*3.4. Sleep Characteristics*

In total, 34 of 124 participants (27.4%) stated that they had problems falling asleep. No significant difference in the amount of coffee consumption could be observed in those patients (Table 4).


**Table 4.** Characteristics of patients with MS regarding sleep.

ESS, Epworth sleepiness scale; h, hours; n, number; p, statistical significance.

Furthermore, 66 of the 124 patients (53.2%) surveyed, said that they regularly woke up more than once during the night. Here as well, no significant correlation with regular coffee consumption could be found. More MS patients laid awake at night who had problems with falling asleep (*p* < 0.001) and had a higher ESS (*p* = 0.013). The frequency of waking up at night was higher in MS patients who had problems with sleeping through the night (*p* < 0.001) (Table 4). Patients with fatigue more frequently replied with "sometimes" or "no" when asked whether they felt fit and well rested in the morning (Figure 1). In contrast no impact of coffee consumption was observed (Figure 2).

**Figure 1.** Distribution of sleep quality data in the two groups "fatigue" and "no fatigue". Patients with fatigue (*n* = 46) stated to feel less active and well rested in the morning (*p* < 0.001), whereas patients without fatigue (*n* = 78) felt more fit in the morning (*p* < 0.001; *p*, statistical significance).

**Figure 2.** Distribution of sleep quality data in the groups "regular coffee" (RC) and "no coffee" (NC). In the group with RC consumption, patients with an average daily coffee intake of more than 0.5 cups (*n* = 104) are shown. In the group of NC, patients with an average daily coffee intake of lower than 0.5 cups (*n* = 20) are shown. There was no difference in sleep quality regarding coffee consumption (*p*, statistical significance).

#### *3.5. Co*ff*ee Habits*

The amount of coffee consumed per day varied from a minimum of one cup to a maximum of 12 cups (mean = 2.67 ± 2.08) among the patients. For further analysis we built four groups, according to their average coffee intake per day (Table 1). Only fourteen patients stated no coffee consumption at all, most of the patients have reported to consume up to four cups per day.

The small group of patients with no regular coffee consumption indicated different reasons for this. By far the most prevalent reason for not drinking coffee was a dislike for the taste of coffee (Figure 3).

**Figure 3.** Reasons for patients not to drink coffee indicated in percentages.

We evaluated the average time of coffee intake in all participants (Table 5). In total 79.9% of all patients consume their coffee until 6 p.m. Only 8.1% of patients declared to consume coffee after 6 p.m. (7.3% whole day [in the morning, afternoon, and evening]; 0.8% in the morning and evening [until 12 p.m. and after 6 p.m.]). Patients with late coffee consumption showed a higher mean coffee intake of 6.6 ± 2.94 cups per day, compared to 2.3 ± 1.59 cups per day (*p* = 0.001).


**Table 5.** Time of coffee consumption.

Never 15 12.0 n, number; p.m., post meridiem (afternoon).

In the morning and evening (until 12 p.m. and after 6 p.m.) 1 0.8 Whole day (in the morning, afternoon, and evening) 9 7.3

The evaluation of a possible correlation between late coffee consumption and the occurrence of sleep problem, showed no significant effect of coffee intake after 6 p.m. (*p* = 0.849).

In the questionnaire, the patients were asked to state their reasons for drinking coffee and the effects they perceived from it. The most frequently selected answer was "I need coffee in the morning so that I can start the day fitter" 46.8% (*n* = 58). While 25.8% (*n* = 32) said that they did not feel any effect from coffee consumption. The effects and side effects did not differ significantly between the groups with different amount of daily coffee intake. The least common reported effect of coffee was stomach problems, such as heartburn (3.2%, *n* = 4). The effects were examined regarding the duration of the illness, for which none of the statements showed a significant difference. Especially the patients of the group "EDSS between 0 and 4" noticed positive effects regarding concentration and attention span (Table 6).



EDSS, expanded disability status scale; *n*, number; *p*, statistical significance.

Comparing the four groups with different daily coffee intake there were no significant differences in the EDSS values, or in ESS and FSS values. No significant correlations to age or gender of the patients could be found. No correlation was observed between the amount of coffee intake per day and the presence of a bladder voiding disorder (*p* = 0.514). The information on the current occupation in all groups was like the distribution of the entire patient collective (*p* = 0.205). Furthermore, no differences could be seen in sleep quality or distribution of difficulties falling asleep.

#### **4. Discussion**

The purpose of this study was to determine the characteristics of patients, for whom coffee consumption might have a beneficial effect on fatigue. This retrospective cohort demonstrated that 46 (37.1%) of the included patients experience severe symptoms of fatigue. The results of this study indicated that fatigue is not related to age, type of diagnosis or duration of the disease. This is different

from previous studies in which fatigue was more common in progressive MS forms [27]. Fatigue had a significant impact on the patients' ability to work with 56.5% of all patients suffering from fatigue stating that they were currently not able to work. 67.4% of these were no longer working due to their disease. This is consistent with previous studies, which identified fatigue as one of the most relevant causes for unemployment in MS [10,12]. Along with this, a significant correlation between a higher EDSS value and a present fatigue could be found.

Looking at sleep quality 27.4% of all patients reported problems with falling asleep. In comparing these patients with those who state no problems, no difference in the behavior of coffee consumption could be found. Even regular late coffee consumption, after 6 p.m. showed no effect on sleep quality and most importantly on the ability to fall asleep. Analyses of the relationship between the ESS value, i.e., the daytime sleepiness and fatigue, showed a positive correlation Other studies found that prevalence of sleeping disorders in MS patients ranged from 25–54% [28–30]. Better objective sleep was not related to self-reported scores of sleep-disordered breathing and fatigue [31]. We investigated which criteria had an influence on whether patients felt fit in the morning. Interestingly in our cohort, it could not be observed that coffee consumption had any effect. Furthermore, it could be demonstrated that coffee consumption, regardless of the amount consumed had no negative influence on sleep quality. There was no association either with daytime sleepiness (ESS value) or fatigue (FSS value). This was in contradiction to the frequent assumption that coffee consumption has a negative effect on sleep. Patients with a higher FSS value showed significantly more problems with sleeping.

Coffee and especially caffeine have beneficial effects on various neurological diseases as demonstrated in different studies [32]. Caffeine has also been investigated in in vitro experiments, where it showed a significant positive effect on rodents with experimental autoimmune encephalomyelitis (EAE) [33,34]. In previous research, coffee could lead to various beneficial effects regarding cognition. The overall mood of the patients who consumed coffee was better, and they showed lower fatigue levels. Tiredness and headaches also occurred less frequently among these patients [35].

In this study it was not possible to measure the exact amount of caffeine intake of patients, due to the retrospective nature of the data collection. We evaluated the amount of consumed coffee, measured in cups per day. However, while present studies have shown that an average caffeine content of about 30–175 mg caffeine per cup (defined as 150 mL) can be assumed [36], most studies including a prospective study on the effect of espresso in daytime-sleepiness in patients with Parkinson disease [23] indicate an amount of 90–100 mg per 150 mL. Since the average coffee consumption in our cohort amounted two to three cups per day, an estimated amount of 250 to 300 mg caffeine intake can be presumed. Previous studies demonstrated that an intake of caffeine up to 400 mg can be considered safe and harmless regarding side effects on human health [22]. In total, only 20 of the patients (16.1%) stated not to drink coffee regularly, 14 of them never consume coffee. The reason most indicated for not drinking coffee was simply a dislike for the taste of coffee. The possible perceived side effects tended to play a rather minor role. No differences could be found in terms of sleeping behavior in the small group of patients reporting side effects linked to coffee consumption.

In contrast, significant differences in the perceived effects of coffee consumption depending on disease severity were observed. Especially in patients with an EDSS higher than 0, but below 4, positive effects on everyday life could be identified. These beneficial effects included an increased ability to concentrate for performing tasks, a more focused attention, and a better structure in everyday life. It can be hypothesized that these patients are able to benefit from the effects of coffee consumption due to their still preserved cognitive reserves. The important influence of the cognitive reserve in MS has been demonstrated [37–39]. There is also data, which states that this protective role is mostly restricted to memory function and does not refer to the development of the disease in general [40].

Patients with an EDSS score of more than 4 points tended to have a higher quantity of CNS lesions [41,42]. The number of lesions has been shown to be associated with cognitive dysfunction in patients with MS [43]. Lesion load, as defined by conventional NMR imaging techniques, does not correlate with fatigue [44]. However, data show a possible contribution of the gray matter on fatigue development [45]. A recent pilot study demonstrated that patients with MS may link neural resources less efficiently than healthy people, which might result in higher levels of mental fatigue [46]. Even though many studies exist on fatigue and its therapy, treatment options remain extremely limited. The most promising therapy so far has been modafinil. Unfortunately, robust positive effects of modafinil could not be reproducibly shown in every published study [47–49]. On the contrary, it has even been shown that physical activity and a well-executed fatigue management in patients with MS have the same, if not a better effect on fatigue than pharmacological therapy [50]. It must be assumed, that various factors, such as diet, activity, and the pharmacological management of MS play an important role regarding fatigue experience [1,51].

A limitation of this study is the fact that the sample size is quite small. Possibly, similar studies could be performed with larger numbers of patients with multicenter recruitment. It is further not excluded that the effects of coffee drinking are not necessarily only due to the consumption of caffeine. Coffee contains high concentrations of other potentially bioactive natural products such as trigonelline and chlorogenic acids with partly undefined effects on the human body [32]. In addition, some beverages like tea and soft drinks often contain caffeine which could influence the obtained results to some degree [32].

### **5. Conclusions**

The lack of therapeutic options of fatigue in patients with MS is the reason why we initiated this study with the aim to evaluate a simple and maybe helpful approach for fatigue intervention in patients with MS. In our cohort, no negative impact of coffee or caffeine consumption on sleep quality could be found and no serious side effects were observed. Especially MS patients with an EDSS score higher than 0, but lower than 4, noted the strongest effect of coffee consumption on their cognitive abilities, mainly regarding a higher mental capacity and a more structured daily routine.

**Author Contributions:** L.H. designed the study, acquired, analyzed and interpreted the data, wrote and revised the manuscript and approved the final version of the manuscript. R.W. had the idea, designed and supervised the, analyzed and interpreted the data, wrote and revised the manuscript and approved the final version of the manuscript. L.H. and R.W. agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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