Wednesday, February 23, 2005

Miscellaneous Essay on Medical Topic:
Differential Diagnosis

Recently I was asked about some of the challenges involved in psychiatric diagnosis of adolescents.  This turns out to be a difficult topic.  Firstly, psychiatric diagnosis is an arcane practice, shrouded in obscurity.  Secondly, adolescents can be rather obscure themselves. 

In order to understand the topic fully, it is necessary to start at the beginning.  That means ancient Greece.  The term diagnosis comes from the Greek roots diagignoskein "discern, distinguish;" and gignoskein "to learn."  Thus, a diagnosis is established when the doctor learns the distinction between the disease that the patient has, and other, similar diseases that might present the same clinical picture.  In order to have a full understanding of the term, diagnosis, one also must understand the term, differential diagnosis

Lets take an example.  A patient comes in to the emergency department and tells the doctor: "I have chest pain and shortness of breath."  Immediately, the doctor thinks 'OK, the differential diagnosis is pneumonia, heart attack, pulmonary embolism.'  (The actual list of possibilities is much longer than that, but let's keep it simple for now.)  A differential diagnosis, then, is a list of possible diagnoses.   Medical people often use the term differential, in this context, to mean differential diagnosis; for example, "What's the differential in this case?"  Once the doctor learns the initial list of symptoms, he or she starts thinking of a differential diagnosis.  The doctor then asks questions and does tests to pare down the list.  A good diagnostician does this is a systematic way.

Back to the emergency department example, the first thing the doctor is going to want to know is: "What is the patient's temperature?"  This question divides the list of possibilities into two groups: febrile illnesses, and nonfebrile illnesses. The next question is: "When did this start?"  This divides the possibilities into acute, subacute, and chronic categories.  If you think of the differential diagnosis as a big circle that contains all the possibilities, then each question draws a line through that circle, cutting out some of the possibilities.  Ideally, it is possible to get to the point that only one possibility is left.  At that point, the doctor has made the diagnosis. 

The alert reader will have noticed that I put the word "ideally" in italics.  The really alert reader already will have guessed why I did that.  I did that to alert the reader to the fact that the ideal is not always achieved.  That is, sometimes the differential cannot be narrowed to a single entity. 

Those of us who tend to see life like a flow chart will start to wonder what happens in such a case, if the differential cannot be narrowed beyond a certain point.  At first, it would seem that you get to a decision point on the chart, then can't decide which branch to take.  A computer program would just stop there, and send an error message to the standard output. 
Operation Not Defined
Fortunately, doctors are not computers (at least not yet).  In such a situation, the doctor looks at the relative probabilities of each item in the differential, weighs the relative risks and benefits of each possible course of action, and decides upon a working diagnosis.  A working diagnosis is a diagnosis that is known to be uncertain, but which is used to define a course of action.  Note that the working diagnosis is not necessarily the most likely item in the differential.  This is a very important point. 

Back to the example.  Let's say that the doctor has interviewed the patient and has done a physical exam.  She or he now thinks that the most likely diagnosis is pneumonia.  However, it still is possible that the patient has a pulmonary embolus .  A PE can be very serious.  It can kill a person within minutes, in fact.  In that case, the patient may be sent down to radiology for a lung scan.  The doctor will write an order.  In the spot for "diagnosis," he or she might put: "Rule out PE."  Thus, for the purposes of the test, the working diagnosis is R/O PE, even though the most likely diagnosis is pneumonia.  When the lung scan is done, the differential diagnosis may be changed.  If the scan gives an equivocal result, in may be designated as "low probability."  Then the working diagnosis may be "pneumonia, R/O PE."  The PE is still on the list, but has been demoted from the top of the list. 

What this illustrates is that the diagnosis is not a static entity.  It also is not something that can be defined in one dimension.  It can change over time, as more information becomes available.  It also can change over time, as the disease process evolves.  Sometimes, a disease starts out with only a few vague, nonspecific symptoms.  As the disease progresses, more symptoms may emerge.  Tests that were negative in the early stage may be positive if repeated later on.  Sometimes patients tell the doctors different things on different days.  Sometimes they notice symptoms that were present before, but which they had not noticed or mentioned at the time of the first evaluation.  Sometimes family members step up and speak out about symptoms that the patient did not mention. 

A couple of years ago, I had a patient that I would have sworn had depression.  He was not getting better.  The reason was a mystery.  One day his sister called and asked, "did he tell you that he drinks a pint of vodka every night?" 

"Ma'am, I can't tell you anything about him, but thank you for letting me know."

Mystery solved. 

Adolescence is a time when everything is evolving.  Thus, the diagnosis is a moving target.  Psychiatric conditions often produce symptoms that are difficult to put into words.  Adolescents tend have varying capacities to describe subtleties, to think in abstract terms, and to disclose private details about their lives.  Usually, a teenager's capacity for self disclosure ranges from "very limited" to "none at all."  Parents, of course, will describe symptoms or behaviors that they are observed, but they tend to not be objective, may have their own agenda, and may have been misled, deliberately.  Sometimes one parent says one thing, and the other says the exact opposite.  For these reasons, and more, the psychiatric diagnosis of an adolescent often remains at the stage of the differential diagnosis for a long time.  Sometimes, kids come it with all kinds of symptoms, the symptoms later go away, and you never find out what was going on. 

For some examples, see the section in the Medscape Resource Center on Schizophrenia.  They have an article called Looking for Childhood Schizophrenia: Case Series of False Positives
Case A was a 12-year-old girl with an 8-month history of auditory/visual hallucinations and paranoid ideations that had been treatment-resistant to antipsychotics. Her premorbid history was fairly functional and family history was noncontributory. On the unit, she functioned well and never exhibited any formal thought disorder. Staff noted clinical improvement off medication and subsequent impairment during times of family conflict. She was discharged off medication and her symptoms subsided when the social stressors in her life were eliminated. Her final diagnosis was psychotic disorder not otherwise specified (NOS).
Note that, by citing this particular article, I do not mean to imply that false positives are common.  Rather, I point out the possibility of false positives in order to make a point.  Although the differential diagnosis of adolescents is fraught with difficulty, the stakes can be high.  As mentioned in this review article in the NEJM:
Immediate treatment of a patient after a first psychotic episode improves his or her long-term outcome and does not obscure the later differential diagnosis.88
As a general rule in medicine, anytime there is an opportunity to improve the long-term course of an illness, that opportunity should be taken.  This underscores the importance of the diagnostic process.  Having a full understanding of the diagnostic process is essential in order to avoid missed opportunities.  Yes, there are risks involved in treatment, and one does not want to be exposed to those risks if the diagnosis is a false positive, but the consequences of missing an opportunity can be serious. 

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Sunday, February 20, 2005

Neuroscience and Substance Abuse

The Society for Neuroscience issued a press release discussing a new finding in the science of understanding substance abuse.  According to Dr. Frenois of Université Victor Segalen Bordeaux 2 (Sciences de la Vie, de l'Homme, de la Santé) memories of uncomfortable drug withdrawal can cause activation of the same brain circuits that are activated during drug withdrawal itself.  In other words, the mere act of remembering withdrawal can cause some of the same physiological anomalies that occur during the actual withdrawal. 
The team found that re-exposure to an environment associated with withdrawal reactivated part of the withdrawal neural circuitry, which can drive behavioral changes causing drug relapse. Addiction, the authors say, is a chronic, recurrent disorder involving motivation, emotion, and memory. Frenois and his team say their work is an important step in helping to determine how specific environments associated with drug withdrawal might encourage drug seeking.
The study was done in rats.  It would be hard to get humans to consent to such a study, and even harder to get an Institutional Review Board to approve it. 

The association between reminders of drug/alcohol abuse, and the occurrence of relapses, is well known.  Persons with substance abuse problems are advised to avoid situations that remind them of drinking or using drugs of abuse.  Frenois' study indicates that there may be another aspect to the role of memory in The risk of relapse.  Reminders of withdrawal may be important, tool.  If a person starts to remember an experience of withdrawal, then starts to have the same physiological effects as those produced by withdrawal, it could lead to craving, and relapse.  Finding a way to interrupt this process could be helpful.  I'm not sure that we would want to do something that interferes directly with memory, but perhaps interfering with the physiological consequences of the memory could lower the risk of relapse. 

Along the lines of the study cited above, Science Blog has a post that describes the action of drugs that can be used to treat alcohol dependence.  The author, know only as BJS, reports on a Cochrane Review of the use of opioid antagonists for alcohol dependence.  Twenty-nine randomized controlled trials of the use of naltrexone and nalmefene were included in the review.  Naltrexone was studied the most; it is what is used in the US, under the trade name ReVia

Naltrexone Structure
Morphine Structure

The authors conclude that naltrexone does have a role in the treatment of alcohol dependence, and that there is not enough evidence to recommend nalmefene.  The results with naltrexone are hardly spectacular: it reduces the risk of relapses by 36%, and the probability of attaining complete abstinence is increased only by 13%.  Still, in treatment centers, in commonly is said that alcoholism is a disease that invariably proceeds to death, unless abstinence is attained.  So a 13% decrease is worth something, at least.  Is naltrexone dangerous?  Who cares?  It is not as dangerous as alcohol is to an alcoholic.

The press release that was the basis for the Science Blog post includes the following:
Dr. Joseph Volpicelli, of the University of Pennsylvania School of Medicine, has been conducting research on naltrexone use for alcohol dependence since the early 1980s. Naltrexone blocks the brain's receptors for natural painkillers, known as opioids, which normally create the feeling of wellbeing associated with drinking.

He explains that the benefits of naltrexone lie not so much in preventing a patient from having one drink, but rather in breaking the cycle where one drink leads to many more. "Naltrexone helps people have more control over the use of alcohol. For me, that's the fundamental issue of what addiction is: impaired control."

However, this approach requires a substantial change from the abstinence-only philosophy that goes back at least as far as Prohibition. Naltrexone is most effective, says Volpicelli, in a treatment program "designed to support the notion that while one drink is not great, what you really want to stop is excessive drinking."
In the Science Blog post, BJS also mentions a drug called acamprosate, marketed as Campral.  The Corpus Callosum reviewed acamprosate in a New Year's Day post.  Acamprosate reduces the cravings for alcohol, but has no effect on the person if he or she drinks.  Neither naltrexone nor acamprosate produces an aversive reaction in the presence of alcohol, the way disulfiram (Antabuse) does.  The mechanism of action of acamprosate is unknown.  In light of the Frenois study, though, I wonder if it acts by dampening the physiological arousal caused by memories of withdrawal.  There's a paper or two in there, for anyone who is interested and has the resources to do the studies. 

The concept of abstinence vs. moderation is a hot controversy in the field.  Adherents of the AA approach insist that abstinence-based treatment is not only the best way, it is the only way to approach alcoholism.  Others agree with Dr. Volpicelli, that moderation of drinking can be a reasonable option.  The nice thing about this controversy is that both sides know that they are right.  Whatever the truth of the matter, I am not sure that the use of naltrexone requires abandoning the goal of abstinence.  In fact, I've prescribed it to persons who are dedicated to the attainment of abstinence.  My position is that abstience should be the first goal, with moderation being a fallback position. 

It is a bit of an inconsistency to tell a person, in essence, that she or he absolutely must not drink alcohol, "but if you do, it will be easier to quit gain if you are taking this drug."  However, I've always been more in favor of practicality than of philosophical purity.  I've seen people taking naltrexone relapse, but limit it to just a one-day binge, whereas in the past any relapse would go on until some catastrophe intervened.  That's not great, but it is better than the alternative.  I've prescribed acamprosate, but so far don't have any impression of its effectiveness.

This post began with a discussion of the role of the memories of withdrawal contributing to urges to relapse, which was hypothesized to play a role in the risk of relapse.  We then reviewed the action of two drugs that are known to reduce the risk of relapse: naltrexone, which acts by reducing the rewarding sensation of substance abuse; and acamprosate, which has an unknown mechanism, but which I casually postulated might act by reducing the arousal caused by memories of withdrawal.  Neither drug is resoundingly successful, though, so clearly there is more to be learned about the subject. 

It is doubtful that any pharmacological intervention alone could result in a satisfactory outcome for a person with a substance abuse disorder.  Psychosocial treatments always will be necessary.

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Bush Apologists At Their Best

Dr. Drezner is a political scientist and economist, who has a weblog.  It's pretty good, certainly more influential than mine.  I don't usually have any major objections to what he writes.  However, today I have tow things to say.  One, his trackback seems not to be working.  Two, his apologistic efforts for our President are lacking, at least in the instance of his 2/15/2005 post, In honor of the Kyoto Protocol...

Dr. Drezner cites another blog, Opinio Juris, which in turn cites an article in The New Republic, which, apparently, requires a paid subscription, which I don't have and am not about to get, but which is generously cited, and so I feel able to comment upon it, even though I have to confess that I have not read the entire thing, since I don't have a subscription, because I don't want to spend any money on this blogging thing, which, after all, is just an idle hobby, and an excuse to write badly formed sentences, with too many commas, and besides, I would never give any money to the publisher of The New Republic, anyway, because they are too damn serious all the time, not like the editors of The Economist, who actually have a sense of humor, and let it show, at least sometimes. 
Over at a new international law blog called Opinio Juris, Julian Ku notes that while the Bush administration is no fan of Kyoto, it is leading the way in reducing methane. He links to this Gregg Easterbrook essay in The New Republic which contains the following:
You'll hear a reprise of outrage that George W. Bush withdrew the United States from Kyoto negotiations. Here's something you probably won't hear about: the multilateral greenhouse-gas reduction agreement George W. Bush approved a year ago. The world's first international anti-global-warming agreement to take force is not the Kyoto treaty. It is a Bush Administration initiative, and you have not heard a peep regarding the initiative because the American press corps is pretending it does not exist....
First, the snarky part.  It is absolutely ridiculous, that is, it is worthy of ridicule, for anyone to say that something the President does is not widely known on account of the "American press corps pretending it does not exist".  Give me a break.  This President has fewer press conferences that any President in modern times.  His Party has mastered the Machiavellian art of manipulating the press.  Even without the Honorable Jeff Gannon, if the President wants people to know about something, he can get the word out one way or another.  So knock it off about the media.  They are not to blame.  This is not some liberal media cabal to squelch the estimable efforts of our dear leader. 

Did it occur to Easterbrook that maybe, just maybe, the press hasn't reported it because it isn't newsworthy

What is this methane deal anyway?  Methane is a hydrocarbon, consisting of one carbon atom bonded to four hydrogen atoms.  It is a greenhouse gas.  On July 28, 2004, the President issued a statement about the Methane to Markets Partnership.  The idea is for the US to spend $53 million over the next five years, in an effort to "expand the use of technologies to capture methane emissions that are now wasted in the course of industrial processes and use them as a new energy source."

There has been some progress. Intrepid Technologies announced on 2/1/2005 that they have succeeded in capturing commercial quantities of methane from animal waste.  This is encouraging, but to claim that it is an achievement of the Bush administration is nutty.  In fact, third-world countries have been doing this for years.
The Philippines is a tropical country with just a dry and a rainy season. Ambient temperature is in the 30°C to 40°C range year-round -- ideal for biogas. The temperature under direct sun can be much higher. (I have to put shades on some of my digesters!) For waste management and pollution control, the Department of the Environment and Natural Resources (DENR) has been promoting biogas production in large pig farms specially those already equipped with waste lagoons. Unlike India and their huge Gobar supply, cattle farms are few in the Philippines. We have many pig and poultry farms.

We don't have a "Gobar Gas Research Station". We have very little information, promotion and programs for biogas specially for small-scale systems. Compared to India's 2.9 million family-type biogas digesters in 2000, there are probably less than 100 such units in the Philippines. (www.undp.org/seed/energy/policy/ch_8.htm)

India had 2.9 million biogas installations in the year 2000, four years before Bush's announcement.  And the EPA has been working on reduction of methane emissions since 1993:
Since 1993, EPA has been working collaboratively with industry through a series of voluntary programs to reduce US methane emissions. Building from these programs, EPA has also implemented activities to reduce emissions in key countries around the world. These efforts have resulted in the successful project development at landfills and underground coal mines and established a solid foundation for the Methane to Markets Partnership. For more information on these international activities, please visit the Coalbed Methane Outreach Program and Landfill Methane Outreach Program sites.
So we see that the effort to reduce methane emissions in the USA actually started during the Clinton years.  As for Bush, he promised a $53 million investment over five years, which is peanuts.  (The war in Iraq costs more than $175 million per day, and it is mucking up the environment.)  What really makes this apologistic load smell like the device pictured above is that Bush has a terrible record on these kinds of initiatives.  No Child Left Behind is not fully funded.  The HIV/AIDS relief for Africa is not fully funded.  The Millennium Challenge Corporation has yet to disburse a single penny.  FutureGen is way behind schedule, and is grossly underfunded.  So excuse me for being skeptical of the guy.  The fact is, his record on humanistic initiatives is just plain lousy.

Next time, before trying to put a positive spin on anything Bush does, spend a little time with Google (although Dogpile might be more appropriate, in this case) and put things in context. 

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