The Medical Detectives Volume I

by Berton Roueche

  The liver, understandably, is the first of the susceptible organs to suffer damage. This damage, however, may not immediately be clinically apparent. When it is, the manifestations are often mistaken for chronic active hepatitis. Many cases of Wilson's disease (at least forty per cent) are at this stage asymptomatic, and the first forceful indications of disease appear only when the accumulation of copper in the brain has reached a bruising concentration. These indications embrace a sweeping range of neurological disturbances—slurred speech, failing voice, excessive salivation, drooling, difficulty in swallowing, tremor (hands, head, trunk), incoordination, spasticity, muscular rigidity, progressing to bedridden helplessness. They may also mysteriously appear in the guise of functional disease, as an adolescent adjustment problem, as anxiety neurosis, as depression, even as schizophrenia. The gravitation of copper to the eye has an equally curious impact. It produces a phenomenon known to medicine (in celebration of two German investigators who were its pioneer observers) as the Kayser-Fleischer ring. A Kayser-Fleischer ring consists of a more or less complete ring of rusty-brown pigmentation—a literal implantation of copper—around the rim of the cornea. It is not known just how the copper is deposited there. The apparition, however, is at once a harmless peculiarity and a signal of the utmost clinical significance. The liver damage that occurs in Wilson's disease and its subsequent neurological disruptions may be perhaps misunderstood by the indifferent diagnostician, but only ignorance can see and ignore the Kayser- Fleischer ring. The Kayser-Fleischer rings are definitive signals of Wilson's disease, and failure to comprehend their meaning is a fateful diagnostic error. For unless Wilson's disease is opportunely recognized and promptly and appropriately treated it is invariably and agonizingly fatal.

  I talked with Dr. Cartwright—Dr. George E. Cartwright—in his office at the hilltop Utah Medical Center, a big, sunny room with a view of Salt Lake City spread distantly out below. Dr. Cartwright, a graduate of the University of Wisconsin and of the Johns Hopkins University School of Medicine, is a sparkling, white-haired man in his late middle years, small and wiry, with three passionate enthusiasms—backpacking, skiing, and Wilson's disease. Indeed, as Dr. Shields was providentially aware, he is generally considered (along with Irmin Sternlieb and 1 Herbert Scheinberg, both of Albert Einstein College of Medicine, in New York, and J. M. Walshe of Cambridge University) to be among the most eminent contemporary students of the disease.

  "Of course I remember Carol Terry," he told me. "Carol is one of my best successes. But it was a very near thing. Dr. Reiser caught her just in time. He had seen a case of Wilson's disease in medical school, and remembered what it looked like. I've somehow happened to see a lot of Wilson's disease—relatively a lot, I should say. We estimate the total number of cases in the United States at only around a thousand. I've seen a dozen or so. Carol was in many ways a classic case. I appreciate that Wilson's disease is not an easy disease to diagnose. Not every doctor has it prominently in mind. And I appreciate that Carol's eyes are not blue or gray or green—she has dark eyes, hazel eyes, which made her Kayser-Fleischer rings a little hard to notice at a glance. But—my lord! I remember the first time I saw her. Dr. Shields had called me and told me about Dr. Reiser's providential memory, and I arranged to have her admitted here as a research patient. I'll never forget the look of her. She looked like Wilson's disease. She had the typical masklike face and the fixed and twisted smile. She had what we call the wing-flapping tremor in her arms. Her fingers were constantly moving in what we call a pill-rolling tremor. She was drooling. I thought her Kayser-Fleischer rings were grossly visible. When I said hello to her, she answered me in that distinctive slurred speech, and in that typically squeaky voice. And then she gave that laugh they have. It's the damnedest laugh—it doesn't come in the usual way, it comes on inhalation. It was all there. She was practically a textbook presentation. I think my secretaries could have made the diagnosis.

  "But, of course, we ran the standard laboratory tests. They confirmed Dr. Reiser's diagnosis and the evidence of my own eyes. Her serum copper determination was fifty-eight. Normal is between eighty-one and one hundred and forty-seven. Her ceruloplasmin—a definitive test—was four point six. Normal is between twenty-five and forty-three. Her urine copper was four hundred. Normal is between five and twenty-five. The tragic thing is that her liver involvement had been noted in all of her hospital stays. Noted, but either ignored or misinterpreted. The trouble is, of course, that cases like Carol's, which present both psychological and neurological symptoms, are almost always diagnosed as psychiatric problems. At least fifty per cent of the cases I've seen or know something about were first diagnosed as functional. And a psychiatric diagnosis tends to stick. I fault psychiatry on that. The psychiatrist should not assume that every patient in the six-to-thirty-two age group who seems to be in need of psychiatric help is actually a psychiatric patient. He should stop and consider the possibility of somatic illness. And in a referral, he shouldn't simply accept the previous diagnosis. He should see for himself. I'll go further. I would suggest that all individuals admitted to psychiatric wards between the ages of six and thirty-two be screened for Wilson's disease with a ceruloplasmin test. It's a simple test—all you need is a blood sample. That would save a lot of misery, even lives.

  "Wilson's disease has always been a rare disease. I'm sure it always will be. But it is even rarer in another respect. It's not only treatable, it is also preventable. That sets it apart from the great majority of diseases. By preventable, I mean this: If the disease is diagnosed early enough—if treatment is started in good time—then its terrible progression of symptoms can be stopped before they start. That's the point of routine ceruloplasmin testing. Treatment isn't to be confused with cure. There is as yet no cure for Wilson's disease, and none in prospect. It is difficult even to conceive of one. It would require some extraordinary genetic manipulation. The treatment of Wilson's disease is basically very simple and straightforward. The idea is to remove the toxic concentration of copper in the body and prevent its reaccumulation. The first relatively effective therapy was initiated by a group of British investigators in 1948. That was the same year in which the role of copper in the disease was firmly established. The investigators used a chemical, dimercaprol, generally known as Birish antilewisite, or BAL. BAL was developed at Oxford during the Second World War as an antidote to an arsenical war gas called lewisite. It was later found to be effective against other heavy metals, of which copper, of course, is one. BAL was of use in Wilson's disease. I used it for some years. Unfortunately, it has its drawbacks. It is administered by injection, and they are very disagreeable injections—long and painful. And also BAL has frequent severe side effects. The treatment now in use was developed by J. M. Walshe, of Cambridge, in 1956. His paper 'Penicillamine, a New Oral Therapy for Wilson's Disease' is a classic. Penicillamine is a derivative of penicillin, but it's not an antibiotic. It's what we call a chelator. It has the ability to combine with—to bind—a metal. In Wilson's disease, it mobilizes copper from the tissue and excretes it in the urine.

  "Penicillamine is truly a life-saving drug. The results can be dramatic. I'm not talking about overnight improvement. But unless the patient has suffered irreparable destruction, the damage can be repaired. Little by little, the liver returns to normal, the Kayser-Fleischer rings fade away, and the neurological manifestations disappear. The standard regimen combines penicillamine and potassium sulfide. Potassium sulfide acts to prevent the absorption of copper by forming an unabsorbable copper sulfide in the gut. Since penicillamine is a treatment rather than a cure, it is continued for the lifetime of the patient. Potassium sulfide is usually discontinued within six months or a year. We started Carol on therapy on April 11—twenty milligrams of potassium sulfide three times a day and one gram daily of oral D-penicillamine in three equal doses. She responded well. The first notable change was the disappearance of her so-called psychiatric symptoms. They departed as soon as she learned the true nature
of her trouble. In less than a month, she was doing well enough to continue her convalescence at home, and I discharged her on May 8. I saw her as an out-patient at intervals through the rest of 1973. I readmitted her for a week of thorough evaluation on December 2. She had continued to progress satisfactorily, and I discharged her. Here's what I mean by satisfactory. I'll read you a few lines from her discharge summary. 'Patient is currently without specific complaint referable to disease, and she has improved dramatically since March, when her disease was discovered and she was placed on penicillamine therapy. Her only residual of the disease is a limp on the right and some mild dysarthria and an occasional tremor, usually brought on by anxiety states.' Dysarthria means slurred speech. Her recovery was really impressive.

  "I was also impressed by her emotional recovery—her character. Carol had had two years of college in California before her first marriage. She went back to school in January of 1974. She enrolled at the University of Utah here. Not only that. She soon began doing volunteer work at the hospital, and then she got a part-time job, as a file clerk with the Bureau of Land Management of the Department of the Interior. She met Michael Terry there, and they were married in June of 1976, and in December she got her degree. And moved to Washington. I see her once a year, though. She was here just a few months ago, visiting her parents. I'm not sure that her walk and her speech will ever be entirely normal. We'll just have to wait and see. But when I remember the way she looked the first time I saw her . . ."

  "Well, yes," Mrs. Terry told me the last time we talked. "I've thought about a malpractice suit. I'm told I have a good case.

  Those psychiatrists—I wouldn't wish them on my worst enemy. But then—I don't know. I guess they're only human. So I think I'll live and let live."

  [1979]

  CHAPTER 23

  The Fumigation Chamber

  A woman I'll call betty page was awakened in the middle of the night, around three o'clock on the morning of Wednesday, May 30, 1984, by a spasm of nausea. She sat up with a lurch and a groan. Her husband, Lewis, lifted his head and asked what was the matter. She told him. She said she didn't understand it—she just felt sick and awful. She crouched there, wondering. Then she had an impulse. She had a sudden craving for milk—for a cup of warm milk. She went down to the kitchen and put some milk in a pan on the stove to heat. She drank a steaming cupful, sipping slowly, cautiously. She began to feel better. She went back to bed and fell asleep, and slept until morning.

  The Pages live in a comfortable fieldstone house in Jenkintown, Pennsylvania, a pleasant suburb of Philadelphia. They also have a weekend cottage on a lake in northern Pennsylvania—a three- hour drive from their home—and a condominium apartment in Aspen, Colorado. Betty Page is a small woman, grayly blond with blue eyes and a wide, smiling mouth, and in May of 1984 she had just turned fifty-seven. Lewis Page—big, bald, serenely poised—was sixty. The Pages are both physicians. Lewis Page (Harvard College, the University of Pennsylvania School of Medicine) is an obstetrician and gynecologist in private practice. Betty Page (Wellesley College and Temple University School of Medicine, where she was elected to Alpha Omega Alpha, the Phi Beta Kappa of medicine) is an internist, and at that time was an assistant professor of clinical medicine at the University of Pennsylvania School of Medicine. She is now, and has been for three years or more, on leave from her academic duties. And for good reason.

  "Lewis and I have been married for thirty-nine years," Betty Page told me in a conversation we had not long ago in her home. "They've been happy years. We have a lot more in common than just medicine. But we have our differences. I like to ski, and he prefers scuba diving. His hobby is mineralogy. Mine is archeology. His glass is always half full. Mine is always half empty. That was the way it was on that Wednesday three years ago, after that night. Lewis was satisfied that it was just one of those things. I wasn't so sure. I was still feeling a little funny. But I had some big distractions that took my mind off myself. Not just my work. Our daughter was getting married in July, on the twenty-eighth, and, as the mother of the bride, a lot of the arrangements devolved on me—for one thing, the invitations, the calligraphy. Plus I was making my own dress. Still, I got through the day on that Wednesday. I didn't feel too bad. At night, I fell right to sleep—and then it was the night before all over again. Except worse. This time, the warm milk wasn't really very effective. I took some Tigan, an anti-nausea medicine, and that helped, but only a little. And along with the nausea I had a little crampy feeling, abdominal cramps— what used to be called green-apple cramps. I got through the night. The next day, I did what I had to do, but it wasn't easy. I had an attack of diarrhea. I tell you, I felt like hell. Thursday night was another bad night. About the only thing that kept me going was the thought of our cottage on the lake. We had opened the cottage on the Memorial Day weekend—May 25, that year— as we always do. Actually, I had done most of the opening, starting on the Friday. Lewis sees patients all day Friday, and until late on Friday evening. He does that to keep his weekends free. So now, a week later—that would have been Friday, June 1—I took off for the lake. I love the lake. I always feel wonderful there. It beckoned to me like a haven.

  "I felt some better when I got there. I began to think, to hope, that I was overreacting. I did the necessary marketing and got settled for the weekend. There was a lot of work to do. It was a little discouraging. I thought we had done all that the weekend before. The cottage is set in a lovely hemlock wood, and when we went up on the Memorial Day weekend there was hemlock pollen everywhere in the cottage. And now, a week later, there was another dusting of pollen all over the place. So I went to work again. Lewis arrived sometime after midnight. I woke up and we talked a moment, and then another wave of nausea came over me. Milk helped, enough to let me get back to sleep. In the morning, it was good being at the lake, but I really wasn't feeling any better. The nausea came and went, and my mouth was always filling with saliva. I kept having to spit. My abdominal cramps continued. And the diarrhea. I didn't complain to Lewis. I tried to keep it even from myself. I took my temperature. It was normal. That was something, but I still felt just punk. Lewis drove back home on Sunday evening, as usual, and I stayed over for another day of rest and then to close up. I drove down home on Monday afternoon. I hated to leave the lake and go back to work. I was sick, and I knew it.

  "Well, now we were into June. I kept thinking, hoping, that tomorrow or the day after or the day after that I'd wake up feeling better. But nothing changed. I never vomited, but I was nauseated almost all the time. I had clammy cold sweats and an awful metallic taste in my mouth. I lost my taste for food. A little milk, some Cream of Wheat—I lived on baby foods like that. My normal weight is around a hundred and ten. Now I was losing something like a pound a week. And I was getting worried—really worried. I had a breast cancer back in 1963, and a radical mastectomy. There had never been any suggestion of a recurrence. But there is something that everybody who has ever had any kind of cancer knows. There is always a sort of subliminal anxiety. An ache, a pain, a feeling not quite normal, and you think, Is it cancer? So I pulled myself together and called a gastroenterologist I knew and made an appointment. Doctors are like lawyers. Lawyers don't represent themselves in court. Doctors don't treat themselves for anything that might be serious. I kept my appointment, and the gastroenterologist heard my complaints and was very concerned. He gave me a full examination—the complete mouth-to-anus workup. The results were negative, entirely normal. That should have been good news. But actually it was frustrating. And the gastroenterologist was frustrated, too. So he did what so many doctors do in a situation like that: he went the functional route. What else? He reminded me that I was almost sixty. He said, 'Betty, your trouble is that you're not growing old gracefully.' He said, 'Wait until the wedding is over. You're simply a nervous mother. Your histrionics are getting out of hand.' He said, 'Take a little nap in the afternoon. Try to relax.' He prescribed a medication. It was a mixture of his own—a mood
elevator and a tranquilizer. I took his nostrum, and I thought I was going to die. I could hardly breathe. It did something to my chest muscles. I didn't have the power to move air in and out of my lungs. I got rid of the nostrum, and at once felt better. I mean, at least I could breathe again.

  "I may have been a nervous mother. I may still be. But that was hardly the cause of my illness. The day of Elizabeth's wedding came, and everything went off very smoothly, very beautifully— and I still felt sick. I had to take a leave of absence from my job. I couldn't manage anymore. I wasn't exactly idle. I had undertaken an ecological study of our lake. There is an association of families who summer there, and I was expected to read my report at the annual meeting, on Labor Day. I thought if I paced myself I could make that deadline. My long weekends at the lake gave me plenty of time to do the necessary research. And rest. I needed rest. The symptoms that sent me to the gastroenterologist were still with me, and I also had some new ones. I was feeling a very unpleasant tightness in my chest, a viselike feeling, and my heart, even at rest, seemed to be skipping beats. You know how we doctors have fragmented ourselves with our medical specialties. My reaction was typical. I was choosing a doctor on the basis of my symptoms. When my symptoms were gastrointestinal, I went to a gastroenterologist. Now my heart seemed to be acting up, so I went to a cardiologist. I don't think he prescribed a nostrum. But the results were much the same as before. He gave me a thorough examination—everything known to cardiac technology. There was apparently nothing wrong with my heart. Then some new symptoms began to develop. I had difficulty reading. After perhaps half an hour, I would begin to get double vision. Another problem was muscle weakness. Another was involuntary twitching in my legs. They twitched like a twitching eyelid. Do you remember Fourth of July sparklers? How we used to light them and then pass our hands through the sparkle and get that funny, pinprick feeling? I began to have that feeling on the bottoms of my feet. That was more than a little frightening. I couldn't help but think of amyotrophic lateral sclerosis—Lou Gehrig's disease. Well, the doctor I went to this time was able to reassure me. It wasn't that. Believe it or not, I was still playing tennis. Or trying to. I wanted to keep up my muscle tone and my muscle strength. I thought that was the way to fight the weakness in my legs. But I was a blob. And my spells of double vision didn't help my game. Pretty soon, it was all I could do to climb the stairs to bed. Even marketing was exhausting. I remember one day at the supermarket. I was pushing my cart along and I just ran out of steam. I left the cart with all my groceries right there in the aisle and crept back home.