**1. Introduction**

Multiple sclerosis (MS) is considered a chronic inflammatory and degenerating disease of the central nervous system (CNS), which often first manifests in early adulthood. What is known so far is that MS is most likely an autoimmune disease with demyelinating processes, which occur in the white and grey matter of the CNS [1]. These lesions, which are visible on nuclear magnetic resonance (NMR) imaging, lead to reduced nerve conductivity in the course of the disease. It is assumed that auto-reactive, myelin-specific T cells are activated in the periphery due to faulty tolerance development. They enter the brain and trigger an immune response by binding to "their" antigen, which leads to an inflammatory process [2]. MS is not a curable disease, but its course can be very positively influenced by medication. MS can manifest in a variety of disease courses. About 85% of patients first develop relapsing-remitting MS (RRMS), which can evolve into secondary progressive MS (SPMS) over a longer period [3]. The other 15% of patients initially develop primary progressive MS (PPMS). The respective diagnosis is made based on the McDonald Criteria [4]. The variety of possible symptoms of MS differs depending on the location and size of the lesions. Common symptoms include visual disturbances, paresis, bladder dysfunction, gait disturbances, as well as paresthesia and hypoesthesia. Another common symptom of MS is fatigue. Fatigue is an extreme exhaustion that usually occurs very suddenly and cannot be compared to being tired [5]. In 2007, the symptoms of patients with MS-related fatigue

were examined in detail and a standardized definition was formulated. They summarized that "fatigue is defined as a reversible motor and cognitive impairment, with reduced motivation and the desire to rest. It either occurs spontaneously, or is triggered by mental or physical stress, infection or after eating. Improvement can be achieved by sleeping or resting without sleep. Fatigue can occur at any time but is usually worse in the afternoon. In MS, fatigue symptoms can occur daily, are usually present for years, and are much more severe compared to fatigue caused by other diseases" [6]. More than 70% of people with MS report symptoms of fatigue [7]. Different studies have shown that 14% of patients perceive fatigue as their worst symptom, 55% of patients report it as one of the symptoms that affects them most [8]. Patients suffering from fatigue often do not manage to get through a whole day without taking breaks. As a result, their ability to work is particularly severely affected [5]. Fatigue is also one of the main causes of unemployment or early retirement in people with MS [9–12]. As therapy, some substances have been tested for their effectiveness. Even a meta-analysis of many pharmacotherapeutic approaches could not define clear therapeutic recommendations [13]. Accordingly, non-drug therapy and comprehensive education about a healthy lifestyle as a therapeutic approach is becoming important, such as the impact of sport and regular physical activity as a preventive measure [13,14]. Therefore, it should be considered whether and to what extent simple therapy approaches, such as coffee or especially caffeine might be an interesting subject for further research. Coffee consists of more than 1000 ingredients, of which caffeine is by far the best studied one. The effect of caffeine is not restricted to a stimulation of the CNS; a short-term improvement of attention, as well as a positive effect on cognition and memory have also been observed [15]. Caffeine reaches its maximum plasma concentration after 20–30 min after intake [16], and caffeine from coffee in particular is absorbed faster as compared to other sources [17]. Due to its hydrophobic structure, caffeine can pass the blood-brain barrier and thus also act on receptors in the brain [16,18]. Its main effect, as a psychostimulant of the CNS, is based on its ability to lower adenosine secretion as an adenosine antagonist on adenosine receptors in certain areas of the brain [19]. Adenosine signals the body that much energy is consumed and causes self-regulation of the body, by having a calming and inhibitory effect via various neurotransmitter-induced pathways [20]. By blocking the adenosine receptors, caffeine prevents adenosine from acting and conversely has a stimulating effect on the CNS. It improves cognitive function, reaction time, concentration, and alertness, as well as motor coordination [21]. The negative reputation of coffee has been reversed in recent years, a coffee consumption of up to four cups per day (a 150 mL, i.e., a total of about 400–500 mg of caffeine) can be considered harmless to human health [22]. Since coffee and caffeine have already shown a positive effect on daytime sleepiness in Parkinson's disease [23], the question is whether this effect can also alleviate the symptoms of fatigue in MS patients. The connection between caffeine and MS-related fatigue has not been investigated yet. The present study intends to evaluate the possible effect of coffee or caffeine on fatigue as well as on the everyday life of the patients. The aim of this work is to better understand the effect of coffee by means of patient interviews and evaluation of further clinical data. Of interest is the possibility of characterizing a specific group of patients for whom consumption of coffee or caffeine could be indicated as a therapeutic approach.

#### **2. Methods**

#### *2.1. Participants*

Questionnaires were distributed to the patients during the weekly consultation hours for MS patients at the Department of Neurology of the University of Regensburg Hospital between March 2018 and September 2018. Inclusion criteria were a confirmed diagnosis of MS and age of majority (18 years). Patients with initial diagnoses, who presented themselves for the first time, were also included. All patients who presented during this period were properly informed about the study and asked to participate. Those who signed the informed consent form were included in the study. The responsible ethics committee of the University of Regensburg approved this retrospective study by data collection in February 2018 (file number 18-890-101).

#### *2.2. Data Collection*

A short, retrospective questionnaire was prepared to provide an overview of coffee consumption habits in patients with MS. A five-page, simply structured questionnaire was designed, asking about the respective preferences of coffee intake. It focuses on fatigue and behavior concerning coffee consumption. To better classify the patients' fatigue, we used the Fatigue Severity Score (FSS) [11], as well as the Epworth sleepiness scale (ESS) [24]. Furthermore, patients were specifically asked about problems falling asleep and/or sleeping through the night. The number of hours awake, as well as the frequency of waking up at night were recorded. In addition, the patients were asked to assess whether they felt fit and well rested in the morning or not. Regarding the behavior of coffee consumption, we focused on the reasons why patients do not drink coffee and the possible associated side effects. They were asked what kind of coffee they prefer or which other caffeinated drinks they consume. This, together with the average number of cups consumed per day, as well as the average time of their coffee consumption should provide a better overview. The times of coffee intake were marked on a timeline. Finally, patients should indicate whether, and if so, what subjective effect of coffee they perceive, on what occasions or for what reasons they primarily consumed coffee and what relevance coffee has in their everyday life. Additionally, all patients were neurologically examined and further clinical data, such as the Expanded Disability Status Score (EDSS) [25] were collected. Data about the course of the disease were supplemented from the files.

### *2.3. Data Analysis*

Data were coded using SPSS version 25.0.0.1, IBM corporation (Armonk, NY, USA), 2019. Descriptive statistics included the calculation, the distribution, the median and the mean with standard deviation. Differences between groups were presented in cross tables and analyzed by the chi-square-test for categorical variables or t-test for all metric variables. A *p*-value of <0.05 was considered significant. Concerning the presence of fatigue, we decided to set the cut-of score as ≥ four points in the FSS, as originally defined by the authors [26].

#### **3. Results**
