Anthony L. Komaroff, MD
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
When does an illness become a disease? When the underlying biological abnormalities that cause the symptoms and signs of the illness are clarified.
The illness now called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was first describedin the mid-1980s. At that time, nothing was known about its underlying biology. Indeed, because many standard laboratory test results were normal, some clinicians ex-plained to patients that “there is nothing wrong.”
There was, of course, an alternative explanation: the standard laboratory tests might not have been the right tests to identify the underlying abnormalities. Over the past 35 years, thousands of studies from laboratories in many countries have documented un-derlying biological abnormalities involving many organ systems in patients with ME/CFS, compared with healthy controls: in short, there is something wrong.
Moreover, most of the abnormalities are not detected by standard laboratory tests. In 2015, the Institute of Medicine of the National Academy of Sciences concluded that ME/CFS “is a serious, chronic, complex systemic disease that often can profoundly affect the lives of patients,” affects up to an estimated 2.5 million people in the United States, and generates direct and indirect expenses of approximately $17 billion to $24 billion annually.1
Over the past several years, the National Institutes of Health (NIH) has expanded its research efforts directed to-ward this disease. It has initiated an unusually comprehensive multisystem study at the NIH Clinical Center, funded 3 extramural ME/CFS research centers and 1 data coordinating center, awarded supplemental support to 7 existing grants, and held regular telebriefings on the illness (as has the Centers for Disease Control and Prevention).2
A 2-day conference at the NIH in April 2019 high-lighted recent progress. New research was presented that both reinforced and expanded on previous reports.Equally important, several plausible models were pro-posed that could explain many of the abnormalities thathave been described.
The Central and Autonomic Nervous System
Since the early 1990s, multiple studies have compared patients with ME/CFS with healthy age- and sex-matched controls and found abnormalities of the central and autonomic nervous system.3
•Neuroendocrine abnormalities were among the first evidence reported and involve impairment of several limbic-hypothalamic-pituitary axes (involving cortisol, prolactin, and growth hormone end products). Ageneral downregulation of the hypothalamic-pituitary-adrenal axis is seen in patients with ME/CFS, in contrast to the upregulation of the hypothalamic-pituitary-adrenal axis seen in major depression
Impaired cognition has been found by many investigators, including slowed information processing speed and impaired memory and attention that are not explained by concomitant psychiatric disorders.
•Magnetic resonance imaging has revealed increased numbers of punctate areas of high signal in white matter. Functional magnetic resonance imaging has demonstrated different responses to auditory and visual challenges and to tests of working memory, as well as altered connectivity between different brain regions.
•Positron emission tomography and magnetic resonance spectroscopy recently have demonstrated that patients with ME/CFS have a widespread state of neuroinflammation (particularly activation of microglialcells) as well as increased ratios of choline-creatinine and increased levels of lactate that correlate with levels of fatigue.4 Spinal fluid contains increased levels of proteins involved in tissue injury and repair.
•Autonomic nervous system abnormalities have been repeatedly demonstrated in ME/CFS, particularly altered systemic and cerebral hemodynamics that correlate with symptoms.5 At the NIH conference, it was reported that with prolonged upright posture, abnormal increases in heart rate and decreases in blood pressure are common; even when heart rate and blood pressure responses are normal, substantial cerebralblood flow reductions are noted.