Brain Freeeeeeeze (Marin IJ)

It’s popsicle-o-clock at the Ballard house and everyone is content… until a horrible shriek reverberates through the home. The perpetrator is three-year-old Holden and his tribal yell quickly morphs into a plaintative wail of “brain freeeeeeeeezzzzze.” In a moment, the pain (for all of us) recedes and our daughter, removing her hands from her ears, asks, “Dad, what causes ‘brain freeze?’” Until recently I would have answered: “Popsicles.” But now, thanks to new evidence, I can instead tell her, “vasodilatation of the anterior cerebral artery.”

This past April, Jorge Serrador of Harvard Medical School and colleagues reported the results of a small study suggesting an explanation for the bodily processes (physiology) involved with brain freeze (known in medicalese as sphenopalatine ganglioneuralgia.) Now, I know what you might be thinking – with autism unexplained and cancer uncured, aren’t there greater priorities for medical research than a painful yet benign experience like sphenopalatine ganglioneuralgia? And, you would be absolutely right. However, there is a bit more to it, and some have long posited that the physiology of brain freeze might be related to that of other (less temporary) conditions – such as post-traumatic and migraine headaches. In fact, prior studies have suggested that migraine sufferers are more likely than other folks to experience brain freeze. So, with that in mind, let’s get back to the research at hand.

Serrador and colleagues recruited thirteen healthy adults willing to suffer through brain freeze in the name of science (and I’m guessing there were other inducements as well). While researchers monitored the blood flow in their brains with transcranial Doppler (ultrasound), the volunteers sipped ice water through straws pressed against their upper palates. Then, they raised their hands to signal the freeze and thaw of brain freeze. Brain blood flow under these conditions was then compared with that of the same volunteers sipping warm water. The results of the study were presented at the Experimental Biology 2012 conference in San Diego and were notable in that the researchers observed that one particular artery, the anterior cerebral artery, dilated rapidly and flooded the brain with blood in conjunction with the freeze sensation. Soon after this vasodilatation occurred, the same vessel constricted (tightened) as the volunteers' pain receded. Now, remember, this was a small study and it’s results have yet to complete the rigorous peer review process associated with manuscript publication. Nonetheless, there do seem to be some important implications in these findings.

1)     Migraine headaches. These are thought to be caused by abnormal dilation of arteries in the brain, and many existing treatments attempt to modulate this process. These results then, support this concept and may lead to greater focus on migraine treatments that prevent dilation in the first place. And, for people with friends or family members with migraines, this study provides us with a way to relate to their pain. For some with migraines, the headache must certainly feel like one long brain freeze. Ouch.

2)     The suddenness of sensation matters. We’ve all heard about the frog that will jump out of a pot of boiling water but will stay in a tub slowly brought from ambient temperature to a boil. One of the aspects of brain freeze that makes it so uncomfortable is the rapidity and severity of its onset. This principle is worth keeping in mind for other situations. Take, for example, removing a bandage. The conventional wisdom is that pulling it off quickly is better, as it gets the pain over and done with. But some researchers, such as Dan Ariely, the author of the fascinating book Predictably Irrational, contend the opposite; the quicker the pain the more severe the pain, and thus the greater the overall discomfort. So perhaps very slowly removing a band-aid is actually more comfortable than yanking it right on off. That’s a topic to be exposed more thoroughly some other time.

3)     Now, I can turn Holden’s occasional freezathon into a spelling lesson for his sister. Ok, here we go, let’s try “sphenopalatine ganglioneuralgia.” S...P...H…

On Breast Cancer Risk (Marin IJ)

Establishing cause and effect is one of the trickiest aspects of medicine. So-called “causality” can be elusive, especially once you move beyond connect-the-dots type circumstances (exhibit A; Mom cuts finger with bagel knife = bleeding Mom.)

Here in Marin, we worry and wonder a lot about breast cancer. Why does a particular woman get breast cancer? How does another woman avoid it? These are difficult and often unanswerable questions. Unlike the knife and finger example, there are a litany of possible reasons why an individual might develop breast cancer. And, even if we expand the question to what increases the risk of breast cancer across a broad population, satisfactory answers are slippery. It is with this in mind that we should view the recent evidence regarding breast cancer in Marin County.

It is well documented that Marin has historically had an abnormally high rate of new breast cancer cases. In particular, data from the late 1990s demonstrate breast cancer rates some 15% higher than those found across the rest of the state. Multiple culprits – lifestyle, hormones, toxins, and genetics – have been proposed and studied, without the emergence of a single smoking gun.

A study recently published in the Journal of the American College of Surgeons has proposed yet another possible cause – genetic differences in Vitamin D receptors. The study, conducted by Dalessandri and colleagues, examined the DNA of 164 Caucasian women living in Marin and diagnosed with breast cancer between 1997-1999. They compared their genetic profiles with those of 174 breast-cancer-free matched controls and found that women at statistically high risk for breast cancer were 1.9 times more likely to have a specific difference (called a variant) in the gene which dictates how the body utilizes Vitamin D (the Vitamin D receptor). Vitamin D has received quite a bit of attention for its possible benefit in deterring certain types of cancers and animal models have demonstrated that it has a beneficial effect on breast cancer tumor growth. Thus, differences in how Vitamin D is processed by its receptors is a logical explanation for why certain women (in Marin and elsewhere) would be at higher risk for developing cancer.

But before you march out to determine your Vitamin D receptor profile, let’s put these findings in proper prospective. First of all, this was a small “pilot” study and should be considered preliminary evidence. Medical practice and investigation is ripe with prominent associations that have not borne out in larger studies; oat bran and heart disease, and (who can forget?) vaccines and autism, and on and on. In fact, there are more disproven associations in medicine than proven ones.

A much larger study of Marin Women (the “Marin Women’s Study” www.marinwomensstudy.org) with 14,000 participants is ongoing and analysis of their DNA samples (there are some 8500 available) should provide more robust data on Vitamin D receptor variants and genetic risk. Furthermore, the genetic data from Dalessandri’s study is from fifteen years ago – during a time when breast cancer rates were peaking – especially in Marin. While multi-factorial, we know that this peak was due, in part, to combined post-menopausal hormone (estrogen and progesterone) therapy – a known risk factor for developing breast cancer, and a treatment more common (at the time) in Marin than elsewhere in California. Thus, we must be careful to extrapolate the findings regarding breast cancer risk from a prior generation to today’s milieu. Finally, one must always be particularly fastidious when reviewing the results of studies that focus on a specific proprietary drug (remember Vioxx?) or test. While this study was funded by state, county and charitable sources, the results quite prominently affect the fortunes of genetic testing company InterGenetics Incorporated, which is marketing OncoVue® - a “genetic-base, breast cancer risk test.”  Thus, while interactions between genes and the environment is certainly a promising field, the jury on Vitamin-D receptors and breast cancer is most definitely still out.

Where then, does this leave us with breast cancer causality? Well remember, this is tricky – proving a clear-cut link between a dietary item, personal habit, or medical treatment and a disease process is fraught with the potential for mis-interpretation. Nonetheless, there are certainly some risk factors that we can confidently delineate. Some genetic risk is clearly proven – and a family history of breast cancer is a known red flag – especially if due to a known BRCA mutation. In terms of risky environmental exposures, an Institute of Medicine committee report released last year summarizes these quiet nicely as “hormone therapy that combines estrogen and progestin, exposure to ionizing radiation…excess weight among post-menopausal women and alcohol consumption.” Other environmental agents – chemicals such as bisphenol A (BPA) – have been implicated and are biologically plausible but at this time unproven. Mary Mockus, a surgeon at Kaiser-Permanente San Rafael and a member of the collaborative Marin Women’s Study team, thinks that the ‘toxic soup’ present in higher socioeconomic areas like Marin County is likely to play some role in the higher breast cancer rates, but that we are unlikely to ever identify one clear cut perpetrator. And, this then, fits quite well with what we know about causality in medicine.

Thus for Marin women, the best advice for preventing breast cancer is probably the best advice for preventing many diseases; sleep well, get regular exercise, know your family’s medical history and discuss individualized screening plans with your doctor…don’t smoke, avoid excesses of alcohol, drugs and ionizing radiation, and eat plenty of green leafy vegetables. And a healthy Vitamin D level (ask your doctor!) won’t hurt either. 

Cannabinoid Hyperemesis (Marin IJ)

Every once in a while in medicine a new discovery comes along that, on its face, seems to make no sense at all. What if I were to tell you that a popular drug – one that’s been sampled by two out of every five Americans and is renowned for its relaxation and anti-nausea properties – could actually cause severe bouts of nausea and vomiting among long-term users? These symptoms are worse in the morning and seem to be most effectively relieved by a long hot shower. Hmmm, smells a bit skunky, right? But, recently published reports seem to confirm the phenomenon. And, you might be more than a bit surprised by the culprit: THC.  

Cannabinoid hyperemesis (THC associated vomiting) was first described in 2004 but remains a relatively unknown and underappreciated malady. A recent case series by Douglas A. Simonetto and colleagues at the Mayo Clinic in Rochester, MN, compiled data on 98 patients with this condition – and in the process they’ve put it on the map as a medical diagnosis.

The accumulating evidence about cannabinoid hyperemesis gives us this typical patient profile: a chronic cannabis user under the age of 50 who develops periodic and severe abdominal pain associated with nausea and vomiting that tends to be worse in the morning and to improve with hot showers or baths.

For example, in Simonetto’s report (published in February 2012 in Mayo Clinic Proceedings), the study team reviewed 1,571 charts of patients seen at their institution between 2005 and 2010 and identified 98 that met their criteria for cannabinoid hyperemesis (long term cannabis users with recurrent vomiting not explained by any other medical illness). Of these, each one was under the age of 50 and the vast majority (95% of those for whom data was available) used cannabis at least twice a week. Of the 57 patients for whom the effect of hot water immersion was documented, 51 (91%) reported relief. Most patients (86%) also reported abdominal pain. From these results, the authors have proposed specific criteria for the diagnosis of cannabinoid hyperemesis – including most of the above characteristics. As to the cause of the paradoxical vomiting due to cannabinoids, several theories have been proposed, including the inhibitory effects of cannabis on peristalsis (the wave-like impulses that propel food through the intestines). It may also be that chronic use changes the effects of cannabinoids on THC receptors in the brain. More investigation is needed, however, and as of now we can only speculate as to why hot showers are such an effective treatment (it could be because hot water draws blood supply away from the gut and to the skin). Despite the uncertainty, this new evidence does have a couple important implications for how we think about cannabinoids.

      1)   Today’s cannabis is not the same as your father’s puff the magic dragon. In particular, synthetic and oral cannabinoids can lead to much higher and prolonged exposure to THC or similar compounds – and this would, presumably, increase the risk of cannabinoid hyperemesis syndrome. In particular, “herbal incense” products like Spice and K2 can cause effects – including prolonged psychosis – that were rarely observed from marijuana alone in the era of dirt grass and flower power. Thus, while the evidence is accumulating that cannabinoids may be helpful in the treatment of a number of uncomfortable medical conditions – including those that cause nausea and vomiting! – one must be careful with the amount and delivery of the drug. Like any drug, cannabis is not risk- or side effect- free.

2)  If you are a long-term cannabis user suffering from severe bouts of nausea and vomiting, there may be simple treatments. First, try a nice, long, hot shower. (I fear I may be setting myself up for public stoning here, but this may help explain why, for years, Fairfax’s medical marijuana clinic was located right next to a Frogs Hot Tubs). But I digress…  the second (and medically advised) treatment for cannabinoid hyperemesis is to stop using cannabis. In Simonetto’s case series, of those reporting have quit cannabis, six out of seven (86%) had complete resolution of symptoms.

In medicine, like in life, it is always good to constantly question and challenge assumptions. The long-standing assumption about cannabis is that it’s main danger is as a “gateway” drug – and that it is otherwise quite safe and side effect free. We are starting to learn that this is not exactly true.