Calorie Restriction is Safe in Multiple Sclerosis, With Positive Impacts on Cognition and Fatigue

Laura Piccio, MD, PhD

A recently published study showed that intermittent calorie restriction (CR) was safe and feasible in patients with multiple sclerosis, and led to decreased serum leptin, a proinflammatory adipokine with a potential pathogenic role in MS. Above all, the study provided mechanistic insights on CR beneficial effects in MS and supported the potential role of diet as an add-on lifestyle intervention to synergize with current disease-modifying therapies in controlling disease activity.

Led by Laura Piccio, MD, PhD, a neurologist and physician scientist at Washington University in St. Louis, the study was published in Neurology, Neurosurgery, & Psychiatry months after it was originally presented at the 2023 Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum. Overall, 42 patients with MS were randomized to either CR or control, and 34 (80.9%) completed the 12-week study. Coming into the study, patients had Expanded Disability Status Scale (EDSS) scores of less than 6, were neurologically stable for 3 months prior to baseline visit, and had a body mass index between 23 and 35 kg/m², although this eligibility widened to 22-38 kg/m² during the study.

The trial used reduction in serum leptin levels, which have been thought to play a role in the pathophysiology and progression of MS, as the primary end point. After 12 weeks, those in the iCR group showed significantly lower leptin levels, with mean decreases of –6.98 ug/dL (95% CI, –28.02 to 14.07; P = .03). Although there was no significant difference in HMW adiponectin levels between the 2 groups, investigators observed nominally increased levels in the iCR group at the 6- (−537 ng/mL; 95% CI, −1043 to –31), and 12-week (−610 ng/mL; 95% CI, −1116 to –104) time points. Notably, there were no changes in cortisol, interleukin-6, CRP, and plasma neurofilament light between the 2 groups and within group over time.

At 12 weeks, investigators observed a nonsignificant, but higher SDMT scores in the iCR group vs controls (mean, 66 [95% CI, 62-71] vs controls: 62 [95% CI, 57-66]). At that time, the iCR group showed a significant increase in SDMT compared with baseline (–6.2; 95%, –3.4 to –9.5; P <.001) whereas there was no significant change in the control group.

In terms of fatigue, there was nominal decreases in MFIS scores in the iCR group in both the cognitive (mean, 2.5; 95% CI, 0.3-4.7) and psychosocial (2.8; 95% CI, 0.8-4.8) scales. For comparison, there were no differences observed in the control group. The iCR group showed a significant improvement in the mental subscale of the MSIS Score from baseline to week 12 (mean change of 7.36, p=0.0002) and a nominal decrease in the physical subscale from baseline to week 6 (mean change of 2.7). No changes were observed in the control group. There were no clinically meaningful differences between the iCR and control groups in the EDSS, 9HPT, PASAT, or T25W scores at 12 weeks.

In the study, five participants from the iCR group and three from the control group withdrew, resulting in dropout rates of 22.7% and 15%, respectively, with no significant difference between groups. Adherence to the fasting regimen was high, at 99.5% for the first 6 weeks and 97.2% for the second 6 weeks.

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The iCR group achieved an average calorie restriction of 21.5% and 23.1% at weeks 6 and 12, respectively. No severe adverse events were reported, though 13.6% of iCR participants experienced mild symptoms such as headaches and fatigue. One control participant developed optic neuritis, treated with corticosteroids. Routine tests showed no clinically significant abnormalities linked to the intervention.

After 6 and 12 weeks of intermittent calorie restriction (iCR), HDL levels increased significantly in the iCR group compared to baseline, with a 5.91 mg/dL increase at 6 weeks (p<0.0001) and a smaller 2.32 mg/dL increase at 12 weeks, although the latter did not reach statistical significance. Other lipid levels (triglycerides, total cholesterol, LDL) showed no significant changes between or within the groups. A nominal reduction in triglycerides was observed at 6 weeks in the iCR group.

In the study, no significant differences in glucose metabolism were found. In immune cell analysis, iCR resulted in nominal changes in T-cell subsets, including a higher number of naïve CD4+ T cells and a decrease in effector memory CD4+ T cells at 12 weeks, compared to controls. Th1 cells were lower in the iCR group at 6 weeks, and CD45RO+ Tregs showed a nominal increase at 6 weeks, though no differences were seen between the groups at 12 weeks.

During ACTRIMS 2023, Piccio caught up with NeurologyLive to discuss the promise behind these data, as well as the feasibility of implementing iCR in patients with MS. At the Forum, she provided context on how this research speaks to where the field is currently, the need for more long-term studies, and the continued commitment to research efforts on dieting and lifestyle factors.

REFERENCES
1. Ghezzi L, Tosti V, Shi L, et al. Randomized controlled trial of intermittent calorie restriction in people with multiple sclerosis. Neurol, Neurosurg, & Psych. Published online August 13, 2024. doi:10.1136/jnpp-2024-333465.