FROM THE NEW (2014) BOOK "THE ART OF MEDICINE" by Dr. Herbert Ho Ping Kong

ENTERING the GREY ZONE

Cure sometimes, treat often, comfort always. — Hippocrates

A few years ago, my former colleague Dr. David Naylor was invited to lecture to the American Osier Society — named, of course, for Sir William Osier, arguably the greatest physician of the modern age. His address provided a trenchant analysis of the two dominant streams of modern medicine. The first is quantitative, evidence-based practice, which, Naylor noted, "is dependent on applying averages and probabilities to individuals, based on inferences from clinical populations." One might reasonably call this the Science stream.

The second, more patient-centric approach line of attack attempts to use all the skills and tools of medicine to determine the right diagnosis, prevention and treatment for a specific "biological profile" — in effect, the Art stream.

But regardless of which approach one uses, the hard reality, Naylor observed, is "that we remain at sea when it comes to understanding and preventing or treating many diseases."

Naylor made another salient point as well. Even where there is strong evidence that drug xyz is likely to combat disease abc, there is no guarantee that what has worked in a clinical study of 300 patients will actually be effective for one more patient — the one you are treating. "These are the Grey Zones of clinical practice where the balance of harms and benefits is uncertain," Naylor concluded. "We are plagued with exponential uncertainty. The more we learn . . . the greater the number of permutations and combinations that might be contemplated in the care of any individual."

In clinical practice, the Grey Zone divides into two distinct domains. In the first are found ailments that yield symptoms — and symptoms, in turn, cause genuine pain or discomfort — but have no specific label or name. As hard as we may search to identify the precise cause of the complaint, we are often left apologizing to the patient. The best we can do in such situations is to help ameliorate the condition.

In the second domain, which I will examine in the next chapter, are illnesses that have a clear physical basis, but, alas, no effective or remedial treatment. Here, the art of medicine can be sharply tested, because the patient may have to bear the burden of the disease for many years. Technology may help us reach the diagnosis but, in these instances, it is no substitute for the care that such patients need.

Many Grey Zone illnesses fall under the broad, autoimmune umbrella. They are problematic because they often present in non-specific ways. And while we have developed considerable expertise in testing for other diseases, blood markers for several autoimmune disorders have proven elusive. Thus, to diagnose lupus, we often use a set of criteria developed by the American Rheumatology Association; if we find five out of 15 possible characteristics, we conclude the patient has lupus.

However, I have seen lupus patients who do indeed exhibit the classic symptoms of the disease — facial rash, vasculitis, pericarditis, pleuritis and sun sensitivity — and yet their blood sample is negative for anti-nuclear antibodies (ANA), one of the key indications of immune system maladies. And I have seen other patients who show all the requisite clinical and laboratory signs of full blown systemic lupus erythematosus and, at the same time, all the symptoms and signs of rheumatoid arthritis. We call this Rupus.

My point is to underline the extraordinary complexity that clinicians encounter in the world of autoimmune diseases — yet another reminder that, for all the distance modern medicine has travelled in delineating the processes and mechanism of illness, our journey is nowhere near complete.

After more than 50 years in medicine, it isn't often that I am presented with an illness that I've never seen or heard of before. But such was the case with Larissa, a married woman and mother in her late 30s. For some time before I met her, she had been experiencing crippling, episodic back pain, often just before sleep. The epicentre of her pain was the 10th thoracic vertebra (TIO). It was sometimes accompanied by low-grade fever, as well as by some shortness of breath and dizziness.

Welcome to the Grey Zone, that expansive landscape that physicians must learn to navigate with skill and care. In this chapter, I want to focus on one province of that zone — patients that present with clear, verifiable symptoms of illness, but what illness that is remains a mystery.

Stymied to explain the condition, Larissa's family doctor thought it might be arthritis and sent her to a rheumatologist. Incredibly, he dismissed her complaints as figments of her imagination. She quickly sought a second opinion. This time, a series of x-rays was ordered, which appeared to indicate a large lesion on her left lung and another one at TIO . Uncertain whether the lesion was malignant, Larissa was quickly dispatched to Toronto's Mount Sinai Hospital for further tests.

No biopsy was conducted but, on the basis of CT and MRI scans, she was told that she had stage 4 lung cancer that had metastasized to the spine — a devastating diagnosis, needless to say. The doctors were responding to what, on the radiological images, certainly resembled cancer. And her other physical symptoms also suggested that cancer might be at work.

Biopsies of the lung and vertebra were carried out. They revealed inflamed fibrous tissue, taken from the lung lesions. Similar fibrous tissue was extracted from the 10th vertebra, but neither mass was cancerous. That was the good news.

The bad news was that Larissa had a rare condition known as inflammatory pseudotumour. This is essentially a term of convenience, because it describes a wide array of illnesses that affect the lungs and other organs, and carries as many as a dozen names, including such tongue twisters as fibroxanthoma and inflammatory myofibroblastic tumour. It's called tumour-like because it looks and behaves like cancer, but is actually something else. But even today, among her team of doctors, there is no clear consensus on what it is. Hence, the Grey Zone: symptoms, signs and pathology without precise diagnosis.

The presence of high levels of inflammation was confirmed by blood readings. Her erythrocyte sedimentation rate (ESR) was 150, versus a norm for women of her age of less than 20. And her C-reactive protein (CRP) reading was 200, the highest I have ever seen (the norm is about 10).

At that point, she was referred to me. I felt badly for Larissa because she was still quite sick. She was close to respiratory failure, breathing at 30 times per minute (versus a norm of 12 to 16), her nostrils flaring with each breath. And I felt badly for her because, in the first instance, she never should have been told she had cancer.

Again, Larissa's story points to our over-reliance on technology. On the basis of lesions shown on the scans, doctors had seen fit to make this incorrect and life-altering pronouncement. It certainly looked like cancer. The growths showed up in both the lungs and the bones. Therefore it had to be cancer.

Well, no. In fact, it did not have to be cancer. And it wasn't cancer. I've seen this exact situation four times in my career. That is four times too many. Doctors need to be careful to tell their patients the truth, even if the truth is that we don't have the answer. Here, it would have been better to say, "It looks serious but, until we biopsy the tissue, we can't be definitive." And if the patient asked, "Is it cancer?" you would say, "It could be, but we can't be sure. That's why we need to biopsy."

A patient's testimony—Larissa T. 

I noticed immediately that Dr. Ho Ping Kong was different. He actually touched my hand and made physical human contact. No other doctor had done that. I could tell he was a kind soul. He watched and listened. He had a different demeanor. I was quite sick and I found his approach quite reassuring.

I had one very serious episode resulting from the use of prednisone. I was on holiday with my family at Disney World and was unable to sleep, at all. I couldn't continue in that state so we came home, cutting the holiday short, and I was admitted to hospital and sedated for a few days. Ultimately, I was diagnosed as bipolar, which maybe accurate, though I think the prednisone was the cause. Because we had to cancel the holiday, my children were upset with me. They weren't talking to me. Dr. Ho Ping Kong gave me a few hundred dollars of his own money and suggested I take my family to the zoo. How many doctors would even think of that, let alone do it?

Today, my lesion has shrunk dramatically and apart from the occasional twinge in my chest, I am pain free. I still take prednisone whenever the inflammation rate creeps up, as well as vitamin D, calcium supplements and milk thistle. I see Dr. Ho Ping Kong every four to six weeks and have blood tests regularly.

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The diagnosis was one thing. The central question was how do we treat this condition? Something needed to be done because, even at rest, Larissa had trouble breathing and was close, in my judgment, to respiratory failure.

We thus decided on a therapeutic trial — an "N of I," as it sometimes called. We use such trials with a single patient for whom a diagnosis has been made, or their disease is known, but for whom no easy or obvious pathway for treatment has been identified. There is nothing scientific about it and such a therapeutic approach should never be confused with randomized, controlled trials.

Of course, some benchmarks are needed to measure the success of whatever therapy is applied. In Larissa's case, there were six — reduced pain, a shrinking of the pseudotumour, lowered counts for ESR and C-reactive protein, a higher hemoglobin count and a general improvement in her sense of well-being.

With those objectives in mind, I started her on a relatively high dosage of prednisone, 60 milligrams per day. Positive results were almost immediate, which was encouraging. But after two weeks on the drug, she developed a swelling on her right arm. Our initial thought was that she developed a deep vein thrombosis. However, an ultrasound of her veins showed no clotting. An MRI revealed nothing specific and, after three weeks, it subsided. We maintained the high dosage of prednisone and added methotrexate, which is widely used to mitigate the negative effects of steroids like prednisone. In the fourth week, a similar swelling occurred on her left side. This time, it lasted only two days. We believed we were on the right track.

After three months, Larissa was almost back to normal, free of pain, her lesions had shrunken and she was able to walk a few kilometres each day.

I have used similar therapeutic trials (N of I) in other cases as well, with equally good results. One case involved Priscilla, a 60-year-old South Asian woman who complained of feeling generally unwell for about six months, with a slight fever and sweating. My initial hypothesis was that it might be a recurrence of an old case of tuberculosis. I took a full history, did a physical exam and ordered tests — chest x-ray, blood work, etc. Everything came back normal. I arranged for a bone marrow test, in order to rule out cancer and to culture for the TB bacillus. But that, too, proved negative. Despite these readings, I still felt that tuberculosis was somehow implicated. If it were TB, several variations were possible — lung TB, bone TB or TB meningitis.

The most likely form, I thought, would be what is known as cryptic miliary tuberculosis, a special form of disseminated tuberculosis. It is termed "cryptic" because it lies hidden and is therefore very difficult to diagnose. In one study, the proper diagnosis was made during life in only seven of 15 cases (47 percent). The name itself derives from the wide distribution of small lesions in the lung that actually resemble millet seed (hence "miliary"). Although the cryptic form is rare, it does tend to strike older women from India and other parts of Southeast Asia.

The more overt form of the disease, miliary TB, is not difficult to diagnose; the classic symptoms include weight loss, profuse sweating, fever and cough. The lesions are typically visible on x-rays and have the appearance of a snowstorm. But some patients do not present in this manner — only with what physicians call a "failure to thrive."

For Priscilla's therapeutic trial, I again established criteria of improvement—general well-being, weight gain, absence of fever, higher hemoglobin counts and a lower ESR (erythrocyte sedimentation rate). We quickly put her on TB medication — standard care includes isoniazid, rifampin and ethambutol — but her stomach did not adapt well to the regimen. Perhaps something else was going on. We then did a test for the presence of H. pylori, the bacteria known to cause stomach ulcers; it came back positive. After we successfully treated Priscilla for that condition, the TB responded well to drugs; within three months, she was back to her normal self.

In general, it is not difficult to enlist the support of patients and their families to participate in such therapeutic trials. After all, they are clearly suffering. Any relief would be welcome and beneficial. At the same time, they understand that it is a trial and that there are no guarantees of success. For physicians, it is critically important to remember Hippocrates' injunction — do no harm. Unless you can establish firm criteria that measure improvement, it will be wiser not to embark on the n of I course.

Perhaps I have a personal soft spot for Grey Zone diseases because I had one myself. In the early 1990s, I was suddenly hit with feelings of overwhelming fatigue. A variety of tests assured me that I had no formal, identifiable disease, but the condition persisted. I don't know what precipitated it, but it might have been a Caribbean holiday, when I developed diarrhea. Returning to Toronto, I was sick for several days and recall not being able to eat.

For the next six or seven years, perhaps more, I was lethargic and dragged myself around. At the office, I would often seize an opportunity to take short naps in my office. I frequently had a bad taste in my mouth. I just didn't feel right and had to rest for an hour before visiting relatives. This was classic chronic fatigue syndrome, a condition many regard as fictitious or psychosomatic. I do not.

Eventually, I recovered. The symptoms gradually disappeared and I regained my normal levels of energy and activity. My experience underscored for me the importance of what I think is often the best medicine. I call it the tincture of time.

Not long ago, Donna, A perfectly healthy 66-year-old retired school teacher came to see me, referred by her family doctor. She had been feeling generally unwell and complained of dizziness and anxiety. On several occasions, she had experienced a rapid heartbeat (tachycardia), and twice had felt compelled to visit a hospital emergency ward. Her blood pressure on those occasions was elevated — 190/120 — and she was sweating. They told her she had experienced a panic attack.

When I saw Donna, she told me that she had not adjusted well to retirement, although she did occasionally travel to the Caribbean island of Grenada to work as a school volunteer with the hearing impaired. I ran a series of tests to check for serious illness and hormonal imbalances. A few rare diseases — including pheochromocytoma, a tumour of the adrenal glands, and carcinoid syndrome, a slow growing tumour of the small bowel — can manifest with panic attacks and over-stimulation of the body's sympathetic nervous system. All the tests, urinalysis and CT scan were normal. However, I did prescribe medications to control her blood pressure and to slow down her heartbeat, which would prevent her from having to visit the emergency room.

After a few visits, I told her that she was fundamentally healthy and that her anxiety would eventually dissipate. All that was needed was the tincture of time. I encouraged Donna to make another visit to Grenada, where she might feel she was making more of a contribution, but that otherwise she should learn to enjoy her retirement, a reward for her many years of service. A month later, she returned. The blood pressure was under control and there had been no further visits to the emergency department. Then she did go off to Grenada and when she returned, six weeks later, she felt cured. And she was cured.

So what was it, in the end? I don't really have an answer. If I had to make a diagnosis, it would likely be labile hypertension (sometimes called serotonin hypertension) that, from time to time, had generated her feelings of panic, sweating and accelerated heart rate. But it was one of those diagnoses that could neither be categorically proven nor disproven.

What I do know is that Donna trusted me — trusted my knowledge and instincts — and I think that was critically important. Beyond that, I would simply say that, every now and then, life presents us with challenges to which the body and the mind react in unpredictable ways. But physicians can, in fact, be helpful and supportive while the patient traverses the tincture of time route.

These moments of crisis can happen to anyone. I recall Cynthia, a 35-year-old mother, a former magazine editor with two well-adjusted school-age children and a good marriage. One day she was completely functional and, virtually the next day, she was fatigued to the point of exhaustion. Unable to manage simple chores like shopping, laundry and cooking, she had to take a leave of absence and hire household help.

She had been fatigued and generally feeling unwell for about five years when I saw her. The origin of these ailments is not clear. Often, it seems to be the legacy of a viral illness, but there can be other triggers as well, including bacterial infections or even the trauma of a stressful event, such as a car accident. I had seen that before.

In these situations, I undertake at least a limited workup, to insure that there is no organic condition that might have been missed. It is unwise, I think, to suggest automatically that this must be chronic fatigue syndrome, because the odds are too good that something else may be going on. And I tell patients like Cynthia that while I will do the best I can, there's a good chance we may not be able to make a precise diagnosis. Most accept that caveat, but others occasionally leave with some anger and resentment that we haven't definitively identified the problem.

On examination, the only physical sign of something amiss with Cynthia were cholesterol deposits in the eyes. My instinct was that these were not significant. Otherwise, her tests were completely normal—hemoglobin, iron levels. When it came time for me to render a verdict, I told her that my best guess was that she had contracted a virus of some kind, although it might even have been caused by a stressful event, like a minor car accident.

I also gave my familiar tincture of time sermon. Having been assured that there was nothing seriously physically wrong, she should take comfort in knowing that the virus, if that is what it was, would eventually burn itself out and that she would return to her normal self. I always recommend the adoption of an exercise regimen. It does not have to be punishing, just something regular, regardless of how reluctant you may be or how unwell you may feel. My exercises of choice are walking, swimming, yoga, dancing, tai chi and transcendental meditation.

What I did not do, and what I try very hard to avoid doing, was prescribe anti-anxiety drugs. I will prescribe supplements if I find iron deficiency, but I never recommend anti-depressants. In fact, I discourage their use. If you can recover naturally, why take medication? With drugs like Valium (tranquilizers), there are problems with long-term usage, including seizures and a propensity to break one's hips when older. Dementia is also more common in those who become habituated to anti-depressants. If a patient insists on a prescription, I will suggest that they ask a psychiatrist to write it.

I saw Cynthia several times over the course of a year. Like Donna, she went away for a holiday in the sun and when she came back, the dark clouds had lifted. She was better.

However, my aversion to the prescription of anti-depressants should not be construed as a critique of psychiatric treatment. The work of psychiatrists can go hand-in-hand with the work of general internists, especially once it has been determined that the patient is not suffering from any physical illness. Even patients with some physical illnesses — cancer and Parkinson's disease, for example — may sink into deep depressions, for which psychotherapy can provide enormous benefit. In fact, at one point, the University of Western Ontario's medical school ran a joint program for the two disciplines, so closely did they perceive the linkages to be.

Nor am I skeptical about the potential efficacy of antidepressants, when other avenues (exercise, diet, meditation, psychotherapy) have proved of no avail. In cases of severe depression, there is no doubt that chemical treatments do help. For some patients, so did electro-convulsive therapy (ECT), when it was widely used four and five decades ago, though I acknowledge its dangers and risks. Some members of the modern pharmacopeia, such as Prozac, also have incurred bad names in recent years. Again, however, in tens of thousands of instances, it and comparable drugs have been effective in lifting the clouds of depressions so dark as to be immobilizing — and often within a much-compressed time frame.

Chronic fatigue and similar syndromes predominantly affect women, but I have treated men for the same condition.

One, Darren, was a 55-year-old physician who, like Donna and Cynthia, had not been feeling right for several months. He reported palpitations, fluctuations in blood pressure, a general feeling of malaise and problems sleeping. He had a coronary workup, everything short of an angiogram, but nothing suggestive of cardio-vascular disease was found.

When I saw him, he told me he was happy at work and had a good relationship with his wife and children. I conducted a number of new tests, including urine collections for possible evidence of carcinoid and adrenal tumour but, apart from a slightly elevated blood pressure, Darren was fundamentally healthy. I told him he had minimal hypertension, which was not uncommon, and was usually treated with beta blockers.

"How do you feel when you go on holiday?" I asked him.

"I don't know," he said. "But I'm going to Cuba in a few weeks and we'll see."

When he returned, he told me he had been fine in Cuba but the anxiety, palpitations and other symptoms had reappeared once he was home. So I prescribed a beta blocker to slow his heart beat and gently lower his blood pressure and, within a few months, he reported feeling better.

Again, my hunch is that part of their recovery relates to their confidence in me — the belief that I am covering all the bases. The patient is assured that if there is a physical problem somewhere, I will find it. And, just as important, if! do not find it, it means that whatever is causing their anxiety and its indicia will not be fatal, and that it will, in time, pass.

In these situations, I often find myself saying, "You will get better." The frequent response is "How do you know that?"

To which I say, "I just do."

And occasionally, I will also tell them the story of my own encounter with chronic fatigue.

Grey zone cases always pose a challenge, but particularly to family practice. Most general practitioners are very busy and the time they can devote to any one patient is necessarily limited. Yet with patients who have genuine symptoms, but no easily identifiable malady, it's precisely time that is often needed most — time to talk and listen and win their trust and reassure them.

Not long ago, Sarah G., a former social worker and now a writer, editor and publisher, came to see me with classic Grey Zone symptoms — dizzy spells, fatigue, migraine headaches, unable to do routine stuff, unable to concentrate. Almost inevitably, some mild depression set in. High achievers are not accustomed to becoming so severely and so suddenly incapacitated. An MRI proved normal, as did the other routine exams and blood work. Of course, I took a full family and personal medical history and examined prior medical records. Eventually, I concluded that no organic illness was present, that nothing was being missed. The task, then, was to persuade Sarah that, despite her symptoms, she was essentially healthy and would recover. She needed to eat well, exercise regularly and enjoy her stable family life. Within a few visits, she felt better.

A patient's testimony—Sarah G.

For no apparent reason, I was suddenly sick. It was like flu, but I just did not get better. I was weak and sweaty and weepy. I was very hot, but did not register a fever. I was emotional and not myself. This lasted for weeks.

I was otherwise healthy. My blood pressure is textbook. I eat well. I don't exercise enough, but I don't drink or use drugs. Nothing psychological happened at the time. I just collapsed.

I went the usual route — first to my GP, an excellent doctor who did all the usual tests and more. But I had to keep coming back because I had no life. Eventually, he referred me to a brilliant woman at Women's College Hospital, and she found nothing. She looked for Lyme disease, autoimmune disorders. You are grateful you don't have a horrible disease, but I was still sick, and completely useless. I could pass as normal, but I wasn't. I could still go out and see friends. But I wasn't myself. I cancelled a lot of appointments because I had to be in bed. A year went by and I started to feel desperate. The doctor said I could come back but that she had nothing to add. At least she did not treat me like a mental case, which often happens to women with these complaints.

I knew someone who was working as a consultant with Toronto Western and asked him to ask if there was a Dr. House working there. "I need a genius," I said. "Not just smart." I was having a bad time. I was in bed and depressed and that is not typical for me.

That was how I arrived at Dr. Ho Ping Kong. The first time I saw him, he spent 90 minutes with me. Who does that? I was blown away. I watched him with my professional social worker eyes and it was an extraordinary experience. We chewed the fat. He just got me as a person. He said right then, "You're going to be fine." I continued to see him every three or four months while we did more tests, but he'd always say you're going to be fine. Once, he did so in the presence of a young resident he was teaching. And when HPK said, "You'll be fine," the resident timidly challenged him and asked, "How do you know that she'll be fine? What is the evidence?"

And HPK wasn't patronizing. He turned to him and said simply, "There are still a lot of things about the human mind and body that we don't understand." It was like a variation on Hamlet's speech, "There are more things in heaven and earth, Horatio, than are dreamt of in your philosophy."

There was never any flavour, any sense that that he was hinting that "it's all in your head." He just repeatedly said I'd get better in time. And I am better. Certainly the trend is up. Until recently I'd have said I was functioning at 95 percent. But I recently spent a week in bed, utterly exhausted, slightly feverish, slightly nauseous, slightly dizzy.

I don't like the word genius but I think HPK is one, indubitably. He has knowledge no one else I have encountered has. It's East and West. It is art and science. I don't have the right words for it, but he has the capacity to look at me and see disease and disorder and weigh it up and yet say you will be okay.

I was a therapist for many years and I know there are therapeutic effects to extending hope to patients. He would say, "I can't tell you why I know you will be better, but you will." And it changed the whole dynamic. So when I have these periods now, I know they will end and they are endurable because of that knowledge. I'm not in pain. I'm not missing work. No one is going hungry. I have one weird thing that makes me slightly less productive. I'm used to writing every day, but I haven't been. It's made me question my commitment to productivity. Who am I working for? So I have this little thing, but in the big scheme of things it's not so bad. I can't complain about my life. It could be a lot worse.

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