Dr. Natelson study of Neurological Abnormalities in CFS

[Nielk]

http://www.research1st.com/2011/08/30/cfs-is-it-all-in-the-brain/

Reading this article about Dr. Natelson replicating a previous study of neurological abnormalities in CFS patients left me with a bad taste.

Why?

Because what he is describing what they are doing is dividing CFS patients by the fact whether they have co-morbid psychiatric diagnosis like Major Depression.

He says that the group who did not have this co-morbid diagnosis, showed more neurological abnormalities than the group who didn't show this co-morbid definition.

To me. it sounds like what he is saying is that patients who have been diagnosed with major depression do not really have CFS. He doesn't leave room for the fact that the major depression could very well be an outcome of patients who are very severely effected and therefore should show even greater neurological problems.

Am I reading this wrong?

 

[Firestormm]

Very interesting follow up Nielk. Am reading through it all now...

Edit: Might help for peeps to see the whole article:

CFS: Is It All In The Brain?

By Benjamin H. Natelson, MD
Director, Pain & Fatigue Study Center, Beth Israel Medical Center
Professor of Neurology, Albert Einstein College of Medicine

An exciting study published in February (2011) in the journal PLoS One by Schutzer et al revealed that a group of CFS patients had more than 700 unique proteins in their spinal fluid as compared to patients with Lyme disease and normal controls. Long-time CFS clinician and researcher Dr. Benjamin Natelson was a member of that research team, and Research1st asked him to comment on the studys next steps.

All of the work in my group is based on the understanding that any clinical syndrome is comprised of subgroups of patients each with its own pathophysiological cause for the same syndromic presentation. Because of the lack of a commonly acknowledged biomarker, we have used clinical differences among patients with chronic fatigue syndrome (CFS) to establish subgroups to test this basic assumption.

The method of splitting patients into subgroups that has produced the most promising results to date uses the presence or absence of co-morbid psychiatric diagnosis, usually major depressive disorder, as its basis. Over the course of the last 15 years, my colleagues and I have found that the no-psych group had more problems with neuropsychological testing, more abnormalities on brain magnetic resonance imaging, more abnormalities in spinal fluid and higher levels of cerebroventricular lactate than patients who had psychiatric comorbidity.

These results lead us to hypothesize the existence of a neurological group, that is, a group of patients with brain pathology as the cause of their illness. While this hypothesis was strengthened by our repeatedly finding more neurological abnormalities in the no-psych group compared to the psych group, a problem existed namely that each was done independently of the other, with different groups of patients participating in the different studies. We thought that an important next step would be to do all these studies on the same patient volunteer.

That idea has been supported by our successful application for an NIH grant to do precisely this. Thus, we will use a structured clinical diagnostic interview for psychiatric illness to determine if a patient falls into the psych or no-psych groups. Then we will assess neuropsychological function using tests of executive motor capacity such as complex reaction time performance and ability to repeat numbers forwards and backwards. We will also do brain imaging, in which we will quantify cerebroventricular lactate and determine if the scan is normal or shows an anatomic abnormality. Finally, we will perform lumbar puncture on our patients to determine if the no-psych group continues to show taps with higher white cell counts or higher protein concentration than patients in the psych group.

We expect to find higher rates of abnormalities in the CFS-no psych group than in the CFS-psych group. That finding would strongly support brain dysfunction as the cause of fatigue in this patient subgroup and will lead to new studies to explore the pathophysiology underlying these findings.

The one requisite for patients volunteering for this study is that they be off any (central nervous system) CNS-active medication for at least 10 days. Thus, to complete this study, we will need the cooperation of physicians in the New York-New Jersey area to consider referring patients to us for study.

While we feel this approach, based on clinical differences between patients, will be helpful in moving our knowledge ahead, we are very excited by the outcome of our collaborative work on the spinal fluid proteome. The method uses high through-put mass spectroscopy to identify all the proteins in one sample. In the one study done to date, we pooled spinal fluid from CFS patients and compared its protein constitution, that is, its proteome, to that of patients with similar symptoms but a known cause Lyme infection.

Importantly, we found a large number of proteins discrete to each of the fatiguing illnesses. Finding these proteins suggest they may be useful as biomarkers of each illness.

However, there are important next steps waiting to be done. First, using samples of spinal fluid from patients not previously studied, we have to determine if we can replicate finding a set of unique proteins that would allow the identification of CFS patients relative to healthy controls. Because of improvements in technique, we will be able to do this on an individual patient basis rather than having to pool samples in order to get the volume needed for assay. Moving from pooled to individual samples will certainly allow us to determine which patients are positive for a diagnostic marker comprised of several uniquely occurring spinal fluid proteins.

And of equal importance, we hope to do additional spectroscopic studies to determine if and how the proteome of the CFS no-psych patient differs from that of the CFS psych patient. If, as we expect, proteomic differences exist between these two subgroups of CFS, we will be well on our way to hewing out a group of patients those with apparent brain dysfunction for specific therapeutic trials based on information provided in their proteome as to the possible metabolic pathways affected.


Benjamin H. Natelson received his bachelors and medical degrees at the University of Pennsylvania in Philadelphia and then did his neurology residency at the Albert Einstein College of Medicine in New York City. Following that, he did two postdoctoral fellowships, one in behavioral neurosciences at the Cornell University Medical Center in White Plains, N.Y.; and the other in physiological psychology at the Walter Reed Army Institute of Research in Washington, D.C. Dr. Natelson moved to the New Jersey Medical School in Newark and the Veterans Administration Medical Center in East Orange. He rose through the ranks, becoming professor of neurosciences in 1981 and leaving in 2008 as an emeritus professor. He had continual funding from the VA through 1999 for his experimental work on stress and chronobiology. With the award of a federally funded research center to explore the causes of CFS in 1991, Dr. Natelson shifted his research to studies of humans with CFS, and more recently has extended those studies to include those with fibromyalgia. He has served as president of the Pavlovian Society and of the Academy of Behavioral Medicine Research. He has over 230 papers published in peer-reviewed journals and has authored three books. In 2008, Dr. Natelson has moved his activities to the department of pain and palliative care at the Beth Israel Medical Center in Manhattan, where he directs the Pain & Fatigue Study Center. In that capacity, he also serves as a professor of neurology at the Albert Einstein College of Medicine.

 

[Firestormm]

So yes is the answer to your question but they have received funding to properly test the hypothesis. It doesn't imply that there are no neurological abnormalities in the 'psych' group but that they are more distinguished in the 'non-psych' group.

A more rigorous evaluation of what constitutes a 'psych' patient or one with co-morbidity will be applied to test this theory. If doctors did their jobs properly (yeah yeah they can't I know) then co-morbidity should be ruled out before diagnosis of 'ME or CFS' - in this case 'CFS'.

Then again, it ain't so straightforward is it? But this is what people have been asking for in a lot of ways and here it is. More important I think is the development of biomarkers. There is nothing to say that those in the 'psych-group' will not have such things - just that in order to better assist in tracking them down they need as 'pure' a sample of patients as possible.

If that sounds a poor interpretation then do say so. It is only my opinion based on the above

 

[Nielk]

So yes is the answer to your question but they have received funding to properly test the hypothesis. It doesn't imply that there are no neurological abnormalities in the 'psych' group but that they are more distinguished in the 'non-psych' group.

A more rigorous evaluation of what constitutes a 'psych' patient or one with co-morbidity will be applied to test this theory. If doctors did their jobs properly (yeah yeah they can't I know) then co-morbidity should be ruled out before diagnosis of 'ME or CFS' - in this case 'CFS'.

Then again, it ain't so straightforward is it? But this is what people have been asking for in a lot of ways and here it is. More important I think is the development of biomarkers. There is nothing to say that those in the 'psych-group' will not have such things - just that in order to better assist in tracking them down they need as 'pure' a sample of patients as possible.

If that sounds a poor interpretation then do say so. It is only my opinion based on the above

I hear what you are saying. In an ideal world, patients who had an initial diagnosis of major depression, should not have been diagnosed as having CFS or ME to begin with.
I just think that many patients who have true CFS/ME develop major depression at times AS A RESULT OF their severe chronic illness state and they should be distinguished from those who have had an initial diagnosis of psychological depression disorder who mimic many symptoms of CFS.

 

[Wonko]

I agree, it seems odd, in one way, to split the patients into psych and non psych before running tests to see if they are psych or non psych patients biologically (according to thsi hypothesis) - surely if they are going to be runngi the same tests anyway it would be better to split after testing and avoid pre-bias'ing the patients?

 

[Valentijn]

It could be that the CFS-psych group is a mixture of people with and without real CFS. So still some CFS-indicative abnormalities, but not the strong correlation as in the non-psych group.

Or maybe it's a different manifestation of ME/CFS that triggers major depression.

 

[Enid]

I don't in any way recall depression as part of the problems as this disease progressed but as all bodily systems - infection or whatever continued a downward spiral I do recall what is known "clinical" depression - that is a "systems" shut down to the point of barely functioning at all - nothing to do with a psychology of depression at all - depressed "systems" is a more accurate description if/when encountered in ME. So one wonders what their definition of depression is (co-morbid or not).

 

[Firestormm]

In the good old UK our physicians have the Map of Medicine to help them diagnose and understand the relevant guidance (relevant to the authorities of course).

Said Map of Medicine in respect of CFS/ME says the following and I think it relevant to this debate:

'Consider differential diagnoses

Many conditions may present with symptoms similar to chronic fatigue syndrome and myalgic encephalopathy (CFS/ME) which may also co-exist with other chronic disorders.

The following are common differentials:

anaemia
autoimmune disorders:
lupus
rheumatoid arthritis (RA; see 'Rheumatoid arthritis' pathway)
cardiopulmonary:
chronic cardiac failure
chronic pulmonary disease
obstructive sleep apnoea (see 'Obstructive sleep apnoea' pathway)
drug use:
antihypertensive agents, especially beta blockers
hypnotics
antidepressants
thyroxine
alcohol or drug abuse
alcoholism
endocrine and metabolic disorders:
hypothyroidism (see 'Hypothyroidism' pathway)
apathetic hyperthyroidism
pituitary insufficiency
adrenal insufficiency
renal and liver decompensation
diabetes mellitus (see 'Diabetes' pathway)
hypercalcaemia
gastrointestinal disorders:
inflammatory bowel disease (IBD)
coeliac disease (see 'Coeliac disease' pathway)
immunodeficiencies
infections:
infectious mononucleosis
viral hepatitis
cytomegalovirus (CMV)
infective endocarditis (see 'Infective endocarditis' pathway)
tuberculosis
HIV infection (see 'HIV' pathway)
inflammatory arthritis or connective tissue disease
neurological and neuromuscular disorders:
multiple sclerosis (MS; see 'Multiple sclerosis' pathway)
muscular dystrophy (see 'Muscular dystrophy' pathway)
post-polio syndrome (PPS; see 'Post-polio syndrome' pathway)
occult malignancy
psychiatric and psychological disorders:
anxiety
depression
somatisation disorders
bipolar disorders
eating disorders
organic brain disease
sleep deprivation

Reference:

Royal College of Paediatrics and Child Health (RCPCH). Evidence based guideline for the management of CFS/ME (Chronic Fatigue Syndrome/myalgic encephalopathy) in children and young people. London: RCPCH; 2004.'

http://healthguides.mapofmedicine.c...rome_and_myalgic_encephalopathy_cfs_me_1.html

I don't want to get into the other differential diagnoses, but the point is if they are able to successful sub-categorise and alternatively diagnose at this point, and treatment works, then patients should not end up with the CFS/ME diagnosis.

However, as has been said, depression can and does become an issue for patients with ANY long-term chronic illness.

Further there have been other studies (brain imaging for example) demonstrating that those with depression primarily can be determined from those with 'ME'.

As I said my own interpretation of the above, is that they will seek a 'pure' sample of 'CFS' patients by excluding those with co-morbid depression. This seems sensible as the preliminary results are indicating that neurological signs are most observable in this 'pure' cohort.

If this is true that the biomarkers i.e. the protein analysis from spinal fluid, might be more easy to define. These could then be looked for among those with co-morbid depression and even other patients in the wider 'pool' diagnosed with 'CFS' such as those with Fibromyalgia perhaps or any other co-morbid diagnosis.

Who know? We will have to wait for the research as per usual.

 

[eric_s]

I would not feel bad about this article, to the contrary. I think the Schutzer et al. proteomics study was one of the most exciting findings besides XMRV for at least some time and it's good to see they are following up on this and they have funding available.

Whatever they will find, if they find something, it will help understand things better. I don't read the article this way that they say people with co-morbid depression don't have "real CFS". I think any new findings, if they are not wrong, help us all and the better they understand ME/CFS, the smaller the chance people will get the wrong diagnosis or wrong treatment.

I was a bit surprised though, that in their first proteomics study they pooled samples. Couldn't it then be that they only had one patient in there where all these abnomral proteins came from? It's good they are now getting a chance to replicate this study.

 

[Firestormm]

I think the original study was on the small side Eric so hopefully now this has pointed to some interesting conclusions the new funding will lead to a bigger and more defined cohort.

I posted some of the original links elsewhere but they might be of use here as well:

This was the original Research into Lymes and CFS Spinal Fluid Proteins. It is what began this story and I noticed the previous links were no longer active:

23 February 2011: Article: http://www.sciencecodex.com/spinal_...sh_lyme_disease_from_chronic_fatigue_syndrome

23 February 2011: CBS News and Video: http://www.cbsnews.com/stories/2011...0035610.shtml?tag=cbsnewsTwoColUpperPromoArea

23 February 2011: Amy Dockser Marcus Wall Street Journal: A Step Closer to Tests for CFS: http://blogs.wsj.com/health/2011/02...or-chronic-fatigue-syndrome-and-lyme-disease/

23 February 2011: Original Research Published in PLoS ONE: Distinct Cerebrospinal Fluid...: In Full: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017287

Hopefully the links work. Fukuda was the criteria used for CFS definition I believe.

 

[Enid]

Yes I agree eric - unique proteins in the spinal fluid was quite a find. Must say at the time of my own neuro investigations (hardly moving and speechless) "high spots" found in MRI brain scan - lumbar puncture all I was told was higher than normal pressure. It was early days but it occurred to me that "something" should have been found then before the years of incapacities.

 

[eric_s]

Your story is really quite unbelievable, Enid. All these symptoms you mention, but they couldn't find anything that's causing it, right? Thanks for the links, Firestormm. I hope it will not take too long for the new study/studies to get published. I think it took a couple of years between the two latest Baraniuk studies (who's looking at similar things), if i'm not mistaken, and that's just too long for us...

 

[eric_s]

Just imagine we had 100 or more people like Natelson working on this same matter with 100 M $ or so at their disposal. That's what moves me to try to do something, the reason we are where we are is just that there are not enough people with too little money trying to figure out how we could be helped.

 

[Enid]

No, no diagnosis at my neuro-investigation stage (this was 8 years ago) but the Consultant did say "could be ME - they think it's viral - find someone who knows and I will release my findings"- but at least it's moved on from there I feel eric. I hope your KDM treatments are aiding.

 

[eric_s]

Maybe best to not take this thread off topic too much, but am i understanding you correctly that in the UK the doctor will decide who he gives his material to? You don't have the right to ask him to hand it out to you? If that's the case i'm really happy i don't live there.

 

[Nielk]

I'll tell you what is my problem with this new study.
I am as excited as the next person that there is funding for further study and it is a study that already showed promise in the past.
I am disturbed about the way they are selecting and dividing the ME/CFS patients and I'll tell you exactly why.
First of all, just by reading different threads here on the forum or other patients' accounts, it is obvious that the more severely affected go through stages of depression and were they tested at those times by a psychiatrist, I have no doubt that they would be given a diagnosis of major depression. We are talking about our sickest patients here.
In addition, I have personal experience with Dr. Natelson. I had gone to him for a consult when I was three years into my illness. At that time, I was taking anti depressants, even thou I was not depressed at the time but that is what my GP advised.
The anti depressants were not helping - they were making me sicker. Since then I have been able to get off them years ago and will not touch the stuff because I know my body is sensitive to it.
Dr. Natelson took some tests - one of them being a form of tilt table test and prescribed support stockings. He also sent me to a sleep study test which showed remarked problems with my sleep. Mainly my sleep being constantly disturbed by intruding alpha waves. He didn't take any MRI, Spect scan or other neurological testing.
When I was fighting with my private disability insurance, I had to tell them all the doctors I had gone to and they requested my file from them and they also asked them the question whether they believe my problem is psychological or biological.
I got a copy of all my file from the insurance company because by law they have to supply it to me if requested.
I was shocked to read Dr. Natelson's answer. He wrote that it's true that this patient suffers from clinical depression (?????) but. the results of her sleep study shows so much alpha intrusion that she lacks proper sleep and therefore he function capabilities are probably decreased.
I don't know how these patients in the study will be diagnosed with major depression. Will it be by a professional psychiatrist? How will they know if the psychological problem is the primary problem or just a result of being chronically sick for many years, being isolated in bed and with constant suffering.
I also think that there is a great fluctuation of how a patient feels mentally and it directly co-relates with the severity of their symptom at that specific time.
How many ME patients have committed suicide? How many more have tried? How many have thought about it? I know I have, a number of times. But, each time it was due to an escalation of my suffering.
I am not convinced that Dr. Natelson understands this distinction.

 

[Esther12]

I think that sub-dividing is absolutely the way to go.

I really doubt that there will be a simple division between 'CFS with psychiatric diagnosis' and 'CFS without' - but there might still be useful differences between the two groups which will lead on to furthering our understanding. There may be useful divisions between 'viral trigger' and 'non-viral trigger', 'with chronic pain' 'without chronic pain', 'with connective tissue problems', etc, etc. I expect that all of us will end up falling in to different little sub-divisions while we move towards understanding what's going on... but this sounds a much more sensible approach than lumping everyone in together, and assuming that only if an abnormality is common for all that it is significant for some.

I understand people's concerns, but at this early point in research, I don't think this approach is going to cause anyone any problems.

While I expect that many of us have different causes for our disability, we all understand what it's like to be seriously ill, and stuck with a disdained diagnosis like CFS. There's a shared understanding and sympathy that would not be broken down by any successful sub-grouping.

 

[Francelle]

What exactly are considered to be the broad subset of neurological symptoms in M.E. as compared to the neurological symptoms for the purposes of this study? They may be different in that the study may not ask about or investigate the broader number of neurological manifestations but may hone in on only certain ones.

For me I have no idea of what a SPECT or fMRI may reveal as I have never had them done. However neurological symptoms have been abundant. These include for instance widespread neuropathic pain 24/7, fasciculations, Gastroparesis (paralysed stomach) & oesophageal dysmotility, balance issues, orthostatic intolerance, as well as, initial extreme fatigue (nowhere near so bad now). I do not have depression. I have other symptoms which I do not know if they are neurological or not like extreme muscle stiffness - like I have climbed a mountain everyday.

ALL of these symptom's onset were within a few months of each other and I had never experienced them prior to July 2007. I have come to see that they are all part of a very specific disease process and not ad hoc occurences. Furthermore apart from the fasciculations which have reduced hugely (from 30,000 per day to about 100 per day) none of the other neurological symptoms have abated.

What other neurological symptoms are commonly experienced by others on this board?

 

[Enid]

All the same as you Francelle together with severe short term memory loss (including non recognition of faces/names/even say non recognition of a plug in a sink and it's purpose) - severe headaches and mental ehaustions along with the physical, restricted speech ability, loss of consciousness twice and severe sleep problems (inability to or the opposite sudden "get up and go" energies). All this has eased but I'm left with the GI, need of much rest,sound/noise, and what appears to be reactive arthritis problems.(Well my Neurologist thought that one). I'm a prime candidate for the Canadian Concensus - the very best description of the lot.

I'm all for spinal fluid researches and catching it all there.

 

[Firestormm]

As I said before my 'take' on this - and it is only a follow-up commentary, is that the neurological signs were stronger in the patient cohort with no depression (whether existing at the time of diagnosis or subsequent to it).

It is a hypothesis that he feels is necessary to explore further. He did say that even in the 'psyche-group' the signs were there just not - I believe - as easy to recognise.

Once the signs (signs being my lay-person's word) have revealed more distinct biomarkers they can then be used in the 'psyche-group' too to better diagnose 'CFS'.

I don't believe this is intended to say 'You do not have CFS' in the least. As Neilk says depression can exist as a secondary symptom of chronic illness - I suffer from it especially badly when I relapse and fall from my hard-won plateau.

The question of recognising correctly whether someone is suffering from depression is such a grey area when it comes to science that it will always - I think - be controversial.

But as was said before one way of determining this might be the way in which you respond to depression treatment. Trouble is - again as Neilk inferred - 'many' people with CFS or CFS/ME in this country are prescribed anti-depressants and not always for depression but for pain.

Still, there are recent studies showing brain imaging identifying those with depression vs. those with 'CFS/ME'. Further to this and to muddy the waters even more, at a recent International Psychiatrists Conference over here in Brighton (June) they were again discussing the role of brain inflammation in depression.

The point remains though that the original study was able to determine through proteins I believe in spinal fluid key differences between Lyme's and 'CFS'. This sub-categorisation (for research purposes only) of 'psyche' and 'non-psyche' (awful names by the way - might lead to a better identification within the 'CFS' cohorts.

In the UK when it comes to who can you see - there is a relatively new means of self-referral. Indeed it is being encouraged in some quarters. I don't know much about it but it came up in a recent meeting I was able to attend with the NHS. So you might be able to shortly ring a neurologist for example and self-refer. Whether we can get to the point where we can 'demand' specific tests and/or treatment I don't know - doubt it really - but hey - power to the people!