The best treatment for pseudotumor is not known, partly because the disease is sufficiently uncommon that large well-controlled studies are difficult to organize and perform. If an inciting factor is found—such as the fish oil in Luisa’s case—it is eliminated, but often, this is not enough. Some patients are left with permanent visual loss. In patients whose disease is associated with obesity, weight loss is important. Repeated lumbar puncture is another treatment, to reduce the pressure on the optic nerves. Another is a medication called acetazolamide, which is a kind of diuretic used to reduce intraocular pressure. Other diuretics are sometimes used as well.
There are also surgical treatments, the most common being a shunt procedure. In this operation, a neurosurgeon inserts a tube with a oneway pressure valve into the subarachnoid space and diverts the spinal fluid into another part of the body, usually the abdominal cavity, where the fluid is reabsorbed into the bloodstream. The pressure valve can be set at a safe level, and if the spinal fluid pressure rises above that number, the valve opens and the fluid is diverted away from the brain and into the abdominal cavity. The last surgical procedure is an optic nerve fenestration. In this operation, an ophthalmologist makes an incision in the membrane that surrounds the optic nerve. It is not clear why this helps, but in many cases it does.
Most patients with pseudotumor cerebri fully recover, but about 10 percent are left blind in one eye, and nearly half will have some decreased vision.
As Urion sits back in his chair, thinking over Luisa’s case in hindsight, he muses, “What it taught me is this. Four of us, all good doctors, had asked about medication ingestion. But none of us asked the question the right way. The family finally helped us out by asking us directly, ‘what are you worried about?’ That helped us to be more direct with our questions and get to the right answer. My lapsing into medical jargon could have affected the care of the patient. Now I ask the question differently, and I learn more about the patients. In the past, when I asked about medications, I’d often hear nothing, either because the patients were embarrassed that they were taking something that had not been prescribed, or just because they didn’t consider some things ‘medications,’ such as herbs or other nutritional supplements.”
“As for Luisa, she underwent multiple lumbar punctures to reduce the pressure; this only worked partially, so we added acetazolamide, which also worked only partially. Then we added furosemide [another diuretic]. She recovered some of her vision, but not completely, and still has occasional headaches.” But the problem was diagnosed, at least, and any further loss of vision was halted.
15 Too Much of a Good Thing
Virginia Palazzo, an internist who lives in Belmont, Massachusetts, wasn’t the kind of mother who worried over every little thing. But she became very concerned in the spring of 1991 when her eighteen-monthold daughter, Christa, suddenly lost her appetite. The odd thing was that, at the same time, she seemed to be drinking all the fluids she could get. Palazzo also noticed that her daughter wasn’t gaining any weight. The situation was even more disturbing when the little girl’s pediatrician could not find anything wrong.
“We couldn’t figure it out. As an afterthought, the pediatrician checked her blood calcium level.”
Meanwhile, in nearby Watertown, Massachusetts, cardiac nurse Lou Goldberg, fifty-eight, wasn’t feeling well either. “At first I thought it was all the night shifts or maybe my diabetes,” she recalls, even though she had been working nights for years and her diabetes was under good control. Her symptoms were as vague as their onset was insidious—fatigue, nausea, abdominal cramps. “Then I began to lose weight,” she says. “I was almost glad, because I’m short and overweight.”
But by mid-June, Lou’s deteriorating physical condition convinced her to have blood tests. “People would say ‘you look awful,’ and coworkers knew I was sick and kept urging me to see a doctor. I really didn’t feel well; I felt nauseous all the time.”
That’s when she got scared and went to see her doctor. He drew blood and sent it off for a fairly standard battery of tests—things like a red and white cell count, sodium and potassium, kidney and liver function tests, and of course a blood sugar. Years ago, doctors would have ordered specific tests, but for at least the past couple of decades many are grouped together as a panel of multiple tests. Partly this is due to the equipment; an automated machine can run dozens of tests on a tiny sample of blood just as quickly (if not quicker) as running a single test on an older machine. One of the tests that is a component of these standard panels is the serum calcium. So Goldberg had that checked too. That result, and that one only, came back as quite a surprise. The results showed hypercalcemia—an alarmingly high level of calcium in the blood.
Reduced to its most basic core, and with the water taken away, the human body is simply a pile of chemicals. Roughly two-thirds of the body’s weight is water, a bit more if you are a man and a little less if you are a woman. For that reason, oxygen and hydrogen are important chemical components, as are carbon and nitrogen. Because of the large quantity of bones, calcium is the next most common chemical component by weight. Sodium, potassium, phosphorus, sulfur, chlorine, magnesium, iodine, and iron are all present in very small but absolutely critical amounts. Without iron, for example, which makes up about one-tenth of 1 percent of a person’s body weight, our red blood cells could not carry oxygen. And certain trace elements such as chromium, copper, and zinc are present in even smaller amounts in the body. But each has its purpose, and without some of these chemical components in the body, we would die.
One could make a shopping list and buy all of these chemicals, and add water. With the right ingredient list and recipe, one could precisely duplicate the concentrations of each of these substances. But of course, we would not have built a human body, a functioning living creature; we would simply have a pile of wet chemicals.
Science fiction aside, no scientist knows the secret that breathes life into this laboratory experiment. Over the past century and a half, though, scientists and physicians have worked out at least some of the more superficial truths. One of the first was Claude Bernard, a Frenchman who is known as the father of physiology. Bernard was born in 1813, and started out dabbling as a writer of vaudeville and theater, but thankfully for humankind, the critics dissuaded him and he ended up in medicine, studying in Paris. Around 1850, Bernard became the inaugural chairman of the physiology department at the Sorbonne. The department lacked a laboratory, but Louis-Napoléon, emperor of France, corrected this deficiency in 1864 and had one built at the National Museum of Natural History.
One of Bernard’s major accomplishments was his Introduction to the Study of Experimental Medicine, published in 1865. He was one of the first scientists to use the scientific method in a rigorous way. “When we meet a fact which contradicts a prevailing theory, we must accept the fact and abandon the theory, even when the theory is supported by great names and generally accepted,” he wrote.
Bernard worked on the effects of various poisons, the importance of the pancreas in digestion, and the role of the liver in maintaining proper levels of glucose in the body. It is this last concept that has an impact on our story. Bernard wrote, “The maintenance of a constant internal environment is the condition for a free and independent life.”
In this one sentence, Bernard expressed the physiological concept of what we now call homeostasis. That term, from the Greek homeo (same) and stasis (standing), was first coined by Walter B. Cannon.
In his book The Wisdom of the Body, published in 1932, Cannon wrote,
Organisms, composed of material which is characterized by the utmost inconstancy and unsteadiness, have somehow learned the methods of maintaining constancy and keeping steady in the presence of conditions which might reasonably be expected to prove profoundly disturbing. For a short time men may be exposed to dry heat at 115 to 128 degrees Centigrade (239 to 261 degrees Fahrenheit) without an increase of their body temperature above normal. On the other hand arctic mammals
, when exposed to cold as low as 35 degrees Centigrade below freezing (31 degrees below zero Fahrenheit) do not manifest any noteworthy fall of body temperature. Furthermore, in regions where the air is extremely dry the inhabitants have little difficulty in retaining their body fluids. And in these days of high ventures in mountain climbing and in airplanes, human beings may be surrounded by a greatly reduced pressure of oxygen in the air without showing serious effects of oxygen want.
Using Bernard’s notions as a foundation, Cannon further developed the concept of homeostasis and described its four basic propositions. To paraphrase, he thought that, first, there must be physiological mechanisms that act to maintain the constancy of the internal environment. He used such examples as glucose concentrations, body temperature, and acid-base balance. Second, he said that there must be a balance of factors that act to change a given state with others that counterbalance the change. Dehydration leads to high serum sodium, which stimulates thirst; drinking water to quench the thirst then corrects the dehydration. His third principle is that the regulation of homeostasis consists of a number of cooperating mechanisms acting simultaneously or successively. If the blood sugar rises, insulin will reduce it back to the normal range; if it falls, other hormones tell the liver to release stored sugar to raise it. And last, homeostasis is not some haphazard or chance event; it requires organization by the body.
Consider the example of homeostasis with regard to serum sodium and potassium levels. There are different compartments in the body: the intracellular compartment (inside of cells), where the potassium concentration is high and the sodium is low; and the extracellular compartment (outside of cells), where just the opposite occurs. Consistent with Cannon’s theory, the physiological mechanism that “maintains the constancy of the environment” is an active energy-dependent pump located in the cell membrane that pumps potassium into the cell and sodium out.
Mechanisms are in place to ensure that the blood glucose doesn’t go too high or too low. Body temperature is regulated to stay within a very narrow range. The acidity of the body’s fluids is also tightly regulated.
One other substance that the body maintains within a very narrow range is the serum calcium.
Although women are constantly urged to get enough calcium to prevent the bone deterioration of osteoporosis, Lou’s diagnosis of hypercalcemia was anything but good news. Excess calcium in the blood can eventually become deposited in tissues and organs, causing them to calcify, or harden; what’s more, the condition can be a sign of various diseases, including cancer.
Hypercalcemia often announces its presence in a variety of subtle ways, as our two cases illustrate—fatigue, decreased appetite, weight loss, nausea and vomiting, stomach pains, increased urination, constipation, and depression. Mildly elevated levels often produce absolutely no symptoms whatsoever. The condition is often discovered only accidentally when a routine blood panel that includes calcium is checked. However, once identified, hypercalcemia should never be ignored; it’s always a sign of an underlying medical problem.
The most common cause of a high blood calcium level is an overactive parathyroid gland, usually resulting from a benign tumor, called an adenoma. If the adenoma pumps out too much parathyroid hormone, or PTH, the action of this hormone causes the body to mobilize calcium from the bone, and the calcium level in the blood can skyrocket.
The second most common cause, especially in older people, is cancer. The cancer can originate from the breast, prostate, kidney, or lung, as well as other parts of the body. These malignancies are often metastatic and often cause other symptoms that are noticed first—back pain from a tumor in the spine, or headache from a brain metastasis, but sometimes hypercalcemia is the earliest and only clue. Together, overactive parathyroid glands and cancer account for nearly 90 percent of cases of hypercalcemia.
Lou Goldberg remembers being frightened. “I was worried about what was causing the high calcium. At first, I didn’t want to pursue a work-up. I figured, ‘this too shall pass.’ But for the first time in my life, I was a little scared. I am not one of those people who, when they get a headache, are worried that it’s a brain tumor. I go 100 percent the opposite way, but this time I was worried.”
Fortunately, Lou tested negative for both of these two possible problems, leaving her physician baffled. What the doctor didn’t know yet was that an alarming number of similar cases were popping up all over the Boston metropolitan area. As it turned out, the cases of eighteenmonth-old Christa Palazzo and fifty-eight-year-old Lou Goldberg were strangely linked.
The reports of this phenomenon, scattered at first, began to surface on the desk of Michael Holick, M.D., Ph.D., a nationally renowned expert in vitamin D and calcium metabolism at Boston University School of Medicine. As time went on, more information became available. Like Lou Goldberg, when these other patients had PTH levels drawn, they were always normal; and when tests for cancer were done, they were always negative. But remember that these two problems cause only 90 percent of the cases of hypercalcemia. There are others. Of the first eight cases that Dr. Holick knew about, two came to light when they were independently presented at a Boston inter-hospital joint endocrine conference. Both had unexplained vitamin D intoxication. Six others became known because they were ultimately referred to one of the endocrinologists who had attended that meeting.
Some of the cases were in adults and others were children. This made it unlikely to be a result of parathyroid problems or tumors. Some of the referring physicians checked for, and ruled out, these other causes. The reports that were sent to Holick showed that the patients all had elevated levels of vitamin D as well as calcium. That was the link. Excess vitamin D is another, though considerably less common, cause of hypercalcemia. But why?
A vitamin is an organic substance that is required by the body, usually in extremely small quantities, for the normal function of some metabolic pathway. Until relatively recently in human history, a person’s diet was the sole source of vitamins; there were, of course, no supplements. By accumulated experience, doctors learned about the importance of vitamins, usually due to natural experiments of privation. Thus the ancient Egyptians learned that eating liver (high in vitamin A) could cure blindness. The eighteenth-century Scottish physician James Lind observed that a malady sailors in the Royal Navy commonly suffered from, scurvy, could be prevented by eating citrus fruits (hence the term “limeys”).
The word “vitamin” comes from the Polish biochemist Kazimierz Funk, who thought that these chemicals were derived from ammonia, or “amines,” and were thus “vital amines.” The “e” was dropped when it was later found that these chemicals were not amines at all, but the word stuck.
Rickets is a disease that has been known since antiquity. The origin of the name is unknown, but the Greek word rachitis, meaning inflammation of the spine, was sufficiently close that scientists used it to mean rickets. The disease is a softening of the bones that results in frequent fractures and severe deformity, most commonly in children. The first clear descriptions date back to 1650 in England. Although the cause was unknown at the time, the disease was quite common. Little progress occurred for nearly two hundred years.
By the late 1800s, rickets was endemic, especially in infants living in northern cities in both the United States and Europe. Theories, but not hard facts, abounded as to its cause. Was it dietary? Or related to poor hygiene? Did it have to do with lack of exercise or of sunlight? In 1889, British scientist John Bland-Sutton showed that lion cubs at the London Zoo, which were fed a diet exclusively of boneless red meat, were developing severe rickets. He found that he could cure the cubs by adding crushed bones and cod liver oil to their feed.
The English physician Edward Mellanby clearly established that diet could play a role in rickets in 1919. American nutritionist Elmer McCollum began a long series of experiments in 1922 that culminated in the discovery of a substance found in the diet that could prevent rickets. It seemed related to, but clearly distinct from, vitamin
A. Because the nomenclature for the vitamins followed alphabetical order, A, B, and C had been discovered, so McCollum called this new substance vitamin D.
One thing was clear: cod liver oil, which contained vitamin D, could cure rickets.
But this was only one part of the puzzle. Rickets seemed to be more common in the winter, and occurred more frequently in northern latitudes than in the tropics. Dark-skinned babies were affected more often than light-skinned ones. None of these facts could be explained by a simple dietary deficiency. Some researchers suggested that the seasonality of rickets had to do with the amount of sunlight the children were exposed to. In a series of carefully controlled experiments carried out in Vienna after World War I, Dr. Harriet Chick demonstrated with certainty that exposure to sunlight could prevent or treat rickets.
Later it was shown that not only sunlight but also ultraviolet radiation was sufficient to cure rickets. Later in the last century many experiments done by several groups across the world would show that vitamin D could be produced in the skin by UV light activating a chemical in the skin. The common denominator for rickets was too little vitamin D, whether by a dietary deficiency, insufficient sunlight, or both.
In 1930, as a result of these findings, dairies in the United States began fortifying milk with vitamin D. That single public health intervention dramatically reduced the incidence of rickets, so that the disease is now exceedingly rare in the United States.
But as with almost everything else in life, one can have too much of a good thing.
So now, Holick had to unravel the second part of the puzzle: what was responsible for the high levels of vitamin D? There were only a few possibilities: excessive sunlight, too much vitamin D in the diet (perhaps from cod liver oil or eating lots of fatty fish), or megadose vitamin supplements. He eliminated the excessive sunlight hypothesis immediately —these cases were occurring in New England, and even lifeguards in the tropics almost never develop high vitamin D levels from sunlight alone.
The Deadly Dinner Party: and Other Medical Detective Stories Page 24