The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy
Introduction
Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a highly debilitating disease of unknown origin that is characterized by severe fatigue for more than 6 months, which does not improve with rest and may be exacerbated by physical or mental activity [1]. In addition, CFS is associated to a wide spectrum of symptoms, including, but not limited to, post-exertional malaise, unrefreshing sleep, memory and concentration problems, lymph node sensitivity, headaches, and joint and muscle pain [1]. Its pathophysiology remains incompletely understood and a variety of abnormalities, including endocrine dysfunction, autonomic nervous system imbalance and altered immunity, among others, have been described in association with CFS [2]. The estimated prevalence of the disease is between 0.1% and 5% [1]. This wide range of prevalence estimates may be in part due to the lack of standardized diagnostic criteria [1]. Currently, in the absence of clinically established diagnostic tests or known biomarkers, CFS is a symptom-based clinical diagnosis, whereby other conditions with similar symptom profiles must be excluded [1], [3]. There are no known curative treatments for patients with CFS at present [4]. The therapy options available for CFS are aimed at symptom relief and improved ambulatory function, and include cognitive behavioral therapy and graded exercise therapy [3]. However, there are serious concerns about the robustness of the claims made about the efficacy of cognitive behavioral therapy and graded exercise therapy [5].
Taken together, the unclear etiology and diagnostic uncertainty of CFS point to the complex and multifactorial nature of the disease. This raises the question of whether CFS is a single disease entity with one definitive cause or represents a variety of conditions each with their own cause but similar symptoms [1]. Moreover, the idiopathic nature of CFS has led to a long-standing debate about whether patients with CFS are suffering from an organic illness, or whether their condition is psychological in nature. Increasing neuroimaging evidence indicates that functional and structural abnormalities exist in the brains of CFS patients. Indeed, previous studies have demonstrated reduced cerebral blood flow and brain volume loss in patients with CFS [6], [7], [8]. This suggests that the central nervous system (CNS) may play a critical role in the pathogenesis of CFS, and that at least some patients may have their illness on a neurological basis. In the absence of a clear understanding of the underlying pathophysiology of CFS, there is a need to clarify the mechanisms responsible for CNS involvement. An increased understanding could lead to the development of promising novel diagnostic and therapeutic strategies for this devastating disorder. In the present paper, we speculate that glymphatic dysfunction may be responsible for at least some cases of CFS, and that cerebrospinal fluid (CSF) diversion may be beneficial to this subgroup of patients by favoring waste clearance and restoring glymphatic flow.
Section snippets
The glymphatic system
Recent research has led to the discovery of the ‘glymphatic system’, a brain-wide network of perivascular channels along which a large proportion of subarachnoid CSF recirculates through the brain parenchyma, facilitating the clearance of interstitial solutes, including amyloid-β (Aβ), from the brain, and which is connected to the peripheral lymphatic system [9]. CSF enters the brain along periarterial channels to exchange with interstitial fluid (ISF), which is in turn cleared from the brain
Conclusions
The underlying pathophysiology of CFS remains unclear and there are no curative treatments for this disorder at present. However, neuroimaging studies of patients with CFS have revealed alterations in brain structure and function, suggesting that the CNS is involved in this disorder and that at least some CFS patients may have an underlying neurological basis for their illness. In the present paper, we speculate that glymphatic dysfunction, causing toxic build up within the CNS, may be
Financial support
No funding to declare.
Authors’ contributions
Dr. Peter Wostyn developed the theoretical part of the hypothesis and drafted and wrote the manuscript. Prof. Dr. Peter Paul De Deyn commented and revised the intellectual content of the manuscript. All authors have read and approved the final version of the manuscript.
Conflict of interest statement
Dr. Peter Wostyn is the inventor of pending patent applications pertaining to chronic fatigue syndrome treatment using cerebrospinal fluid diversion procedures, and to Alzheimer’s disease treatment using a cerebrospinal fluid pump system. Prof. Dr. Peter Paul De Deyn declares no conflicts of interest.
Acknowledgements
Not applicable.
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