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The CFS/ME Brain Is Inflamed

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By Richard N. Podell, M.D., MPH

For most people with Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) central nervous system function is abnormal. However, we don’t understand the mechanisms involved. Many experts suspect an inflammatory component, but the results from cytokine studies of cerebrospinal fluid have been uncertain.

Now, researchers at the RIKEN Center for Life Science Technologies in Hyogo, Japan, have directly measured neural inflammation using a combination of PET scan and MRI imaging. (1)

Their key findings: Compared to healthy controls, nine patients with CFS/ME showed evidence of abnormal activation of microglia and/or astrocyte immune cells within the brain. In specific brain areas the degree of immune activation correlated closely with the severity of the patients’ symptoms.

Positron emission tomography (PET) is a nuclear medicine technique that produces a three-dimensional image of physiological processes within the body. PET works by attaching a gamma ray emitting tracer to a biological molecule that is normally processed by specific cell types. Appropriate computer soft ware can construct a three-dimension image of the tracer’s concentration. A concurrent MRI or CT scan further defines the anatomical locations.

The tracer for this study (called 11-C-(R)-PK111995) attaches to a specific translocator protein called TSPO. When microglia or astrocytes are metabolically active TSPO is expressed. PET scan imaging of TSPO is a standard technique for studying inflammation in neurological disorders.

For the nine patients in this study the intensity of PET imaging was substantially higher among the CFS/ ME patients compared to controls in the following brain areas: The cingulate cortex, hippocampus, thalamus, mid brain and pons.

Equally impressive, there was a high correlation between the TSPO image intensity and the severity of the patients’ reported symptoms. For example, the peak value signal within the left thalamic intralaminar nucleus was highly correlated with the cognitive impairment score. (r=0.86; P=0.0028) and also with the patients’ intensity of fatigue (r=0.63; P=0.0683).

If further studies confirm these findings, we should ask the following questions:

Why are the brain’s immune cells inflamed?

  1. Is there an on-going infectious process? Did an initial but no longer active insult trigger sustained inflammation? Is the inflammation responding to other nervous system damage e.g. over-activity of neurons to compensate for the functional limitations caused by CFS/ME?

  2. Would it be useful (or harmful) to suppress this inflammation using drugs or natural products?

As a clinician I’ll focus on the second question.

Standard anti-inflammatories such as ibuprofen and prednisone do not help. However, other anti-inflammatories work through different pathways. Might these be worth trying?

For example, low dose naltrexone (LDN) is believed to have a “calming” effect on brain microglia cells. Two double blind studies from Stanford Medical School show improvement in fibromyalgia symptoms with LDN treatment. (2)

The tetracycline derivatives Minocycline and Doxycycline have well recognized anti-inflammatory effects. Colchicine, and pentoxifylline can act as anti-inflammatory. Quite a few herbs do as well. These include curcumin, panax ginseng, green tea, resveratrol, and Ginger. (3) None of these have been systematically tested for CFS/ME. All could be considered to be “relatively” safe.

In contrast, Rituximab, a powerful and potentially toxic B cell suppressor has one double blind study from Norway. This found a statistically significant advantage for Rituximab over placebo, dramatically reducing the symptoms of CFS/ME. (4) Fortunately, the investigators were able to fund a replication study, which is now under way.

In contrast, in the USA and most other countries CFS/ME remains an orphan disease. So it’s not likely that we will see double blind studies of treatments any time soon In the meantime, should CFS/ME clinicians selectively offer (with proper informed consent) empirical treatment with anti-inflammatory medicines or herbs? Your thoughts will be appreciated.


(1) Nakatoni, Y, Watanabe, Y, Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11 C-R-PK11195 PET Study, J Nucl Med published on March 24, 2014 as dol:10.2967/jnmed.113.131045 

(2) Naltrexone and Fibromyalgia: Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014 Apr;33(4):451-9. doi: 10.1007/s10067-014-2517-2. Epub 2014 Feb 15. Note; You can read the free article here.

(3) Natural Products and Microglia: Choi, D, Koppula, S, Suk, K, Inhibitors of Microglial Neurotoxicity: Focus on Natural Products, Molecules, 2011, 16, 1021-43l doi =L 19,3390/molecules 1602021

(4) Fluge Ø1, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, Næss H, Dahl O, Nyland H, Mella O. Benefit from B-lymphocyte depletion using the anti-CD20 antibody Rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10):e26358. doi: 10.1371/journal.pone.0026358. Epub 2011 Oct 19. Note: You can read the free article here.

Richard Podell, M.D., MPH is a graduate of Harvard Medical School and the Harvard School of Public Health. He has been treating patients with ME-CFS and Fibromyalgia for more than 20 years. A clinical professor at New Jersey’s Robert Wood Johnson Medical School, Dr. Podell see patients at his Summit, NJ and Somerset, NJ offices.

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7 thoughts on “The CFS/ME Brain Is Inflamed”

  1. skeptik2 says:

    The Japanese PET studies are very interesting and very important. I am grateful for their work, and for Dr. Podell highlighting them in this article.

    There is only one problem: when it is suggested that ME/CFS clinicians treat patients with the suggested medicines and/or natural products, my first thought is this: do I really want to travel at least 200 miles to get a script or suggestion and be followed for symptom relief.

    You see, probably 900,000 of us do not live near a clinician that even has a clue. Maybe the other 100,000 do live near one, but it all boils down to one thing:

    No Tests=No Treatment

  2. shewolfdc says:

    I took my daughter overseas to get her set up to go to school. I was desperate to be able to be there for her and not have a relapse while there. Since those of us with ME have nothing to take to help us, I just started taking ibuprofen like candy. Three or four every four hours. I knew it was bad for me but I was desperate to share this experience with my daughter. To my surprise I was able to complete the trip without a flare. I told my doctor about that and suggested to him that inflammation might be an issue. He works with a elderly doctor who he said swears by flurbiprofen so he prescribed some for me. I’ve been taking this for several years and see amazing results in the clarity of my brain and ability to do things without a flare. I particularly notice its affects on my mood. When I start to feel depressed it’s often that I realize that I forgot to take the drug for a couple of days. If I’m going to do anything active that I know might trigger a flare, I will take two of these before the activity. I know this article says that ibuprofen doesn’t work but maybe you just have to be desperate enough to take an unhealthy dose. – which I am not suggesting anyone do. Please don’t do it. I just end wanted to explain from my own personal experience how I discovered that inflammation may indeed be a factor.

  3. friend_of_cfs says:

    I take supplements and over time have found many that are helpful. I usually have to educate my doctors about what and why. Antivirals have been very helpful, both herbal and pharma, so I figure the herpes family viruses that I take them for cause the neuroinflammation that the Riken group found. Other stuff that works for me are hydrocortisone (also anti-inflammatory, it helps clear my thinking), s-acetyl glutathione (brain and liver detox), idebenone (a Co-Q10 analogue that stimulates nerve growth hormone) and BH4, or tetrahydrobiopterin, which is a critical cofactor for synthesizing serotonin, dopamine, NO2 and for clearing ammonia and peroxynitrite. I also like phospholipids and low dose DMSA. And bio-identical estrogen and progesterone. Low estrogen in older women causes lots of dementia and is rarely tested for. It does seem to help my cognition so I like it a lot.


  4. friend_of_cfs says:

    As to your question, should clinicians offer them. Sure, why not. If you are a dedicated physician, you’ll do whatever works. And if they are non-toxic, or nearly so, there’s not much risk. I muscle test everything and get other people to test me once in a while, but even if I don’t, I rarely have problems, and I’ve been doing this for years. When I couldn’t afford health insurance, I became my own doctor, and really, we all are, we just don’t know it. But it’s what you do on a daily basis that makes a difference more than anything. My prescription is diet, nutritional supplements, and a careful selection of drugs, plus sunshine, mild exercise and being out in nature. If you meditate, or have some spiritual or energetic practice that can clear your system, that really helps. But the most important thing is to make a good effort, and not passively wait for someone else to heal you. To me, a doctor is a teacher, and a partner for my healing journey. My job is to listen and to learn and then use my best judgement.

    1. WendyBurnett says:

      I also became my own doctor when I lost my insurance back in 2008, and have also discovered the inflammation link. I use several anti-inflammatory herbs (ginger and turmeric are the main ones, but I also use others) and multiple supplements when I can afford them. I can actually manage my fibromyalgia much better with herbs and supplements than I ever could with the extremely expensive medications I was on before, and I don’t have any side effects or negative reactions with them. No more polypharmacy for me! I have less pain, less fatigue, and a much better quality of life now, and have even been able to go back to work (doing a very physical job that I could never in a million years have handled on all the medications.)

    2. I'milltoo says:

      3 years later and this all went very quiet … any news?

  5. Mattiera says:

    Very informational article. I have taken LDN. Received no help from it. I just started using Curcumin about a month now and I think I am feeling some help. I am going to add Reservatal. I take extra B 12 and B Complex with Magnesiumn and 1500 mg of Vit. C. all of this seems to help but I still can’t deal with good or bad stress which makes my body and mind dysfunctional. This is hard to live with. My neurologist has me on 0.5 Clonasapam, 2 at bedtime. I also can take up to 2 more during the day as needed. It is hard to predict when you are going to stress out, so by the time you take the medicine you are already stressed , and the body and mind are already not functioning normally. My blood work shows no Inflamation in my body???

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