Praxeon Blog

Generating a Differential

During my internship, an attending said to me, "There are two essential qualities of a great physician: Being able to generate a robust and thorough differential and knowing your limitations."  I can definitely agree with both points.  In particular, the failure to consider a disease within the diagnostic possibility can be a common source of preventable, medical error.  Although there are many tools available to look up information on specific diseases and drugs, there are a lack of resources to assist physicians with the assembly of a complete and exhaustive differential diagnosis.  However, Curbside.MD has the ability to assist in this process.

As an example, let's take a look at this week's American Academy of Neurology (AAN) "Test Your Knowledge" question: An 87-year-old woman was found disoriented and confused and subsequently suffered a generalized tonic-clonic seizure. Her blood pressure was 245/141 mm Hg. What is the most likely diagnosis?   There are accompanying radiographic images with this clinical vignette.

Even without the benefit of the scans, Curbside.MD can assist in the generation of the differential diagnosis.  We can start the process by entering the following search: An 87 year old woman was found disoriented and confused and subsequently suffered a generalized tonic-clonic seizure in the setting of severe hypertension. Typically we might start our search for an answer by scanning the overview of all hits on the first results page (or Consult Page).  But instead, since we have a specific clinical goal in mind for this search (namely diagnosis), we can just click right away to one of the  archetype tabs at the top.  The differential diagnosis tab allows us to review all of the relevant evidence pertinent to our task at hand.

On the differential diagnosis page, we have 200 results.  There is also a "Filter by Disease" list that contains a list of all of the disease concepts extracted from this hit list.  In essence, this "Filter by Disease" list becomes the basis for our differential diagnosis.  In this particular example, the list is fairly robust and includes not just seizure disorders, but also hypertensive encephalopathy - a leading contender for this particular case.  Clicking on any of these disease concepts allows us to filter the hit set and review the published material more rapidly.  Overall, the differential from the disease concept scope is pretty good - especially considering that we did not have the benefit of the patient's radiographic interpretation. 

This was a fairly simple example.  But as with other queries in Curbside.MD, the more in-depth and detailed the information that can be provided, the better the results from our search.

The next time you run into a challenging or confusing case, enter in the history, exam and diagnostic results within a Curbside.MD search.  Just type away like you were talking to a colleague.  Then, just click on differential diagnosis and review the disease list within the Content Scope.  Let me know your results and thoughts on the differential.  Hopefully, you'll find it as a great jumping point for diagnosing your patient, and maybe even avoiding a diagnostic misstep or error.

Practical, evidence based management of intracerebral hemorrhage

Recently, the American Academy of Neurology (AAN) posted the following "Test Your Knowledge" question on their website: "Which  interventions would be most likely to decrease the risk of intracranial hematoma expansion in an 87 year old man with a history of hypertension and warfarin treatment for previous stroke?"

This is a tough clinical scenario.  If you're ever been in this kind of situation (I know I have!) you're going to throw everything you can at the patient, including the kitchen sink.  Your options include Vitamin K, fresh frozen plasma (FFP) and most recently, recombinant factor VIIa.  Unfortunately, the ideal therapeutic strategy remains unclear.  A Curbside.MD search confirms this ambiguity in the medical literature.

If we enter in the Curbside.MD search "Which intervention would be most likely to decrease the expansion of an intracerebral hemorrhage in a patient on warfarin?" , the fourth article in best hits reflects some of the latest thinking and evidence in this area.  The article, Treatment of warfarin-associated intracerebral hemorrhage: literature review and expert opinion, from Mayo Clinic Proceedings asked leading hematology and neurology experts to select the ideal method of warfarin anticoagulation reversal for three clinical scenarios.  Even among the experts, there was no consensus opinion on the ideal management strategy and the relative indications for either Vitamin K, FFP or recombinant factor VIIa.

If we hit the "See Related" button for this article, the entire title and abstract become the basis for the search.  This more focused and precise view into the literature confirms a wide variety of therapeutic strategies and little underlying evidence to support a definitive answer.

This clinical scenario also raises a number of additional questions that are also commonly encountered in the management of warfarin related intracerebral hemorrhage. 

• In cases of life threatening bleeding in patients on warfarin, what is the preferred route for the administration of vitamin K - intravenous or subcutaneous?

Curbside.MD answer: Multiple hits indicate that intravenous vitamin K is the definitive route for the reversal of life-threatening bleeding in patients with therapeutic or supra-therapeutic INRs.

• In my experience, nurses are sometimes reticent to administer intravenous vitamin K.  So, what is the safety of intravenous vitamin K for the reversal of warfarin anticoagulation?

Curbside.MD answer: Intravenous vitamin K administration is extremely safe and there should be no hesitation for its administration in the appropriate clinical setting.

• Recently, I've noticed younger physicians are eager to administer recombinant factor VIIa for all cases of warfarin-related intracerebral hemorrhage, without fully understanding the financial costs and the risks.  What are the risks and adverse events associated with the administration of recombinant factor VIIa for warfarin-related intracerebral hemorrhage?

Curbside.MD answer: Articles under both under "Best Hits" and  "Clinical Trial Outcomes" confirm that recombinant factor VIIa is associated with a small, but not insignificant risk, of increased thromboembolic events.  The highlighted articles also confirm that this is a non-approved indication for recombinant factor VIIa and requires further evidence and study (Currently enrolling clinical trials are listed in the "Clinical Trials" section). 

As you can see, this is an incredibly complex area with a great deal of evidence and material to distill and synthesize for a clinical setting.  Curbside.MD becomes an important tool for making evidence-based decisions for these types of real clinical situations.

Guiding Keywords into Questions

As you know, Curbside.MD specializes in delivering evidence-based answers to real medical questions. However, we also field a significant number of keyword queries, mostly drug and disease names. In some cases, a simple keyword query may be submitted by a user who is new to Curbside.MD and wants to ‘kick the tires’. In other cases, the user may be a returning Curbside.MD user who is looking for the best professional information about a drug or disease. So we asked ourselves, what is the best page of medical evidence that we can show in response to a drug or disease keyword? And if the user is new to Curbside.MD, how can we introduce that person to the habit of submitting their real, complex medical questions?

For drug keywords, we have decided to solve this problem by combining authoritative drug reference information with ‘smart links’ that lead the user into more complex questions. Until recently, reliable drug information has been rather hard to organize effectively, because drug labels (also called ‘package inserts’) have been submitted to the FDA as unstructured PDF documents whose structure is hard for a computer program to interpret. However, the FDA now presents structured drug label information for many drugs through their DailyMed site. Using this resource, Curbside.MD is now able to fetch and organize reliable drug information directly from the FDA and use it to answer both keyword and complex medical questions. In response to a drug keyword, the next release of Curbside.MD will show a compact tabbed view of the different sections of the label, including Indications, Adverse effects, Dosage, etc. In addition, we apply our Document DNA technology to each section of the drug label in order to prompt the user with common follow-up questions. For example, the Indications section describes the diseases that the drug is FDA-approved to treat. We recognize each of the disease names within this section, and present each one as a link to follow up questions. Requip is a drug approved to treat Parkinson’s disease and restless legs syndrome. Clicking on the word ‘restless legs syndrome’ within the Indications section prompts the user with links to questions such as ‘What is the efficacy of Requip for restless legs syndrome?’ Curbside.MD recognizes this question as an example of the Treatment archetype and answers it with focused evidence boxes such as Best Hits from literature, Guidelines, Systematic Reviews, and Clinical Trials.

In this way we are able to provide complete and authoritative drug reference information, and display it in such a way that it is ‘live’, facilitating further exploration and investigation.

You say Segment, we say Archetype

The subject of search segmentation has been coming up lately in the mainstream search engine world. Because we are focused on a particular user group, medical professionals, the notion that each search is directed towards completing a particular task jumped out at us right from the beginning. In fact it's one of the first concepts that Rishi Sikka, our CMO, contributed to Curbside.MD when we began working with him.

Curbside.MD has been operating for over a month now, and we have answered many thousands of questions. Recently, we took a slice of those searches and analyzed them, looking at the questions and the answers that Curbside.MD delivered. We realized that the questions people ask can be binned into at least one well-defined category. Rishi coined the term 'archetype' to describe these categories, and we have been using that word ever since.

So, without further adieu, here is a pie chart showing the distribution of archetypes for professional medical questions (people sometime ask Curbside.MD questions that do not relate to the practice of neurology; these are discarded). As you can see, the most popular archetype is Therapy. These questions concern the best way to treat a patient, and account for about 50% of the total. For example:

• Should sacral meningocele surgery be performed in adults?
• Management of acute myocardial infarction in the setting of multi-trauma

The 4 next most common archetypes are about equally common. They are:

Differential Diagnosis

•       What brain lesions can cause a patient to develop a ptosis?

Work-up

• What is the work-up for a patient with tinnitus and vertigo?

Epidemiology

• Is there a geographic trend to MS?
• Depression and weight gain

Research

• What are the underlying causes of Parkinson's Disease?

For some questions the intent is not clear, or does not fit cleanly into one of the archetypes. We'll be taking a deeper look at these questions and refining our ability to answer them.

Our research on archetypes has given us great ideas for ways that we can improve Curbside.MD, and we'll be describing and implementing many of them in the coming months.

If you have a question about the meaning of a particular archetype, or about an archetype that I haven't mentioned, please submit a comment and I'll collaborate with Rishi to get your answer.

A United Front

You know that you’re on a good path when you have the company of people you trust.  That has been our feeling as we march through the hurdles in creating a trusted medical community.  That company in our case is the Myelin Network.  The network includes organizations such as the Accelerated Cure Project, National Multiple Sclerosis Society, The Montel Williams Multiple Sclerosis Foundation, Hunter’s Hope, The PMD Foundation, and The Transverse Myelitis Association.  We have all united in a mission to do what we can to help improve the health standards for people with medical ailments.

The members of the network are helping by spreading the word about Curbside.MD through newsletters, postings, blogs, and links.  Most recently, we attended the American Academy of Neurology (AAN) conference in Boston along with Art Mellor’s team at the Accelerated Cure Project booth.  Art and his team were kind enough to share their booth with us so that we could present Curbside.MD to people attending the conference.  The conference was a great success and we very much enjoyed the company of Art, Julie, and the other volunteers during our week at the expo.

We believe that our partnerships will soon benefit tremendously by the most recent addition to the Curbside.MD team: Jacqueline Kinlow.  Jacqueline was most recently the Executive Director of the Myelin Project.  She was tremendously influential in creating the network in the first place and now we are delighted to have her lead the charge and expansion of our partnerships.

In addition, the Curbside.MD team is hard at work at creating other tools that we believe will help our partners.   For starters, we are creating a Curbside.MD remote search box that organizations can use to power their sites with our unique medical search technology.  This will provide their visitors with natural language medical search to better find the information that they are looking for.  Secondly, we will soon be rolling out the Curbside.MD Medical Forum that will be context-driven and enhanced by our very own Curbside.MD Consultant.   Our automated Consultant will participate by recognizing medical ideas and providing the most relevant medical evidence to further advance discussions.   Each of our partners will have their own meeting rooms where they will invite members to join and we believe that this will have a big impact in the way that people share their medical thoughts with each other.

We are very excited by these developments and are greatly appreciative of the support that we’ve received to date from our partners.

Mr. Wang's Syrup

IMAGINE a world in which healthcare professionals can freely enter networked spaces and pick up conversations with other healthcare professionals who might be next door or living in a small village in the steppes of Central Asia, each practicing their art under wildly different conditions. Conversations might be concerned with how to treat a local viral outbreak with unknown causes to managing treatment of a young patient with autism or another less well understood neurological disease. All done without access to a vast pharmacopoeia or specialized devices and auxiliary care units. Why can’t these conversations occur now? Well they can and there are examples but there’s one important ingredient missing…well apart from the necessary internet connection and the professional “culture” that encourages doctors and the like to enter social networks and interact.

IS IT BECAUSE PHYSICIANS ARE TOO BUSY or is because they just don’t trust the experience and expertise of the people they might be interacting with? Well, yes, all of that, but the single most important missing ingredient is the perceived value of this network to them and their professional community. And yet the value is clear, it’s just not recognized as such. Much of the world operates under healthcare conditions that are very different from the US or other parts of the developed world. Little or no access to doctors, clinics, pharmacies, medical advice, all of the things that we take for granted. Doctors are functioning alone, without access to the network of professional help that underpins the practice of medicine in the US and Europe and most large cities throughout the world.

WE NAMED OUR MEDICAL SEARCH Curbside.MD because it meant something very important to us, and to other physicians in the US.  “Curbside” is the name given to the practice of calling on colleagues to help with diagnosis and treatment of patients by providing a “sounding board” for ideas and giving advice where it’s needed. This is truly a powerful element of our medical culture, one based on discussion, arriving at a better solution to a set of signs and symptoms or the best method of treatment than if one were to think, decide and act alone. Even in the US where the standard of medicine is very high, there is still a need for all physicians not to treat based on impulse but to entertain alternate possibilities and to discuss these with colleagues. This has been the subject of a new book by Jerome Groopman, “How Doctors Think” which really draws attention to the idea that the best solutions to medical problems comes from a careful consideration of all the possibilities.

SO, RETURNING TO THE IDEA OF ONLINE NETWORKS of physicians available to provide ideas and informal consultation. We envision that Curbside.MD, our medical search engine, can underpin physician professional networks providing real-time evidence-based material from the medical literature and providing a way to search and access professional conversations as you are engaging in an online conversation of your own. We believe that there are a number of physicians who want to be involved in a more global and altruistic way with their profession. They may already be perceived as key-opinion leaders, experts in their fields, or they may have years of experience practicing their profession and find that they have more time now but less opportunity to engage in their profession. These are the people we want to form the basis of our Curbside Network. We would love to have the involvement of highly skilled professionals actively engaged in an online professional network that is providing real-time help and advice to their colleagues trying to do the best that they can under the conditions they are forced to work under. Let us know if this resonates with you and we’ll proceed together to create this network.

WHAT HAS THIS GOT TO DO WITH MR WANG’S SYRUP? Well, May 6^th, 2007 New York Times article “From China to Panama, a Trail of Poisoned Medicine” by Walt Bogdanish and Jake Hooker, reinforced the need for informal professional networks in my mind. The report describes how Mr. Wang and others like him have poisoned many people throughout the world by substituting drug grade components in medicines with low grade or even similar but toxic components making very dangerous money. These components make their way from supplier to supplier and eventually into medicines and into unsuspecting patients.

 
“The kidneys fail first. Then the central nervous system begins to misfire. Paralysis spreads, making breathing difficult, then often impossible without assistance. In the end, most victims die. Many of them are children, poisoned at the hands of their unsuspecting parents. The syrupy poison, diethylene glycol, is an indispensable part of the modern world, an industrial solvent and prime ingredient in some antifreeze. It is also a killer. And the deaths, if not intentional, are often no accident.”, NYT May 6^th, 2007.

 

THIS MASS POISONING has created medical emergencies and mysteries throughout the world, emergencies that could benefit from highly dynamic networks of physicians examining signs and symptoms, forming connections based on observing a world-wide medical network and acting as a resource for online medical consulting.

 

“In Bangladesh, investigators found poison in seven brands of fever medication in 1992, but only after countless children died. A Massachusetts laboratory detected the contamination after Dr. Michael L. Bennish, a pediatrician who works in developing countries, smuggled samples of the tainted syrup out of the country in a suitcase. Dr. Bennish, who investigated the Bangladesh epidemic and helped write a 1995 article about it for BMJ, formerly known as the British Medical Journal, said that given the amount of medication distributed, deaths “must be in the thousands or tens of thousands.””, NYT May 6^th, 2007.

The Face of Decline

 

 

Self-Portraits Chronicle a Descent Into Alzheimer’s

Denise Grady, New York Times Oct 24, 2006.

When he learned in 1995 that he had Alzheimer’s disease, William Utermohlen, an American artist in London, responded in characteristic fashion.

“From that moment on, he began to try to understand it by painting himself,” said his wife, Patricia Utermohlen, a professor of art history…

…The paintings starkly reveal the artist’s descent into dementia, as his world began to tilt, perspectives flattened and details melted away. His wife and his doctors said he seemed aware at times that technical flaws had crept into his work, but he could not figure out how to correct them.

“The spatial sense kept slipping, and I think he knew,” Professor Utermohlen said. A psychoanalyst wrote that the paintings depicted sadness, anxiety, resignation and feelings of feebleness and shame.

Dr. Bruce Miller, a neurologist at the University of California, San Francisco, who studies artistic creativity in people with brain diseases, said …“Alzheimer’s affects the right parietal lobe in particular, which is important for visualizing something internally and then putting it onto a canvas,” Dr. Miller said. “The art becomes more abstract, the images are blurrier and vague, more surrealistic. Sometimes there’s use of beautiful, subtle color.”

Mr. Utermohlen, 73, is now in a nursing home. He no longer paints.

 

WILLIAM Utermohlen’s paintings chronicle his decline into dementia over nearly 40 years. Once a keen draughtsman, the images snapshots express the steady degeneration of his brain and the loss of his technical abilities. At first he knew he was making technical mistakes but was unable to correct them and as the disease progressed, the images became more and more surreal and abandoned.

AROUND 2000 researchers thought that the causative agent of Alzheimer’s disease (AD) was the accumulation of amyloid beta (Ab) in the brains of AD patients. Ab is a by-product of amyloid precursor protein (APP) and may have a functional role in neurons. In fact, early onset AD in some individuals can be traced to mutations in presenilin proteins which are part of the machinery that processes APP creating Ab (the proteolytic complex). When the Ab concentration reaches a sufficiently high level, the once short soluble proteins aggregate into insoluble amyloid plaques and fibrils markers of AD in the brains of dementia patients.

RECENTLY Ab has found a new, more disquieting role: Soluble Ab, once thought to be naïve now appears to be central to many of the protein-folding disorders including AD and Huntington’s disease and perhaps the presence of Lewy bodies in Parkinson’s disease and the Lewy body variant of AD.  This new role suggests that the insoluble amyloid tangles once thought to be the causative agent of AD are in fact protective stores of the real trouble-maker Ab.  Ab molecules appear to join together in punching holes in membranes including the mitochondrial membrane leading to neuronal death; the so-called Ab pore hypothesis. (Curbside.MD provides a direct overview of these new developments).

IN a recent conversation with Susan Lindquist (Claudia Dreifus, “On the Trail of Parkinson’s, Through Yeast Cells”, New York Times, April 24^th, 2007), the renown biologist, Howard Hughes Fellow and a founder of FoldRx, a startup in the area of mis-folded proteins, expanded on the view that Ab pores are perhaps the key to many degenerative neurological diseases. Her research reinforces the idea that the membrane permeabilization releases a cascade of events leading to cellular dysfunction and eventual death. There are a myriad of ways for a neuron to head towards cellular catastrophe including calcium imbalance, generations of reactive oxygen species, apoptotic collapse, activation of the proteosome-ubiquitin complex etc.  Of these, one of the most damning is calcium dys-homeostasis (imbalance) because of the role of calcium in synaptic plasticity. The damning aspect of calcium signaling is its importance in synaptic plasticity which is partly the mechanism of memory storage, clearly a hallmark symptom of AD.

WRITING this I can’t help thinking about my reaction I had the first time I saw Utermohlen’s paintings, a strong feeling of fear and insecurity, watching a lifetime quickly change from attention to detail and care to vagueness and an inability to grasp one’s own image . I’m also reminded of Bacon’s paintings. Although not a result of dementia, Bacon’s self portrait seems to capture the disparity between the way we see ourselves and the way others see us, a sharp reminder of the frailness of the human mind.

Self-Portrait

Francis Bacon (1909-1992) 1971; Oil on canvas, 35.5 x 30.5 cm (14 x 12 in); Musee National d'Art Moderne, Centre Georges Pompidou, Paris.

 

The Real Cost of Neurological Disorders.

PERHAPS it’s a good time to revisit the impact of neurological disease on populations given a report in the Science Daily “Updated Rates Of Common U.S. Neurological Disorders” describing a Jan 2007 Neurology article estimating the rise of certain neurologic diseases in the US and with the American Academy of Neurology meeting on-going in Boston this week (May 1-3, 2007).

 

STRAIGHT to the chase: The impact of neurological disease on individuals and their families and communities is vastly underestimated by governments, corporations and society as a whole. Stigma and discrimination are often associated with these diseases preventing affected individuals from seeking treatment. This results in an enormous opportunity cost to society.

 

THE WHO published a report earlier this year (January 2007) with some startling statistics about the incidence of neurological disorders across regions, age groups and socioeconomic divisions. The excerpt below is a summary of their findings:

 

“An estimated 6.8 million people die every year as a result of neurological disorders which affect up to one billion people worldwide while in Europe the economic cost of neurological diseases was estimated at about 139 billion Euros in 2004.

These alarming figures are among the findings of the first ever WHO report entitled Neurological Disorders: Public Health Challenges launched in Brussels on January 27 2007.

The Report reveals that of the one billion people affected worldwide, 50 million suffer from epilepsy and 24 million from Alzheimer's and other dementias. Neurological disorders affect people in all countries, irrespective of age, sex, education or income.“

 

CLEARLY loss of life due to disease is the most basic statistic of health outcome. However, how do you measure the years of lost opportunity caused by debilitating diseases such as epilepsy, multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD) and other neurological syndromes? Add to that the cost of depression and other neuro-psychological disorders on human life. The mortality statistics for these disorders dramatically underestimate the real disease burden to society, families and individuals. The following conclusions from the WHO report, powerfully summarizes this tragedy:

 

“The burden is already high and is increasing further…

Neurological disorders and their sequelae are currently estimated to affect as many as a billion people worldwide. These disorders are found among all age groups and in all geographical regions. Increased life expectancy and reduced fertility have resulted in a demographical transition from predominantly youthful populations to older and ageing ones, causing increases in the neurological disorders such as Alzheimer and other dementias and Parkinson’s disease… It is forecast that the number of people affected by dementia (already counted in tens of millions) will double every 20 years.  While predictions point to higher risk among poor people, children, adolescents and elderly persons, no population group is immune to neurological disorders. …Pain is a significant symptom in several neurological disorders and adds significantly to emotional suffering and disability. …The socioeconomic demands of care, treatment and rehabilitation put a strain on entire families, seriously diminishing their productivity and quality of life.”

Why is this Important to Us?

STATISTICS such as these reaffirm our decision to start development of Curbside.MD around neurology. Neurology is a “rich” area scientifically and clinically and presents an especially difficult challenge for doctors to “get their arms around” neighboring specialties. Clearly this provided us with a challenge which we have met with the latest release of Curbside.MD. Neurology covers a large number of diseases and syndromes, all interrelated in a complex way.  For us this provides a way to show the value of Curbside.MD to the medical community in a single source of information that taps into the vast amount of peer-reviewed and evidence-based literature.  Neurological disease has a devastating effect on the quality of life and has a huge economic and social impact. We have provided Curbside.MD “free-of-charge” to the medical community and want to keep it that way. We are providing a sorely needed service that has obvious value in diagnosis, treatment, patient support and research.

AN Aside: If you read the complete report you’ll have to get used to the idea of DALY’s, Disability Adjusted Life Years.  The reason this is important is because it measures in one number the burden of disease on life both through disability and death (morbidity and mortality).  Think of it as the loss of opportunity to society caused by disease. If you look at neurological diseases in this light, the impact on society is staggering as mentioned in the WHO report.