Diagnosis - Kartini Clinic for Children and Families

The Promise of Personalized Medicine

September 4, 2014 by Julie O'Toole

Advances in medicine come in all shapes and sizes: vaccines, antibiotics, anti-virals, immune system boosters and reducers, technological changes and recently, the hope that faster, cheaper and more accurate genetic analysis can bring us the new approach to medicine and medications: personalized medicine.

As I have mentioned in a previous blog, a leading proponent of personalized medicine has been Dr Eric Topol, editor-in-chief of Medscape and director the Scripps Translational Science Institute. Translational science is an important concept. It means taking the bench sciences and research and translating them into actionable information for people who actually care for patients. Dr Topol, himself a cardiologist, has written a great book on the subject called The Creative Destruction of Medicine. Check it out.

At Kartini Clinic we are always searching for better ways to deal with medication for our patients. We have often found it helpful to use the antipsychotic drug Olanzapine, in small doses, for the delusional fear of food and fat in anorexia nervosa. It is the mainstay of our success with young patients with food phobia. But we can’t use it in every patient, nor would we want to, and when we do use it we want to use it for the shortest period of time that we can. For some patients Olanzapine is a game changer; for others it helps a little, and some seem to show little to no effect.

And, of course, like all clinics which treat many patients with complex brain disorders, such as an eating disorder AND depression or an eating disorder AND obsessive compulsive disorder or an eating disorder AND anxiety, we have experience using the class of drugs called SSRI’s (Prozac, Paxil, Celexa, Lexapro, etc). Once again, some patients respond brilliantly, some respond a little, and some seem to get no help at all. Frustrating.

So in thinking about medication and kids with eating disorders, we have piloted a few programmatic approaches to deal with safety and efficacy which, as far as we can tell, appear to be unique to Kartini Clinic. As Dr Moshtael and I are both pediatricians, we tend to be conservative with medication. Adult doctors seem to throw one medication after another at adults and see what sticks. “Just try it”, is often the motto. We hate this approach and refuse to use it with our children, who, after all, have young, growing brains and are precious beyond telling to their parents. So our general philosophy has been: “keep the formulary small and try to use one or at most two medications at a time”, “use no sleeping pills”, and “use no addictive drugs such as benzodiazepines to treat anxiety”. We also say: “use the smallest dose that’s effective and for the shortest period of time you can.”

Well, that’s all very well and good, but it’s not advanced science, it’s just a conservative approach to safety.

A few years ago, when thinking about my own experience with tuberculosis and leprosy as a young doctor in the South Pacific, and gnashing my teeth over the fact that our young patients were often “non-compliant” with their medication, I hit on a game changing approach for us: “directly observed therapy”, such as is practiced for multiple drug-resistant TB. Directly observed therapy means that a parent, in the case of our patients, (a community health nurse in the case of resistant TB in the Pacific islands and elsewhere) is placed in charge of all medication and gives it directly to the child every day “babybird style” directly into their mouth, followed by two sips of water and swishing the mouth. Such directly observed administration follows our model of having parents in charge of food in family-centered treatment.

Suddenly, safety and efficacy improved for our patients immensely. Why don’t all doctors who treat children do it this way? Well, for one, they don’t have the family-centered treatment approach that places parents in charge. In the past, as a general pediatrician, I have seen adults abdicate control of insulin to their diabetic six year olds. Don’t get me started! These are dangerous and important drugs, folks, be they insulin, metformin, Olanzapine, Prozac or anything else, and we must insure safety, at least for children. These medications are too important to take for three days and forget on the fourth.

So DOT BB S&Sx2 our shorthand for “directly observed therapy, baby-bird style, swish and swallow twice” has gone a long way towards ensuring stability and accuracy of dosing as well as reducing non-accidental overdose in teenagers, but it is still the shallow end of the pool.

What is the deep end of the pool in personalized medicine? Genetic testing. And we have just begun to use it.

A new firm called Genomind reached out to us about non-invasive (cheek swab or saliva) genetic tests which focus on testing for individual response to psychoactive medication. To be certain that this was what it purported to be, I had myself tested first. That way I could feel free to discuss the results, if any, with our families and my readers.

The results? I discovered that I carry a variant of the gene SLC6A4 which codes for “slow response, poor response and/or likelihood of adverse events with SSRI’s”. Good to know!

They further elaborate on my genetics, saying: “The serotonin transporter protein is a presynaptic transmembrane protein responsible for serotonin reuptake. The patient (me) exhibits a variant of the serotonin transporter gene which the literature suggests may result in reduced reuptake of serotonin, less satisfactory response to SSRI-based treatments, and potentially a greater risk of adverse effects, compared to patients without this variant.” Citations are included for all of these assertions.

They go on to say: “This variant has been associated in published literature with lower stress resilience and higher rates of PTSD”. Well, I don’t know about lower stress resilience, as I have had a fair amount of stress to deal with in my life and have seemed fairly resilient, but it is true that my own father, obviously one of my closest genetic relatives, suffered from PTSD from severe combat experiences during WWII.

Further, the study states, I have a variant of the 5HT2C gene which means I would be at high risk for the side effect of weight gain were I ever to use Olanzapine. (Glad not everyone carries this gene variant!) I also have a deletion in the DRDR2 gene which means that Olanzapine would not only affect my weight metabolism, but it also likely would not work. Again, good to know.

I fortunately have the normal MTHFR (no jokes, please) gene variant which means I would respond to drugs affecting the methylenetetrahydrofolate reductase system, such as Deplin, which we occasionally use in depression. I have normal CY2D6 genes as well. Were this not the case I would likely metabolize psychotropic medications too rapidly and/or unpredictably, altering their response to them.

We have been very excited about the possibilities of adding this personalized genetic information to our prescribing armamentarium. It would be great to know in advance which drugs should or should not be expected to work in an individual patient. This may turn out to be the ultimate weapon in increasing safety and efficacy and go a long way towards making sense out of who responds to medication for depression, anxiety and other brain disorders and who does not. We have just begun to test those patients whose parents wish it and whose insurance will cover it.

Our patients and their parents are excited about the possibilities. We are excited. Targeted genetic testing is no doubt the future of personalized medicine. And we, at Kartini Clinic, intend to embrace it.

The Stigma of Mental Illness

July 17, 2014 by Julie O'Toole

Lots of ink is been spilled on the subject of the stigma associated with having an eating disorder. And in order to discuss the subject sensibly we need to get a few terms straight. It was considered a giant step forward in our field when Dr. Thomas Insel, head of NIMH, began blogging, writing and speaking about the fact that all mental illnesses are brain disorders, and that anorexia nervosa in particular was a severe mental illness. Prior to that it had been possible to trivialize anorexia nervosa as a psycho-cultural dysfunction, a “choice”, the result of family dysfunction, and/or attributed to reading too many fashion magazines. Bulimia nervosa had even been described as “regurgitating the mother”.

A new era of understanding the brain has brought some clarity to the subject, but hasn’t really touched the issue of stigma.

So, if eating disorders such as anorexia nervosa are severe mental illnesses, and by definition brain disorders, I think it seems clear that disorders of the brain should be no more stigmatized than disorders of the pancreas, disorders of the heart, or disorders of the liver. As the pancreas produces insulin, the brain produces behavior, and this, I think, is what lulls us into believing that disorders of the brain are somehow “different”.

What to do about the stigma? It is first important for us to examine our own role in furthering any stigma associated with eating disorders. Let’s start with doctors.

To be more specific, let’s start with psychiatrists. It has long gone unchallenged that a higher level of “privacy” needs to be afforded psychiatrists, who, after all, deal with mental illnesses. It is not uncommon for psychiatrists and other therapists to have waiting rooms that do not allow patients to see each other or to know who else might be waiting, they may even have separate entrances and exits for this purpose. On the face of it that sounds good, but what’s the message?

The message is that, contrary to a visit to a gynecologist, which certainly can involve information as sensitive as any psychiatric information, a visit to a psychiatrist needs to be kept “private” (read: secret). Your gynecologist might say hello to you in the grocery store, your psychiatrist will probably act as if they do not know you unless you acknowledge them first. Again, what’s the message? Psychiatric medical records are treated differently than other medical records. On Epic, a widespread form of electronic medical record, even other doctors cannot access a patient’s psychiatric records without first “breaking the glass” to enter über-protected territory. As long as we physicians continue to treat brain disorders differently than other disorders, we too are responsible for perpetuating the stigma.

As parents we are naturally protective of our children. It’s not uncommon for people to enter online forums anonymously, and the most cited reason for such anonymity, is to protect the privacy of their child.

I think we must boldly ask ourselves, though, whether we are protecting our child’s privacy or we are somehow buying into the belief that mental illness is a “flaw” in our child, in our family, in ourselves. Some families choose to conspire to keep the fact of their child’s eating disorder from their school, from their church, and even from their friends. Occasionally even other family members are left out of the loop. And while I completely sympathize with attempts to “control the message” at the time of initial diagnosis, I think that in the long run it will be critical to unambiguously send the message to our own family and our own children that there is no reason to feel stigmatized for having an eating disorder. And that, in fact, to the contrary, we will fight this false belief together. As Pogo said “We have met the enemy, and he is us”. Only sunshine into the dark places will evaporate this unnecessary pain.

Once upon a time tuberculosis was a terribly stigmatizing illness. Even now, when taking histories from some Southeast Asian families, it is common for the fact of a family member’s tuberculosis to be concealed. It is medically unhelpful not to know who is vulnerable to what disease, but the stigma of TB was, and to a certain extent still is, far too great for many families to challenge.

With the evaporation of insurance denials based on “pre-existing conditions”, we no longer need fear that our child will not be able to get insurance if the fact of their eating disorder becomes known. With the many recent articles on the genetics of mental illnesses, the public statements reiterating that families do not cause eating disorders, and the air-clearing acknowledgment of eating disorders as brain disorders, we can finally begin to attack the stigma together.

Let us not be that enemy. For the sake of our children and all children, let’s find the courage — whether we are physicians, therapists, dietitians, parents, or patients — to cease contributing to the stigma, to stand our ground, to turn around and fight back.

Mixed Symptoms

April 3, 2014 by Julie O'Toole

Recently I was making our daily rounds at Randall Children’s Hospital and received a lesson from a very young patient of ours. I say it over and over: “your patients are your teachers”, and it is really true. I was first told this by Dr. Mizuo Tottori, pediatrician and mentor to many other pediatricians in Hawaii. And life itself has borne out the truth of it, again and again.

This particular little patient has anorexia nervosa and has done very well. Her parents are competent and loving; but her illness is relentless and merciless. She had been in good remission until the latest bout of symptomatic resurgence. The twist on the usual story has been the new emergence of “food phobia-like” symptoms along with the anorexic difficulties of eating at all. She struggles to swallow and pools her saliva. Had presented like this initially, we would have made the diagnosis food phobia and consequently missed the early-onset AN, or at least for a while. What we have discovered is the “magic food phobia dose” of Olanzapine (7.5 mg) seems to work as well for this mixed presentation as it does for pure food phobia (see also previous blogs). For strict AN we don’t usually need this high of a dose. Once we titrated our little girl up to 7.5 mg, her food phobia-like symptoms improved.

So walking back to the office from making rounds, her sweet face in my mind’s eye, I began to think about diagnoses in general and hers in particular. I tried to think of other medical situations where we have a “mixed diagnosis”.

All diseases have a natural history. Their natural history encompasses the totality of “how they act”, meaning what the onset is like (sudden, gradual, insidious), expected course of symptoms (rash, fever, weight loss, pain, appetite changes, sweats, etc., etc.), expected duration and course, etc. Is it acute? Chronic? Does it wax and wane/remit and exacerbate? How does it respond to treatment? Is it fatal? Is it contagious? Does it burn itself out if the patient lives?

For example, if you diagnose a patient with smallpox, we know something about the natural history of this illness: it is caused by the variola virus (therefore “contagious”), there is an incubation period of about 10-12 days (before skin symptoms appear) and a prodrome towards the end of that period involving high fever, back ache, and diarrhea. Then the characteristic rash appears, first in the mouth and then all over the skin: multiple raised spots which blister all at the same time before finally going away (often with severe scarring). 30-35% of people who acquired smallpox (when it existed on planet earth) died of it.

So now you know its natural history. You can see why it matters to know this, both to the treating doctor and — importantly — to the patient.

But let’s say that, in the middle of a smallpox epidemic, you incorrectly diagnosed a patient with variola when what they really had was an infection with varicella (chickenpox). Even if you could not do cultures or viral tests, you could likely tell that you had made a mistake by their differing, evolving natural histories. Chickenpox is also contagious, with an incubation period similar to that of smallpox and a prodrome not entirely dissimilar either: nausea, loss of appetite, aching muscles, and headache. If you were very experienced you might notice the lack of severe back pain. But once the rash appeared you would know the difference: the chickenpox are pox at all different stages of blistering, redness and healing or rupture, not a mass of many pox all at the same stage, as is true for smallpox. Ah hah! They have a different natural history. And to underscore why this is vital, almost no one will die of chickenpox.

So are AN and food phobia like that? Well, yes, in the sense that they have differing natural histories. But how about a patient who shows features of both?

To think about that, I need to think about more complex illnesses and nothing’s more complex than rheumatology….

Let’s say your patient has a strong family history of autoimmune disease (Hashimotos thyroiditis, type one diabetes, multiple sclerosis, etc.) and is suffering from joint pain, muscle inflammation, fevers, exhaustion and a strange thickening in the skin of the hands. You first think scleroderma or lupus (SLE). But then, they have features of rheumatoid arthritis and dermatomyositis… confusing. After a period of watching their illness evolve and seeing how it responds (or doesn’t) to treatment, you decide they have “mixed connective tissue disease” (MCTD) with features of many autoimmune rheumatic illnesses, but a natural history somewhat different than any one of them.

Is AN with food phobia-features like this? I believe it probably is.

Interestingly, MCTD does not seem to morph into SLE, for example, although they can share common diagnostic features. Likewise, we do not have experience of food phobia morphing into anorexia nervosa; they seem to be independent illnesses, even when they both result in food avoidance.

I guess the bottom line is that we clinicians are still stuck in the 19th century folks, that’s right — the 1800’s — where the primary tool we have at our disposal is basically observation of the natural history. We know what to do, what seems to work, but we are not sure why. The basic biology of childhood eating disorders is still almost entirely unelucidated (not to mention the genetics). And until they are, until genetics and biochemistry replace observation of natural history as our teachers, our patients retain that honor.

In other words, Doctors, pay attention to your patients!

Thinking About Obesity

February 27, 2014 by Julie O'Toole

Thinking about obesity: calmly, rationally and outside the box

When I was a rotating intern at Sacred Heart Medical Center, long ago, I attended rounds with the then head of medicine Dr. Patrick Tennison. Dr. Tennison was a thin, dark haired, intense guy who years later would save my life, but at that time was obsessed with imbuing young doctors with a sense of urgency about diagnostic dilemmas. He was more like a highly competitive detective than your typical doctor.

“The main thing,” he told us “is to be the first to make the right diagnosis.” What he actually said was more medical-speak: “be the first to make the dx”.

Make the dx. How could I disagree? Well I didn’t, of course, though I took issue with the “be the first” bit, since that seemed unnecessarily competitive to me. Who cares if you’re the first? The important part (from the patient’s point of view) is that you make the correct diagnosis.

I have thought about Dr. Tennison’s intensity around ‘making the diagnosis’ for many years. And nowhere does it seem more important to me now than in the field of obesity. Allow me to explain.

Now, in my trying to figure out how to think about the clinical dilemmas of obesity, add the fact that I went to Reed College (like Steve Jobs) and dropped out (also like him). Why do I mention Mr. Jobs, or Reed for that matter? Because he later became famous for (among other things!) the logo “think different”, which was taking a page from Reed’s playbook in a big way. When you have a big problem, you need to think different.

And we have a big problem. That problem is obesity.

If you read my blogs you have heard me say that science will save us all. Obesity is a domain in desperate need of translational science — i.e. science that goes from the “bench” or lab to the clinic or patient. The field of obesity treatment, and the deluge of articles and books written on the subject, are riddled with the confounders of personal orientation towards fat people, fat prejudice, outdated beliefs about the efficacy of dieting, the worship of exercise as a solution to all problems, a glut of research dollars available to anyone saying they are working on obesity related problems, lack of good medications, poor understanding of the basic science of human metabolism and weight homeostasis… and by a failure to think clearly about diagnosis. So back to Tennison.

In our search for a “cure” for obesity and its attendant medical problems I think we need to go back to diagnostic basics. The most basic start would be making the right diagnosis in the first place.

It seems likely to me that the word “obesity” is rather like the term “pulmonary disease”. If you have a “pulmonary disease” this could mean you have: A. cancer of the lung B. asthma C. cystic fibrosis D. a common cold E. tuberculosis… you get the idea. It’s not a diagnosis, it’s a category, and it encompasses conditions that are terminal and those that are trivial. I think that the term “obesity” is going to turn out to be like that.

In my opinion, there are not only going to be grades of high body weight (e.g. overweight by some definition, obese, massively obese and obese such that it is not compatible with life even in the short term), but there are going to be different etiologies (causes) of obesity. In other words, there will not be one kind of obesity but rather a slew of different clinical entities whose final common pathway is a higher than average—even much higher than average —body weight. Understanding this will be critical to understanding when/if intervention is called for and what kind of intervention is likely to work.

I suspect that there will be obesity caused by binge eating. In this scenario, the condition or illness is not “obesity”, it is binge eating disorder. Obesity would be a symptom, as cough is a symptom of lung disease.

I suspect there will be leptin resistance-caused or promoted obesity.

We know there are rare genetic conditions which result in obesity (Prader Willi, absence of leptin, etc.).

There may be infectious obesity.

There may be obesity caused by our intestinal flora.

There may be diet-induced obesity, or rather, dieting induced.

There may be endocrine disruptor induced metabolic disease, which results in metabolic derangements related to leptin, grehlin, MSH 3 & 4 receptors or other hormones.

There is (rare) hypothyroid-induced obesity.

There may be simple hyper-alimentation (overeating) induced obesity, although I suspect that such overeating will be found to have a brain-based cause, given the massive social disincentives to being fat.

Another way to say it is, “obesity is not one condition, it is several”. Or “there are many different kinds of obesity”.

So, first get the diagnosis.

Second, throw out the prejudice.

Third, look for the science.

Let’s get started.

How to diagnose the child who “won’t eat”

January 30, 2014 by Julie O'Toole

This blog will be short as I am preparing to attend and speak at the F.E.A.S.T. conference in Texas this week. Very exciting!

Recently I was asked to consult on a child who “won’t eat” and who hasn’t eaten for several weeks. Her situation is complicated by English not being the family’s first language and by her entrance into the medical “system” being through the emergency room, but it did remind me how complicated making the correct diagnosis can be in a child who won’t eat. This girl is 11 years old, she has always been a robust eater and a happy kid. Early this year, she got sick with a viral infection and vomited several times. Nearly simultaneously she started her first period and expressed severe anxiety about this to her mother. Thereafter she refused to eat, citing fear that she would vomit again and saying her throat hurt. The ER doctors examined her throat extensively and could find nothing. She would accept only sips of water from them or anyone else. Quite understandably, her parents were frantic.

So what’s the diagnosis? Mother and ER social worker were very fixated on the appearance of this food refusal and the timing of her period. Could she be afraid to “grow up?”

So I decided to write a few simple ways to sort out the major eating disorder diagnoses of childhood from each other, as there are a few useful sorting points.

There are basically three big diagnostic categories pertinent to this and similar presentations:

Anorexia Nervosa and ARFID (treated as one for the first level of sorting, as the treatment is the same).
Food Phobia
Selective Eating

The initial sorting point is what we call “acuity” or speed of onset.

If the refusal to eat has been since early childhood and is actually “refusal to eat normally or in adequate amounts” the diagnosis is likely selective eating.

If the onset is abrupt in a child who formerly ate normally, the diagnosis is highly unlikely to be selective eating, so now we must sort anorexia nervosa and its relatives from food phobia. The distinction is important as the treatment and natural history of the illnesses will be different.

If the child refuses to swallow anything solid regardless of food composition (i.e. not restricting on the basis of fat or caloric content) this is likely to be food phobia. In food phobia the onset will be abrupt in a child who formerly ate normally.

Commonly, food phobia is preceded by either a choking episode or a viral illness involving vomiting, as in the patient above. Older children may tell you directly that they are afraid of choking, or believe their throat to be blocked or may report being afraid they will vomit. Younger children may refuse to tell you “why” they won’t swallow. But crucially, the onset will be abrupt, and this is an important sorting point.

If only young children with anorexia nervosa (AN) always told you that they were afraid to get fat, or were afraid they were already fat, the diagnosis of AN would be easy. But famously, children do not behave as miniature adults, and the world of pediatric eating disorders is not unlike the world of other pediatric illnesses in this regard. “Non-fat/weight phobic” childhood AN has finally been reflected in the DSM 5, which makes diagnosis more complicated even while it is a better reflection of reality.

However, for initially distinguishing AN (and ARFID) from food phobia, the reported speed of onset of symptoms will be critical. AN has a more insidious onset. Children with AN may report “stomach ache” or “too full”, but not fear of choking. They will eat and drink, just highly edited foods or highly edited amounts. A child who expresses no overt fear of fat, but who has gradually cut back on the amounts of food eaten and/or avoids sweets and fats, is likely to have anorexia nervosa.

Of course, in medicine, as the Germans say: “es gibt nichts was es nicht gibt” (roughly, “anything is possible”), but these basic sorting points should help guide parents and practitioners through any diagnostic dilemma in their quest to decide what to do next.

The Promise of Personalized Medicine

The Stigma of Mental Illness

Mixed Symptoms

Thinking About Obesity

How to diagnose the child who “won’t eat”

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