Drinking away fatigue in multiple sclerosis

The symptom of fatigue occurs in a majority of patients with multiple sclerosis (MS) and is the most disabling symptom for many. Fatigue is a major factor influencing employment status in individuals with MS ¹ and can be an enormous burden to the individuals themselves and those close to them. Even though there is a large body of literature on MS fatigue, the etiology is not straightforward; it is likely multifactorial with certain factors predominating in individual patients. ² Investigators have separated potential causes into primary or disease-related factors and secondary factors, which include comorbidities and treatments. However, the differentiation between the primary and secondary factors may be difficult. It is also important to differentiate between predictors that are and are not potentially amenable to treatment in an individual patient. Potentially modifiable factors account for a large proportion of MS fatigue. ²

It is apparent that the disease process itself is important in the genesis of the symptom. Both immune-related processes and neurodegeneration may contribute to fatigue. Whole blood stimulation studies have provided some evidence for the importance of cytokines in MS fatigue. Moreover, with the introduction of more effective immunomodulatory treatments in recent years, there are data indicating that fatigue can stabilize or improve, providing further support for a neuro-inflammatory etiology for MS fatigue. Magnetic resonance imaging studies have found that there is no simple association between white and gray matter lesion load and fatigue. Rather, lesions in certain regions of the brain, such as the frontal and parietotemporal lobes, as well as thalamus and basal ganglia have been linked with fatigue. ³ Diffuse axonal dysfunction in the brain, assessed with magnetic resonance spectroscopy, is associated with MS fatigue. ⁴ MS disability is a potential disease-related predictor of fatigue and has been related to fatigue in some, but not all studies.^2,5–8 A Cochrane review concluded that multi-disciplinary rehabilitation in MS can improve disability (activity impairment) in the short term, but there was limited evidence that out-patient rehabilitation can improve fatigue. ⁹

In addition to the disease process itself, investigators have identified many potential secondary causative or contributing factors to MS fatigue. These include sleep abnormalities, psychological factors (such as depression, stress, and reduced self-efficacy), pain, and deconditioning. We have studied sleep disorders in MS. A majority of our MS patients evaluated with in-laboratory overnight polysomnography had obstructive sleep apnea–hypopnea. The presence of this disorder was strongly linked to fatigue, ¹⁰ and treatment of sleep abnormalities (primarily obstructive sleep apnea–hypopnea) ameliorated fatigue in a controlled, non-randomized study. ¹¹ Another important factor to identify in MS patients is depression, especially since its treatment improves fatigue. ¹² Stress and self-efficacy (the belief that one can effectively manage a challenging situation) are associated with fatigue and are potentially amenable to treatment. Pain occurs in many MS patients and is a potentially treatable factor associated with fatigue.^2,13 Since deconditioning is linked to fatigue, exercise may be useful in improving this symptom. A review of the effect of exercise therapy on fatigue in MS ¹⁴ concluded that exercise has the potential to reduce fatigue, but findings to date have been conflicting, likely because many studies included non-fatigued study populations, and fatigue was not the primary outcome.

In this issue of Multiple Sclerosis Journal, Cincotta et al., ¹⁵ using data from 50 women with MS, report that high hydration status (assessed with urine specific gravity (SG)) was associated with lower fatigue scores. In addition, low hydration status was more common in MS subjects with impaired bladder control. Normally, the body’s solutes and water are distributed in plasma, as well as the extracellular and intracellular compartments, and water can be added to or lost from all compartments (“total body water”). The key questions to consider—is fatigue related to regulatory changes in total body water and are low or high urine SG measurements informative about total body water when an individual is in a steady state? As Cincotta et al. ¹⁵ point out, to manage bladder issues, individuals with MS tend to limit their fluid intake. This will typically reduce urine volume and increase SG secondary to the stimulation of vasopressin, but it is unlikely that modest water restriction would reduce total body water in a steady state. ¹⁶ The individuals with low hydration in the study were not dehydrated. ¹⁵ Conversely, drinking a large amount of water chronically would suppress vasopressin, increase urine volume, and decrease SG, but not expand total body water appreciably. ¹⁶ Therefore, the study appears to be indirectly examining the association of fatigue with the amount of water intake or perhaps levels of vasopressin. One should also consider that water intake is influenced by salt (sodium) intake. Sodium is the major determinant of extracellular and plasma volume, and variation in plasma volume may be linked to vasopressin and urinary concentration. Urine SG would not distinguish among individuals with low versus high salt intake. Thus, accuracy and interpretation of hydration indexes are exceedingly complex. ¹⁷ A limitation of the Cincotta et al.’s ¹⁵ study is that the conclusions rely on a single colorimetric measure of urine SG in each patient. Urine SG is likely to vary from day to day based on water and salt intake, physical activity, time of day, and ambient temperature. Ideally, a mean urine SG value of several samples should be determined for each individual and be supplemented with measurements of urine osmolality, as well as 24-hour urine volume and sodium excretion. To the credit of the authors, plasma sodium and osmolality were analyzed and appeared normal, excluding potential defects in thirst mechanisms.

In order to use urine SG as a valid index of hydration, it is essential that the study individuals have normal urinary concentrating ability. Cincotta et al. ¹⁵ excluded patients with kidney disease based on estimated glomerular filtration rate (eGFR). A defect in urinary concentrating ability—a feature of early kidney disease—may be present even with a normal eGFR. Many patients in this study had significant urinary frequency and nocturia, likely indicating bladder dysfunction, which may lead to impairment in urine concentration. In the high hydration group, the mean urine SG was 1.010, suggesting urine isotonicity. Does this reflect a primary high water intake or impaired urine concentrating ability with compensatory high water intake driven by thirst? It would be ideal to show that in the context of water depletion, subjects with low urine SG can actually concentrate their urines.

A number of studies have considered the effects of fluid intake on various health outcomes, without reaching solid conclusions, and illustrating difficulties in methodologies and design of such studies.^17,18 There may be much to learn about hydration and water consumption. The study by Cincotta et al. ¹⁵ is an important attempt to improve our understanding of MS-related fatigue, a highly prevalent symptom in MS with negative impact on quality of life. Linking fatigue to hydration in MS represents a novel concept, which has not been addressed in earlier studies. Nevertheless, given the limitations in mechanistic insights and design, the study should be viewed as preliminary, pending confirmation by more rigorous methodologies in the future.