Komaroff is an Idiot

I have to revise the high opinion I had of Anthony Komaroff. He jumbles all kind of definitions together and muddies the waters (when he should know better):

… What is fatigue? It's a sensation of sleepiness, muscle weakness, or a feeling that you don't have the energy to do something - either physical or mental. It's the brain that experiences fatigue; that means there are certain chemical changes in the brain that lead to fatigue - even though those chemical changes may be triggered by many different illnesses. …

Komaroff, what the heck????

No, no, no. Fatigue is not "sleepiness". Sleepiness is the urge to sleep – and you can be fatigued without being sleepy. Somnolence is "sleepiness". "Tiredeness" is maybe a combination of fatigue and "sleepiness". But one can be very well fatigued without being tired. Being chronicly "sleepy" and being chronicly "fatigued" are two different symptoms! Were you find one, it is not unusual to find the other, but they a separate sensations.

And fatigue is not the feeling of "muscle weakness". Yes, fatigue and the feeling of "muscle weakness" can go together (e.g. after doing way do much physical work) – but one can be very well fatigued without having the feeling of "muscle weakness".

Yes, one could say fatigue is the feeling that one is "lacking energy".

But for crying out loud, what is the problem with saying:
Fatigue is the feeling of EXHAUSTION.

Or you could bloody well say:
Fatigue is having the urge to rest.

And no, no, no. Fatigue (like for example the feeling of pain) is not simply "chemical changes in the brain". Both pain and fatigue are signals of the physical state of your body – if pain is the gauge of the engine temperature, then fatigue is the gauge of the petrol tank. If pain tells you "Mate, if you keep doing that, something is going end up on the fritz pretty soon", then fatigue tells you "Mate, you are running on reserve, take a rest and replenish your energy or you'll end up with power". Pain is (usually) alleviated by stopping the action that causes the pain, and fatigue is (usually) alleviated by resting. The cause is (usually) not in the brain, it is only registered in the brain.

Words fail me how someone like Komaroff, who is so seemingly methodical, can be so confused with elementary definitions of the diseases he deals with. And I find it shocking that he spreads this confusion.

PS: It is however interesting that he mentions both mental and physical fatigue, but alas, he does it not in a way that is helpful.

Komaroff and his Ampligen Vote

Anthony Komaroff voted against the FDA approval of Ampligen. Now there is some huffing and puffing in the ME/CFS blogosphere about this (which I will not dignify with a link): Some are writing that he is removed from the ME/CFS patient population (and that could as well be from Mars, not from Earth). Some paint him as a sort of underhanded malicious villain (and presumably bought by someone).

Personally, I think this is utterly stupid.

There is an article posted on "Medscape Medical News" (via) that sheds some little light on Komaroffs decision:

Anthony Komaroff, MD, Simcox/Clifford/Higby Professor of Medicine at Harvard Medical School, Boston, Massachusetts, voted no on both efficacy and safety. "As a physician who has cared for many of these patients for nearly a quarter of a century, nothing would please me more than solid evidence of an effective therapy, but I think there are enough questions about the conduct of the studies that it does not meet the standard of adequate evidence."

Even if I don't know the details behind his decision, I think his explanation is reasonable. It is reasonable to vote agains a drug, if one thinks that there are questions about the conduct of the drug studies. And my impression is that Anthony Komaroff never says or does anything without having the facts to back him up. If he says the FDA should not approve Ampligen, we should better listen.

And just because there is no currently approved drug for ME/CFS, that does not mean we should accept badly done drug studies.

What if Ampligen does not work as we hope? What if its efficiency or safety are actually worse than what the patient anecdotes suggest? In that case an approval could do us some serious harm. Directly, by harming patients who receive the drug and by costing money needed for proper research. And indirectly because "we" lobbied for an ineffective and/or dangerous drug. This would play right into the hands of the psychobabblers.

And what is really awful, that we see like in 2010 with the XMRV-fraud the same stupid behavior by "patient advocates" and "patient activists", who treat critics like villains. Case in point in 2010 was John Coffin who (rightfully) criticized Mikovits, who said nothing but the truth (and that in a very polite and unassuming manner), and who in turn was portrayed by "patient advocates" and "patient activists" as if he were the baby-eating-anti-christ himself.

And now it seems that Komaroff is the target of this misguided anger.

So, let me tell all those stupid "patient advocates" and stupid "patient activists" out there:
It is you, who are malicious. By ignoring valid criticism. By ignoring the valid reasons behind the criticism. By ascribing malicious motives to critics, motives that only exist in your head.

With friend like these "patient advocates" and these "patient activists", we don't need enemies.

ME/CFS Study: EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients - A case control study

You have to hand it to Anthony Komaroff, he makes sure that his work is solid (even if that means moving the research ahead a bit slower...). Not only did he enroll 70 patients with ME/CFS (which already is a lot) and 24 patients with major depression, but furthermore he enrolled 148 (!) patients with "general fatigue" (not evaluated whether they meet CDC/Fukuda) and 390 (!) healthy controls.

EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients - A case control study
Abstract (provisional)

Frank Duffy, Gloria McAnulty, Michelle McCreary, George Cuchural and Anthony Komaroff

Background
Previous studies suggest central nervous system involvement in chronic fatigue syndrome (CFS), yet there are no established diagnostic criteria. CFS may be difficult to differentiate from clinical depression. The study's objective was to determine if spectral coherence, a computational derivative of spectral analysis of the electroencephalogram (EEG), could distinguish patients with CFS from healthy control subjects and not erroneously classify depressed patients as having CFS.

Methods
This is a study, conducted in an academic medical center electroencephalography laboratory, of 632 subjects: 390 healthy normal controls, 70 patients with carefully defined CFS, 24 with major depression, and 148 with general fatigue. Aside from fatigue, all patients were medically healthy by history and examination. EEGs were obtained and spectral coherences calculated after extensive artifact removal. Principal Components Analysis identified coherence factors and corresponding factor loading patterns. Discriminant analysis determined whether spectral coherence factors could reliably discriminate CFS patients from healthy control subjects without misclassifying depression as CFS.

Results
Analysis of EEG coherence data from a large sample (n=632) of patients and healthy controls identified 40 factors explaining 55.6% total variance. Factors showed highly significant group differentiation (p<.0004) identifying 89.5% of unmedicated female CFS patients and 92.4% of healthy female controls. Recursive jackknifing showed predictions were stable. A conservative 10-factor discriminant function model was subsequently applied, and also showed highly significant group discrimination (p<.001), accurately classifying 88.9% unmedicated males with CFS, and 82.4% unmedicated male healthy controls. No patient with depression was classified as having CFS. The model was less accurate (73.9%) in identifying CFS patients taking psychoactive medications. Factors involving the temporal lobes were of primary importance.

Conclusions
EEG spectral coherence analysis identified unmedicated patients with CFS and healthy control subjects without misclassifying depressed patients as CFS, providing evidence that CFS patients demonstrate brain physiology that is not observed in healthy normals or patients with major depression. Studies of new CFS patients and comparison groups are required to determine the possible clinical utility of this test. The results concur with other studies finding neurological abnormalities in CFS, and implicate temporal lobe involvement in CFS pathophysiology.

Over at ME/CFS forums, Forbin has made this observation:

For part of the study, they also recruited patients who complained of prolonged, unexplained fatigue (with other conditions ruled out) but who had never been worked up for CFS. About 45% of those people had results consistent with the CFS group. The paper suggests that this is broadly consistent with a previously published estimate that 35% of such a group might be expected to be classified with CFS. They speculate that “the less than 100% accuracy of our spectral coherence based classification function could reflect a deficiency in the CDC criteria for CFS...”

So it seems to me that at least a one third of "significantly fatigued patients (where no underlying diagnosis can be securely established)" (sfP) suffer from "genuine" ME/CFS – and up to two third of sfP might have something different (or might be patients with ME/CFS who are less symptomatic).

90% of patients with CDC-CFS (diagnosed by Komaroff?) have abnormal EEG. So in the right hands (and with a large enough cohort) the CDC criteria aren't so bad for research (up to 10% false positive and no false negatives), but might be better suited for clinical diagnoses than research.


From what I have read so far, I have a feeling the CCC might reject some patients with "genuine" ME/CFS (and not include false positives) and so might be better for research, especially when in the hands of less experienced researchers... It would be nice if they would do something like this: "xx% of our CFS-subjects qualified for both CDC and CCC. Hindsight analysis showed that CCC improved specificity to yy%, but decreased sensitivity to zz%. ..."