Changed thinking about the mind

In 1994 rheumatologist Elliot Pellman chaired the NFL’s council on Mild Traumatic Brain Injury (TBI – there is NO ‘Mild’ in this issue). “Concussions are part of the profession, an occupational risk,” … a football player is “like a steelworker who goes up 100 stories, or a soldier. Veterans clear more quickly than rookies…They can unscramble their brains a little faster, maybe because they’re not afraid after being dinged“.

“There’s going to be some controversy about you going back to play.”  Pellman personally sent a concussed Wayne Chrebet back onto the field soon after he had been knocked unconscious by a hit, reportedly telling him, “This is very important for your career.” Days later, Wayne is sluggish and his head aches. In 2005 Pellman et al published their seventh study in the official journal of the Congress of Neurosurgeons, concluding: “Return to play does not involve a significant risk of a second injury either in the same game or during the season.” And remember that the identities of the physician peers who reviewed and approved this nonsensical article are kept secret.

This may be perplexing to non-US residents. The opening of 2012 Southpark episode ‘Sarcastaball’ explains why taking a massive hit is a game tradition, using the naivete of kids.

0Forensic pathologist Dr Bennet Omalu’s investigations from 2002-’09 are documented in the book by Jeanne Marie Laskas, ‘Concussion’ (and now a Ridley Scott film). An outsider to medicine despite attaining eight degrees,  his strongly principled clash with the industry is a repeat of the tobacco deception. Right down to the NFL sharing the same law firm, Covington & Burling! US Congress questions were the turning point for transparency over subsequent years, and not the medicos. NFL boss Roger Goodell still thinks the concussion protocol just needs tweaking.

Self-regulation failed again.

It was only a month ago that the National Institutes of Neurological Disorders & Stroke, and of Biomedical Imaging & Bioengineering defined the ‘neuropathological criteria for the diagnosis of chronic traumatic encephalopathy‘ (CTE). Mostly unintelligible to layfolk, it’s nonetheless of sufficient importance to be published in a public journal. Like boxing, CTE is estimated in about a quarter of gridiron players, and is manifest in mental disturbances – but the tau tangles are invisible to imaging, until staining of brain slices post-mortem. Higher risk is posed to the spectrum of disease from Alzheimers to Parkinsons, and the month prior funds were allocated to research on diagnostic tests in the living. Although the NFL contributed nothing, the Players Union did. Professor Stern’s lab website is linked, and the urgency of guidelines for safer ages to start playing football fires discussion of their work, since the myelin sheath on neurons improves protection after the age of 14. Demyelination diseases include MS, so research implications go far beyond these elite professionals turning violent. Omalu also found CTE in a TBI war veteran who suicided, hence the penny has dropped regarding ‘Walking Wounded’.

I clashed with our Ski Patrol MO, then a Resident at Box Hill hospital, over management of a teenager who’d bounced off a tree. His mother’s concern was that the subdued manner was totally opposite to his usual bouncing off walls. A doctor trumps a paramedic, and I was chastised for trying to turn him into a victim. She sent them home, saying “Don’t worry about vomiting, he’s likely to be carsick“. Next day I rang the family – he slept for 21 hours.

How can this come to pass? I suspect the teaching in a medical degree that anything above the ears is the province of psych, must be addressed first. Holistic medicine is the only sensible way to treat.



‘The Strange Case of Dr Jekyll and Mr Hyde’ was an 1886 novel written to contrast public and private lives of a reputable gentleman. Duplicity is a constant failing, but often what’s revealed is just an iceberg’s tip above massive issues. Thanks to the only mandatory Pfarma reporting in Oz, Medicine Australia’s Education Events, we know that Pfizer spent an average of $12k on each of the 23 rheumatologists they recently sent to European and American conferences EULAR and ACR. The full reports give an insight into specialist’s lives outside the surgery, as $43.3m was spent on them in the 6 months to Sept 2015. Worse still in 2010 pharmaceutical companies reported $637m expenditure on research, but nobody knows who received the money *. There is monumental potential for conflict-of-interest as the scope of new-gen bio-agents increases (monoclonal antibody drugs, hereafter referred to as the  _mab drugs).

Tony Abbott recovers after finishing Pfarma-sponsored 'Pollie Pedal' in 2013

Tony Abbott recovers after finishing Pfarma-sponsored ‘Pollie Pedal’ in 2013

Amgen sponsored 799 events in the last 6 months. Focusing in more closely, we really can’t be sure just how safe is their anti-inflammatory _mab for arthritis, Enbrel. Regulatory authority TGA advises physicians under Adverse Effects: “In placebo-controlled trials, no increase in the incidence of serious infections (fatal, life-threatening, or requiring hospitalisation or intravenous antibiotics) was observed“. Uhuhh.

Allegations it caused Eagles frontman Glenn Frey’s death due to pneumonia can’t be verified. In the latest EULAR journal ‘Annals of Rheumatic Diseases’ Winthrop & Smolen et al suggest it’s a good idea to track outcomes of _mabs. ‘Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases’ reveals the shortcoming that “no consistent OI [Opportunistic Infection] definition was identified across [368] studies“. Hence a list of OIs was drawn up, topped by the pathogen responsible for pneumonia. The best evidence for their recommendations was the publicly accessible meta-analysis by Kourbeti, Ziakas, & Mylonakis which put the odds of infections 1.8 times higher for _mab recipients than controls (usually patients on frontline med, methotrexate)  in Rheumatoid Arthritis (RA) trials – a small but significant risk. But note that RA doubles that risk over healthy comparators already.

That’s short term though, a trial median of around 6 months for the drug to prove its worth. Aust Rheumatology Association’s Rachelle Buchbinder established the ARAD tracking database a decade ago to determine _mab safety. It’s paid for by Pfizer, BMS and AbbVie. The few reports published in journals thus far inform us of customer satisfaction such as subjective Quality of Life surveys, and that no increased risk of cancer occurs, and that herpes/shingles virus infection rates are 1.7 times higher. Specifically for Enbrel, this result came after a median of 3 years followup. So the longterm prognosis is much like the brief studies would indicate. A worsening, but hardly deadly. Glenn’s manager wisely declares he has taken legal advice to limit his accusation.

This drug inhibits TNF, a cytokine messenger that augments our innate immunity system. As understanding of the molecular basis of many diseases improves, an inflammatory aspect is a recurring theme. The prospects for treatment with anti-TNF therapy look promising, but for the fact that the body needs to be regulated by internal controls. And not shareholders, salesfolk, or Jekyll. Interestingly, a trial for Enbrel in Alzheimers found that TNF levels rose. Feedback systems are adaptive.

Future studies could well heed the EULAR belief that their “… list of infections should be considered potential indicators of alterations in host immunity, and that this list and the associated case definitions should be used to standardise reporting of OIs in future biologic and other disease modifying antirheumatic drug clinical trials“. It’d also be helpful if an outcome tracking registry reported on all OIs, instead of the trickle of data from ARAD. But unease over industry manipulation of research is fuelled by the doctors themselves. When a weakened version of the US Sunshine Act for disclosing contents of the unmarked envelope was being considered by the Aust Competition and Consumer Commission, the AMA submission sought a deferral: “A twelve month delay in implementing the ACCC’s condition would allow health practitioners to think about and plan for their ongoing relationships with pharmaceutical companies.”

Gap payments cover the weekender, the kid's schooling ....

Gap payments

EULAR 2016 is in London. The UK has an Office of Research Integrity, let’s hope some fresher ideas than creative accounting are brought home.

* Source: College of Psychiatry submission to the ACCC. They’re concerned: “Clinical research should be included in the transparency model. All payments above the threshold that are made to individual researchers, or research institutions, including hospitals, should be publicly reported. This would better enable doctors and other health professionals to interpret the research outcomes while taking into account their funding sources.”

A rhetorical question posed by the bard leads Prof Muhammad Yunus (no, not the Nobel Laureate – this guy was merely responsible for the pioneering 1982 study of fibromyalgia) to muse: “…anything that is not currently viewed as a disease is viewed as predominantly or exclusively psychological and benign and is not taken seriously by the health care providers”. For fibro’s status to be promoted from a syndrome to a disease requires an understanding of causality. That would allow treatment of cause, rather than merely alleviating symptoms.20090221_whats-in-a-name_poster_img

Wherever symptoms outweigh evidence from signs the patient is relegated to a diagnostic dumping ground of functional somatic syndromes. Somatization disorder sufferers are characterized by pain and headaches resulting from distress. The recent version of Diag & Stats Manual of Mental Disorders (DSM-5) has grouped these along with hypochondriacs into the category Somatic Symptom Disorder. Other simplifications result in broadening the size of the SSD patient market sixfold over DSM-IV criteria (Rief et al 2011). Thankfully it advises that many individuals with fibromyalgia would not satisfy the criterion necessary to diagnose somatic symptom disorder (ie any one of either: Disproportionate and persistent thoughts about the seriousness of one’s symptoms, Persistently high level of anxiety about health or symptoms, or Excessive time and energy devoted to these symptoms or health concerns.©) Otherwise anyone on disability benefits, or income protection insurance could be critically judged by their practitioner as catastrophising. But of course, fibromites have rheumatology specialists managing their treatment, otherwise secondary care escalation would be straight to psychiatrists and everyone would be on anti-depressants [cue hollow laughter].

How much of fibro is in your head remains enigmatic, just as much so as attempting to explain specificity due to exact locations of the 18 tender points in the 1990 ACR criteria (this week I’m bagging psychs, not rheumys since I need help in understanding enthesopathy!). The selectivity of the blood brain barrier means that the hormone and neurotransmitter levels that matter won’t ever be measured in blood serum. Not that this affects the presumption of a dysregulated hypothalamus-pituitary-adrenal axis , and hypothesized low levels of serotonin (in) or cortisol (out) aren’t seen as necessary to be monitored in order to be prescribed a serotonin reuptake inhibitor. The anti-depressant drug mechanism relies upon lifting the use-by time for the chemical to come in for recycling and thus ensures plenty of serotonin. Blind trust & guesswork are valuable skills in applying neuroendocrinology theories to each individual, and the patients & research consultants to pharma have these attributes respectively ….  in spades ♠

Naval exercises in training for battle involves scenarios whereby the ability to fight is reduced, so then priority shifts to preservation of the vessel. The CO called this ‘move’, but as it’s my blog I can call it fleeing to refuge *. If immobilized, all focus is redirected onto staying afloat. Fibromyalgia is considered a dysfunction of the ‘fight or flight’ autonomic nervous system, the symptoms testing ones strength and endurance much like my military example.

blowfishA Patient Reported Outcome site ranks consumer opinions of generic treatments. The highest rated treatment for fibromyalgia with more than just a few believers is guaifenesin protocol. Promoted by Dr Paul Amand, it’s based on a cough mixture and restricted dietary exposures. The only controlled investigation of effectiveness found no benefit during a yearlong double-blind trial, although they were unconcerned about alleviating any discomfort due to snot and sicca – secondary Sjogren’s. An Eli-Lilly advisory board member Prof Bennett assures us of no medical basis for any of the claims (regardless of its history as a muscle relaxant). Alternative medicine provides hope of refuge, but empirical evidence should be sought before fleeing the healthcare system. Ask on a patient forum …… and then flee.
The first dozen treatments are all off-label and appear ahead of the three US FDA approved medications. These two SNRI anti-depressants and an anti-convulsant have been re-tested for effectiveness in 5 trials each, and the Cochrane Collaboration concluded in review that the two SNRIs “provided a small incremental benefit over placebo in reducing pain”, and no effect on fatigue or sleep. Pregabalin gave “small benefit over placebo in reducing pain, fatigue and sleep problems”, and only 11% more participants reported much improvement. Life-preserving dependence upon pain relievers offers the sufferer little more than help to stay afloat.
A few patient advocates have taken up the fight to resolve FM. This blog adds to their voices.

* The RAN mission is to ‘Fight and win at sea’. Glad their intent isn’t to get a draw, or do it up the rivers. Contrast the Indian Navy: ‘Hit first, hit hard, and keep hitting’.  When the Oz and US Navy’s still had their heads down on Somali piracy doing Hazard Risk and Cost Benefit Analyses, the Indian ships went in pursuit. Successfully, without the need to make movies about it.