A recent consensus review on Chronic Fatigue Syndrome (CFS) and Myalgic Encephalomyelitis (ME)1 concluded that CFS/ME is significantly underdiagnosed and that the condition is likely caused, in part, by viruses. These findings are in line with my clinical work. Together, these two sources of data point to a pathway which may help the 2.5 million sufferers of this disease in the United States.
In February, the Institute of Medicine (IOM) completed its committee review on CFS/ME. This study was sponsored by the Department of Health and Human Services, the National Institutes of Health, and the Centers for Disease Control, among others.1
A comprehensive literature review and critique was completed by the Agency for Healthcare Research and Quality in December as part of this process.2 Many important advancements in the medical conceptualization of CFS/ME are included in this 282 page document.
Perhaps the most important evolutionary step was the clear message delivered on page 15 of the introduction: CFS/ME is underdiagnosed and misunderstood. More than 80% of patients go undiagnosed, while 65% of patients spend more than a year seeking the correct diagnosis. A lack of understanding of this disorder has contributed to many patients feeling maligned, blamed, and undertreated.
Some patients told the committee that they felt belittled, dismissed, and ignored by their health care professionals. Patients also have reported that some treatment strategies, including the oft-cited graded exercise regimen, exacerbated their symptoms.3
Equally striking in this report was the clear assertion that CFS/ME likely has an infectious etiology and that viruses, in particular Epstein-Barr virus (EBV), are high on the list of suspected agents.1
My clinical work has focused on the viral and immunological pathogenesis of CFS/ME. In my clinic, I have treated over 200 adults and over 30 adolescents with what the IOM now says should be called Systemic Exertion Intolerance Disease (SEID). While I have not published my adult cases, a case series of adolescents was published last year.4 What has emerged from my work is that over 85% of patients with SEID (diagnosed by Fukuda criteria5) respond to antiviral therapy. Among adolescents, the outcome is better with 92% responding.
A critical second conclusion of my work is that a subset of patients diagnosed with depression — particularly treatment-resistant depression — actually had SEID. The adolescents in the case series were all referred for evaluation of depression or mood disorder. They all presented with marked fatigue, exertion induced malaise, brain fog, and impaired academic performance.
In addition, most reported daily naps and unrefreshing sleep.4 They had not responded to adequate trials of antidepressants and the duration of symptoms ranged from 6-96 months. There was no history of abuse or neglect, although this has been suggested as an etiology of SEID in the past.6,7 Patients completed the Children's Depression Inventory8 and the mean score was 14 (+2.83), below the typical cut-off for depression.
Patients were treated with the antiviral, valacyclovir (Valtrex), at a dose of 1000 mg twice a day. Only one patient experienced nausea and discontinued the antiviral. Improvement occurred over the course of 3-5 months. Eighty-six percent of the patients responded by 3 months, and 92% responded by 5 months. Symptoms of fatigue, exertion induced malaise, excessive sleep, napping, unrefreshing sleep, headaches, cognitive symptoms, and emotional symptoms all resolved.
Fatigue was specifically measured with the Fatigue Severity Scale,9 the Fatigue Symptom Inventory,10and the Multidimensional Fatigue Symptom Inventory-Short Version (MFSI),11 which also allows assessment of cognitive symptoms, emotional symptoms, pain, and vigor. The general score on the MFSI dropped from 23.31 (+1.11) to 1.1 (+1.37) and the vigor score rose from 4.54 (+2.40) to 16.50 (+3.37). All changes were statistically significant.4 All of the responders had improved school performance, and five of seven who had previously dropped out of school had re-enrolled.
These data stand in stark contrast to the trials of cognitive-behavioral therapy (CBT) or graded exercise therapy (GET) wherein a response rate of about 60% is reported and response is defined as an approximate 10% improvement in fatigue scores.2,3,12 Moreover, the PACE trial, the largest study of CBT/GET,12 was an unblinded study whose data has garnered criticism for its biasing of the score threshold.
While these data are from a subset of 15 adolescent patients, it accurately reflects the experience with a much larger subset of clinic patients. Patients who present with depression include a subset who instead have SEID. This is particularly true for patients with treatment-resistant depression as seen in our ketamine infusion therapy clinic (www.ketamineinfusioncenters.com).
As discussed in the National Academy of Science report, these patients can be differentiated by symptoms of fatigue, post-exertional malaise, frequent naps, unrefreshing sleep, headache, lightheadedness, and cognitive dysfunction.
The MFSI and Fatigue Severity Scale are also useful tools, as well as the DePaul Symptom Questionnaire.1 Laboratory data which I consistently find to be abnormal include: Decreased NK cell numbers, decreased NK cell function, elevated EBV antibody titers, elevated HHV6 antibody titers, and, to a lesser extent, elevated cytomegalovirus antibody titers. Some patients have obtained perfusion Single Photon Emission Computed Tomography (SPECT) scans which show diffuse hypoperfusion consistent with findings in the literature.13,14
Response to valacyclovir is slow, as often an interval of 3 months or more is necessary. Duration of treatment is variable, ranging from 8 months to years. Cessation of antiviral treatment can sometimes precipitate a relapse of symptoms.
These data are also consistent with prior studies of antiviral treatment of SEID. Lerner and colleagues found significant and persistent improvement in symptoms and in cardiovascular function in SEID patients who were treated with the valacyclovir.15,16 Montoya and colleagues reported a 75% response rate to another antiviral, valganciclovir, in SEID patients with high IgG titers to EBV and HHV-6.17Antiviral therapy may be a powerful tool in the fight against SEID.
Theodore Henderson, MD., PhD, is a psychiatrist in Denver, Colo., who specializes in the diagnosis of complex adult, child, and adolescent psychiatric cases. His website iswww.childpsychiatristdenver.com.
Smith MEB, et al. Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Evidence Report/Technology Assessment No. 219. Rockville, MD: Agency for Healthcare Research and Quality. December 2014.
Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. www.iom.edu/Reports/2015/ME-CFS.aspx. Accessed February 21, 2015.
Twisk FN and Maes M. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS). Neuro Endocrinol Lett. 2009; 30(3):284-99.
Henderson TA. Valacyclovir treatment of chronic fatigue in adolescents. Adv Mind Body Med. 2014; 28(1):4-14.
Fukuda K, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study: International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953-959.
Rangel L, et al. Family health and characteristics in chronic fatigue syndrome, juvenile rheumatoid arthritis, and emotional disorders of childhood. J Am Acad Child Adolesc Psychiatry. 2005; 44(2):150-158.
Heim C, et al. Arch Gen Psychiatry. 2006; 63(11):1258-1266.
Smucker MR, et al. Normative and reliability data for the Children's Depression Inventory. J Abnorm Child Psychol. 1986;14(1):25-39.
Jason LA, et al. Fatigue scales and chronic fatigue syndrome: issues of sensitivity and specificity.Disabil Stud Q. 2011; 31(1):pii1375.
Hann DM, et al. Measurement of fatigue in cancer patients: development and validation of the Fatigue Symptom Inventory. Qual Life Res. 1998; 7(4):301-310.
Stein KD, et al. Further validation of the multidimensional fatigue symptom inventory-short form. J Pain Symptom Manage. 2004; 27(1):14-23.
White PD, et al. PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377(9768):823-36.
MacHale SM, et al. Cerebral perfusion in chronic fatigue syndrome and depression. Br J Psychiatry. 2000; 176:550-556.
Schmaling KB, et al. Single-photon emission computerized tomography and neurocognitive function in patients with chronic fatigue syndrome. Psychosom Med. 2003; 65(1):129-136.
Lerner AM, et al. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today (Barc). 2002; 38(8):549-561.
Lerner AM, et al. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007; 21(5):707-713.
Kogelnik AM, et al. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol. 2006; 37(suppl 1):S33-S38.