**3. Results**

This study analysed a sample of 51 MS patients, divided into an intervention group and a control group, whose socio-demographic and clinical characteristics are shown in Table 1.


**Table 1.** Socio-demographic and clinical characteristics of the population of the study.

Z: U de Mann Whitney; CG: control group; IG: intervention group; MS: multiple sclerosis; EDSS: Expanded Disability Status Scale; IL-6: interleukin 6; STAI: State-Trait Anxiety Inventory; BMI: body mass index; SD: standard deviation.

After the 4-month intervention, the changes in the analysed variables of the study are shown in Table 2 as the mean and standard deviation. Regarding the intervention group, a significant decrease in serum concentration was produced for IL-6: patients' anxiety for this group also varied after the diet, significantly decreasing state anxiety, and a significant improvement is shown in functional capacity. Regarding the control group, a significant decrease in the levels of IL-6 in blood is also observed. However, there is no improvement in the level of state or trait anxiety. No change was observed in terms of functional capacity. It is also noteworthy that there was a significant decrease in BMI in both groups.

**Table 2.** Differences between the study variables after intervention.


EDSS: Expanded Disability Status Scale; IL-6: interleukin 6 (mean value of normal IL-6, 1.4 pg/mL); STAI: State-Trait Anxiety Inventory; \*: statistically significant differences *p* < 0.05; Z: Wilcoxon signed-rank test; BMI: body mass index; SD: standard deviation.

### **4. Discussion**

Among the most representative inflammation biomarkers that activate the immune system caused by stress is IL-6 [36]. This explains that in an immune disease like MS with high oxidative stress, its levels are increased [4]. In this sense, both EGCG and ketone bodies obtained from following ketogenic diets show anti-inflammatory effects [37,38], thus decreasing the levels of IL-6 in blood: EGCG as it negatively regulates its gene expression [39], and ketone bodies block NMDA receptors [40]. After conducting our study, indeed the results prove a decrease in IL-6 levels in the group that received both EGCG and coconut oil. Nonetheless, this significant improvement has also been observed in the control group. This could be explained by the high levels of antioxidants in the Mediterranean diet followed by both groups. The Mediterranean diet is characterised by containing soluble or low molecular weight antioxidants, such as vitamin C and vitamin E, phenolic compounds and carotenoids, and other macromolecular antioxidants that are polymeric phenolic compounds or polyphenols and carotenoids linked to macromolecules of plant foods, which contribute to the antioxidant capacity of the diet [41]; including polyphenols that are greatly contained in fruit and drinks such as tea, red wine and coffee, or in vegetables, pulses and cereals in the Mediterranean diet [30]. In addition, a significant improvement in BMI is observed in both groups that, according to other studies, is positively correlated with IL-6 in blood [42,43], which could explain the decrease in the proinflammatory cytokine in both the control group and the intervention group.

In terms of assessing the psychological variables, although both depression and anxiety disorders are the most frequent nosological entities in MS, the repercussions of symptoms of depression in this pathology have been studied more, and fewer studies assess the impact of anxiety. However, the relation with functional performance and cognitive capacity for MS is only established with levels of anxiety and not with levels of depression [44]. On the other hand, two kinds of anxiety can be differentiated: state anxiety and trait anxiety. According to Spielberger (1972) [45], state anxiety entails an immediate "emotional state" that can be modified in time, while trait anxiety is considered to be relatively stable. In this sense, hyperactivity of the limbic system has been observed in anxiety disorders that could be a result of: a decrease in the inhibitory neurotransmitters (γ-aminobutyric acid, GABA), an increase in the excitatory neurotransmitters based on the action of glutamate or a combination of both [46].

Regarding our intervention, the association of EGCG and ketone bodies causes a significant improvement in state anxiety. This fact seems to be explained through both their action mechanisms. On the one hand, EGCG increases inhibition mediated through the GABA neurotransmitter, which would generate a similar activity to that caused by some medications, such as benzodiazepines [47–49], also decreasing levels of occasional anxiety and causing an anxiolytic effect, as observed after administering it in MS patients [28]. Completing this EGCG activity and based on mechanisms that trigger state anxiety, the action mechanism that ketone bodies have that improves anxiousness [19,20] is based on the inhibition of the activation of NMDA ionotropic glutamate receptors. These receptors have an essential role, not only on a cognitive level [50], but also regarding the presence of anxiety [51]. On the other hand, anxiety is felt both on a physiological level, as well as on a cognitive and a mental level [52]; therefore, symptoms have a negative effect on the cognitive function of those who suffer from anxiety. Anxiety symptoms are especially associated with a lower cognitive function [53] in MS, showing a similar pattern to that observed in people with other immune-mediated inflammatory diseases (IMID) and in individuals without an IMID [54]. Therefore, anxiety in MS patients is related to functional disability and constitutes an indicator of the level of this disability [15]. Our results are in line with this idea, as the patients from the intervention group whose levels of anxiety decrease also show a significant improvement in functional capacity. Nonetheless, we must remember that regarding the two types of anxiety, it is state anxiety that significantly improved, therefore it seems that functionality is more directly related to this kind of anxiety and not trait anxiety. These findings would be supported by the results obtained by other authors, who observed how state anxiety (consisting of a temporary emotional state or condition of the human organism that can vary over time and whose intensity can vary), yet not trait anxiety, predicts the performance in the executive function index. Thus, we can conclude that improving state anxiety improves patients' functionality [44].

However, these results need to be confirmed as this study is somewhat limited. These limitations include a small sample and the lack of intervention groups to study the single contribution of EGCG and coconut oil to improve different variables. Therefore, future research should involve a larger sample leading to a more complex statistical analysis, as well as studying different groups of patients using EGCG, coconut oil and Mediterranean diet, separately.
