In this study, we analysed the COI of ALS in Germany related to the already well established and disease-specific King’s staging system. As far as we know, our study investigated the greatest patient cohort in Germany by now and presents an estimate for the COI of ALS, which is based on current health-economic recommendations. Our estimates give an assessment basis for further cost effectiveness studies and payer negotiations. As far as we know, cost effectiveness studies are rare in the field of ALS as it is a rare disease and treatments are limited up to date [32-35]. Nevertheless, the necessity of these studies is currently increasing due to the investigation of different new treatment approaches [36-38]. However, the conduction of cost analyses in ALS is difficult, since the health insurance companies in Germany are not transparent about their expenses . Real-life expenditures of the German health system would provide a fruitful comparison; however, these are not accessible to the greater public. Our estimates for mean annual costs varied from 30,086€ (King’s stage 1) to 125,871€ (King’s stage 4B). This demonstrates a high socioeconomic burden even in early stages of the disease. The mean annual total COI per patient was 78,256€, which is 17-times higher than average costs per capita in Germany (4,544€) . The highest cost components were informal care costs (46.2%) and direct medical costs (35.9%; formal care 11.4% of total COI), while indirect costs constituted 15% of total COI. Patients’ family members are the main contributors to informal care in Germany [40, 41]. In our cohort, in 94.1% of the cases the main caring person was a family member. This plays a significant role not only in terms of the psychological burden but also from a socioeconomic perspective. Caregivers of patients with chronic diseases are reported to have poorer mental and physical health compared to non-caregivers . This may result in even higher ALS-related costs caused by an additional need for treatment and loss of productivity on the caregivers’ side.
Compared to previous studies in neuromuscular disorders (NMD), we estimated higher informal care costs (46.2% vs. 27% in Duchenne muscular dystrophy (DMD), 20% in Becker muscular dystrophy (BMD), 29% in spinal muscular atrophy (SMA) and 33.6% in Charcot-Marie-Tooth neuropathies (CMT)) [17, 18, 43]. Among different NMD, associated costs of ALS were the highest regarding both, informal care costs and total COI, which also corresponds to similar studies in the past [12, 13, 15]. In contrast, indirect costs were much higher in DMD, BMD, SMA and CMT. While in our cohort direct medical and non-medical costs were correlated to increase in clinical severity, indirect costs did not. A possible explanation for these differences may involve our cohort’s demographics: as the median age was 65 and 60% were already retired at the time of the survey for non-disease related reasons, productivity loss because of ALS was low and independent from clinical severity throughout our cohort. Our study did not consider indirect costs due to premature mortality. However, these costs may probably be negligible due to the late disease onset and as the majority of patients was already retired.
We showed that COI was higher and HRQoL was lower in more advanced disease stages. The influencing factors with the highest impact on COI were the ALSFRS-R score and invasive ventilation. On the other hand, HRQoL was significantly influenced by individual impairment in daily activities and classification into a care level. Common influencing factors on both, COI and HRQoL, were wheelchair dependency and the need of presence of an additional caregiver 24 hours per day. This shows that progressive loss of autonomy and increasing functional impairment throughout disease progression is the main cause of cost increase while additionally determining a reduced self-rated quality of life.
Our analysis of HRQoL showed a difference between EQ-VAS score and index value; patients reported their health state on the EQ-VAS score to be worse than what the index value showed (Median of 40/100 versus 0.59/1). Those results, however, are not surprising as the EQ-VAS score is known to be also influenced by factors such as perceived control, education, ethnicity, smoking and age , while the latter proved to be an influencing factor on EQ-VAS in our linear regression model as well.
ALS patients experience major impairments in their everyday lives and need a lot of support to maintain at least a residual independence. This is underlined by our patient cohort, in which 80% needed supportive devices, on average seven different devices per patient. In contrast, supportive devices only constituted 3.6% of total COI. While this figure may seem low, a study from the United States, which had access to “true costs” from insurance companies, confirmed this result . Concerning the supply of supportive devices, we made the following substantial observations: 20.2% of patients who stated to have impairment of their mobility according to the EQ-5D-5LTM did not use any mobility device. Moreover, 28.9% who were impaired in self-care did not use special devices and 75.6% who were impaired in daily activities, also did not use support in this regard. While depression is known to occur in 22.8% of patients with ALS , only 5.8% made use of psychological support. Interestingly, of 52 patients who stated a need for improvement in disease related support, 15 (28.8%) wished for support in the application for supportive medical devices and 12 (23%) for better and easier accessible psychological support. Similarly, regarding the ALSFRS-R results, of 88 patients who experienced dyspnoea, 52 (59.1%) did not use any breathing assistance. These findings strongly suggest a supply gap in these areas and maybe especially in the medical supply with more costly devices like ventilators (and the associated care that is needed with them). Better access to support and, perhaps, even costlier devices to maintain a higher grade of autonomy would raise the ratio of costs for supportive devices. Nevertheless, a supply in agreement with standards of care is necessary and not only increases the individual quality of life but also may lower other cost factors like informal care costs or indirect costs.
Our estimate of a total annual COI of 78,256€ in Germany is higher than previously assumed by Schepelmann et al. in 2010 (36,380€) . Compared to previous studies in other countries, e.g. Spain (36,194€) , US (63,693$)  and Korea (90,000$) , our estimates are on the higher side of estimated costs. However, direct comparisons must be done with caution due to respective healthcare systems and different approaches in cost estimation. Regardless, previous studies also described disease severity, need for a caregiver, wheelchair dependency and invasive ventilation as main cost influencing factors [12, 15], which further validates our model.
Compared to other NMD such as Myasthenia gravis (14,950€) , CMT (17,427€) , facioscapulohumeral muscular dystrophy (26,240€)  and BMD (39,060€)  total COI of ALS is notably higher, similar to those of DMD (78,913€)  and SMA (70,566€) . Due to a higher prevalence of ALS, the Germany-wide annual cost was 519,776,352€ which is more than three times higher than the estimates for DMD and nearly five times higher than the estimates for SMA.
To estimate informal care costs, we used a replacement cost approach, which is known to result in overestimation due to informal care being considered less efficient than formal . On the other hand, the associated psychological and physical burden of the caregivers who provided informal care was not reflected and may result in substantial underestimation of costs. Since our questionnaire was rather detailed with more than 120 questions, a selection bias towards more motivated patients might be likely. Moreover, patients were asked to answer questions regarding use of medical resources up to one year in the past, which probably led to recall bias, and further reduced total COI. Another limitation of our study is the monocentric design and coverage mainly of Northern Germany. A multicentre Germany-wide study that employs a greater patient cohort would be desirable to achieve an even more representative result. Thus, further studies of disease burden of ALS that also consider the burden of the caregivers are necessary.