Friday, April 17, 2015

Can light therapy help heal the brain?



When NIH doesn't fund research for your illness, what do you do? You look at results from studies on other diseases that have an overlap in symptoms. One such illness is Gulf War Illness, which shares so many symptoms with ME/CFS that Nancy Klimas has said it is clinically "identical."

The body has a limited number of ways it can respond to injury. It can produce inflammation, thereby isolating the injury. It can raise or lower pH and temperature to help eradicate a pathogen. But it cannot morph into another form, grow another limb, or start all over again. There are organisms that can do all these things, but we can't. We can, however, repair the injured part.

When the brain is injured, whether due to a toxin, inflammation, or hypoxia, it has the capacity for self-repair. It doesn't really matter to the brain how it was injured, because the self-repair mechanisms are the same. In the case of GWI vets, brain injury was generated by a toxin, but the resulting neurological symptoms and cognitive impairment are similar enough to ME/CFS to warrant a look at how the injury in GWI vets is being treated. In the procedure being investigated by Dr. Margaret Naeser, the mitochondria of the brain are stimulated by LED light to increase their function.

Given the known mitochondrial defects in patients with ME/CFS, coupled with hypoxic conditions in the CNS, a treatment that could stimulate repair of brain tissues would be of enormous benefit.

A follow-up study sponsored by the VA is currently recruiting.

Photo: A staffer in Dr. Margaret Naeser's lab demonstrates the equipment built especially for the research: an LED helmet (Photomedex), intranasal diodes (Vielight), and LED cluster heads placed on the ears (MedX Health). The real and sham devices look identical. Goggles are worn to block out the red light. The  near-infrared light is beyond the visible spectrum and cannot be seen. Credit: Naeser lab
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Can light therapy help the brain?

An innovative therapy that applies red and near-infrared light to the brain is being tested for GWI, traumatic brain injury, and PTSD.

Press Release: Veterans Affairs Research Communications, April 2, 2015. Following up on promising results from pilot work, researchers at the VA Boston Healthcare System are testing the effects of light therapy on brain function in veterans with Gulf War Illness.

Veterans in the study wear a helmet lined with light-emitting diodes that apply red and near-infrared light to the scalp. They also have diodes placed in their nostrils, to deliver photons to the deeper parts of the brain.

The light is painless and generates no heat. A treatment takes about 30 minutes.

The therapy, though still considered "investigational" and not covered by most health insurance plans, is already used by some alternative medicine practitioners to treat wounds and pain. The light from the diodes has been shown to boost the output of nitric oxide near where the LEDs are placed, which improves blood flow in that location.

"We are applying a technology that's been around for a while," says lead investigator Dr. Margaret Naeser, "but it's always been used on the body, for wound healing and to treat muscle aches and pains, and joint problems. We're starting to use it on the brain."

Naeser is a research linguist and speech pathologist for the Boston VA, and a research professor of neurology at Boston University School of Medicine (BUSM). She is also a licensed acupuncturist and has conducted past research on laser acupuncture to treat paralysis in stroke, and pain in carpal tunnel syndrome.

The LED therapy increases blood flow in the brain, as shown on MRI scans. It also appears to have an effect on damaged brain cells, specifically on their mitochondria. These are bean-shaped subunits within the cell that put out energy in the form of a chemical known as ATP. The red and near-infrared light photons penetrate through the skull and into brain cells and spur the mitochondria to produce more ATP. That can mean clearer, sharper thinking, says Naeser.

Naeser says brain damage caused by explosions, or exposure to pesticides or other neurotoxins--such as in the Gulf War--could impair the mitochondria in cells. She believes light therapy can be a valuable adjunct to standard cognitive rehabilitation, which typically involves "exercising" the brain in various ways to take advantage of brain plasticity and forge new neural networks.

"The light-emitting diodes add something beyond what's currently available with cognitive rehabilitation therapy," says Naeser. "That's a very important therapy, but patients can go only so far with it. And in fact, most of the traumatic brain injury and PTSD cases that we've helped so far with LEDs on the head have been through cognitive rehabilitation therapy. These people still showed additional progress after the LED treatments. It's likely a combination of both methods would produce the best results."

The LED approach has its skeptics, but Naeser's group has already published some encouraging results in the peer-reviewed scientific literature.

Last June in the Journal of Neurotrauma, they reported the outcomes of LED therapy in 11 patients with chronic TBI, ranging in age from 26 to 62. Most of the injuries occurred in car accidents or on the athletic field. One was a battlefield injury, from an improvised explosive device (IED).

Neuropsychological testing before the therapy and at several points thereafter showed gains in areas such as executive function, verbal learning, and memory. The study volunteers also reported better sleep and fewer PTSD symptoms.

The study authors concluded that the pilot results warranted a randomized, placebo-controlled trial--the gold standard in medical research.

That's happening now, thanks to VA support. One trial, already underway, aims to enroll 160 Gulf War veterans. Half the veterans will get the real LED therapy for 15 sessions, while the others will get a mock version, using sham lights.

Then the groups will switch, so all the volunteers will end up getting the real therapy, although they won't know at which point they received it. After each veteran's last real or sham treatment, he or she will undergo tests of brain function.

Naeser points out that "because this is a blinded, controlled study, neither the participant nor the assistant applying the LED helmet and the intranasal diodes is aware whether the LEDs are real or sham. So they both wear goggles that block out the red LED light." The near-infrared light is invisible to begin with.

Besides the Gulf War study, other trials of the LED therapy are getting underway:
  • Later this year, a trial will launch for veterans age 18 to 55 who have both traumatic brain injury (TBI) and posttraumatic stress disorder--a common combination in recent war veterans. The VA-funded study will be led by Naeser's colleague Dr. Jeffrey Knight, a psychologist with VA's National Center for PTSD and an assistant professor of psychiatry at BUSM.
  • Dr. Yelena Bogdanova, a clinical psychologist with VA and assistant professor of psychiatry at BUSM, will lead a VA-funded trial looking at the impact of LED therapy on sleep and cognition in veterans with blast TBI.
  • Naeser is collaborating on an Army study testing LED therapy, delivered via the helmets and the nose diodes, for active-duty soldiers with blast TBI. The study, funded by the Army's Advanced Medical Technology Initiative, will also test the feasibility and effectiveness of using only the nasal LED devices--and not the helmets--as an at-home, self-administered treatment. The study leader is Dr. Carole Palumbo, an investigator with VA and the Army Research Institute of Environmental Medicine, and an associate professor of neurology at BUSM.

Naeser hopes the work will validate LED therapy as a viable treatment for veterans and others with brain difficulties. She foresees potential not only for war injuries but for conditions such as depression, stroke, dementia, and even autism.

"There are going to be many applications, I think. We're just in the beginning stages right now."

Journal Reference: Margaret A. Naeser, Ross Zafonte, Maxine H. Krengel, Paula I. Martin, Judith Frazier, Michael R. Hamblin, Jeffrey A. Knight, William P. Meehan, Errol H. Baker.Significant Improvements in Cognitive Performance Post-Transcranial, Red/Near-Infrared Light-Emitting Diode Treatments in Chronic, Mild Traumatic Brain Injury: Open-Protocol Study. Journal of Neurotrauma, 2014; 31 (11): 1008 DOI: 10.1089/neu.2013.3244

Wednesday, April 15, 2015

Dr. Martin Lerner's Treatment Protocol for ME/CFS

Dr. Martin Lerner has been a long-time proponent of antiviral therapies for treating ME/CFS. His background as an infectious disease specialist naturally led him to explore antimicrobials because he believes that microbial infections lie at the heart of ME/CFS symptomatology. He has authored numerous papers on antiviral treatments for ME/CFS, and has treated patients for decades.

Below is his guide to treating patients with ME/CFS using antimicrobial agents. He also includes the roster of tests he uses for diagnosis, and a section on patient care.

Dr. Lerner makes the disclaimer that his guide has not been peer-reviewed, but that does not make it any less valid. The guide is a summary of decades of clinical experience and, as such, stands on its own.

You can read the original document here:

http://www.treatmentcenterforcfs.com/documents/MECFSTreatmentResourceGuideforPractitioners.pdf

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DISCLAIMER: The information contained in this document is meant for informational purposes only. The management of ME/CFS in any given patient must be approached on an individual basis using an Infectious Diseases’ specialist’s best judgment. This document is a culmination of over 20 years of ME/CFS practice and peer reviewed articles. This document is not a peer reviewed publication.

ME/CFS Treatment Resource Guide for Practitioners

By A. Martin Lerner, M.D., M.A.C.P.

Beaumont Health System Treatment Center for Chronic Fatigue Syndrome


Diagnostic Methodology

Initial patient visit:

Complete history, physical examination, chest X-ray, electrocardiogram, complete blood count, urinalysis, serum aspartate and aminotransferases (AST, ALT), glucose, thyroid stimulating hormone, sodium, potassium, uric acid, alkaline phosphatase and creatinine measurements performed.

ME/CFS analysis:

Energy Index Point Score® assessing physical functional capacity in activities of daily life documenting limitations. The EIPS® system defines the severity of patient fatigue, 0-10, through measurement of real-life situations including one’s ability to sit, stand, be out of bed, work, perform housework, socialize, exercise. The EIPS® level is determined through discussion between the physician and patient. A change in EIPS® level of one is a significant change in health and lifestyle for the patient, as ME/CFS symptoms decrease when the EIPS® increases.

Cardiac testing:

–24-hour Holter monitor - symptoms recorded (syncope, chest pain, palpitations, muscle aches)
–Standard 12-lead resting electrocardiogram – if original ECG abnormal
–Rest/stress myocardial perfusion study – if original ECG abnormal
–Multigated (radionuclide) MUGA rest/stress ventriculographic examination – if original ECG abnormal
–Monitor Blood Pressure (laying, sitting, standing)
–Monitor Heart Rate (laying, sitting, standing)


Viral testing for EBV, HCMV, HHV6:

–EBV serum IgM viral capsid antibodies (VCA) - Diasorin, Inc., Stillwater, MN
–EBV early antigen diffuse (EA) - Diasorin, Inc., Stillwater, MN
–ELISA HCMV(V) IgG and IgM serum antibodies to viral capsid, strain 169 HCMV - Diasorin, Inc., Stillwater, MN
–HHV6 IgM and IgG serum - Lab Corp, Dublin, OH

Co-infection testing:

–Western blot and ELISA to Borrelia burgdorferi (IgM and IgG) - Lab Corp, Dublin, OH
–IgM and IgG of Babesia microti - Lab Corp, Dublin, OH
–IgM and IgG of Anaplasma phagocytophila - Lab Corp, Dublin, OH
–IgM and IgG of Mycoplasma pneumoniae - Lab Corp, Dublin, OH
–Anti-streptolysin O (ASO) titer ≥400 units - Lab Corp, Dublin, OH

Note Lyme and Lyme co-infections can be elusive. Lyme disease can present clinically as ME/CFS. A significant portion of Lyme disease cases have negative Lyme serologic tests. We prefer Lab Corp for Lyme testing and use all 4 tests. The antigens used are those used by the CDC. An appropriate rural exposure, a tick bite, a bull’s eye rash, can all add to the likelihood of Lyme disease. Due to the need for both clinical and diagnostic evaluation in Lyme disease, it is recommended to consider an Equivocal (not negative or positive) lab result, as positive and begin Lyme treatment.

Follow-up:

–Every 4-6 weeks - Complete blood counts, sodium, potassium, AST, ALT, alkaline phosphatase, creatinine and urinalysis.

–Every 3 months – Serum assays for EBV VCA IgM, EBV EA, HCMV(V) IgM and IgG, HHV6 IgM and IgG and all co-infections which are positive originally


EIPS® - A Functional Capacity Measurement Tool For Chronic Fatigue Syndrome (CFS) Patients

To Physicians Caring for Patients with CFS

The Energy Index Point Score (EIPS) chart provides the severity of patient fatigue. A change in EIPS level of one is a large significant change. The EIPS level is determined by agreement of physician and patient with the EIPS chart easily available for viewing at out-patient visits. As the EIPS level increases, CFS symptoms lessen and disappear.

How to use the EIPS system in four easy steps:

1) Post the EIPS chart in examining room
2) Ask patient to evaluate their level of activity based upon the prior two weeks
3) Question the patient’s EIPS evaluation
4) Record and track the EIPS level. Report every 6-12 weeks.*



* The EIPS is not assessed if the patient has an intercurrent infection (respiratory, gastroenteral, ...). At the same visit the following 4 symptoms are regularly categorized: 1) chest pain 2) palpitations 3) muscle aches 4) lightheadedness - noting whether absent or present. If present, when (beginning or end of day, how frequent), where, severity, etc. All of these factors are included in the EIPS assessment.


Antiviral Treatment of EBV

General Information

A diagnosis of Epstein-Barr virus(EBV) infection is made with a positive EBV EA antibody diffuse and/or a positive VCA IgM antibody.

Treatment

Valacyclovir (Valtrex) is remarkably effective and safe. The one concern is that valacyclovir is excreted by the glomerulus and secreted by the tubules and can cause acyclovir stones and obstructive uropathy. This will not occur if the patient drinks at least six 8-ounce glasses of water daily. Occasionally diarrhea may be caused by the valacyclovir. If the patient weighs 70 kg, the dosage is 1 gram four times daily, ideally every six hours; however safe to take four hours after the last dosage (it is not necessary to awake in the middle of the night for a dose). It is important that the patient take four doses for treatment. A higher dose of Valtrex may be necessary with patients who weigh more than 175 pounds and this must be done carefully. A patient who weighs more than 175 pounds may require 1.5 grams of Valtrex, valacyclovir four times daily. Please note valacyclovir is now available in generic form. While I have not had experience with all distributors of generic forms yet, I have had patients move to the generic form of valacyclovir by Teva and Mylan with no issue.

Famvir at the same dosage can be substituted and although there is not the strong evidence that we have for valacyclovir, it likely is equally effective. One does not have the worries concerning renal calculi with Famvir and it has also been extraordinarily safe. It does not cause diarrhea.

An initial worsening of symptoms with normal laboratory at a two-week special visit with worsening symptoms is a Jarisch Herxheimer reaction and predicts a good response. Initial benefit is usually not noted for the first six weeks’ of therapy and then occurs thereafter. A minimum period of therapy is one year. Usually benefit is not apparent until after 3.5 months of therapy.

We have not seen thrombocytopenia with Valtrex, valacyclovir. However, an elevated mean corpuscular volume is seen. This is not a toxicity, and does not require one to stop medicines.

Antiviral Treatment of HCMV & HHV6

General Information

A diagnosis of cytomegalovirus(CMV) infection is made with an elevated CMV IgG titer. The IgM titer for CMV is inaccurate and insensitive. The higher the CMV IgG titer, the greater the viral load. Human herpes virus 6 infection is made with an elevated titer at least twice normal. The diagnosis of EBV, CMV, or HHV6 ME/CFS meets the Canadian consensus and Fukuda CFS criteria.

Treatment

The usual treatment for either/both is valganciclovir (Valcyte) one 450-mg capsule daily for three days, followed by two 450-mg capsules in the morning daily. Liver function tests are studied very carefully. If there is any abnormality, one alters the dosage. Given the patient’s ability to safely tolerate two 450-mg capsules, dosing can be increased to two, 450-mg capsules in the morning and a one additional 450-mg capsule twelve hours later. Liver function tests, again, must be studied carefully and frequently.

Both valacyclovir and valganciclovir are absorbed with a 20% increment if there is food in the stomach. The most common side effect of valganciclovir is hepatotoxicity. If this occurs, the drug is stopped, the dosage is decreased, and is again restarted. When monitoring reveals AST and ALT are normal, the monitoring can continue every four to six weeks, but more frequent with hepatotoxicity. The rule is no valganciclovir at all if there is any abnormality in liver function.

The duration of valganciclovir and therapy for CMV and/or HHV6 is aimed at one year to start with no improvement expected for the first four to six months. It is a general rule that the shorter the duration of ME/CFS, and the earlier appropriate therapy is started, the earlier recovery will occur. Recovery is a continuing, gradual process.

We have not seen thrombocytopenia with Valcyte, valganciclovir. An elevated mean corpuscular volume is seen. This is not a toxicity to stop medicines.

Antibiotic Treatment of Co-infections

Background

If the diagnosis of ME/CFS is made by the accepted criteria and there is no coinfection, one begins antiviral therapy promptly. However, if there is coinfection with a diagnosis of Lyme disease, Babesiosis, Ehrlichiosis, Mycoplasma pneumoniae, or adult rheumatic fever, these conditions are addressed first. After these conditions are addressed, ME/CFS is treated with antiviral therapy. Should one or more of these co-infections occur mid- antiviral treatment, do not stop but treat in parallel.

Treatment of Lyme Disease

The protocol for Lyme disease, serologically positive or epidemiologically positive and serologically negative, that I use is a six-week’s course of intravenous therapy. Ceftriaxone is preferred. If there is a history of allergy to penicillins and it is not an immediate allergy, I routinely refer the patient to an allergist for cephalosporin testing. Under ordinary circumstances if this is negative, ceftriaxone is given; depending on the size of the individual 1-1.5 grams intravenously every 12 hours. The patient is seen weekly. They are asked not to travel further than 45 minutes from this office, because a PICC lines has been placed and infection of the PICC line site or side effects to the cephalosporin can occur; particularly biliary dyskinesia or abnormal liver function tests with ceftriaxone. Cefotaxime may be substituted for ceftriaxone in the case of biliary dyskinesia. If there is biliary dyskinesia, Unasyn, or ertapenem may be used. If diagnosis of Lyme occurs after antiviral treatment has commenced, and patient shows liver sensitivities with Valcyte dosing, Unasyn is recommended. Unasyn is given 2 grams IV piggyback every 12 hours. Ertapenem is given 2 grams IV piggyback every 24 hours. The same dosage of cefotaxime (as ceftriaxone) of 1-1.5 grams is used, but the administration of cefotaxime IV is every 8 hours, rather than every 12 hours, for ceftriaxone. Cefotaxime has no hepatotoxicity. Cefotaxime is excreted by the kidneys.

The goal of Lyme therapy, of course, is a well patient, but particularly a negative serology. Oral suppressive therapy is continued for at least three months or until the Lyme serology is negative. Typical medicines used for Lyme suppression after the original six weeks are amoxicillin; in a 70-kg individual 750 mg before every meal and at bedtime. Doxycycline 100-150 mg twice daily after meals and with a full glass of water may be given in the place of amoxicillin for suppression.

Treatment of Mycoplasma Pneumonia

We use LabCorp less than 300 as a normal level. The patient is not considered to have persistent Mycoplasma pneumoniae infection unless the initial titer is 600 or more. Mycoplasma pneumoniae is treated intravenously with doxycycline 150 mg IV piggyback for six weeks followed by oral suppression with doxycycline 100-150 mg twice daily or moxifloxacin 400 mg once daily for three months. The goal of this therapy is a serum level which is less than twice the normal. The duration of time again is six weeks intravenously plus a minimum of three months oral suppression.

Treatment of Adult Rheumatic Fever

The diagnosis of adult rheumatic fever is made with an ASO titer of over 400. Echocardiograms are done in all patients with ME/CFS originally and any changes in the mitral valve, either thickening or mitral valve prolapse are additional supports for the diagnosis of adult rheumatic fever. A patient who meets the criteria for ME/CFS with an ASO titer of 400 or more is considered to have adult rheumatic fever and treated accordingly.

Chest pain, joint pain, rash, life-altering fatigue are all common to ME/CFS and adult rheumatic fever. Patients are diagnosed with adult rheumatic fever with the following criteria:

(1) EIPS <5

(2) Diffuse, multi-joint pain

(3) Antistreptolysin O titer ≥ 400 (critical to diagnosis)

(4) Abnormal 24 hour Holter monitor with tachycardia and oscillating T-wave flattening, with or without T-wave inversions

(5) A thickened mitral valve at echocardiogram.

If there are symptoms of sinus disease, a CT of the sinuses is done to make certain there is no obstructive sinusitis which may need sinus surgery.

Patients are treated with intravenous Unasyn 3grams IV piggyback every 12 hours for 4-6 weeks, followed by 2.4 million units IM (1.2 million units each hip every 30 days) until ASO titer is ≤200.

Patient Management

Patient Visits and Testing

Check-ups with labwork should occur every 6 weeks in-person.

Diet and Exercise

A healthy, well balanced diet is a must. Minimize sugar intake. Minimize caffeine intake. Absolutely no alcohol allowed, as it may be a cardiac toxin for ME/CFS patients.

No physical exertion or exercise until above a 7 Energy Index Point Score. Stretching regularly is recommended. Once the EIPS is 7, modest exercise can and should begin. The ultimate test is - Are you tired the next day after exercise? If you are, then the exercise that you have done is too much. Start out very slow. Just a few minutes, allowing for breaks and recovery time.

Lifestyle

10-12+ hours of sleep per day and daily naps until the EIPS is at least a 6. Avoid germs (think airplanes, libraries, churches). Stretch daily, minimize exertion, seek assistance with housework/chores/errands. Keep feet elevated, promote a network for assistance and ask for help. 

Daily energy envelope management is a must. Do not push until a crash. This is not productive. As much as possible, do not allow yourself to get overly tired. Healing is a slow process.

Publication Resources


•Dworkin, H.J., Lawrie, C., Bohdiewicz, P., and Lerner, A.M.: Abnormal Left Ventricular Myocardial Dynamics in Eleven Patients With TheChronic Fatigue Syndrome. Clinical Nuclear Medicine 19:675-677, 1994

•Lerner, A.M., Zervos, M., Dworkin, H., Chang, C.H., Fitzgerald, J.T., Goldstein, J., Lawrie-Hoppen, C., Franklin, B., Korotkin, S., Brodsky, M., Walsh, D., O’Neill, W.: New Cardiomyopathy: Pilot Study ofIntravenous Ganciclovir in a Subset of the Chronic Fatigue Syndrome. Infectious Diseases in Clinical Practice 6:110-117, 1997

•Lerner, A.M., Zervos, M., Dworkin, M., Chang, C.H., O’Neill, W.: A Unified Theory of the Cause of Chronic Fatigue Syndrome. Infectious Disease in Clinical Practice 6:239-243, 1997

•Lerner, A.M., Goldstein, J., Chang, C., Zervos, M., Fitzgerald, J., Dworkin, H., Lawrie-Hoppen, C., Korotkin, S., Brodsky, M., O’Neill, W.: Cardiac Involvement in Patients with Chronic Fatigue Syndrome asDocumented with Holter and Biopsy Data in Birmingham, Michigan, 1991-1993. Infectious Diseases in Clinical Practice 6:327-333, 1997



•Lerner, A.M., Beqaj, S.H., Deeter, R.G., Dworkin, H.J., Zervos, M., Chang, C.H., Fitzgerald, J.T., Goldstein, J., and ONeil, W. Asix-month trial of valacyclovir in the Epstein-Barr virus subset of chronicfatigue syndrome improvement in left ventricular function. Drugs of Today 38 8:249-561, 2002

•Carruthers BM, Jain AK, DeMeirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles AC, Sherkey JA, van de Sande, MI. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical WorkingCase Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome 11 1:7-115, 2003

•Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT: IgM SerumAntibodies to Epstein-Barr Virus are Uniquely Present in a Subset of Patientswith the Chronic Fatigue Syndrome. In Vivo 18:101-106, 2004

• LernerAM, Dworkin HJ, Sayyed T, Chang CH, Fitzgerald JT, Beqaj S, Deeter RG, Goldstein J, Gottipolu P, O'Neill W: Prevalence of AbnormalCardiac Wall Motion in the Cardiomyopathy Associated with IncompleteMultiplication of Epstein-Barr Virus and/or Cytomegalovirus in Patients withChronic Fatigue Syndrome. In Vivo 18:417-424, 2004


•Lerner, Beqaj, Deeter, Fitzgerald. Valacyclovir treatmentin Epstein-Barr virus subset chronic fatigue syndrome: thirty-six monthsfollow-up. In Vivo 21(5): 707-713, 2007


•Lerner AM, Beqaj SH, Fitzgerald JT, Gill K, Gill C, Edington J: Subset-directed antiviral treatment of 142 herpesvirus patientswith chronic fatigue syndrome. Virus Adaptation and Treatment 2010:2 47-57

•Lerner AM, Beqaj SH, Gill K, Edington J, Fitzgerald JT, Deeter RG: An Update on the management of glandular fever (infectiousmononucleosis) and its sequelae caused by Epstein-Barr virus (HHV-4): new andemerging treatment strategies. Virus Adaptation and Treatment 2010:2 135-145


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Patent Information

•A US patent (CFS LLC and The Ohio State University) is underway to be filed, February 2012, describing serum antibody to molecular markers EBV EA(D), EBV dUTPase and EBV DNA polymerase for diagnoses of EBV subset ME/CFS.

•CFS LLC has a US patent application pending entitled Methods for Diagnosis and Treatment of Chronic Fatigue Syndrome. Inventor Lerner, Albert Martin. Agents Barry, Thomas F. et al: Venable LLP, P.O. Box 3485 Washington, DC 20043-9998 (US). This patent differentiates Group A and Group B CFS.

Further information concerning patents owned by CFS LLC can be found in US Pat Nos 5,872,123; 6,258,818; 6,399,622; 6,537,997 and 6,894,056.

© 1998 - 2008 Dr. A. Martin Lerner CFS Treatment Center ; Last revised: February 2011
EIPS® and Energy Index Point Score ® are trademarks of the Dr. A. Martin Lerner CFS Treatment Center. All rights reserved. This document may be copied for use by physicians and patients, but may not be modified, sold, or distributed promotionally in any form without express written permission.

For more information visit: treatmentcenterforcfs.com

Monday, April 13, 2015

SEID Definition Captures People with Major Depression, Autoimmune Diseases, and Cardiopulmonary Diseases

In the following commentary, Leonard Jason defends the use of self-reporting measures for the diagnosis of ME/CFS. While self-reporting has its merits, it also has drawbacks (e.g. human error). Nevertheless, Jason's comments about the IOM's new definition should be given serious consideration. 

Jason is correct in pointing out that the new IOM criteria will capture patients with a number of other illnesses, especially now that there are no exclusionary diagnoses. Neuroborreliosis, an infection of the CNS by the Lyme disease bacteria of the genus Borrelia is indistinguishable from ME. (That is because inflammation in the CNS is common to both.) Lyme disease, including neuroborreliosis, would fit the new definition, as would Gulf War Illness, many autoimmune diseases, heart failure, and major depression.

Given that autoimmune diseases such as lupus and Hashimoto's are hard to detect, and that illnesses such as GWI and major depression have no confirmatory tests, it is likely that the IOM definition will result in exactly what it purported to change - a vague, overly broad diagnostic tool that will result in skewed research results and inappropriate treatment recommendations.

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COMMENTARY

Differentiating myalgic encephalomyelitis and chronicfatigue syndrome: a response to Twisk (2015)

By Leonard A. Jason. Center for Community Research, DePaul University, Chicago, IL, USA

(Received 4 March 2015; final version received 6 March 2015)

Twisk (2015) first suggested that there was an assumption in the article by Jason et al. (2015) that myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are identical illnesses. This was neither stated nor endorsed in Jason et al. (2015). In fact, my position on this issue is rather different from what this reviewer suggested, and my position is also different from the recent announcement by the Institute of Medicine (IOM, 2015a, p. 45) regarding the newly defined systemic exertion intolerance disease (SEID), where “the committee uses the umbrella term ‘ME/CFS’ to refer to ME and CFS throughout this report”. In contrast, in the Jason et al. (2015) article, each of these terms refers to a different case definition, with CFS referring to Fukuda et al. (1994), ME/CFS referring to Carruthers et al. (2003), and ME-ICC (International Consensus Criteria) referring to Carruthers et al. (2011). The article by Jason et al. (2015) identified a sample that had been diagnosed by a licensed physician using either the Fukuda et al. (1994) CFS or Carruthers et al. (2003) ME/CFS case definitions. Twisk (2015) mentions that it is not possible to draw conclusions regarding “the” illness because some individuals within this sample met different criteria (CFS, ME/CFS, or ME-ICC).

However, if an investigator desires to compare those who meet a more liberal criteria, such as with CFS, to those that meet a more specific criteria, such as with ME-ICC or the four empiric items identified in Jason et al. (2015), then it is critical to have a larger, more varied sample that represents both groups. In other words, to identify different groups of patients, which is what was found in the article, then a larger, more heterogeneous sample is required. In fact, our article did find that those who met the more specific four-item empiric criteria had significantly more symptoms and impairment than those that did not.

This approach to identify different types of patients becomes even more important with the new IOM (2015a) position on exclusionary conditions for SEID. Within IOM’s SEID Report Guide for Clinicians (IOM, 2015b, pp. 4), it states: “The presence of other illnesses should not preclude patients from receiving a diagnosis of ME/CFS (SEID) except in the unlikely event that all symptoms can be accounted for by these other illnesses.” The word “unlikely” conveys the impression that most other illnesses would be considered comorbid (and not exclusionary) as they probably would not account for the unique SEID symptoms.

The problem for diagnosticians in interpreting these guidelines is that the core IOM symptoms are not unique to SEID, as other illnesses have comparable symptoms (e.g. cancer, Hashimoto’s, lupus, chronic heart failure, multiple sclerosis, etc.). So, many illnesses that had previously been exclusionary under past case definitions will now be comorbid, leading to an expanded number of individuals meeting SEID criteria. This will be particularly problematic for those with primary affective disorders, who could be now be diagnosed as having SEID. If individuals with primary affective disorder are misdiagnosed with SEID and provided cognitive behavioral treatment, they will more likely have positive outcomes. These outcomes would then create more difficulties in understanding the effects of these interventions for those who have ME.

Some patients with major depressive disorder also have chronic fatigue, sleep disturbances, and poor concentration; therefore, it is possible that some patients with a primary affective disorder could be misdiagnosed as having SEID. However, ME symptoms including night sweats, sore throats, and swollen lymph nodes are not commonly found in depression. Furthermore, illness onset with ME is often sudden, occurring over a few hours or days, whereas primary depression generally shows a more gradual onset. Hawk, Jason, and Torres-Harding (2006) used discriminant function analyses to identify variables that successfully differentiated patients from those with major depressive disorder and controls. Using percent of time fatigue was reported, post-exertional malaise severity, unrefreshing sleep severity, confusion/disorientation severity, shortness of breath severity, and self-reproach to predict group membership, 100% were classified correctly.

Mood disorders are the most prevalent psychiatric disorders after anxiety disorders: for major depressive episode, the one-month prevalence is 2.2% and lifetime prevalence is 5.8% (Regier, Boyd, & Burke, 1988). If the SEID criteria now include people with primary psychiatric conditions, a rather large percent of those diagnosed with SEID will be from this group, so it is now even more important to differentiate these individuals from those that have ME, or those with more severe symptoms and disability, such as what occurred in the Jason et al. (2015) four-item empiric criteria. About a decade ago, a prior CFS case definition was developed by the Centers for Disease Control and Prevention (CDC) (Reeves et al., 2005) which considerably increased prevalence rates of CFS. Yet, these findings were challenged by Jason, Najar, Porter,  and Reh (2009), who found that 38% of those with a diagnosis of a major depressive disorder were misclassified as having CFS using the CDC empirical case definition of Reeves et al. (2005). Fortunately, few adopted the Reeves et al. (2005) empiric case definition, but the IOM (2015a) has considerably more prestige and influence, so their proposed SEID case definition criteria could ultimately have more far reaching effects.

Another issue brought up by Twisk (2015) was that our questionnaire omitted Ramsay’s (1988) essential ME criteria – muscle fatigability and prolonged muscle weakness. Therefore, Twisk (2015) stated, if our sample had been represented by patients with ME, we would have found that 100% of them would have had muscle weakness and muscle fatigability. Twisk (2015) implied that our sample did not have this important characteristic. In fact, 100% of the patients who were identified by our four-item empiric criteria indicated that they were “Physically drained/sick after mild activity”. Although it is true that our questionnaire did not assess Ramsay’s muscle fatigability, we did include the following items: “Muscle weakness”, “Physically drained/ sick after mild activity”, “Minimum exercise makes you physically tired”, “Next-day soreness after non-strenuous activities”, and “Dead, heavy feeling after starting to exercise”, and these items were among the best discriminators of patients versus controls. The primary goal of this article was to identify symptoms with strong discriminatory power to distinguish patients from controls; muscle weakness was more prevalent among healthy controls than the symptom “physically drained/sick after mild activity”.

A third issue brought up by Twisk (2015) was that the presence of symptoms should be assessed with objective measures, rather than just self-report items. However, if self-report measures are highly correlated with these markers, then they represent less expensive methods to conduct initial evaluations. Those identified by less expensive self-report questionnaires could then be more rigorously evaluated during comprehensive medical examinations, and with a variety of more objective measures. For example, Jason, Brown, Evans, and Brown (2012) found that TH2 shift and impairment to the immune system among patients was associated with self report measures, and Tryon, Jason, Frankenberry, and Torres-Harding (2004) found continuous waist activity provide evidence of a blunted circadian rhythm in patients.

With the recent IOM (2015a) report, it is even more importance to conduct studies to determine whether distinct categories or continuous measures best capture patient differences, and  such investigations can and should be addressed by employing both large data sets and sophisticated research methods. Ultimately, we need an empiric, collaborative, open, interactive, and inclusive process to make recommendations regarding specific aspects of the case definitions, where all parties, including key gatekeepers including the patients, scientists, clinicians, and government officials, are involved in the decision-making process.

Disclosure statement: No potential conflict of interest was reported by the author.

References

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Carruthers, B. M., van de Sande, M. I., De Meirleir, K. L., Klimas, N. G., Broderick, G., Mitchell, T.,… Stevens, S. (2011). Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. Advance online publication. doi:10.1111/j.1365- 2796.2011.02428.x

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Jason, L. A., Kot, B., Sunnquist, M., Brown, A., Evans, M., Jantke, R.,…Vernon, S. D. (2015). Chronic fatigue syndrome and myalgic encephalomyelitis: Toward an empirical case definition. Health Psychology and Behavioral Medicine, 3, 82–93.

Jason, L. A., Najar, N., Porter, N., & Reh, C. (2009). Evaluating the Centers for Disease Control’s empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies, 20, 93–100. doi:10.1177/ 1044207308325995

Ramsay, M. A. (1988). Myalgic encephalomyelitis and postviral fatigue states: The saga of royal free disease (2nd ed.). London: Gower.

Reeves, W. C., Wagner, D., Nisenbaum, R., Jones, J. F., Gurbaxani, B., Solomon, L.,…Heim, C. (2005). Chronic fatigue syndrome – a clinical empirical approach to its definition and study. BMC Medicine, 3(19). doi:10.1186/1741-7015-3-19

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Tryon, W. W., Jason, L. A., Frankenberry, E., & Torres-Harding, S. (2004). Chronic fatigue syndrome impairs circadian rhythm of activity level. Physiology & Behavior, 82(5), 849–853.

Twisk, F. N. M. (2015). Commentary on Jason et al. (2015): towards separate empirical case definitions of Myalgic Encephalomyelitis and chronic fatigue syndrome. Health Psychology and Behavioral Medicine, 3(1). doi:10.1080/21642850.2015.1027705

Health Psychology and Behavioral Medicine 113
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*Email: ljason@depaul.edu


This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Tuesday, April 7, 2015

Immune Activation, Chronic Inflammation and Mitochondrial Dysfunction in Autoimmune Disease and ME/CFS

Michael Maes and his colleagues have a long history of delving into immune system and mitochondrial abnormalities, not just in ME/CFS but in a number of diseases.

In this comprehensive article, they support the hypothesis that inflammation and subsequent mitochondrial disruption are features shared by several autoimmune diseases and neuroimmune disorders as well as ME/CFS.

The article below, which is fully available under a Creative Commons License, is the most comprehensive cross-illness review of inflammatory markers, mitochondrial dysfunction and oxidative stress that has been published to date. In it, the authors present research findings in MS, Lupus, Parkinson’s disease, major depression, ME and CFS. Their conclusion is that:
" ... there are sufficient robust multiple lines of evidence to support the proposition that the severe fatigue and profound disability experienced by people with the neurodegenerative, neuro-immune and autoimmune diseases discussed here is largely driven by peripheral immune activation and systemic inflammation either directly or indirectly by inducing mitochondrial damage."
In their review of markers associated with CFS and ME, the authors point out that "elevated levels of TNF-α and IL-1B [pro-inflammatory cytokines] are, in fact, particularly commonplace observations in patients recruited into studies using the internationally agreed diagnostic guidelines." They also discuss abnormal muscle mitochondrial function and defective aerobic metabolism that are "uncharacteristic of muscle disuse" (i.e. deconditioning), as well as abnormal lactate production after exercise.

Neuroimaging studies reveal "considerable ... evidence demonstrating impaired blood flow in the cortex and cerebellum in many patients with a diagnosis of CFS." Additional studies show reductions in white and gray matter, hypometabolism of glucose (which transports oxygen to the brain), and astrocyte dysfunction CFS patients (astrocytes comprise 20%-40% of all glia in the brain, and help maintain the blood-brain barrier). The researchers ascribe all of these impairments to sustained inflammation.

At the end of their review, there are several suggestions for treatment of inflammation and oxidative stress due to inflammation, including Omega-3s, zinc, curcumin, CoQ10, N acetylcysteine, methylfolate and dimethyl fumarate.

_________________________________________

Morris G, Berk M, Walder K, Maes M. Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses. BMC Medicine. 2015;13:28. doi:10.1186/s12916-014-0259-2.

Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses

By Gerwyn Morris, Michael Berk, Ken Walder, and Michael Maes

Abstract

Background

The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson’s disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.

Discussion

Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson’s disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.

Summary

It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.

_____________________

Background

There is copious evidence establishing the causative role of peripheral immune activation and inflammation, evidenced by elevated levels of proinflammatory cytokines in the genesis of debilitating fatigue in neuro-inflammatory, autoimmune and inflammatory disorders [1,2]. Activation of pathogen recognition receptors by pathogen associated molecular patterns leads to the production of nuclear factor NF-kappaB and subsequent production of proinflammatory cytokines by the myeloid differentiation primary response gene (88) (MYD88), which is a universal adapter protein that is used by almost all Toll-like receptors (TLRs) in dependent and independent pathways [3-5]. Systemic inflammatory stimuli, resulting from the presence of proinflammatory cytokines in the peripheral circulation, enter the brain via a number of routes [1,6] activating microglia and astrocytes inducing the production of proinflammatory cytokines and other neurotoxins leading to an environment of neuroinflammation [7,8]. This sequence of events ultimately underpins the genesis of fatigue and other signs and symptoms associated with acute pathogen invasion [1,9,10]. Many people suffering from a range of neuroimmune and autoimmune diseases also suffer from debilitating or intractable fatigue.

The existence of chronically activated immune and inflammatory pathways in the periphery and their causative role in the genesis of neuroinflammation has been established in a range of neuroinflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer’s and Parkinson’s disease [11-16]. Many individuals with neuroinflammatory and neurodegenerative diseases also suffer from fatigue. For example, upwards of 80% of multiple sclerosis patients suffer from fatigue [17]. A study by Beiske and Svensson reported that between 37% and 57% of patients with Parkinson’s disease also experience incapacitating fatigue [18]. Fatigue is one of the characteristics of major depression [19,20]. Chronic systemic inflammation and the presence of activated microglia are also found in patients with major depression [19-22]. Chronic systemic inflammation and immune activation is also an invariant finding in many patients diagnosed with chronic fatigue syndrome (CFS) even without evidence of increased pathogen load [17].

Severe chronic fatigue is also experienced by many people with an autoimmune disease. Thus, upwards of 67% of people with Sjogren's syndrome [23], 76% of patients with systemic lupus erythromatosis (SLE) [24] and 70% of people with rheumatoid arthritis [25] suffer incapacitating levels of fatigue. Peripheral systemic inflammation and immune activation, as evidenced by elevated levels of proinflammatory cytokines and other inflammogens, is seen in patients with rheumatoid arthritis [26,27], SLE [28,29] and Sjogren's syndrome [30,31]. It is interesting to note that neurological sequelae are seen in up to 80% of patients with SLE and 70% of patients with primary Sjögren's syndrome [32,33]. In addition, the presence of neuroinflammation, in the shape of activated microglia, has been confirmed in patients with SLE [34]. Neurological complications are also commonplace in patients with rheumatoid arthritis [35].

The question arises as to the factors involved in creating a chronically activated immune system in these patients. While there is some evidence linking viral infections to the development of multiple sclerosis [36,37], the situation in Parkinson’s disease is different, where there is considerable evidence suggesting environmental toxins in the etiopathogenesis of the illness [38]. One of the key drivers in the development of chronic immune activation in the absence of bacteria or virus infection is the development of chronic inflammation as evidenced by elevated levels of cytokines and oxidative and nitrosative stress (O and NS) and characterized by activated NF-kappaB [6,39]. Indeed, the production of proinflammatory cytokines and other inflammatory molecules by macrophages and other sentinel cells, even in the absence of pathogen invasion, and the subsequent activation of NF-kappaB are early events in the genesis of chronic inflammation [40,41]. Activation of this transcription factor leads to the upregulation of cytokines and O and NS [6,42-44]. These players can engage in a feed-forward manner to maintain and amplify chronic inflammation and immune activation in a TLR radical cycle [4].

Briefly, elevated levels of proinflammatory cytokines can amplify the activity of NF-kappaB by stimulating the canonical pathway leading to a cycle of mutually elevated activity [45,46]. The relation between O and NS and NF-kappaB is a little more complex, but the upregulation of O and NS can directly increase the activity of NF-kappaB [47]. Moreover, O and NS may damage lipids, proteins and DNA, leading to the formation of redox-derived damage-associated molecular pattern molecules (DAMPs) [48,49]. Once formed, these redox-derived DAMPS engage with TLRs further amplifying production of NF-kappaB, cytokines and O and NS [4,50]. Hence, chronic inflammation and immune activation can be maintained and amplified by engagement of TLRs by DAMPS [4].

Chronically elevated levels of NF-kappaB, proinflammatory cytokines and O and NS, in turn, lead to a disruption of epithelial tight junctions in the intestine allowing translocation of gram-negative bacteria, containing lipopolysaccharides, into the circulation, which can further amplify the TLR-radical cycle by acting as a pathogen-associated molecular pattern (PAMP) [1]. Translocation of bacterial lipopolysaccharides (LPS) from the gut and engagement with TLRs, due to a state of increased intestinal permeability driven by the effector molecules of chronic inflammation is another cause of chronic immune activation that may play a role in major depression, CFS, neuro-inflammatory disorders and some systemic autoimmune disorders [6,7]. For example, further evidence of chronic immune activation in these neuroimmune and autoimmune illnesses is provided by data demonstrating TLR activation and upregulation in multiple sclerosis (MS) [51] and SLE [52].

Given the established association between chronic inflammation and the genesis of incapacitating fatigue [1], the TLR-radical cycle can potentially explain the development of incapacitating fatigue in patients suffering from these and other illnesses. This association may be explained by chronically increased levels of proinflammatory cytokines and reactive oxygen and nitrogen species (ROS/RNS) produced by the TLR-radical cycle upon stimulation by PAMPs and DAMPs [4].

We have reviewed previously that some proinflammatory cytokines, including IL-1β, TNF-α and IL-6, and increased O and NS processes may cause fatigue in some vulnerable individuals [1,4,6,7]. Mitochondrial dysfunction likely plays a major role in the progression of MS. Electron transport chain (ETC) complex I, complex III and complex IV activity is grossly reduced in normal appearing gray matter and in normal tissue within the motor cortex in patients suffering from this illness [53,54]. There is also direct evidence of globally impaired energy production and longitudinal depletion of ATP levels leads to increased levels of physical disability [55].

Multiple lines of evidence demonstrate the existence of mitochondrial dysfunction in many, but by no means all, patients afforded a diagnosis of CFS [56]. These abnormalities include loss of mitochondrial membrane integrity and oxidative corruption of translocatory proteins [57,58]. Other findings include abnormal muscle mitochondrial morphology and defective aerobic metabolism uncharacteristic of muscle disuse [59]. Several other teams have reported significant downregulation of oxidative phosphorylation in striated muscle [60,61]. Complex I deficiency is seen in the frontal cortex and substantia nigra of Parkinson’s disease patients [62], and this defect is also observed in peripheral tissues, such as skeletal muscle [63], strongly indicating a widespread reduction in complex I activity in Parkinson’s disease. Impaired complex III function has also been reported in the platelets and lymphocytes of patients with this illness [64]. There is also accumulating evidence that inflammation and subsequent mitochondrial dysfunction drive the symptoms of major depression [65,66].

Localized or global mitochondrial dysfunction is also an invariant feature of autoimmune diseases. Persistent mitochondrial membrane hyperpolarization and increased O and NS production combined with depleted levels of glutathione and ATP is an invariant characteristic of T cells in SLE [67,68]. The release of DAMPS into the systemic circulation, consequent to necrosis, acts as a mechanism by which localized mitochondrial pathology can lead to self-perpetuating systemic inflammation which, in turn, amplifies mitochondrial dysfunction in a vicious feed-forward loop [56,69]. The association between chronic oxidative stress, systemic inflammation and mitochondrial dysfunction and chronic oxidative stress is also firmly established in Sjogren's syndrome [70]. There is also evidence of widespread nitric oxide (NO)-induced inhibition of complex III and V of the ETC in patients with rheumatoid arthritis [71,72]. The causative role of chronic inflammation and oxidative stress and mitochondrial dysfunction is explained by the presence of elevated levels of ROS and RNS in such environments.

These entities cause damage to proteins, DNA and lipid membranes [56]. NO and peroxynitrite have the capacity to inhibit crucial enzymes within the ETC and can inactivate crucial enzymes in the tricarboxylic acid cycle leading to, often critical, reductions in the generation of ATP [7]. Peroxynitrite, in particular, also has a destructive influence on the mitochondrial membrane leading to the loss of potential difference between the outer and inner membrane needed to manufacture ATP [7]. The products of lipid peroxidation driven by elevated levels of ROS are also toxic to mitochondrial membranes. It is noteworthy that inhibition of the ETC leads to the formation of even higher concentrations of oxygen radical species which, in turn, leads to further impairment of mitochondrial function [7]. Needless to say there are numerous studies demonstrating that the origin of severe intractable fatigue seen in people with syndromic mitochondrial diseases lies in mitochondrial pathology and depleted generation of ATP. The reader is referred to the work of [56] for further details.

In this narrative review we will review the evidence pertaining to the genesis of intractable debilitating fatigue in multiple sclerosis, Parkinson’s disease, SLE, Sjogren’s disease, rheumatoid arthritis, major depression and CFS with a view of forming a conclusion as to whether such evidence justifies the viewpoint that the debilitating fatigue commonly suffered by those patients diagnosed with various illnesses is immune, inflammation or O and NS-mediated either directly or indirectly by causing abnormalities such as mitochondrial dysfunctions and central, neuropathological or functional processes [56,73-75]. These specific disorders were selected as examples along a spectrum of imbalance involving various degrees of activation of immune-inflammatory and O and NS pathways, and mitochondrial and brain metabolic dysfunctions in systemic auto-immune, immune-inflammatory and neurodegenerative disorders. Figure 1 shows the underlying processes and pathways associated with secondary fatigue, which we will discuss in the following sections.

(Figures can be found HERE.)

Multiple sclerosis

Fatigue in MS

Fatigue is recognized as one of the most disabling and common symptoms of MS affecting up to 80% of sufferers [17,76,77]. Numerous studies have demonstrated that the Expanded Disability Status Score (EDSS) correlates positively with patient self-reported fatigue scores using a variety of fatigue scales in patients with MS [78-81].

Immune activation, chronic inflammation and mitochondrial dysfunction

Chronic activation of the peripheral immune system is a characteristic observation in MS patients. Many studies report elevated levels of activated Th17 and Th1 T cells, and impaired function of regulatory T cells [17,82,83]. The evidence demonstrating an associative relationship between chronic activation of the immune system and the genesis of neuroinflammation is strong in MS due to the proven effectiveness of rituximab [84] and natalizumab [85], which are monoclonal antibodies which primarily target leucocytes but significantly reduce objective markers of disease activity in the central nervous system (CNS) [86]. It is also noteworthy that increased levels of TNF-α in the periphery are often predictive of the development of active disease. Peripheral TNF-α levels are also predictive of disability levels as estimated by the EDSS [87-89]. Peripheral levels of this and other cytokines correlate positively with fatigue severity which affects the vast majority of people with this illness [17,90-92]. TLR4 receptors are also upregulated in the brain and peripheral immune system in patients with MS [93-95]. There is also copious evidence indicating that chronic systemic inflammation and oxidative stress play a causative role in the etiopathogenesis of MS [96-98]. Elevated markers of chronic inflammation and oxidative stress are found in the brain, cerebrospinal fluid (CSF) and various blood compartments [82,99]. Oxidative stress levels increase quite dramatically during relapses but drop to barely detectable levels in patients during the remission phase [100]. It is also noteworthy that levels of chronic inflammation and oxidative stress in the CSF and blood correlate positively and significantly with disability levels as estimated by EDSS [101,102]. Finally, the extent of gadolinium-enhanced lesions appears to correlate significantly and positively with levels of oxidative stress [102].

It appears that although the genesis of pathology in early disease is mainly driven by inflammation [103], mitochondrial dysfunction likely plays a pivotal role in disease progression. Oxidative damage to mitochondrial DNA and impaired complex 1 activity is a characteristic finding in active MS lesions [104], but complex I, complex III and complex IV activity is also reduced in normal appearing gray matter and in normal tissue within the motor cortex [53,54,105].

The use of nuclear magnetic resonance (NMR) spectroscopy has found direct evidence of globally impaired energy production and increased lactate production in the CSF [106-108]. In a longitudinal study, progressive central depletion of ATP over a three year period correlated positively and significantly with increased indices of physical disability as measured by EDSS changes, which strongly suggests a global impairment of ATP synthesis in MS [108].

Neuroimaging and neuropathology

Until recently, all studies investigating the phenomena had failed to find any significant correlation between increasing self-reported fatigue during the performance of sustained cognitive tasks and changes in brain activity using any neuroimaging modality [109]. It has been argued that this situation has arisen because self-reported fatigue is not an objective or accurate indicator of cognitive performance in the first place [109]. However, the first evidence displaying a positive relationship between cognitive fatigue and changes in brain activity during a task was provided in a recent study [109]. While the relationship between self-reported fatigue and neuroimaging changes is still a matter of considerable debate, the positive association between changes in brain activity and objective measures of cognitive fatigue is generally accepted [110,111]. The bulk of evidence demonstrates that these changes in activity occur in several areas of the brain with most studies reporting this phenomenon in the basal ganglia and the prefrontal cortex [109].

Overall, the results of these studies have been interpreted as support for the hypothesis that the origin of fatigue seen in patients with MS and other neurological diseases arises as a result of failure of integrative processes within the basal ganglia which normally coordinate inputs from the limbic system and outputs to the motor cortex [109,112]. MS was once considered to be a disease of white matter but there is now overwhelming evidence that gray matter pathology occurs early in the disease often before the advent of white matter involvement [113,114]. Conventional magnetic resonance imaging (MRI) is of limited value in revealing gray matter pathology but newer MRI approaches based on FLAIR technology and NMR spectroscopy appear to display adequate sensitivity [114,115]. Gray matter atrophy occurs in very early stages of disease and is seen in people with clinically isolated syndrome (CIS) [115-117]. Indeed, this phenomenon is detected in people with first attack MS [118]. The extent of gray matter atrophy correlates significantly and positively with the degree of physical disability and cognitive impairment seen in many patients with this illness [119,120]. It is noteworthy that reduced gray matter perfusion is seen in very early disease without any loss of volume or other visible sign of gray matter (GM) pathology [121]. Cortical inflammation and metabolic abnormalities, such as reduced choline and N-acetyl aspartamine levels, are also evident in early MS without evidence of any kind of gray or white matter abnormalities [114,119,122]. Other studies, when viewed as a whole, have established a clear relationship between global or localized gray matter atrophy and hypoperfusion in the development of fatigue [123-126]. Other observations include an association between fatigue and glucose hypometabolism in the basal ganglia and frontal cortex [127-129] and a decreased N-acetyl aspartamine/creatine ratio in the basal ganglia, suggestive of gliosis [130].

Finally, Calabrese et al. reported a positive association between increased fatigue and widespread atrophy of the basal ganglia and prefrontal cortex [131]. It is tempting to speculate that these observations could arise from astrogliosis and underlying loss of astrocyte numbers and the normal regulatory functions of the surviving astrocyte population. Recent evidence indicates that reactive astrogliosis may play a major causative role in the development and progression of MS [132,133]. It is also worthy of note that astrocyte loss is a characteristic feature of this disease [134]. Protoplasmic astrocytes are primarily found in gray matter and form the vast bulk of cells located in this tissue [135]. These glial cells in particular have crucial roles in coordinating neurometabolic and neurovascular coupling and, hence, the delivery of oxygen and energy to neurons [136,137]. Given that astrocytes form the vast bulk of gray matter it seems likely that the loss of gray matter seen very early in the development of the disease is due to loss of astrocytes [138]. It is also interesting that the magnitude of gray matter loss correlates positively with severity of inflammation [138]. The presence of reactive astrogliosis would suggest that the regulatory performance of the remaining astrocytes could be compromised and, thus, would go some way to explaining the abnormalities in perfusion and glucose metabolism and the development of fatigue seen in these studies. This state of affairs could explain, in part, the regulatory dysfunction seen in the basal ganglia which seems to underpin the observations surrounding the changes in brain activity and the development of cognitive fatigue noted earlier.

Chronic fatigue syndrome

Fatigue in chronic fatigue syndrome

Pathological levels of fatigue unrelated to activity and not relieved by rest is a mandatory requirement for a diagnosis of chronic fatigue syndrome under the current internationally accepted diagnostic guidelines [139]. The original diagnostic criteria contained another mandatory element, namely a clinical picture whereby the patient’s global symptoms represent a unitary illness with a single pathogenesis and pathophysiology.
It is more likely that a diagnosis of CFS represents a spectrum of illnesses where different pathophysiological processes converge to produce a very similar phenotype [140]. Hence, any information regarding immune abnormalities, chronic inflammation, mitochondrial dysfunction and neuroimaging should be viewed with these issues in mind [141]. (Emphasis added.)

Immune activation, chronic inflammation and mitochondrial dysfunction

Numerous research teams have reported a wide range of peripheral immune abnormalities in people afforded a diagnosis of CFS [1,142,143]. The presence of circulating activated Th1, Th2 and Th17 T cells have all been detected. Recent evidence has challenged the view that people with CFS display immune abnormalities consistent with a Th2 pattern of T cell differentiation, and now data reveal that while some patients present with a Th2 profile and a preponderance of anti-inflammatory cytokine production, others present with a Th1 or possibly Th17 profile, with the synthesis of proinflammatory cytokines being dominant [144-146]. Elevated levels of TNF-α and IL-1B are, in fact, particularly commonplace observations in patients recruited into studies using the internationally agreed [139] diagnostic guidelines [144,147-151]. We have reviewed previously that patients with CFS and Myalgic Encephalomyelitis (ME) show different cytokine profiles, for example, a Th1-like pattern, with increased levels of IFN-γ, IL-2, IL-12 and IL-2 receptor, or a Th2-like pattern, with increased levels of IL-10, IL-4 and IL-5, or combinations thereof [1]. Two recent studies reported evidence of activated TLR4 receptors [152-154].
The causative relationship between chronic inflammation and the development of fatigue is perhaps strongest in patients afforded a diagnosis of CFS, with many studies demonstrating a significant positive correlation between surrogate markers of inflammation, oxidative stress and symptom severity [17,155-159]. (Emphasis added)
Miwa and Fujita (2010) demonstrated that a rapid decline in inflammation and oxidative stress of patients corresponded with a decline in severity of fatigue and amelioration of their entire symptom profile [160]. Markers of chronic inflammation and oxidative imbalance have also been detected in skeletal muscle and levels of oxidative stress in this patient population correlated positively with objective measures of muscle fatigability [161]. Numerous authors have reported abnormalities consistent with mitochondrial dysfunction in patients afforded a diagnosis of CFS [56]. These abnormalities include loss of mitochondrial membrane integrity and oxidative corruption of translocatory proteins [57,58,162].

Other findings include abnormal muscle mitochondrial morphology and defective aerobic metabolism uncharacteristic of muscle disuse [59,163]. Several other teams utilizing 31-P NMR spectroscopy have reported significant down regulation of oxidative phosphorylation [60,61,164-167]. Other studies reported the presence of abnormal lactate responses to exercise indicative of a shift to glycolytic energy generation in at least some patients with a CFS diagnosis [168]. In a recent review, Filings and others [169] conclude that there was ample evidence of mitochondrial dysfunction and impaired bioenergetics performance in patients afforded a diagnosis of CFS, but once again it was confined to patients diagnosed according to internationally agreed criteria and not apparent in all patients [169].

Defects in oxidative phosphorylation and ATP generation have also been revealed in exercise testing with the pattern of physiological responses being characteristic of mitochondrial dysfunction [170]. Exercise performance was examined in a cohort of CFS patients and a loss in the linear relationship between heart rate and cardiac output and the dissipation of oxygen concentration gradient between venous and arterial blood characteristic of mitochondrial dysfunction was reported [171]. Finally, authors ultilizing NMR spectroscopy have reported that some patients with CFS display significantly elevated ventricular lactate levels, again suggestive of a shift towards aerobic glycolysis [159,172,173].

Neuroimaging and neuropathology

There is now considerable neuroimaging evidence demonstrating impaired blood flow in the cortex and cerebellum in many patients with a diagnosis of CFS [174-176]. Other studies report loss of gray matter volume [177-179]. Interestingly, this phenomenon has also been observed in patients given a primary diagnosis of fibromyalgia which is held by many to be an overlapping illness. Kuchina et al. reported that patients displayed levels of gray matter loss which were some three times greater than expected for their age [180]. Another study using 3-T voxel-based morphometry MRI reported reduced occipital lobe gray and white matter volume in the CFS group [181]. Cook and fellow workers, using functional MRI (fMRI) reported a significant positive association between perceived severity of fatigue and responsiveness in the cingulate frontal, temporal and cerebellar regions [182].

Another research team demonstrated impaired fMRI activation in the dorsolateral, dorsomedial and prefrontal cortices during a fatigue provocation task [183]. Glucose hypometabolism, especially in the prefrontal cortex, has also been demonstrated [184,185]. Finally Barden et al. [186] once again using 3 T MRI-based morphometric analysis reported evidence of astrocyte dysfunction and failure of autoregulatory mechanisms in patients in their trial cohort [186].

Parkinson’s disease

Fatigue in Parkinson’s disease

Pathological fatigue, often described as a state of overwhelming exhaustion not necessarily related to physical effort, is recognized as a major, and possibly the most common, non-motor symptom of Parkinson’s disease [187,188] and often presents an insurmountable problem for patients and their caregivers [189,190]. Profound fatigue is experienced by some 82% of patients with advanced (HY stage 5) disease and the prevalence of fatigue increases with disease severity [191]. Although fatigue has been clearly established as an independent non-motor symptom of Parkinson’s disease, it is often confused with depression or excessive daytime sleepiness in clinical practice [189]. Some authors have actually adduced evidence indicating that fatigue could even be a pre-motor feature of Parkinson’s disease [192,193]. Schifitto et al. reported the presence of fatigue in just over a third of untreated non-depressed patients [194]. Furthermore, several other authors have reported that pathological levels of fatigue occur in non-depressed patients who are also untroubled by sleep problems [187,189].

Immune activation, inflammation and mitochondrial dysfunction

Numerous authors have reported that the serum and CSF of Parkinson’s disease patients contain elevated levels of activated CD4 and CD8 T cells and IL-1β, TNF-α, and IL-2 [195-199]. Increased frequencies of activated CD4+ T cells expressing the programmed death receptor Fas [198] and increased numbers of IFN-γ-producing Th1 cells, decreased numbers of IL-4-producing Th2 cells, and an overall decrease in CD4+CD25+ T cells have been found in the peripheral blood compartment of patients with this illness [200]. Studies have demonstrated that elevated peripheral cytokine production influences the progression of this illness. Parkinson patients display increased serum levels of TNF-α and TNF-α receptor 1 when compared to healthy control subjects, which makes an independent contribution to the pathogenesis of this illness [197,201,202]. It is also noteworthy that elevated plasma IL-6 concentrations significantly and positively correlate with increased risk of developing the illness [203].

Neuropathy and functional central processes

The increased frequencies of activated peripheral and memory T-cell subsets and activated T cells in the substantia nigra indicate the putative roles of T cells in the progression of Parkinson’s disease. There is also evidence that the balance of regulatory or effector T lymphocytes at inflammatory foci can either attenuate or exacerbate neuroinflammation and, hence, the subsequent development of neurodegeneration [13].

The intimate association between Parkinson’s disease and chronic inflammation has been revealed in different studies [204-208]. It is now recognized that chronic systemic inflammation plays a major role in the pathophysiology of Parkinson’s disease [209,210]. Nitrated proteins, DNA damage and lipid peroxidation bear testimony to the presence of elevated oxidative and nitrosative species [211,212]. The detection of extracellular HMGB1 and corrupted protein, DNA and lipid derived entities suggests substantial DAMP activity [213]. The weight of evidence indicates that the engagement of high-mobility group protein B1 (HMGB1) and alpha synuclein plays a major part in exacerbating the pathology of Parkinson’s disease [214,215]. Due to its modified conformation alpha synuclein behaves as a DAMP by activating TLR4 receptors on microglia resulting in the release of a plethora of neurotoxic entities, toxic molecules, including O and NS and proinflammatory cytokines and prostaglandin E2 (PGE2), thereby exacerbating neuro-inflammation [216,217].

Mitochondrial dysfunction in Parkinson’s disease in the shape of Complex I (CI) impairment has been suggested to be one of the fundamental causes of the illness [218,219]. This complex I deficiency is seen in the frontal cortex and substantia nigra in the patients [62], and in peripheral tissues, such skeletal muscle [220-222] and platelets [63,223,224], strongly indicating a widespread reduction in complex I activity in Parkinson’s disease. This defect is likely due to oxidative damage to complex 1 and possibly mis-assembly, as this latter phenomenon has been observed in isolated Parkinson’s disease brain mitochondria [225]. This complex I inhibition can induce the degeneration of neurons via a number of different mechanisms, such as excitotoxicity and increased oxidative stress [226]. A decrease in complex III function has also been reported in the platelets and lymphocytes of patients with this illness [64,223]. An association between the level of impairment of mitochondrial complex III assembly leading to a subsequent increase in ROS production and the development of Parkinson’s disease has also been reported [227]. This elevation in free radical production and release likely stems from the increased leakage of electrons from complex III. An alternative, but not mutually exclusive, explanation is that the inhibition of complex III assembly results in a severe reduction in the levels of functional complex I in mitochondria [228], again leading to an increase in ROS production via complex I deficiency. It is also noteworthy that the complex I and II electron acceptor ubiquinone is also reduced in the mitochondria of patients with Parkinson’s disease [229].

Neuroimaging and neuropathology

An almost bewildering array of neuroimaging abnormalities have been observed in patients with Parkinson’s disease and overall it is now clear that the various manifestations of the disease cannot be attributed to basal ganglia dysfunction alone [230,231]. Numerous studies employing voxel based morphometry have revealed a global pattern of gray matter loss and conformational abnormalities in Parkinson patients [232,233]. These gray matter changes are associated with cognitive and memory impairments which are seen in patients with very early disease [234,235]. Nagano-Saito and others reported that gray matter density displayed a positive and significant correlation in the dorsolateral prefrontal cortex and parahippocampal gyrus [236]. Loss of gray matter volume is apparent in treatment naive patients, once again bearing testimony to the existence of these abnormalities at the earliest stages of the disease [237].

The use of NMR spectroscopy has revealed neurometabolic abnormalities particularly a decrease in N-acetyl aspartate levels [238]. Finally, the use of the same technique has revealed the existence of widespread mitochondrial dysfunction in the brains of people with Parkinson’s disease even in the absence of any overt clinical manifestations [239]. Treatment naïve patients also display glucose hypometabolism in the dorsal pons, putamen and ventral thalamus [240-242]. Positron emission tomography (PET) imaging has revealed cortical hypometabolism in Parkinson’s disease. The severity and topography of glucose hypometabolism in the frontal and occipital cortex seen even in prodromal patients [243] intensifies and involves the lateral parietal and prefrontal cortices [242,244,245] and may also include the medial frontal and occipital regions [243,246] in patients with mild cognitive impairment (MCI). The severity and location of this hypometabolism may reflect the degree and extent of cognitive dysfunction [243,245,247,248]. The widespread cortical hypo-perfusion reported by many authors is also apparent at very early stages of disease and also appears to be related to the development of cognitive dysfunction [246,249,250].

Major depressive disorder

Fatigue in depression

Fatigue of variable severity occurs in practically 100% of people with a diagnosis of depression [251,252]. It is worthy of note, however, that a systematic review reported that almost 80% of patients still experienced chronic debilitating levels of exhaustion following treatment of their depression [253]. This is perhaps to be expected given that several studies have now demonstrated that antidepressants have no positive modulatory effects on fatigue [254-257].

Immune activation, inflammation and mitochondrial dysfunction

The existence of increased levels of circulatory proinflammatory cytokines in these patients is now a textbook truism [20]. The picture regarding patterns of cytokine imbalance is complex with elevated levels of anti-inflammatory cytokines often reported [258]. There is copious evidence of chronically activated T cells with Th1, Th2 and Th17 patterns of differentiation [20,259,260]. It is worthy of note, however, that T cells appear to be dysfunctional, displaying an overall pattern of abnormalities consistent with a state of anergy [261]. Until recently, evidence of TLR activation in depression was limited to an animal model [262] but recently a study reported elevated levels of TLR4 in the brains of depressed patients displaying suicidal ideation [263]. Chronic systemic inflammation and oxidative stress play a major role in the etiology of depression [19,20]. Elevated levels of redox-damaged DAMPs, including oxidized low density lipoprotein, oxidized phospholipids, and malondialdehyde (MDA)-adducts are also consistently found in patients suffering from this illness [48]. Compromised epithelial barrier integrity is also a finding in depression and the resulting bacterial translocation into the systemic circulation is intimately involved in the pathogenesis of the disease [20,155]. Mitochondrial dysfunction affects neuronal function, synaptic plasticity, energy metabolism and neurotransmitter release and, hence, it is not surprising that there is increasing evidence that mitochondrial dysfunction and inflammation drive the symptoms of major depression [65,66]. Gardner and Boles highlighted the fact that research has failed to confirm a consistent relationship between serotonin levels and depression and that compromised bioenergetics should become a focus of research into the pathogenesis of the illness [264].

Neuroimaging and neuropathology

Hamilton and fellow workers reported the results of their meta-analysis of studies ultilizing various modalities of functional neuroimaging in patients with depression [265]. These authors concluded that a synthesis of the studies revealed a pattern of higher baseline neural activity in the pulvinar nucleus [265]. They further reported that studies ultilizing negative stimuli demonstrated a significantly greater neural response in certain areas of the brain, such as the amygdala, and lower responses in other regions, such as the prefrontal cortex, possibly indicating impaired contextual processing and reappraisal of visceral inputs [265]. In another meta-analysis, Kempton and others reported that patients with a diagnosis of depression and bipolar disorder displayed increased rates of hyperintensities in subcortical gray matter and increased volume of the lateral ventricles compared to healthy controls [266].

Interestingly, this meta-analysis also revealed distinct differences in neuroimaging abnormalities between depression and bipolar disorder, with the former having reduced rates of hyper-intensities in white matter and smaller basal ganglia and hippocampi compared to bipolar patients [266]. There is evidence that patients in a state of depression display reduced gray matter volume in the hippocampus compared to healthy controls or patients in remission [267]. Other investigators analyzing studies involving voxel based morphometric analysis have reported more widespread loss of gray matter in many different areas of the brain, especially in the prefrontal cortex [268-270]. It is noteworthy that gray matter reduction is evident in patients with first episode depression [271]. Impaired perfusion in frontotemporal regions has been reported [272] and a recent study has reported global cerebral hypoperfusion [273]. Interestingly, the degree of hypoperfusion in the prefrontal cortex correlates positively with the severity of depressive symptoms in patients with Alzheimers disease [274]. Another research group has recently reported that regional cerebral blood flow abnormalities in the prefrontal cortex and anterior cingulate cortices reverse during remission [275]. Glucose hypometabolism has been demonstrated in depressed patients both in the prefrontal cortex [276] and in several other regions [277]. An intriguing connection between glucose hypometabolism was proposed in a study by Hirono and others, who reported a positive significant association with the presence and severity of depressive symptoms in Alzheimer patients and decreased glucose metabolism in the frontal lobe [278]. Finally, the presence of activated microglia in patients suffering from depression has been established via the use of in vivo non-invasive neuroimaging [279].

Systemic lupus erythematosus

Fatigue in SLE

Fatigue is an extremely common and disabling symptom affecting some 80% of patients with SLE [280]. Fatigue severity scores are significantly higher than population norms and similar to levels seen in patients with MS and Lyme disease [281,282]. Chronic debilitating fatigue is a major cause of morbidity in patients with SLE [283], that decreases quality of life [284-286] and increases work disability [287,288]. The aerobic capacity of patients with mild SLE is comparable to that observed in patients with severe cardiopulmonary disease [289-291]. Disease activity appears to be a major factor in the genesis of fatigue although this relationship is not evident in all studies [280,283,292,293].

Immune activation, inflammation and mitochondrial dysfunction

There is extensive evidence of activated T cells in the peripheral immune system of patients with SLE [294]. Elevated levels of proinflammatory cytokines play a key role in the pathophysiology of SLE [295]. Salbry et al. [296] reported a significant positive correlation between levels of TNF-α and IL-6 and objective markers of disease activity [296]. The weight of evidence indicates that significantly elevated levels of proinflammatory cytokines in the systemic circulation also plays a causative role in the development of systemic inflammation [297,298].

The presence of a chronic inflammatory state in people suffering from SLE has been reported by several research teams [28,299]. Wang and colleagues reported a significant positive correlation between elevated markers of O and NS with disease activity in this illness [300]. A range of TLRs are involved in initiating and maintaining the pathology of SLE, including TLR4, TLR3, TLR9 and TLR7 [301,302]. Impaired clearance of apoptopic cells is a pathological feature of SLE and, hence, the blebs and modified cellular contents act as autoantigens and are recognized by the immune system as DAMPS with the resultant activation of TLRs especially TLR4 [303,304]. The impaired clearance of these cells sets off a sequence of biochemical events allowing the escape of extramatrix debris once again acting as an autoantigen and recognized as a DAMP with the consequent activation of TLR4 and, indeed, a range of other TLRs as well [304]. Interestingly, polymorphisms in TLR4 (and CD14) genes are now thought to play a significant role in the etiopathogenesis of SLE. Persistent mitochondrial membrane hyperpolarization, increased O and NS production combined with depleted levels of glutathione and ATP is characteristic of T cells in SLE [67,68]. This environment sensitizes T cells towards necrotic cell death and the consequent release of DAMPS into the blood stream affords a mechanism by which localized mitochondrial pathology can lead to self-perpetuating systemic inflammation [69,305].

Neuroimaging and neurological abnormalities

Neurological symptoms in SLE are commonplace, affecting upwards of 80% of sufferers [32]. These neurological abnormalities occur even in the absence of the various systemic disease manifestations [306]. Voxel based morphometric analysis revealed widespread gray matter volume reduction in patients diagnosed with SLE [307-309]. Other studies have revealed the presence of white matter hyper-intensities, whose prevalence in an individual is predictive of disease progression [309-311]. The presence and severity of fatigue in patients with SLE is associated with white matter hyperintensities [312]. These authors reported that the White Matter Hyperintesity score correlated positively and significantly with fatigue severity [312]. The pathophysiology of ‘neuropsychiatric’ Lupus is mediated by cytokines, complement components and autoantibodies leading to the development of neuroinflammation and, ultimately, apoptosis of neurons and glial cells [313-316]. It is perhaps no surprise that the presence of activated microglia have been confirmed in patients with SLE [34].

Sjogren's syndrome

Fatigue in Sjogren's syndrome

Fatigue and pain are, again, the most common extra-glandular symptoms of Sjogren's syndrome [317,318]. A total of 70% of patients with Sjogren’s syndrome suffer from fatigue and many patients state that fatigue is one of the most disabling symptoms of their disease [319]. There are a number of studies reporting a significant positive association between the severity of fatigue experienced by patients and various surrogate markers of disease activity [320-322]. The fatigue levels are associated with higher sicca symptoms, lower salivary volume, increased serum anti-Sjögren’s syndrome A antigen, immunoglobulin G (IgG) and proinflammatory cytokine levels [323]. Further evidence suggesting cytokine involvement in the genesis of fatigue was provided by Norheim and fellow workers who reported that patients’ fatigue levels were reduced by some 50% following blockade of IL-1β [324].

Immune activation, inflammation and mitochondrial dysfunction

Predictably there is copious evidence demonstrating the existence of a chronically activated innate immune system in patients diagnosed with this illness [325]. There is a wealth of data demonstrating disturbed cytokine networks [326], with cytokines secreted by activated Th1 and Th17 T cells being commonly detected in various blood compartments [327,328]. Epithelial cell activation leading to TLR upregulation is considered by many to be a pivotal early event in the pathogenesis of Sjogren's syndrome [329,330]. A range of TLRs, including TLR2, TLR3 and TLR4, are chronically up-regulated in sufferers of this illness [329,331]. Chronic systemic inflammation is an almost invariant finding in Sjogren's syndrome patients [332]. The existence of chronically elevated O and NS and subsequent oxidative stress has also been repeatedly demonstrated in patients with this disease [70,333]. The link between mitochondrial dysfunction and chronic oxidative stress is now firmly established in Sjogren's syndrome [70].

Neuroimaging and neurological abnormalities

A wide range of abnormalities in the central and peripheral nervous system occur in up to 70% of patients with Sjogren's syndrome, which may precede diagnosis in over 90% of cases [33,334,335]. Those interested in the details of these neurological abnormalities are invited to consult an excellent review by Tobon et al. [33]. There is some evidence that CNS pathology is immune mediated [336] and many patients display abnormalities on MRI with increased signaling intensity in T2 weighted images being the commonly noted finding [337,338]. These white matter hyperintensities (WMH) are indicative of widespread hypoperfusion [336,339-341]. Voxel based morphometry has once again revealed a global pattern of gray matter volume loss [340,342] and very recently loss of cerebral white matter was observed for the first time [343].

Rheumatoid arthritis

Fatigue in rheumatoid arthritis

Patients with rheumatoid arthritis commonly complain of severe intractable fatigue with prevalence rates of up to 80% depending on definitions of fatigue used [344]. A study employing a fatigue measuring instrument reported that 40% of patients with rheumatoid arthritis experienced unremitting severe fatigue of the same level and pattern as fatigue experienced by patients with a diagnosis of chronic fatigue syndrome [345]. From a patient perspective fatigue is often described as extreme, unremitting and unrelated to activity and is associated with a failure to perform routine daily activities and non-refreshing sleep which, when considered together, are more debilitating than pain [346,347]. Reducing inflammation with disease modifiers significantly reduces fatigue [348]. Considerable evidence now exists demonstrating that the severity of fatigue experienced by patients suffering from this disease correlates significantly and positively with levels of disease activity [349,350].

Immune activation, inflammation and mitochondrial dysfunction

Numerous research teams have adduced evidence of a chronically activated immune system in rheumatoid arthritis patients as evidenced by significantly increased serum Th1, Th2 and Th17 cytokines [351-353]. Blockade of Th1 and Th17 cytokines can result in significant clinical benefit in patients with rheumatoid arthritis, strongly indicating their role as causative agents in the disease [354,355]. The frequency of Th17 T cells and associated cytokines strongly correlates with a poor prognosis which again suggests that these entities play a major causative role [356]. There is also good evidence that the use of biologic agents results in significant improvements in fatigue, strongly implicating elevated levels of these species in the genesis of intractable fatigue in patients with rheumatoid arthritis [357,358].

There is also considerable evidence demonstrating the activation and upregulation of TLRs in this disease with upregulated TLR2, TLR3 and TLR4 being commonplace findings [359-361]. Rheumatoid arthritis is recognized as being a systemic inflammatory condition [359] and chronic inflammation and accompanying oxidative stress play a causative role in the illness [362,363]. Perhaps unsurprisingly then, it has been demonstrated that levels of inflammation correlate positively with measures of disease activity [364]. The positive association between inflammation and fatigue genesis is evidenced by the fact that reducing inflammation with disease modifiers significantly reduces fatigue [348]. The effector molecules of chronic inflammation and oxidative stress can induce irreversible genetic changes and one such change, mutations in p53, has been suggested as a ‘turning point’ in converting a state of chronic inflammation into chronic disease [365]. There is evidence of somatic mutations in the mitochondrial DNA (mtDNA) within synoviocytes of rheumatoid arthritis patients which may confer immunogenicity on mtDNA derived proteins which consequently adopt the character of DAMPS and be one of such entities thought to play a major role in the etiopathogenesis of this disease [366]. A positive association has been reported in these cells between the extent of these mutations and the expression of cyclo-oxygenase 2 (COX-2), prostaglandin (PG)E2 and IL-8 [367]. The existence of these inflammatory markers is highly suggestive of NO-induced inhibition of complex III and V of the electron transport chain [72,368].

Neuroimaging and neuropathology

There is no direct evidence supporting the existence of chronically activated microglia and neuroinflammation in patients with rheumatoid arthritis, but neurological sequelae are commonplace and the role of chronic systemic inflammation in establishing such sequelae is accepted [35]. Wartoloska et al. reported widespread cortical atrophy in their patients with rheumatoid arthritis using unbiased voxel morphometric analysis and a pattern of increased gray matter density in subcortical areas notably the basal ganglia with the latter finding being suggestive of decreased dopamine levels [369]. An earlier MRI imaging study by Bekkelund and fellow workers also detected cortical atrophy in rheumatoid arthritis patients but only in those with longstanding disease [370].

Cross-talk peripheral and CNS inflammation

There is now copious evidence that chronic or intermittent inflammation, as observed in the abovementioned systemic disorders, can worsen or trigger neuroinflammatory or neurodegenerative processes via the induction of primed microglia [8,12]. Briefly, prolonged or intermittent peripheral inflammation and immune activation act to prime microglia which thereafter become exquisitely sensitive to future inflammatory stimuli [8]. Once microglia have achieved this sensitized status, subsequent peripheral inflammation and proinflammatory cytokine production mediated by a number of insults (for example, biotoxin exposure or pathogen invasion) provokes an exaggerated response from microglia and the production of excessive concentrations of neurotoxic molecules, such as nitric oxide, peroxinitrite, prostaglandins, cyclo-oxygenase 2 and cytokines [6,7]. The secretion of these neurotoxins and alarmins leads to the activation of astrocytes and the combined activation of these glial cells provokes dysregulation of brain homeostasis, development of chronic neuroinflammation and neurotoxicity. Both humoral and neuroendocrine routes mediate proinflammatory signaling to the brain. The neural route operates via the dorsal motor nucleus of the afferent vagus nerve [6]. The humoral route is facilitated by circulating proinflammatory cytokines that communicate their presence to the brain via direct and indirect routes.

Such pathways involve engagement with specific transporters in the blood brain barrier (BBB), the activation of endothelial cells and macrophages, creating a mirror pattern of production on the adluminal side of the BBB, and passive diffusion into areas of the brain lacking a functional BBB (for example, circumventricular organs) and thereafter into the glial limitans [1]. The cumulative effects of proinflammatory cytokines and activated astrocytes cause disruption of the BBB allowing abnormally high numbers of activated T cells and B-cells to circulate between the peripheral immune system and the brain, acting as more channels of communication between the peripheral and central immune system [13]. It should be noted that cytokines are able to diffuse from the CNS into the bloodstream as well [13]. Finally, the presence of proinflammatory cytokines in the brain activates the hypothalamus instigating the cholinergic anti-inflammatory pathway designed to terminate the immune response [1,6]. These processes are depicted in Figure 2.

(Figures can be found HERE.)

All disorders reviewed here, except Parkinson’s disorder, are more frequent in women than in men. For example, in patients with rheumatoid arthritis a four to five greater incidence is found in women than in men when less than 50 years old, whereas these differences are less pronounced in 60- to 70-year old individuals. The female predilection is also observed in depression, CFS, MS, Sjogren’s syndrome and systemic lupus erythematosus [371-375]. In Parkinson’s disorder the male/female incidence rate ratio is 1.6 to 1 [376]. One main difference between Parkinson’s disease and the other disorders discussed here is that the autoimmune component is less pronounced in Parkinson’s disease. An increased incidence rate in women is observed in most autoimmune disorders [371]. Nevertheless, also in Parkinson’s disease autoantibodies are observed and they are associated with specific symptom profiles, including depression [377]. It is argued that these sex-related differences in incidence may be explained by endogenous sex-hormones.

Estrogen, progesterone and testosterone play important immunomodulatory roles and influence the quantity and pattern of cytokine secretion by antigen presentation cells and T lymphocytes and immunoglobulin production by B cells. Sex hormones also regulate the Th1/Th2 balance of the immune system, the production of regulatory T cells and the functionality of granulocytes and natural killer cells [378,379]. An interested reader is referred to an excellent review by [380] for a detailed consideration of the mechanistic effects of sex hormones on individual classes of immune cells. In the light of the discussion above, it also seems noteworthy that estrogen is neuroprotective in many animal models of neuroimmune and neurodegenerative disorders essentially by down regulating the expression of neuroinflammatory genes in glial cells, such as those coding for elements of the complement system, proinflammatory cytokines and TLRs [381]. Thus, excessive estrogens but less androgens may favor activation of B cells, a Th2-like response and increased numbers of autoimmune cells and, thus, autoimmune responses [371]. Nevertheless, the precise effects of sex- or gender-related factors on the increased incidence of autoimmune-related disorders has remained elusive. Future research should delineate not only sex but also gender-related effects according to the gendered innovations approach [382].

These parameters and elevated number of circulating T cells seen in premenopausal women may be one reason for the powerful prolonged activation of inflammatory pathways and adverse reactions to aluminum adjuvants seen in women following administration of a range of vaccines [383,384]. The engagement of TLR receptors by aluminum, as well as the activation of the NLP3 inflammasome, could create a state of chronic inflammation and oxidative stress in a person with functional polymorphisms in immune genes as discussed above and, hence, could be a cause of Autoimmune Inflammatory Syndrome Induced by Adjuvants (ASIA), alternatively known as Schoenfield’s Syndrome [385-387]. The activation of TLR4 by silicon [388] could also explain the connection of this element with the development of ASIA and the chronic activation of TLRs can potentially explain many environmental contributions to the ‘mosaic of autoimmunity’ [389].

Sex effects may also determine responsivity to drug therapy as, for example, in MS. Thus, postmenopausal women are poorer responders to rituximab than men of the same age [390,391]. This might seem a little counter intuitive from the frame of reference that rituximab exerts its effects mainly on the B cell population and that B cell levels do not appear to differ in postmenopausal women and age equivalent men to any significant extent [392]. However rituximab also exerts modulatory effects on the T cell compartment [393]. Numerous researchers have reported that the clinical benefits seen following the use of rituximab in rheumatoid arthritis and other autoimmune conditions are associated with the antibody’s capacity to increase the expression of FOXP3 [394], suppress the expression of retanoic acid-like orphan receptors ultimately suppressing the production of Th17 T cells and IL-17 [395] and reducing the expression of cytokines by Th1, Th2 and Th17 T cells [396]. It is possible that the Th2 shift in the immune system seen in postmenopausal women negates the benefits of rituximab on a Th1/Th17 biased immune system [392]. The positive benefits of rituximab and natalizumab on MS [84,85] is probably most easily explained by the modulatory effects of rituximab and, likely, natalizumab on the T cell compartment as well as their well-documented effects on B cell depletion.

Summary and conclusion

Figure 3 shows a diagram illustrating the causal links being described in the above sections synthesizing the significant pathways that lead to secondary fatigue in these different neurodegenerative and systemic (auto)immune disorders. There is clear evidence of a positive relationship between fatigue severity and levels of disability in MS. It is of interest that levels of peripheral inflammation, oxidative stress and TNF-α also display a positive correlation with objective markers of disease activity and disability levels and that levels of proinflammatory cytokines correlate positively with levels of fatigue. The existence of gray matter atrophy before the advent of white matter abnormalities, and the existence of metabolic abnormalities before the advent of gray matter pathology, rather argues against the proposition that the chronic peripheral immune activation and oxidative stress seen in early disease is secondary to the release of inflammatory mediators from the CNS. These observations, coupled with data demonstrating that the severity of neuro-inflammation depends on the level of peripheral immune activation and that inflammation drives the development of disease, emphasizes the likely causative role of peripheral pathology.

The strong association between the severity of fatigue and disability and the level and geographical distribution of glucose hypometabolism and gray matter hypoperfusion strongly indicates that these elements are driven by generic rather than disease specific pathology. These kinds of generic abnormalities are also evident in Parkinson’s Disease where peripheral immune activation, oxidative stress, GM atrophy and widespread glucose hypometabolism are all evidenced in the very earliest stages of disease development. It is also noteworthy that the prevalence of severe intractable fatigue increases with the degree of disease progression and that the degree of peripheral inflammation and levels of proinflammatory cytokines are predictive of disease development and severity. When viewed as a whole these observations also support the view that severe intractable fatigue results from processes which are not disease specific but involved in disease pathogenesis.

The existence of chronic peripheral inflammation and immune activation together with GM atrophy and glucose hypometabolism in patients with first episode depression is now a textbook truism. Interestingly, the pattern of neuroimaging abnormalities and GM pathology appears to be quite distinct from that seen in patients with neuroimmune and autoimmune diseases for reasons which are not yet clear. This pattern of peripheral inflammation and immune activation is also found in autoimmune diseases with levels of oxidative stress and proinflammatory cytokines having a causative role in the pathophysiology of SLE and displaying positive correlations with objective markers of disease severity. This is also true of patients with Sjogren's syndrome where objective markers of disease activity are reduced by cytokine blockade. There is also evidence demonstrating that the severity of fatigue is associated with the degree of white matter hyperintensities in people with SLE and evidence that the neuropathology in Sjogren's syndrome is immune mediated.

The widespread mitochondrial dysfunction seen in people with autoimmune diseases could also make a significant contribution to the development of fatigue. Widespread mitochondrial dysfunction, in otherwise normal tissue, is also seen in patients with MS, Parkinson’s disease and in many patients with apparently idiopathic fatigue. Given that many such patients also display evidence of peripheral immune activation, oxidative stress, gray matter pathology, glucose hypometabolism, hypoperfusion and metabolic abnormalities in the prefrontal cortex, basal ganglia and elsewhere, it would seem reasonable to investigate all such patients for the presence of these abnormalities. Standard MRI is unlikely to be helpful but other approaches discussed in the main body combined with serum measures of immune activation and oxidative stress may well bear fruit.

(Figures can be found HERE.)

As these mechanisms are extensively inter-related, it should be underscored that without a solid prospective timeline and known systems biomedicine, it has remained difficult to distinguish causation from association. Therefore, future research should delineate: 1) the overwhelmingly complex and dynamic interactions between these different pathways and the intracellular networks that modulate them; and 2) the multifactorial triggers that cause secondary fatigue by activating the networks/pathways in those disorders, including viral and bacterial infections, bacterial translocation, psychosocial stressors, exposure to adjuvants, nicotine dependence, sex- and gender-related factors, and so on. Towards this end, a systems biomedicine approach is essential to delineate the genetic and molecular signature of fatigue in these disorders and the non-linear interactions between the many pathways, networks, and trigger and genetic factors that underpin secondary fatigue.

Multi-targeting these interlinked dysfunctions may show benefit in these diseases. For example, a number of antioxidant compounds have demonstrated efficacy in modifying pathways leading to chronic inflammation, oxidative stress and immune dysregulation at relatively high doses for a long duration [7]. N-acetyl-cysteine is an example of a multi-target therapeutic approach having the capacity to decrease the levels of ROS/RNS, increase the levels of cellular antioxidants, such as reduced glutathione, and normalize the production of proinflammatory cytokines and immune cell functions [397]. This supplement has demonstrated the capacity to improve fatigue and disease activity in SLE, CFS and major and bipolar depression [7,398]. Omega-3 polyunsaturated fatty acids (PUFAs) and zinc are also very effective antioxidants and anti-inflammatory compounds and supplementation has produced clinical benefit in patients diagnosed with depression and chronic fatigue syndrome [7,399,400]. Omega-3 PUFAs also show a clinical efficacy in SLE and rheumatoid arthritis [398,401,402].

Curcumin, another nutraceutical with anti-inflammatory and antioxidative effects, is useful in the treatment of depression and rheumatoid arthritis [403,404]. Coenzyme Q10 is another powerful antioxidant and anti-inflammatory compound which also has positive effects on mitochondrial function and which displays disease modifying effects in Parkinson’s disease and produced clinical benefit in patients with a diagnosis of CFS [56]. Other approaches aimed at upregulating antioxidant defenses include N acetylcysteine, methylfolate and dimethyl fumarate, with the latter displaying disease modifying properties in MS [140]. Methylfolate produces a similar quantum of benefit in MDD as antidepressants and can often be effective in treatment-resistant depression [140].
It is concluded that there are sufficient robust multiple lines of evidence to support the proposition that the severe fatigue and profound disability experienced by people with the neurodegenerative, neuro-immune and autoimmune diseases discussed here is largely driven by peripheral immune activation and systemic inflammation either directly or indirectly by inducing mitochondrial damage. (Emphasis added.)

_____________________

Funding: There was no specific funding for this specific study.

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Competing interests: The authors declare that they have no competing interests.

Authors’ contributions: All authors contributed equally to the paper. All authors read and approved the final manuscript.

Contributor Information

Gerwyn Morris, Email: moc.liamg@ailgorcimdetavitca.

Michael Berk, Email: ua.gro.htlaeHnowraB@ebekiM.

Ken Walder, Email: ua.ude.nikaed@redlaw.nek.

Michael Maes, Email: moc.liamtoh@seamleahcim.rd.

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