The putative glymphatic signature of chronic fatigue syndrome: A new view on the disease pathogenesis and therapy

Abstract

The underlying pathophysiology of chronic fatigue syndrome remains incompletely understood and there are no curative treatments for this disorder at present. However, increasing neuroimaging evidence indicates that functional and structural abnormalities exist in the brains of chronic fatigue syndrome patients, suggesting that the central nervous system is involved in this disorder and that at least some chronic fatigue syndrome 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 central nervous system, may be responsible for at least some cases of chronic fatigue syndrome. We further postulate that cerebrospinal fluid diversion such as lumboperitoneal shunting may be beneficial to this subgroup of patients by restoring glymphatic transport and waste removal from the brain. Although recent evidence indicates that at least some chronic fatigue syndrome patients may benefit from cerebrospinal fluid drainage, further studies are needed to confirm this finding and to determine whether this can be attributed to enhancement of glymphatic fluid flow and interstitial fluid clearance. If confirmed, this could offer promising avenues for the future treatment of chronic fatigue syndrome. Clearly, given the relative invasive nature of cerebrospinal fluid diversion, such procedures should be reserved for chronic fatigue syndrome patients who are severely debilitated, or for those with severe headaches. Anyhow, it seems worthwhile to make every effort to identify new therapies for patients who suffer from this devastating disease, especially given that there are currently no effective treatments for this condition.

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.