Acta Neurol Scand 2014: 130: 283–291 DOI: 10.1111/ane.12220

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA

Association between neurological disorders, functioning, and mortality in the elderly Czira ME, Baune BT, Roesler A, Pfadenhauer K, Trenkwalder C, Berger K. Association between neurological disorders, functioning, and mortality in the elderly. Acta Neurol Scand: 2014: 130: 283–291. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives – In aging populations, the prevalence of neurological disorders increases, which imposes high population burden in terms of mortality, disability, and impaired quality of life. The aim of this study was to assess the prevalence of common neurological disorders and signs and their association with functioning and mortality in an elderly general population. Materials and methods – We used data from the Memory and Morbidity in Augsburg Elderly (MEMO) project, a population-based study of 385 individuals aged ≥65. The prevalence of neurological disorders and signs was assessed by physical examination and medical interview. The basic and instrumental activities of daily living were assessed (ADL, IADL). We assessed the association of neurological disorders and signs with everyday functioning and prospectively analyzed their relationship with mortality. Results – We observed considerably impaired functioning for cases with stroke, TIA, PD, and mild motor parkinsonian signs (MMPS). All-cause mortality was significantly increased in participants with stroke and MMPS, even after adjusting for co-variables (HR = 2.71 and 1.80, respectively). Conclusions – We found that not only specific neurological disorders, but also earlier symptoms are related to impaired functioning and predict mortality in the elderly. These findings have potential clinical relevance for screening and early detection of individuals at risk.

Introduction

In aging societies, the burden of common neurological disorders such as Parkinson’s disease, stroke, or restless legs syndrome (RLS) presents a considerable challenge to healthcare systems with regard to acute management, rehabilitation, long-term care, and costs (1–5). While life expectancy increased considerably in developed countries, the relative mortality burden related to neurological disorders also increased substantially in the last decades (6). Although cerebrovascular diseases have the highest mortality rate, other neurological disorders significantly contribute to the overall mortality (6, 7). Neurological disorders comprise a substantial percentage of all disability-adjusted life years (DALYs) and are often associated with a wide range of physical and psychological impairments, which

M. E. Czira1,*, B. T. Baune2,*, A. Roesler3, K. Pfadenhauer4, C. Trenkwalder5, K. Berger1 1 Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, Germany; 2Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia; 3 Department of Neuroradiology, Zentralklinikum Augsburg, Augsburg, Germany; 4Department of Neurology, Zentralklinikum Augsburg, Augsburg, Germany; 5Paracelsus Elena-Klinik, Kassel, Germany

Key words: elderly; function; mortality; neurological disorder M. E. Czira, Institute of Epidemiology and Social Medicine, University of Muenster, Muenster D-48149, Germany Tel.: +49 251 83 58331 Fax: +49 251 83 55300 e-mail: [email protected] *This is to indicate that both authors contributed equally to the present work and should therefore both be regarded as first authors. Accepted for publication December 18, 2013

require an interdisciplinary management (8, 9). Knowledge about the association between the neurological disorders with everyday functioning and their association with mortality would be of great importance to the planning and delivery of health care services. Modern clinical diagnostic methods, such as brain imaging, are rarely used in population-based studies, due to cost and logistics. In addition to neurological diagnoses derived from clinical examination, these methods enable to assess subclinical morphologic changes of the brain which might also be related to functional impairment. For example, white matter lesions (WML), commonly found on brain MRI scans of the elderly, have been associated with cognitive and physical dysfunctions (10, 11). However, their clinical relevance is still a matter of debate (12). 283

Czira et al. In this study, we assessed the prevalence of common neurological disorders and signs, as well as morphologic brain changes, and analyzed their association with everyday functioning and longterm mortality in an elderly community-based population. Methods

The Memory and Morbidity in Augsburg Elderly (MEMO) Study is a follow-up project of the 1989-1990 World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) Survey-Augsburg (13). For this second MONICA Survey, a random sample aged 20–74 years was drawn from the population register of the Augsburg area. The MEMO Study is a follow-up of those participants of the second MONICA survey, who were 65 years or older on October 1, 1997, and lived in the city of Augsburg or one of two neighboring suburbs. MEMO examined cognitive function and risk factors for neurodegenerative diseases in the elderly (14). It was part of the Cardiovascular Determinants of Dementia (CASCADE) Study, a European multicenter study with the objective to evaluate the effects of cardiovascular risk factors on brain morphology in community-dwelling elderly individuals (15). The overall response rate among those eligible (n = 635) was 60.6%, yielding a total of 385 participants in the MEMO Study (see Fig. 1.). Informed consent was obtained from all study participants. The study was approved by the Ethics Committee of the University of Muenster, Germany. Assessment of medical and family history

All participants were examined by one of two physicians, specifically trained for 3 months in an outpatient clinic for movement disorders, following a standardized neurological examination protocol. General medical history, history of neurological and psychiatric diseases, and family history (parents, grandparents, siblings, or children) for neuropsychiatric disorders were assessed in interview form. Histories of seizures and of head injury were self-reported during lifetime. Head injury was restricted to commotio cerebri with loss of consciousness and/or traumatic intracranial hemorrhage and/or skull fracture. Neurological assessment

Mild motor parkinsonian signs (MMPS) were assessed with items from the motor score of the 284

Inhabitants of German nationality of the Augsburg area N = 349,050

WHO MONICA Survey Augsburg 1989/90 (S2) Random sample N = 4,940

Follow-up: MEMO study (1998) Participants of the MONICA S2, who were aged ≥65 on October 1, 1997 N = 635

N = 250 (39.4%) non-responder

Participants of the MEMO study N = 385

Figure 1. Flow chart of participant selection.

Unified Parkinson’s Disease Rating Scale (UPDRS) (16) that was part of the standardized neurological examination. A symptom was scored as ‘present’ if its severity was at least moderate in the respective items, corresponding to scores of ≥2. Presence of head distortion was assessed by clinical examination. Cases of PD were identified based on a self-reported diagnosis and on the presence of at least two of three cardinal signs, that is, resting tremor, rigidity, and bradykinesia in individuals not receiving anti-Parkinson medication. Participants on anti-Parkinson medication were included if one or more cardinal signs had improved by this treatment. Participants without response to anti-Parkinson treatment or without progressive disease over the last 15 years were not included as a PD case. Stroke was assessed with a specific stroke symptom questionnaire (15) and validated by medical records following an established procedure (17, 18). Strokes were classified as ischemic, hemorrhagic or undetermined stroke, or TIA based on the clinical information provided in the medical records. The assessment of restless legs syndrome (RLS) was conducted in face-to-face interviews with a short questionnaire that had been previously validated against physician classification (19). The questions included the standard criteria published by the International Restless Legs Syndrome

Neurological disorders, function, and mortality Study Group (20). The three answer categories included ‘Yes’, ‘No’, or ‘Don’t know’. Participants were only classified as RLS positive if they answered all symptom questions with ‘Yes’. The reliability of the RLS assessment was analyzed by comparing the classification based on these questions with the RLS diagnosis provided by the respective physician. Inter-rater reliability for both classifications was j = 0.67 (19). For all participants, a neuropsychological test battery was also completed that included a standardized version of the Mini-Mental State Examination (MMSE) (21). Assessment of general functioning

The assessment of activities of daily living was carried out separately for basic activities by means of the Activities of Daily Living Scale (22, 23) (ADL, e.g., bathing, dressing, etc., total 10 items) and the more complex activities that are not necessary for fundamental functioning, but allow one to live independently in a community. The latter was assessed by the Instrumental Activities of Daily Living Scale (IADL, e.g., using a telephone, shopping, ability to prepare food, ability to handle finances, handling medication, etc.; eight items) designed by Lawton and Brody (24). In this study, we used a simple combination of the two scales, as previously described (25). Based on the skewed distributions of the variables, the ADL and IADL scores were each summarized in a dichotomized variable, expressing the need for support in one or more of the ADL and IADL items. MRI assessment

Additionally, we performed brain MRI in a subset (n = 268) of the participants (70%) who were free from contraindications to MRI. All MRI scans were made with a Phillips 1.5 tesla machine at the department of radiology, Central Hospital of Augsburg. MRI reading was carried out centrally at the CASCADE core radiology center (Department of Radiology, Daniel Den Hoed Cancer Center, Rotterdam, the Netherlands) by a single reader using an established rating scale (26, 27). A detailed description of the method and the reading protocol is described elsewhere (15). In this study, subcortical white matter lesions (WMLs) were categorized by size (small: 10 mm). Cortical atrophy was assessed on a semi-quantitative scale with four categories (0–3) applied to each lobe and to the Sylvian fissure. The lobar scores were

summarized to the total cortical atrophy score with a range from 0 (no atrophy) to 15 (maximal atrophy) (26). A score >10 was defined as the presence of cortical atrophy. Biventricular atrophy was defined as a ratio larger than 0.35 between the biventricular width and the width of the brain at the level of the caudate nuclei. Follow-up of all-cause mortality

Vital status of all MEMO Study participants and time of exit was documented prospectively until December 31, 2007. Death certificates were obtained from local health departments. None of the participants were lost to follow-up. Statistical analysis

Differences in proportions were compared using the chi-squared test or the Fisher’s exact test. For differences in continuous variables, Student’s t-test or Mann–Whitney U-test was used, as appropriate. To assess the association between the different neurological symptoms or diagnostic findings and general functioning, we dichotomized the ADL and IADL scores as ≥1 that is ‘help needed in at least one item on the scale’. To examine whether these relationships were independent of other clinical and socio-demographic variables, we built multivariate logistic regression models with the corresponding dichotomized outcome variable, adjusted for age, gender, years of education, smoking, alcohol consumption, history of cardiovascular disease, and bone and joint disease. We also examined the association of the neurological symptoms and MRI findings with long-term all-cause mortality in multivariate Cox proportional hazard models, with the aforementioned co-variables. In the multivariate analyses, the reference group consisted of those participants who were free of all of the examined neurological disorders. In supplementary analyses, we also performed the aforementioned analyses on the subset of participants, who underwent MRI examination. In this case, the reference group was also free of pathological signs on the MRI. Results

The characteristics of the study population are shown in Table 1. Median age was 73 years; nearly half of the participants had hypertension and 10% had diabetes. The prevalence of the examined neurological disorders in the study population can be seen in Table 2. Parkinson’s disease and lifetime history of seizure affected about 285

Czira et al. Table 1 Socio-demographic and clinical characteristics of the sample (n = 385) Age, years (median, range) Women (%) Living with partner (%) Years of education (median, range) Early retirement due to health reasons (%) Body mass index ≥ 30 (%) History of hypertension (%) History of diabetes mellitus (%) History of myocardial Infarction (%) Current smoker (%) Ex-smoker (%) Non-smoker (%) Alcohol consumption (%) Women > 20 g/day Men > 40 g/day Mini-Mental State Examination (median, range) Participants with MRI (N = 268) (%)

73 (65–83) 47.3 68.1 10 (8–17) 22.4 24.4 47.4 10.7 8.9 9.9 41.0 49.1 10.0 17.3 26 (11–30) 69.6

1

MRI, magnetic resonance imaging.

Table 2 Prevalence of neurological disorders and signs Disorder Stroke total (%) Ischemic stroke Hemorrhagic stroke Undetermined stroke TIA (%) Parkinson’s disease (%) Head distortion (%) Restless legs syndrome (%) History of head injury1,2 (%) History of epilepsy1 (%) Mild motor parkinsonian signs3 (%) at least one Rigidity Resting tremor Postural tremor Any head tremor Bradykinesia Family history1 (%) Stroke Parkinson’s disease Dementia Free of any neurological diseases and MRI signs4 (%)

Discussion n = 385 6.8 3.4 1.0 2.3 3.1 1.3 2.4 9.8 19.2 1.0 11.7 1.9 3.1 5.2 1.8 6.1 27.3 3.4 13.3 43.4

1

Self-reported. Including commotio cerebri with unconsciousness, skull fracture, or traumatic intracranial hemorrhage. 3 UPDRS score ≥2. 4 Based on participants, who had all data including MRI results (n = 249). TIA, transitional ischemic attack; MRI, magnetic resonance imaging. 2

1–1% of the participants, while the stroke and TIA prevalence was 6.8% and 3.1%, respectively. Almost 10% of the participants presented all RLS symptoms, and 11.7% had at least one mild motor parkinsonian sign of moderate severity. In multivariate logistic regression models, most of the examined disorders and signs (stroke, TIA, MMPS and PD) were associated with a more frequent need for support in at least one ADL or IADL (Table 3). Apart from PD, where all cases 286

had help needs, the highest odds ratios (OR) were found in participants with a history of TIA, followed by those with MMPS or a history of stroke. Need for help was also significantly increased in participants with pathological findings on the MRI scans (Table 4). The median follow-up period was 9.9 years (0.5–10.2 years). The total number of participants deceased was n = 116. In multivariate Cox regression models, the history of stroke was significantly associated with a 2.7-times higher risk of mortality compared to those participants who were free from all of the examined neurological disorders and signs. The presence of at least one mild motor parkinsonian sign showed a 1.8-times increased mortality risk, and cortical atrophy on the MRI was associated with a hazard ratio of 2.5 (Table 3 and Table 4).

In this study, we report that common neurological disorders and signs comprise an increased risk of functional impairment and mortality in an elderly general population. The WHO Global Burden of Disease Study (8) highlighted the role of neurological disorders in terms of mortality and disability both in developed and developing regions. In countries with decreasing overall mortality rates, the spectrum of causes of disease and death undergoes a shift toward non-communicable, chronic, and degenerative disorders, thus increasing the relative burden of disorders of the nervous system (28). The study by Wittchen et al. (29) reported that disorders of the brain are currently the largest contributor to the all-cause morbidity burden in the EU. Currently, little is known about the association of individual neurological symptoms with mortality risk and their association with everyday functioning. In this study, we assessed the prevalence of a broad range of neurological disorders and signs and their association with activities of daily living and mortality in a community-dwelling sample of elderly individuals. Our findings are in accordance with the literature regarding the prevalences of the neurological disorders in the elderly general population, where the prevalence of PD, epilepsy, and stroke is generally estimated around 1%, 1%, and 8%, respectively (30–33). Determining the real prevalence of TIA presents a great challenge, mainly due to the transient nature of the symptoms. The prevalence reported in the literature ranges between 1 and 6% (34, 35), in accordance with the 3.1% prevalence found in our study. Due to the differences in the method

Neurological disorders, function, and mortality Table 3 Association of neurological disorders and signs with help needs in activities of daily living and mortality IADL ≥ 11

ADL ≥ 11

History of stroke (n = 26) History of TIA (n = 12) Mild motor parkinsonian signs3 (≥1 sign) (n = 39) Parkinson’s disease (n = 5) Head distortion (n = 12) Restless legs syndrome (n = 36) None of the examined disorders and signs (n = 247)4

Mortality2

%

OR

95% CI

%

OR

95% CI

%

HR

95% CI

42.3 66.7 48.7 100 25.0 33.3 26.8

2.2 6.8 2.4 NA 0.8 1.3 1.0

0.9–5.8 1.6–29.2 1.1–5.2

61.5 75.5 59.0 100 33.3 47.2 33.3

2.8 9.2 2.6 NA 0.9 2.2 1.0

1.1–7.0 1.8–47.7 1.2–5.5

57.7 25.0 53.8 60.0 25.0 13.9 26.3

2.7 1.2 1.8 1.9 0.9 0.7 1.0

1.4–5.1 0.4–3.8 1.1–3.1 0.3–14.3 0.3–2.8 0.3–1.7 Reference

0.2–3.4 0.6–2.9 Reference

0.2–3.7 1.0–4.7 Reference

1

Derived from multivariate logistic regression model (adjusted for age, gender, years of education, smoking, alcohol consumption, history of cardiovascular disease, and bone and joint disease). 2 Derived from multivariate Cox proportional hazard model (adjusted for as in 1). 3 rigidity, tremor, or bradykinesia ≥2 on the UPDRS, excluding individuals classified as Parkinson’s disease cases (n = 5). 4 Reference group. ADL, activities of daily living; IADL, instrumental activities of daily living; MRI, magnetic resonance imaging; TIA, transitional ischemic attack; WML, white matter lesion; NA, not applicable.

Table 4 Association of MRI findings with help needs in activities of daily living and mortality IADL ≥ 11

ADL ≥ 11

Cortical atrophy on MRI ≥1 large WML (>10 mm) on MRI None of the examined disorders or signs, including MRI findings3

Mortality2

%

OR

95% CI

%

OR

95% CI

%

HR

95% CI

48.3 40.6 18.7

2.6 2.5 1.0

1.1–6.4 1.2–5.2 Reference

51.7 43.6 26.2

2.3 1.7 1.0

1.0–5.2 0.8–3.5 Reference

50.0 35.6 19.7

2.5 1.5 1.0

1.3–4.8 0.8–2.8 Reference

1 Derived from multivariate logistic regression model (adjusted for age, gender years of education, smoking, alcohol consumption, history of cardiovascular disease, and bone and joint disease). 2 Derived from multivariate Cox proportional hazard model (adjusted for as in 1). 3 Reference group. ADL, activities of daily living; IADL, instrumental activities of daily living; MRI, magnetic resonance imaging; TIA, transitional ischemic attack; WML, white matter lesion.

of assessment and the examined severity, the prevalence of RLS in the elderly general population varies. Previous studies carried out in Germany that used similar diagnostic criteria to ours reported an RLS prevalence of around 10%, ranging between 3% and 19% (36). Our finding of 9.8% is also in accordance with the literature. Similarly, mild motor parkinsonian signs have also been defined variably in the literature. Studies, which used similarly rigorous criteria as we did, found a prevalence of around 15–23% in the elderly participants (37–40). The 11.7% prevalence found in this study can be considered relatively low. As the prevalence of MMPS increases with age, a possible explanation to our finding could be that our study population consisted of relatively ‘young’ elderly participants (mean age 73 years vs. 75–79 in other studies). The prevalence of head distortion in our study is higher than the reported prevalence of cervical dystonia (0.4%) (41); however, we included all kinds of non-straight head-holdings or head tilts in this

group, which could have been caused by a number of other diseases apart from torticollis. Independent functioning is usually compromised in patients with neurological disorders. Stroke is a leading cause of disability exceeding that of cardiovascular diseases and cancer (42). Reportedly, 25–75% of stroke survivors requires some assistance or is fully dependent on caregivers in their everyday activities (43). Our findings agree with these data, as 42% of participants with stroke needed help in at least one ADL and 62% in at least one IADL item. Less is known about the help needs in everyday functioning of individuals who experienced a TIA, as after the symptoms pass these patients are usually considered fully recovered. However, our results showed surprisingly high prevalence of help needs and highly increased risks for needing help in at least one ADL or IADL in participants who previously experienced TIA. These findings are in accordance with those of Verbraak et al. (44) who reported that 1 month after suffering a TIA, 287

Czira et al. all patients had some difficulties in ADL. A possible explanation to this finding could be that patients diagnosed with TIA frequently have in fact suffered a light stroke with most of its longterm consequences; however, they do not receive rehabilitation and special care, because they are assumed to be fully recovered (45). Additionally, it can be assumed that this finding has been influenced by non-responding, as those who had experienced a more severe stroke, and thus probably needed more support in their everyday life (e.g., who were bed-ridden), were more likely to refuse to participate in the study. Parkinson’s disease imposes greater health problems in the elderly than heart disease, diabetes, stroke, or chronic back pain, although its prevalence is lower than that of the other diseases (46). PD also leads to physical and emotional dysfunctions, and the functional impairment in these patients is well established (47). It is not uncommon that similarly to our findings, most or all PD patients require help in performing everyday activities (48), although others have previously found high functioning in PD patients (49). Despite being a common neurological disorder, PD is rare compared to the prevalence of single mild motor parkinsonian signs not severe enough to classify an individual as having PD. There seems to be a void in the literature on this topic, although a study by Louis et al. (50) reported substantial impairment in the independence regarding everyday activities in patients with MMPS, and the severity of the MMPS significantly correlated with the activity scores. We showed that the presence of at least one of rigidity, tremor, or bradykinesia of moderate severity (UPDRS ≥ 2) is also associated with a significantly elevated risk of need for support in basic and also in the instrumental activities of daily living. The association of head distortion with the risk of ADL or IADL impairment has not been examined before. We did not find elevated risk of help needs in this community-dwelling sample of elderly individuals with head distortion compared to those who were free of any neurological disorders and signs. The association of RLS with everyday functioning has also rarely been examined in the elderly (51). In this study, we did not find significant associations between the presence of RLS and help needs in ADLs or IADLs, although the latter association was marginally significant. We prospectively examined the association of several neurological disorders and signs with mortality. Our results are in agreement with the published literature regarding the unequivocally 288

increased mortality risk of individuals with a history of stroke. It has been shown previously that tremor is also associated with higher mortality risk (52), although other individual MMPS have rarely been examined. In this study, the association of PD with mortality was not significant, possibly due to the low number of cases having PD. However, we found a significantly higher mortality risk of participants with at least one MMPS that do not classify an individual as having PD. The individual signs have been previously found to be associated with functional disability and mortality (38, 50, 53), although most studies failed to control for co-morbidities, socio-demographic, or lifestyle factors. Here, we show that the presence of MMPS is associated with an almost twice higher mortality in the elderly, independently of such factors. We did not find higher mortality risk in case of RLS and head distortion, suggesting that these conditions did not interfere with the life expectancy of the community-dwelling elderly individuals in our sample. Few studies have examined the association of RLS with mortality, giving inconsistent results (54–56). One recent study from the general population has also shown no association of RLS with mortality (55). As supplementary analysis, we also examined the aforementioned associations in a subgroup of participants, who underwent MRI examination (Table 4). Although large WMLs on the MRI have previously been reported to be associated with cognitive impairments, activity limitations, and even mortality (57, 58), their clinical relevance is still a matter of debate (12). In this study, we found a marked association of ≥1 large WML with mortality, but it did not reach statistical significance. However, the mortality risk was increased for individuals, whose MRI showed signs of cortical atrophy. On the other hand, similarly to most of the examined neurological diseases, we found significantly increased help needs in at least one item of the activities of daily living for both cortical atrophy and large WML on the MRI compared to those participants, who were free from all examined neurological disorders, signs, and MRI findings. These results confirm the relevance of the MRI findings and suggest that not only clinically obvious symptoms, but also diagnostic work-up findings are associated with impaired functioning and increased mortality risk. Most studies report the consequences of a specific neurological disorder and do not mention the significance of individual symptoms in detail. It is possible that there is a publication bias in this field, as usually the group of patients who have a

Neurological disorders, function, and mortality disorder or an abnormal finding is compared to those, who do not have that particular disorder or finding, but might have others, that can also influence life expectancy or everyday welfare. As in many cases these symptoms are present in parallel (59, 60), it is easy to overlook the underlying associations. We attempted to avoid this problem and examined neurological disorders, signs, and morphological abnormalities compared to those participants who were free of these disorders and findings within the same population. Our study has several strengths and limitations. Among the limitations is the notion that our results should not be generalized to the elderly population without further considerations. In the MEMO Study, the response rate was 60.6%, which is high for the included age group, but might have caused a selection bias in our sample toward a lower symptom and disease severity. Individuals with more severe neurological diseases and those who need more help in their everyday activities were probably less likely to participate. A main strength of our study is that we examined a wide range of neurological disorders and signs, based on a standardized evaluation by a physician, including a brain MRI. Disease classifications followed established and published procedures and had been used in this and other population studies before. In summary, our study demonstrates a strong association between common neurological disorders and general functioning and mortality in a community-based elderly western population. Not only manifest neurological disorders, but also gradual neurological dysfunctions are strongly related to impaired general functioning and subsequent mortality. The resulting support needs pose a particular challenge to the health care systems in aging societies. Acknowledgments The MEMO Study is supported by the German Research Society (Deutsche Forschungsgemeinschaft, grant: BE1996/1-1). Data assessment was carried out within the framework of the Cooperative Health Research in the Augsburg Region (KORA). The sponsor, the German Research Society, had no role in the design, methods, subject recruitment, analysis, and preparation of the paper.

Conflict of interests MEC: Grant for institute (German Research Foundation). BTB: Board membership (Lundbeck), employment (University of Adelaide), grant/grant pending (NHMRC), payment for lectures (pharmaceutical industry). AR: none. KP: none. CT: Travel support (UCB, Boehringer Ingelheim, Mundipharma), board membership, employment (UnivProf.

of Neurology, University of the Paracelsus-Elena-Klinik lectures (UCB, Boehringer Grant for institute (German

Goettingen, Medical Director of Kassel, Germany), payment for Ingelheim, Mundipharma). KB: Research Foundation).

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