Placebos, sham surgeries and CCSVI

Recently GPs took part in a survey which showed that 97% of them had used placebos at some point in their careers. The truth is inevitably more nuanced than that headline figure: 97% had used what the researchers called "impure" placebos such as antibiotics for viruses, and the figure for "pure" placebos, treatments containing no active ingredients at all, was in fact 10%.

"Pure", inactive placebos such as sugar pills may seem the more dangerous, but "impure" placebos may be actively dangerous to health. For instance, antibiotics can have side-effects and may promote antibiotic resistance.

Most of the doctors questioned thought that any risk of damaging the trust between doctor and patient was unacceptable, but that it was possible to prescribe a placebo to a patient without actively lying to them. For instance, half of the doctors told the patient that the intervention had helped others.

Is this ethical, particularly if it's possible that the patient would have got better anyway? If something is at the extreme ends of a range of measurements, the likelihood is that it will move towards the average. This is the statistical phenomenon called regression to the mean. The medical application of this is that if someone is ill, on the whole they're likely to get better whether there's any intervention or not.

There may be a psychological effect from receiving a placebo, even if the patient knows that's what it is. One study found that even when the patient was fully aware that their treatment had no active ingredients, the placebo effect was still seen. However there were methodological flaws in that study. More research is needed, to see if the results can be replicated.

Placebos are commonly used in trials to assess whether a new medication is better than no treatment at all. How can a surgical intervention be tested? Sometimes sham surgery is used. Sham surgery forms an important control, as anaesthesia, the incision, post-operative care, and the patient's perception of having had an operation are the same.

However again there are ethical issues, as all surgery has the potential to harm the patient. As a result, sham surgical procedures are rare in human subjects.

In a classic study in 2002, patients with osteoarthritis in the knee either had standard surgery, had their knee joint washed out, or had an incision made in the skin and sewn up again. All the patients in the trial therefore experienced "surgery" of some sort, but didn't know which type. All three groups reported similar levels of pain reduction and improvement in mobility, suggesting that the standard surgery produced no advantage over placebo.

A sham surgery trial has recently reported relating to the controversial CCSVI theory of the causation of MS, which hypothesises that MS is caused by compromised drainage of blood from the central nervous system. The proposed treatment is balloon venoplasty, whereby a small balloon is threaded into the vein and then inflated to clear the blockage. Since 2009, around 30,000 MS patients worldwide have had this treatment, almost always privately rather than as part of a trial.

In this small trial, 30 patients received either the balloon venoplasty treatment or a sham surgery. The treatment did not provide sustained improvement in patients. In fact in some cases, there was a deterioration.

Clearly this was a small study, and more research is needed. But in the meantime, the researchers, who studied under Paolo Zamboni, the developer of the CCSVI theory, have urged patients to enroll for trials rather than pay for the treatment privately.

Overall I believe placebos certainly have a valuable place in research, assuming of course that patients know they may receive the placebo rather than the active treatment. In the GP surgery, I'm not so sure. We should be using evidence-based medicine: that means the best available treatment for the condition, not sugar pills or inappropriate antibiotics. I suspect placebos will always be with us though, one way or the other.

MS and CCSVI: the state of play

There is currently a lot of research going on, either directly into connections between CCSVI and MS or some of the issues around it. What I'm covering here is only a few of the studies I've noticed over the last month or so.

First, a very quick introduction, for those new to the subject.Over the last couple of years CCSVI (chronic cerebrospinal venous insufficiency) has become a "hot topic" in the MS community. The theory goes that rather than being an auto-immune condition, as is the received wisdom, MS is in fact caused by malformations of veins in the neck and trunk. These malformations lead to blood backing up in the brain, and consequent deposits of iron, which cause the immune system to attack the myelin coating the nerves.

If it is decided that there is a blockage, the area is widened using venoplasty or (on some occasions) stents. This has been termed the "Liberation Treatment". It's not without its risks: there have been complications, including deaths, particularly when stents have been used.

Large studies are currently in progress to establish whether there is a link between CCSVI and MS, and whether the "Liberation Treatment" is effective. Many people are not prepared to wait for the results of these studies, and are seeking treatment abroad, sometimes under rather dubious circumstances, as the clinic that diagnoses them as having blockages will also be charging them a large sum of money for the procedure.

So, some recent studies. I'll try to put them in some sort of logical order - not chronologically as they came out, but from diagnosis through symptoms and so on.

A clinically isolated syndrome (CIS) is an individual's first neurological episode, caused by inflammation or demyelination of brain tissue. It may be indicative of MS. In this study, a group of researchers in Italy scanned the veins of 50 patients with CIS, as well as groups of healthy controls and people with another neurological condition. There was  no evidence of CCSVI in the patients with CIS. This result does not support the idea that there is any cause and effect relationship between CCSVI and MS.

A group of German researchers have found no supportive evidence for the presence of CCSVI in people with MS. They scanned the veins of people with MS and healthy controls, without knowing which was which, and found them equally likely to have blocked veins.

If CCSVI causes blockages in the veins draining the brain, you would expect there to be a back-up of blood in the brain, and therefore MS patients to have higher intercranial pressure than people without MS. German researchers have checked this, and found that MS patients have normal intercranial pressure. Again, this does not support the CCSVI hypothesis.

Most mammals (including us humans!) have a part of our genes called the major histocompatability complex (MHC for short). The molecules made by these genes play a large part in our immune systems and in auto-immunity. The MHC in humans is called HLA (human leukocyte antigen), and it comes in various "types", which are identified by letters and numbers. We already know that people with MS are more likely to have the type HLA DRB*1501. Now researchers in Buffalo, NY and Alabama have found that there is no association between HLA DRB*1501 and CCSVI. They suggest that the role of the underlying associations of CCSVI in MS should be treated with caution.

Paolo Zamboni is the Italian doctor who first came up with the CCSVI theory. A new study from his research group has found that people who have undergone the procedure have significant improvements in reported fatigue. The researchers suggest that chronic fatigue may be the symptom most associated with CCSVI.

A positive result is of course a positive result, and I'm glad these people got relief from their fatigue: but it is of note that the studies which measured something objective found no evidence of a link between CCSVI and MS, while it was the study reporting a subjective, self-reported measure that did find a link.

Scans and treatments for CCSVI are carried out by Interventional Radiologists. The Cardiovascular and Interventional Radiological Society of Europe has issued a commentary on the treatment of CCSVI. It states that since no trial data are available, and the basis for the "Liberation Treatment" is anecdotal evidence and internet testimonies, this is not a sound basis on which to offer a new treatment.

Finally, an interesting commentary from Scientific American on how social media can shape medical practice. In this connected, internet-enabled age, doctors are playing catch-up. Even before Zamboni published the results of his first study, they had been posted on an internet forum along with useful links and a Facebook page. With MS, as with some other conditions, the problem is in knowing whether any improvement is really down to the treatment or to the natural ups and downs of the disease. It is vital for neurologists and other doctors to be aware of what patients are seeing and reading online.