As a longtime fan of Dr Lisa Sanders’ New York Times column on diagnosis, I was excited to listen to Every Patient Tells A Story (Random House Audio, 2009). I happily looked forward to an anthology of favorite cases that she had already presented. However, when I started to listen to the Audible book, read by the author, I quickly realized that Dr Sanders’s book is so much more than a best hits collection. As the subtitle – Medical Mysteries and the Art of Diagnosis – alludes to, the topic here is diagnosis looked at from top, bottom, this way and that. The story, and it does unfurl as a page-turner, was so absorbing that I slowed down listening to the book as I neared the end because I didn’t want it to be over.

Not only do I not want to steal Dr Sanders’s thunder, but I could not even if I wanted to. This book narrates a personal journey from journalist to physician to “diagnosis-specialist.” Among many topics that Dr Sanders hits on are:

• The enormous importance of a diagnosis to a patient’s sense of control and satisfaction with medical care
• The patient’s story is enough to reach a correct diagnosis in roughly 70% of cases
• The under-utilization and lack of appreciation of the physical exam’s ability to inform diagnosis as a cheap alternative to a “test” or as a unique contributor to diagnosis.
• Morbidity and mortality caused by mis-diagnosis and delayed diagnosis
• The role for computer algorithms in patient diagnoses (hint: answer is nuanced)

If you are interested in any of these topics, go read the book, period. Here I want to relay just a few thoughts that take off from Dr Sanders’s themes.

My favorite story

As befits her specialty in internal medicine, Dr Sanders relates cases of primarily infectious or metabolic diseases. In one case, however, the star of the show was the nervous system and not surprisingly this was my favorite case; I give a brief version here.

Randy and Leslie are engaged to get married and are excitedly planning their wedding together. [Dr Sanders changed the names of the patients and physicians featured in her book. I have used the pseudonyms that she used.] They have a date and a venue. But as I have learned from my brother’s recently wedded children, there is a great deal more to planning a wedding than those two necessities. Essentially, as a modern-day wedding approaches, planning occupies pretty much all of a couple’s time outside of work. In this vein, Randy and Leslie travel for the weekend to Leslie’s hometown where the wedding is to be held in order to make wedding arrangements. Randy is confused and feels a little off. To Leslie, he appears unusually quiet, a bit distracted, and she worries that he is getting cold feet. On Monday following the weekend away, they each go off to work. When Leslie gets to work, she gets a text:

Randy: Something is wrong.
Leslie: What do you mean?
Randy: My memory is all f—ed up. I can’t remember anything. Like I can’t tell you what we did this weekend.
Leslie: When is our wedding date? Can you tell me that?
Randy: No.
Leslie: Call the doctor. Do it now. Tell them this is an emergency.

In the next 30 mins, Randy calls his doctor three times. But every time, he immediately forgets what the doctor tells him. When Leslie hears this, she insists that Randy get one of his work friends to take him to the nearest hospital. The ER physician at the local hospital blames the memory lapses on Ambien, a sleeping pill that Randy has taken. The physician tells Randy to lay off the Ambien and that all will be well. Randy conveys this to Leslie who is sure that this is total bullocks. She says, “Don’t go anywhere. I am going to come pick you up.” Of course, by the time she gets to the hospital a half hour later, Randy is wandering the streets with no idea as to why he is there. He is not sure who Leslie is. Leslie takes Randy to his own doctor who examines him and sends him right to Brigham and Women’s Hospital, a Harvard associated hospital in Boston.

At “the Brigham,” Randy is seen by Dr William Abend, a neurologist who learns that slight memory problems had creeped up a few months earlier but that they had sharply increased in severity over the past weekend. In the standard test for memory function, a physician asks a patient to repeat a short list of words. After the patient does, the physician goes on with the exam, coming back after a short interval to ask the patient to recall the list of words. Abend asks Randy to remember automobile, tank, jealous. Randy easily repeats the words but cannot even come up with one of the words when asked only 30 seconds later.

Tests showed no signs of seizures, an infection, stroke, or brain tumor. However, the MRI showed abnormalities bilaterally in the temporal lobe where the hippocampus is located. As it turns out, the problem was a paraneoplastic disease. Randy had a Hodgkin’s lymphoma tumor in his chest. As Randy’s immune system attacked his tumor, it made an antibody that crossed the blood-brain-barrier and attacked hippocampal neurons. The hippocampus is necessary for taking experiences and preparing them for permanent storage as memories so that they can be recalled at some later time. Without the hippocampus, memories do not form. Randy’s cancer was treated and within about 4 weeks, his memory started to return.

Dr Sanders uses this remarkably poignant story of neurology gone bad and then reclaimed to illustrate the power of diagnosis. Mark Lean, a medical student assigned to Randy’s case, became fascinated by it and took it upon himself to become an expert. He used this expertise to translate medical-speak into everyday language, explaining the disease to Randy and Leslie. Proof of Mr Lean’s explanatory talents come from Randy’s attitude toward his cancer treatment. Since he understood that he would regain his self once the cancer was beaten back, Randy had a bring-it-on attitude toward surgery (tumor removal) and chemotherapy (kill any cancer stowaways). Happily, Randy made a full recovery.

The power of diagnosis: Neurology as a case in point

The classic knock against neurology is that all a neurologist can do is “just” diagnosis. This putdown fails to resonate with me for a couple of reasons. One is that neurology is not alone in providing more diagnoses than cures. The same could be said of virtually any specialty. Second, and more to the point here, a diagnosis is a gift. It validates the person’s experience. When paired with a prognosis, diagnosis is, as Dr Sanders points out, “a roadmap” into the future, providing control. People want to know that they are not crazy, they want a name by which to refer to their experience and they want an idea of what the future holds.

I was once at a party and met a man who was telling me about his mother who had died of Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s disease). I asked him how he felt when his mother received the diagnosis. He immediately brightened, saying, “It was great. We hadn’t known what was wrong. We could see that Mom wasn’t doing well but we had no clue what was going on. We were worried and felt at sea. When the diagnosis came, we knew what we were dealing with. We knew roughly how much time we had and we could arrange our lives accordingly. I was able to spend lots of time with my mom in her final months.” The power of explanation, understanding, and narrative cannot be overestimated.

The importance of a name: Rare diseases

Rare when applied to disease is a relative term. Different governments and agencies define it differently. The U.S. Rare Diseases Act uses a cutoff that corresponds to one in 1,500. [The cutoff is actually put in terms of the number of people in the U.S. are affected – 200,000 – which in a population of just over 300 million corresponds to about one in 1,500.] The European Union uses a rare disease cutoff of one in 2,000. Thus, using commonly accepted criteria, a rare disease can afflict as many as 5 million people worldwide. For a multitude of rare diseases, there are only a few hundred or a few thousand cases known worldwide. At least one disease known only in a single individual has been reported.

Despite being uncommon, some rare diseases are relatively well known. Examples include:

• Duchenne’s muscular dystrophy: one in 3,300 males
• Scleroderma: one in 4,100
• Addison’s disease (JFK had this): one in 8,500
• Huntington’s disease: one in 10,000
• Familial Dysautonomia: fewer than one in 1,000,000 but one in 3,600 among Ashkenazi Jews (not present outside of the Jewish population)
• Congenital insensitivity to pain: fewer than one in 1,000,000

By definition, the number of people with any one rare disease is small. Yet, there are many, many rare diseases so much so that some percent (maybe even in the double digits) of the world’s population has a rare disease. Thus, it is strange to say but it is true that having a rare disease is fairly common.

For every Huntington’s disease, there are dozens of conditions with unrecognizable names or no name at all. A group in the UK advocates for and supports “families affected by a syndrome without a name,” leading to its name of SWAN-UK. This group wants to transform unknown, unnamed syndromes into named diagnoses.

Really rare conditions are described not named. Take Ian Waterman, whose remarkable resilience in the face of profound neurological loss has been chronicled in two books by Dr Jonathan Cole (Pride and a Daily Marathon, MIT Press, 1991; and Losing Touch, Oxford University Press, 2016; both books are highly recommended). At the age of 19, Mr Waterman had a viral illness that resulted in the permanent loss of nerve fibers that signal touch and proprioception from the neck down. Now, this condition could be termed acquired large fiber sensory neuropathy. Yet that “name” is just a description of a condition that was not present at birth (acquired), involves the loss of peripheral nerve fibers (neuropathy) that code for touch and proprioception (sensory, large fiber).

As a result of his condition, Mr Waterman initially could not move. As he describes in a BBC documentary, Mr Waterman slowly taught himself how to move. My Neuroanatomy class in Paris was lucky enough to hear Mr Waterman’s story from Dr Cole, Mr Waterman’s neurologist, friend and biographer. Afterwards, one of the students said, “it seems that Ian learned to use his own body as though he was learning to use a fancy piece of robotic machinery, except he had to make up the instruction manual.” Essentially, Mr Waterman acts by deliberately making a plan and then closely supervising the execution of the movement using vision. Some movements, such as getting on and off an escalator, are not possible.

Remarkably, when people ask him about his condition, Mr Waterman regularly says simply that he has a bad back. Why? Well, imagine the alternative. “Well, actually I have a large fiber neuropathy that killed my ability to sense touch. I also have no sense of proprioception which means that I don’t know where my body is and I have no feedback from my muscles and therefore no motor reflexes.” You can just imagine the listener’s eyes glaze over. While acquired large fiber sensory neuropathy is a name or could at least be construed as a name for Mr Waterman’s condition, it holds no communicative power. It is not a shorthand for anything meaningful to the average person or even the average physician. Mr Waterman might as well employ the words in Greek or Swahili for cannot-move-in-the-dark.

Along with the lack of a diagnosis comes ignorance of prognosis. As time goes by, the patient, or patient’s parents in the case of pediatric cases, and physician figure out the disease course as it happens. This is not a prognosis; rather it is simply an evolving description that changes across time.

Many rare diseases are genetic and are present at birth. Imagine parents, excited to welcome their child into the world, realizing that something is wrong with their baby. In the case of a rare condition, the parents may struggle to get a diagnosis. They and the physicians that they see may not appreciate the full ramifications of the baby’s condition for years. Understanding the seriousness of a rare, unnamed condition does not happen immediately. It takes time, ramping up as a gradual process over the course of a child’s infancy and childhood.

Without a show-stopping diagnosis, it is difficult for the parents of a child with a rare disease to communicate their reality with friends and family.

Friend: “Congratulations! How’s [Mom]? How’s the baby?”
Parent: “[Mom] is fine but the baby needs to stay in the hospital a bit longer.”
Friend: “What’s wrong?”
Parent: “We’re not really sure. They need to run some tests.”
Friend: “Oh I am sure everything will be fine…”

In reality, getting to “fine” will take a great deal of time and a large amount of luck; and may in fact never happen. Denying the reality of the parents’ struggle is not helpful. Contrast the above with a parent telling friends that their child has a recognizable disease such as Cerebral Palsy or congenital deafness. Typically, the response is compassion – “Oh I am sorry” – and validation of the present and future challenges that face the affected family.

Recognizing disease entities

I want to end by considering how diagnoses are born. Common disease names were not handed down from God. Multiple sclerosis, amyotrophic lateral sclerosis, and myasthenia gravis all had to be recognized, carved out as single entities from all the other possible human states, and then named. Jean-Martin Charcot, a physician at the Hôpital Salpêtrière in Paris, and arguably the father of Neurology as a discipline, described a number of diseases including multiple sclerosis.

Just before leaving Paris, I spent the day in the Bibliothèque Interuniversitaire de Santé. This is a library housed at the Université Paris Descartes (a medical school). This is not a library where you can wonder through the stacks and browse through any volume that catches your eye. Instead you have to request the specific volumes that you want, down to the title, author and page of the journal article within a journal volume.

Anyone can walk in to the Library and use the quiet space to study and work. However, in order to request a book, one must be registered. Since I wanted to see two specific books, off I went to register with the librarian at the Central Desk. She was a kindly looking middle-aged woman with rosy cheeks, strawberry blond hair and a ready smile. She spoke French, period. No English. My French is okay for understanding and pretty terrible for speaking. I showed her the book titles that I wanted and tried to say that I wanted to be registered so that I could look at these books.

The librarian asked me if I had I.D. I said no, as I felt my stomach lurch to subterranean depths. Then I quickly started to blather on about coming from the states and returning back there in two days, the University of Chicago, and how I so wanted to see these books, blah, blah, blah. I think she finally got sick of hearing my French – and really who knows what I actually said? She asked me a question that included “votre visage” and “internet.” I looked at her, realizing that she just asked me whether she would be able to find my visage (face) on the internet. I blinked and said quickly, “Biensûr” (yes, for sure). She proceeded to google my name, pull up plenty of pictures of me, and saw that I was indeed a Professor at the University of Chicago. She gave me a registration card. She was kind to me throughout this process, equally so to the un-credentialed person and the verified Professor. She epitomized caring, creativity, and generosity and I am grateful.

Upon receiving the two books I requested, I spent several delightful hours reading slowly through the articles I was interested in. While this required that I look up plenty of words, reading scientific French is not out of my reach and I can fairly easily read 20 pages in a few hours. When I had completed my study of the material that I had come for, I did the equivalent of wondering the stacks: I browsed the books I had in front of me.

Photographed from “Sur deux cas d’Acromégalie” by Pierre Marie in Revue de Médicine, vol 6, pp 297-333, 1886.

As I leafed through the volume of Revue de Médicine, my gaze was arrested by a photograph of the unmistakable visage (lovely word) of a person with acromegaly. The picture was in an article by Charcot’s student Pierre Marie with a title that translates to “On two cases of acromegaly.” Marie explains that two cases appeared simultaneously on the service of Jean-Martin Charcot where Marie was a student. He goes on to propose that overgrowth of the feet, hands and face constitute “une entité morbide spéciale” which literally translates to a specific unhealthy entity, aka a disease. He names this diease, acromegaly. Marie examines the literature and asks around but does not hear of other cases and concludes that, while impossible to know the actual prevalence, this new disease may be rare. Indeed, acromegaly occurs today in fewer than one in 15,000 and thus certainly qualifies as rare.

As an aside, for anyone interested in acromegaly, please read Mike Scalise’s excellent account of his own experience: The Brand New Catastrophe: A Memoir (Sarabande Books, 2017).

I bring up the definition of acromegaly by Pierre Marie in 1886 because it powerfully illustrates the fact that the first diagnosis of a malady is the result of a human recognizing and categorizing a pattern. It is the critical hurdle that reifies human suffering into an entity that can then be studied and investigated. Discovering the natural course of a disease, its pathophysiology, and any potential treatments that may ameliorate its effects can only happen after an alert person, typically a physician, picks the needle out of the haystack and names it.  A person must recognize the commonality of a disease even in the face of many individual differences in presentation as well as any number of random and irrelevant distractors.

Conclusion 

Diagnosis is powerful. It validates and gives a name to human suffering. It can return some sense of control to the community of people affected by one person’s malady. Once a diagnosis has been created, knowledge of prognosis starts to build straightaway. With time, diagnosis and prognosis provide a chart of the unfamiliar seas where the patient, family, and friends find themselves of a sudden. And yes, the weather that each patient faces differs so that the course of each individual’s disease varies. Nonetheless, a diagnosis is the gift that provides people with the best possible guess as to what the present and future are likely to hold.