described outside the pacific in sporadic and familial cases, both with and without dementia [35-37]. Neurodegenerative diseases such as ALS and Parkinson's disease certainly share common pathomechanisms and therefore occur frequently conjointly. A recent multicenter genetic analysis suggests that mutations in the angiogenin gene could provide a genetic link between ALS and PD [38]. Also, the recently identified hexanucleotide repeat expansion in C9orf72 can result in a combination of ALS/FTD and parkinsonism [39]. According to the multivariate regression analysis, ALS patients with parkinsonism had a significantly slower disease progression. However, this result has to be rated with care because of the low case number.

In our cohort, 1.6% of patients with ALS suffered from epilepsy, which was a slightly higher rate than in the general population. There are no data about the prevalence of epilepsy in patients with ALS. The survival of ALS patients with epilepsy was significantly longer. Neuroprotective effects of anticonvulsant drugs like valproic acid have been found in ALS mouse models [40], but could not be verified in a clinical trial in patients with ALS [41]. Although our patient sample is probably too small to demonstrate a neuroprotective effect of anticonvulsant drugs, they may be a possible reason for the longer survival of patients with epilepsy.

Conclusions

The analysis of comorbidities in large ALS databases can provide hints for ALS risk factors or disease modifiers. This could become relevant for disease prevention or early therapeutic intervention. According to our results, patients with beneficial metabolic/cardiovascular risk profile seem to be at higher risk of developing ALS, indicating a protective effect of vascular risk factors. However, our data do not confirm their previously suggested impact on disease progression or survival. Future studies should address the impact of specific comorbidities on disease progression in a prospective manner to better differentiate between pre-existing and newly occurring conditions.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information

The authors thank Andreas Niesel and Dagmar Conradt for technical assistance.

Disclosure of Conflicts of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information

The authors declare no financial or other conflict of interests.

Reference

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. Disclosure of Conflicts of Interests
  9. Reference
  10. Supporting Information
FilenameFormatSizeDescription
ene12015-sup-0001-TableS1.docWord document37KTable S1. Distribution of patients according to age, sex and region of onset. The gender ratio was 1.3 (male): 1 (female). It is visible that a bulbar onset is significant more often in older and female patients (Chi²-Test P = 0.001 respectively Chi²-Test P = 0.014).

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