Practice Makes Imperfect

I once dated a man who was in the process of becoming a doctor. His apartment was cluttered with study guides for his chosen profession, which I often perused for amusement. One of the most game-worthy of the books was aimed at preparing for diagnostic exams and featured hypothetical cases and their symptoms. For laughs, boyfriend would read the descriptions of the imaginary patients to me and I would try to guess what was wrong with them, largely based on what I’d “learned” from episodes of ER. He didn’t need to read far, “24 year old female with abdominal pain…” before I would shout out my uneducated guesses without waiting to hear the rest of the case, “Ectopic pregnancy!” I was right with alarming frequency. He said that I would make a good doctor, that I had a knack for finding the most likely option in the “differential diagnosis”.* Had I gone to medical school, his prediction would likely have been proven wrong. My conclusion-jumping approach would have made me a less-than-stellar physician, but apparently there are plenty more like me out there.

The Journal of the American Medical Association had a theme issue recently on medical education and one of the articles addressed the problem of diagnostic errors that result not from lack of knowledge but, ironically, from a greater amount previous experience. It focused on the availability bias – a cognitive error that leads someone to perceive the likelihood of a thing based on how readily it is brought to mind (rather than actual frequency of occurrence). For instance, restless leg syndrome isn’t especially common but for while there it seemed that half of the nation thought they were afflicted with it. It had been well advertised due to a recently introduced medication that allegedly treated the problem.

The study presented involved first and second-year medical residents in the Netherlands. In a laboratory setting (which is to say, they were reading cases rather than examining humans†) participants completed 3 phases of simulated malady-diagnosing. In Phase 1 each case with which they were presented also came with a possible diagnosis. The participants were asked only to rate the likelihood (as percentage) of the diagnosis being correct. They were given no feedback on how they fared with each case. In Phase 2 the residents were presented with new cases, half of which bore similarities to some of the cases they had seen in Phase 1, but were in fact different ailments. For example, chest pain is a symptom common to both heart attacks and viral inflammation of cardiac tissue. This time no diagnosis was offered and the residents were asked to produce their own diagnosis (and to hurry up about it). The authors predicted that the similar cases would bring to mind the diagnoses encounter in Phase 1 and thus, thanks to availability bias, be more frequently misdiagnosed than the non-similar ones. Again no feedback was provided.

Phase 3 examined whether the use of analytical reasoning would undo the potential inaccuracies brought on by the availability bias. Participants were asked to revisit their hasty Phase 2 decisions, on the similar cases only, and given a step-by-step procedure that would encourage them to actually think about what they were doing.

So what happened? Well, as predicted, the 2nd-year residents botched more of the similar cases in Phase 2 than the non-similar ones. The 2nd-year residents were expected to be especially susceptible to the availability bias due to their greater clinical experience, which reportedly increases this cognitive problem. A bit more surprising was the observation that 1st-year residents actually fared better with the similar cases than with the non-similar cases.

The authors offered a possible explanation for this trend. Being less experienced, 1st-year residents were less confident in their choices and therefore employed more analytic reason even in the rushed Phase 2. That’s all fine and well, except that it wouldn’t explain why they made more mistakes with the non-similar cases. I’d like to take a shot at this and suggest that first-year residents, being closer to medical school than the 2nd-years, unintentionally employed a very different bias. What I would call “standardized test-taking bias”‡ in which students get uncomfortable when the same answer comes up twice in an exam and therefore search to find an alternative solution. The thinking goes something like, “Wait, I already answered acute viral hepatitis. It can’t be acute viral hepatitis twice…” While useless in a clinical setting, where diseases appear in whatever order and volume they happen to occur in, this may have actually helped the1st-year residents by alerting them to the similar cases and making them try again.

Phase 3 reflection did improve the scores of both first and 2nd-year residents. Although, amusingly, the 1st-years still bested the 2nd-years even after the benefit of Phase 3 reflection. Residencies can be exhausting, or so I’ve heard. Perhaps they were just a bit mentally burned out. Given the opposite trends observed in the accuracy of the two sets of residents in Phase 2, it would be helpful to see what would have happened if Phase 3 analytical reasoning had been applied to all the Phase 2 cases, and not just the similar ones selected to evoke the availability bias. There may be a broader take-home lesson trying to creep through the data - something along the lines of “thinking is useful” or “sleep is nice”.

While the authors acknowledge that their results should not be generalized to higher years of residency or to more experienced doctors without further experimentation, it doesn’t bode well for one’s chance of getting a correct diagnosis during the next trip to the emergency room (a environment that is hardly conducive to careful reflection). And greater experience can also make physicians more prone to “anchoring effect” – the tendency to stick to whatever conclusion they reached for first. In fact, cognitive biases abound. There are far more ways to be wrong than you would ever dream of. Your best bet is to just try not to get sick.

*A short and not especially exhaustive list of all the possible ailments that might be causing the patient’s symptoms.

† While the participants didn’t interact with real patients, it is worth noting that the lists of symptoms and test results presented were based on actual clinical cases, rather than Platonic ideals of how these ailments would manifest.

‡ The actual cognitive bias that most closely resembles this would perhaps be Gambler’s Fallacy, in which people erroneously believe that the next round of a coin toss (or some other chance-determined game) is influenced by the outcomes of previous rounds. Getting heads 5 times in a row does not increase the odds of getting tails on the next try. So long as the coin still has two sides, the probability remains 1:1. And unless you are given a list of fill-in-the-blank answers and specifically instructed to only use each once, there is no reason to infer that an answer couldn’t appear twice on a test.

Fever and Chill Pills

There’s a new medication in the works for malaria. Are you excited? Well, you should be, because many of the existing ones are kind of scary. Not only that, but signs of resistance to artemisinin (the most recent addition to the treatment options for the disease) have already been reported in Cambodia. The Thailand-Cambodia border is the region that spawned chloroquine-resistant malaria 50 years ago. Prior to that, Chloroquine had been effectively treating malaria since the 17th century, but nowadays it is useless against all but a few regions’ malaria parasites. Drug resistance is a big concern in treating and preventing malaria.

Before you start freaking out, I should backtrack and explain a few things. To begin with, if you’re reading this from the United States (or some similarly climated and industrialized nation) you’re not in any immediate danger. Most cases of malaria in the U.S. are diagnosed in people returning from trips to parts of the globe where the disease is endemic, often to visit family members. Even foreign travel may not put you in harm’s way. Urban and costal areas are often trouble-free while rural villages just a few hours away may be considered high-risk destinations. This is in part because the anopheles mosquito, which spreads the disease, will only travel a distance of about 1 km over its entire life.

Malaria is caused by a protozoan parasite, which makes the creation of a vaccine more challenging than for a smaller organisms such as bacteria and viruses. There are 4 main species of parasite that cause malaria in humans. This article will focus on Plasmodium falciparum, which accounts for the most lethal form of the disease. P. falciparum has a complex and disgusting life cycle. It splits its time between two hosts - humans and mosquitoes. It needs both of these animals in order to survive and replicate. Mosquitoes spread the mature form of the parasite to humans, but it is in humans that gametocytes (the first stage of reproduction) are generated. These reproductive cells then infect additional mosquitoes* where they grow into gametes, fuse into a zygote and mature into a parasite ready to infect more humans. It’s the circle of life.

P. falciparum ‘s stint within the human body is also divided into 2 portions. Initially, it finds its way into the liver, where it replicates within the hepatic cells. Eventually these rupture and the now copious parasitic cells make their way into the blood and infect the red blood cells. The process in blood cells is similar to that in liver cells – replication which leads to bursting of the cell and release of the parasite into the blood. Some of the released parasitic cells will infect more red blood cells, while others are the gametocytes that can now infect blood-sucking mosquitoes. Only the blood stage of parasitic infection produces symptoms†, and most malaria medications focus on killing this stage of the parasite. Treatment and prevention of malaria are not such different concepts. You should be horrified to know that with 2 of the 3 most commonly used prophylactics‡, even if you dutifully start a course of prescribed antimalarial drugs before ever stepping foot in your disease-ridden travel destination, P. falciparum can still set up camp in your liver and reside there comfortably until it enters your blood. This is the reason your doctor may tell you to continue taking the medication for several weeks after you return. You’re essentially waiting for the liver-stage parasites to hatch before the pills can kill them.

The newest antimalarial hopeful is a class of chemical compounds called spiroindolones. A study on one of these, the whimsically named NITD609, was recently published in Science and found the drug to be effective in killing P. falciparum in rodents. Sadly, this drug too acts only on the blood stage and not the liver stage of the parasite. More reassuring is that its mechanism of action (suppression of protein synthesis) is different enough from that of existing antimalarials that the authors were hopeful it would not be subject to the drug resistance threatening the efficacy of these. The manner in which this novel antimalarial was identified also represents a return to an older method of drug development. In the wake of easier availability of genomic data, much research over the past decade had focused on understanding the molecular structure of the parasite and attempting to identify specific targets for possible medicines. The older approach focused on whole parasites and worked by sequentially blasting said parasites with everything from the chemical library until something worked. While it doesn’t tell us the exact genetic target being hit, this approach has the advantage of being considerably faster.

Despite the potentially encouraging news, NITD609 and friends still need further safety testing before they will be ready for human clinical trials. In the meantime, those of you traveling to Thailand or Haiti or wherever will have to make do with the currently available options. In addition to Malarone, whose pros and cons are discussed in the notes, the other 2 drugs recommended for travelers wishing to avoid falciparum malaria are Mefloquine hydrochloride (aka Lariam) and Doxycycline hyclate (aka Vibramycin) each with its own charming side effect profile. Doxycycline comes with the unglamorous but reasonably manageable woes of sun sensitivity (bring a hat) and possible yeast infections. Mefloquine is a bit more intriguing. Its most widely-publicized side effects are nightmares (common) and psychosis (rare).§ Because these side effects are so potentially disagreeable to travelers, the drug is started a few weeks prior to leaving home to ensure that it can be “tolerated”. A case report in Psychosomatics tells of a 25 year-old woman who experienced paranoid delusions and both auditory and visual hallucinations while taking the drug during a trip to Nigeria. She came to believe that her husband was the Devil and suffered auditory hallucinations that included hearing “conversations between Heaven and Hell”. Keep in mind that psychosis is not the standard result of Mefloquine ingestion, but one can see how this might pose more hindrance than sunburn and stomach aches.

By now you’re probably wondering which, if any, antimalarial drugs you should take for your upcoming trek through the jungle. Thankfully for me, I am not your doctor and needn’t worry myself over this. The Center for Disease Control has a handy guide to risk assessment by country on their website. Whatever you decide, I’d recommend bringing along a lot of bug spray. Bon Voyage.

* The mosquitoes do not appear to suffer any ill effects from their infection with the malaria parasite and are often referred to as a “vector” for the disease. But I try not to marginalize insects, so I’m granting them “host” status here. It seems more dignified.

† Clinical malaria consist of fever, chills, sweating, nausea and vomiting in its “uncomplicated” form, and in its severe form can also feature anemia, respiratory distress, kidney failure, various neurological abnormalities, etc, etc, and also death. It’s no fun. Furthermore these symptoms repeat in attacks as the parasite runs through its cycle of bursting and then re-infecting blood cells.

‡ Atovaquone-proguanil (aka Malarone) is effective against the liver stage of the P. falciparum parasite. It’s expensive but pretty low on side effects as far as malaria pills go. (Nausea, vomiting, stomach pain, headache, or diarrhea, may occur….Ask your doctor about it…)

§ Mefloquine got a lot a bad press back in 2002 when it was considered as a possible cause for a rash of suicides and spousal homicides that occurred over the course of a single summer at the Fort Bragg military base.

Who told you this?

Center for Disease Control website: www.cdc.gov

World Health Organization website: www.who.int

Rottman, M. et al. 2010. “Spiroindolones, a Potent Compound Class for the Treatment of Malaria.” Science 329: 1175-1180.

Wells, T.N.C. 2010. “Is the Tide Turning for New Malaria Medicines?” Science 329: 1153-1154.

Freedman, D.O. 2008. “Malaria Prevention in Short-Term Travelers.” New England Journal of Medicine 359: 603-612.

White, N.J. 2008. “Qinghaosu (Artemisinin): The Price of Success.” Science 320: 330-334.

Kukoyi, O. and Carney, C.P. 2003. “Curses, Madness, and Mefloquine.” Psychosomatics 44: 339-341.

Put the Line in the Coconut

I can’t speak for the rest of the country, but the city of Austin is currently cuckoo for coconut water. It’s in every health food store, supermarket and gas station, and people can’t shut up about its purported heath benefits – “more hydrating than water”, “more potassium than a banana” and the well-worn ambiguous standard, “boosts your immune system”. Personally I prefer to stave off dehydration with a more traditional 2:1 mixture of hydrogen and oxygen, but it’s nice to see people drinking something other than soda and I’m certainly not out to rain on civilization’s latest nutritional fad parade. However, I did hear one claim about coconut water that seemed to require my immediate investigation. Here is the rumor as it was told to me, “During WWII, coconut water was used for emergency transfusions during times when blood (or proper blood type) was in short supply. It worked because coconut water is isotonic to blood.”

Isotonic is a fun word to say at parties, and a useful property when one wishes to avoid having cells shrivel or explode (the consequence of being immersed in fluid of too high or too low solute concentration) but this hardly seems like it would prevent someone from bleeding to death. The quality that we most enjoy about blood isn’t that it takes up space in our veins and arteries, but that it contains hemoglobin, which transports oxygen to our various organs. To my knowledge, coconuts lack this vital ingredient. Furthermore, I argued when the tale was relayed to me, the only thing rarer than type O negative blood* would surely be a coconut in the middle of Europe prior to the era of wide-scale shipping of produce. Doubts aside, I typed “coconut water blood transfusion” into my search engine and was greeted with a large number of hits, as well as a much-needed reminder that WWII was fought not only in Europe, but also in the Pacific, where doctors would conceivably have access to coconuts.

Not surprisingly, medical literature yielded no reports of coconut water functioning as a suitable substitute for blood. However, I did find documentation of the fluid being successfully used for emergency hydration in locations where the usual sterile IV saline solution was unavailable and coconuts were plentiful. Immature coconuts are the best choice for IV hydration as they contain the most liquid, or coconut water. Coconut “milk”, it turns out, is not the fluid inside a coconut, but rather an emulsion made from the grated coconut meat. So please take a moment to replace your mental image of the iconic bark-like brown coconut with a young green one and please envision its interior as an almost clear whitish fluid rather than the opaque syrupy stuff you use to make curry. Coconut water is actually hypotonic to blood plasma (that is, it has lower solute concentration) and more acidic. It also contains far less sodium and far more potassium than either plasma or saline solution. It is therefore a non-ideal IV hydration fluid. Nonetheless, it is seems to work in a pinch, as a Solomon Island patient who received the coconut IV treatment was reported to have eventually left the hospital without any peculiar complications.

As for the lighter claims about coconut water, it’s potassium content relative to a banana is easy enough to establish. The 14 oz bottle of coconut water I purchased while researching this article boasted 569 mg of potassium, whereas a banana is estimated to contain somewhere around 450 mg. But, as noted above, high potassium content is not a desirable quality for IV hydration. Excessive potassium in blood can even cause a condition called hyperkalemia, which can in extreme cases be fatal.

Aptitude for (oral) hydration is a bit harder to establish, but luckily somebody did bother to design an experiment comparing coconut water to regular water and also to “carbohydrate-electrolyte beverage” (Gatorade and its ilk) †. Subjects ran on a treadmill and then consumed of 1 of the 3 beverage types. Here coconut water fared better than plain water, although so did the Gatorade. Part of the advantage is that people can choke down more coconut water or sport beverage than they can plain water. Optimum post-exercise rehydration is achieved by consuming liquid amounting to 120% of what was lost through sweating. That’s potentially a lot of water (about 1 liter per hour), especially when exercising in hot environments. The electrolytes in coconut water and sports drinks help maintain the sensation of thirst, so people keep drinking them past the point where they would have put down the water bottle. Additionally, subjects drinking plain water were more likely to report nausea during the rehydration period. The coconut water drinkers also reported experiencing less stomach upset and feelings of fullness than either plain water or sport beverage drinkers.

If you ask me, coconut water tastes funny. The hydration article participants claimed it tasted sweet (it does have a higher glucose content than plain water, which has none) but I found it somewhat salty. In fact, it tasted rather like how I imagine bottled sweat would taste, which is hardly the makings of a desirable beverage. The bottle I purchased languished in my refrigerator awaiting mixers until a friend offered to add it to a breakfast smoothie. Perhaps the stuff tastes better during a hydration emergency, but it didn’t stick around long enough to find out.

* In actuality, AB- is the rarest blood type in the human population. However, you probably think O- is the rarest and I didn’t want to confuse or disappoint you. O- is still fairly uncommon. Additionally, O- is the “universal donor” and patients with this blood type cannot be transfused with any other type, thus its rarity is potentially more problematic. The AB- people can make do with a number of other blood types.

† Electrolytes aren’t just some word made up by sports drink manufacturers. They’re ions in solution and are critical to a variety of cellular activity. Sodium and chloride are the predominant ions in blood plasma, whereas coconut water is heavy on potassium, calcium and magnesium.

Who Told You This?

Campbell-Falck, D. et al. 2000. “The Intravenous Use Of Coconut Water.” American Journal of Emergency Medicine 18: 108-111.

Pummer, S. et al. 2001. “Influence of Coconut Water on Hemostasis.” American Journal of Emergency Medicine 19: 287-289.

Saat, M. et al. 2002. “Rehydration after Exercise with Fresh Young Coconut Water, Carbohydrate-Electrolyte Beverage and Plain Water.” Journal of Physiological Anthropology 21(2): 93-104.

Dog/Racoon/Bat Bites Man

I live in a city of 1.7 million people and 1.5 million bats. Mexican Free-tailed bats set up camp under the Congress Avenue Bridge where they spend the spring through autumn months before heading south for the winter. Amidst gathering throngs of tourists, the colony emerges from the bridge nightly to stretch their wings and eat some bugs (we have quite a few of those as well). It’s an impressive spectacle. Bats are fascinating little animals. They’re also one of the principle agents implicated in the spread of rabies from animals to humans in the United States. * I’ve heard the word rabies more in my 2 years of living here than in the 2 decades prior.With the advent of post-exposure prophylaxis, rabies fatalities are now relatively rare in the US †, but the disease still kills about 55,000 people worldwide each year, mostly in Asia and Africa. What rabies lacks in numbers it makes up for with its dismal prognosis – it is nearly always fatal once symptoms are observed and the death it delivers is not a humane one, to say the least.

Rabies is a zoonotic virus that causes severe inflammation of the brain. It is transmitted to humans when the saliva of an infected animal enters a wound or a mucous membrane. Usually this happens via an animal bite. The virus travels through the peripheral nerves to the central nervous system. This incubation period can last weeks to months, and during this time the victim exhibits no symptoms. Eventually, the virus breaches the blood-brain-barrier and enters the brain, where it is conveniently out of reach of medication. There it multiplies and also enters the salivary glands. Now the symptoms appear. These start as flu-like complaints of fever, headache and general weakness but rapidly snowball into agitation, delirium, hallucinations, seizures, the characteristic drooling and inability to swallow, and eventually coma and death. After the onset of symptoms, it typically takes between 5 and 7 gruesome days to die from rabies.

As a child growing up in suburban Minneapolis, I was somewhat aware of the existence of the rabies virus. We fed raccoons and approached stray dogs as children everywhere do. Mostly, I knew that the prescribed medical intervention, where one of these adorable animals to bite me, sounded as ghastly as any disease. Back then, the vaccine was administered as a series of intraperitoneal injections (that means a needle jabbed into your stomach, in case you’ve never been threatened with such a thing), ranging from 10 to 20, depending on who was telling you the story. It seemed almost suspiciously sadistic, something cooked up by parents weary of their children playing with dubious wildlife. Modern rabies prophylaxis is less dread-inspiring, consisting of a mere 4-dose regimen of rabies vaccine, given intramuscularly (ie, hurts about as much as a tetanus shot), and a single dose of human rabies immune globulin (HRIG) to provide immediate antibodies while the body gets to work on generating its own.

This is a small price to pay considering the alternative. Having covered the broad strokes of the disease, I now offer the following As to your possible Qs....

Q: I was scratched by a stray cat, what are my chances of getting rabies?
A: Slim to none, leaning heavily toward none. Remember, rabies is transmitted through saliva, so unless the cat stuck around to lick the wound it inflicted, you’re probably in the clear.

Q: Hypothetically speaking, let’s say I was bitten by a rabid animal, and that I didn’t opt for the vaccine, and that I then did develop rabies symptoms, would there be any options still available?
A: Not really. In 2004 a 15-year-old girl survived rabies following the onset of symptoms and having received no post-exposure prophylaxis. Doctors at a Wisconsin hospital employed an experimental treatment in which the girl was placed into an induced coma in order to minimize damage to the brain while giving her own immune system time to fight off the virus. After a long hospitalization and subsequent rehabilitation, the patient emerged with only mild neurological impairment. ‡ This caused quite a stir in the medical world, but subsequent attempts to employ the treatment, referred to as “The Milwaukee protocol”, on similar cases have failed. There is some question as to whether other factors, such as an unusually weak strain of the rabies virus, contributed to the one-time success of the treatment. The only other record of possible survival of rabies without post-exposure prophylaxis is dodgier still. § Just get the shots, ok. It’ll only hurt for a second.

Q: I’m a raging hypochondriac, should I be concerned about anything else in regard to this disease?
A: Absolutely. In 2004 (apparently, it was a big year for rabies) 4 patients developed rabies and died after receiving organs from a single donor who was eventually determined to have been infected with the virus at the time of his death. Previous cases of rabies transmission through corneal transplants have also been documented. In a 2005 New York Times article about the changing standards for acceptable donor organs, CDC rabies expert Charles Rupprecht is quoted as saying, "I doubt very much that this is the only time," (that rabies has killed transplant patients) "And I doubt that it will be the last time." With this in mind, the first step in protecting yourself from rabies is trying to stay off the organ transplant recipient list. So take good care of your internal organs. Avoid saturated fats, excessive consumption of alcohol and all the other usual culprits. Holding on to your original organs will also help to ensure a greater supply (and ideally higher quality) of donor organs for those people requiring transplants due to less avoidable misfortune, such as traumatic injury and genetic ailments.

* Most cases of rabies in the US are reported in wild animals. Bats, accounting for 26.4% of cases, are second only to raccoons (34.9%). And if you need an additional reason to avoid skunks, you might note that they’re in third place (23.2%).

† About 2-3 deaths per year in the past decade. So your chance of dying from rabies in this country is about 0.009% of your chance of dying in a car accident (26,689 deaths in 2008, not including cyclists and pedestrians).

‡ A 2008 Scientific American article notes lingering problems as being slower speech and a list to one side while walking. However, the girl was studying Biology in college by this time, so it’s safe to say she was doing pretty well cognitively.

§ In 2009 a 17-year-old Texas girl recovered from a series of neurological episodes possibly caused by the rabies virus. Though admitted to hospitals on multiple occasions, she never required intensive care. The doubts about whether she was actually infected with rabies arise from an absence of some of the classic symptoms, such as hydrophobia and malfunctioning of the autonomic nervous system (the part that controls heart rate and breathing and such). Additionally, rabies virus-neutralizing antibodies were only detected after she had already received a dose of rabies vaccine and HRIG. However, no other possible cause for her symptoms was found and she did have a run in with bats about 2 months prior to her illness.

Who told you this?

Center for Disease Control website: www.cdc.gov

World Health Organization website: www.who.int

Willoughby R.E. et al. 2005. “Survival after Treatment of Rabies with Induction of Coma.” New England Journal of Medicine 352: 2508-2514.

Srinivason, A. et al. 2005. “Transmission of Rabies Virus from an Organ Donor to Four Transplant Recipients.” New England Journal of Medicine 352: 1103-1111.

“Presumptive Abortive Human Rabies.” 2010. Morbidity and Mortality Weekly Report 59: 185-190.

Lite, J. “Medical Mystery: Only One Person Has Survived Rabies without Vaccine--But How?” Scientific American. October 8, 2008.

Reynolds, G. “Will Any Organ Do?” New York Times Magazine. July 10, 2005.