This ability is exceedingly important. In terms of vision, the retina is where the rubber meets the road. When photons of light strike the nerve cells of the retina, the physical energy of the light is transformed into electrical energy in the retina’s rod and cone cells, and the electrical impulses are transmitted via the optic nerve to an area in the back of the brain called the occipital lobes. Here, the signals are interpreted, and that is how we see objects.
In the developing embryo, the retina grows from the brain, so it is actually nerve tissue, a part of the central nervous system. When doctors look at the retina, they are examining a part of the brain itself. The poets say that looking in the eyes offers a window to the soul; for doctors, quite literally the retina is a window to the brain. The veins and arteries of the retina will often show the same changes as the veins and arteries of the brain itself. The central portion of the retina is called the optic disc. This is the place where the nerve fibers of the optic nerve enter the eye; because the bundles of fibers are large, there is a slight raised area, which is called the papilla.
Papilledema is swelling (edema) of this area of the central retina and is a sign of elevated intracranial pressure.
Because the brain lies in a tight bony box—the skull—directly measuring the pressure of the brain within the cranium (intracranial pressure) involves surgically placing a metal pressure gauge through a hole drilled into the skull. Looking at the papilla of the retina, however, will sometimes allow doctors to diagnose high intracranial pressure without such a drastic step. Some patients, though, have elevated pressure in the head without having papilledema. In those cases, the veins of the retina will supply a clue, albeit a very subtle one. The veins of the retina will normally pulsate with the heartbeat. The loss of these normal pulsations can be a clue that there may be raised intracranial pressure.
Although Luisa did not have papilledema, Dr. Urion, the most experienced of the physicians who examined her, could not see any venous pulsations. Without frank papilledema, there was no way to know if the absence of venous pulsations indicated a problem or not, but it was just one more piece of a puzzle that suggested the possibility that Luisa’s headache was not a minor, primary headache disorder.
“She had already been scheduled for a head CT scan by about this time,” Urion remembers, “and the scan was done and was interpreted as normal. But there still seemed to be something amiss.” This is an example of an experienced clinician following a gut instinct, a factor that cannot be measured or quantified, but something that every doctor understands. For this reason, the team persisted in the evaluation. Fortunately, the patient had come in during the morning of a weekday, which made some options more easily available than during off hours. So after some discussion with the neuroradiologists, the clinicians finally persuaded them to perform a second brain scan: a magnetic resonance imaging study.
As good as a CT scan is, the MRI, especially of the brain, is a far superior imaging technique. It takes longer and is less readily available in many parts of the country and times of the day, but it shows detailed anatomy of the brain that the CT does not. The MRI is also much better in looking at the backmost reaches of the brain—the posterior fossa—which is where the cerebellum lies. The cerebellum is the part of the brain responsible for coordinated movement and balance.
“The main thing I was concerned about was the possibility of missing some process in the posterior fossa, perhaps an infiltrating tumor,” said Urion, “because recall that she had the history of bumping into things and clumsiness. Finally the radiologists agreed to do the MRI and they used gadolinium, a contrast agent that might better define a tumor if that was the problem.
“The initial report showed ‘something funny.’ There was a group of neuroradiologists huddled around the scans as if in Talmudic discussion. The films were in front of them and they were discussing the results,” recalled Dr. Urion.
Patients, victims of television shows about doctors, often think that x-rays and CT scans and MRI scans show clear-cut black-and-white results. A given diagnosis either is established or is excluded. Unfortunately for all involved, this simply is not the case. Some interpretation is necessary. Even after performing one of the most sophisticated brain imaging studies known, and even though some of the brightest and most experienced pediatric radiologists in the world were looking at the images, there remained a significant amount of ambiguity after these studies were done.
To have an MRI, the patient is placed on a stretcher that moves inside a large cylindrical and very powerful magnet. Before sending a patient into an MRI machine, technicians go through a meticulous checklist to make sure that there is no metal in the patient’s body—a heart pacemaker or a small piece of metal from prior trauma. All the medical equipment in the room is free of ferrous metals. Otherwise, when the magnet is turned on, any of these objects could move inside the patient’s body or fly through the room. Serious accidents and injuries have occurred from both of those situations.
The scientific basis for the MRI is that water molecules are affected by magnetic energy. Small differences in water content in adjacent tissues, or between normal tissue and abnormal tissue, will appear different on an MRI. To the trained eye, these subtle differences are the hallmark of diagnosis. Slight shades of gray can have enormous diagnostic significance, but slight shades of gray are also open to interpretation. One person’s gray is another’s white or black. Increasingly, radiologists are no longer working with hard copies of x-ray (or CT or MRI) films anymore; the images are digitized and then viewed on high-tech computer work stations.
When Urion went back to the radiology department after the MRI had been done, he saw that “they were moving the cursor back and forth and playing with the knobs and the dials on the screen to measure the pixels and adjust the contrast. The ‘something funny’ turned out to be some enhancement [showing a brighter signal] of both optic nerves. So we asked for an ophthalmology consultation, and they agreed and said send her up to the clinic, where we have all of the equipment and it will be easier to test her. Well, when the ophthalmologist fellow called back on the phone with his report, you could almost hear him grinning like the Cheshire cat over the phone. He said to us, ‘Did you know your patient is almost blind, doctor?’”
Luisa’s visual acuity was 20/400 in the left eye, and there was almost no vision in the right eye. “Well, now we had an explanation for her bumping into things. But beyond the extremely poor vision, they didn’t find anything precise on the retina exam. They just thought that it looked ‘funny,’ but they could not diagnose any particular ophthalmologic problem.”
By mid-afternoon, Luisa had already undergone an extensive evaluation—a neurology consultation, an ophthalmology consultation, a CT scan, and an MRI scan. The only thing she still lacked was the most important of all—a diagnosis. Dr. Urion decided to examine the brain in the one way that they had not so far. They would do a lumbar puncture, or spinal tap.
The first lumbar puncture was performed in 1891 by a German neurologist, Heinrich Quincke. Even in that era there was a robust dissemination of medical information, and Dr. Arthur Wentworth soon performed the procedure in the United States, at Boston Children’s Hospital, on a two-year-old girl who was thought to have tuberculosis of the brain. He described the procedure: “We punctured the spinal canal . . . and withdrew six cubic centimeters of a clear fluid which looked like distilled water. No TB bacilli were found. . . . Immediately after tapping the canal, the child became restless, throwing herself about the bed, clutching at her hair, and giving vent to short cries. The pulse rose to over 250 per minute, the respiration was superficial, and the skin was cool and slightly livid. Subcutaneous injections of brandy and ether were given, heaters applied, and the foot of the bed raised. The condition persisted about the same for three-quarters of an hour, and then the child became quieter.”
As tests go, it is not a favorite of patients. But it is a very safe and usually easily accomplished procedure, Dr. Wen
tworth’s harrowing experience notwithstanding. After cleaning and anesthetizing the lumbar area, a doctor places a needle into the patient’s back. The needle is angled in such a way as to go between adjacent bones of the spine and enter the subarachnoid space, where cerebrospinal fluid resides. Among a number of other functions, this fluid acts as a shock absorber in head trauma and serves some nutritive role for the brain and spinal cord. It is important for patients to know that the needle is inserted several inches below where the spinal cord itself ends, and serious side effects from a lumbar puncture are extraordinarily rare.
When the doctor performs this procedure, a specimen of the spinal fluid, which is normally crystal clear like water, is sent to the lab to be tested for cells, chemical composition (such as protein and glucose levels), and the presence of microorganisms, among other things. The doctor usually also measures the pressure of the spinal fluid, as this is one way to directly gauge the intracranial pressure. The fluid from Luisa was clear like water. The protein and glucose were normal. There were no abnormal cells or bacteria. But the pressure was two and a half times the normal level.
“So now we had a diagnosis, but it was a diagnosis that only raised another series of questions,” recalls Dr. Urion. “She had pseudotumor cerebri. To have that diagnosis in a skinny five-year-old was pretty unusual in itself.”
Pseudotumor cerebri comes from Latin, meaning “false tumor of the brain.” A few years after the first lumbar puncture, Heinrich Quincke and another eminent German neurologist, Max Nonne, discovered this entity, although earlier case reports of patients that seem to have had the problem predated their seminal work. One of Nonne’s distinctions is that he was among the four physicians who attended Vladimir Lenin, architect of Russia’s Bolshevik revolution, who had a series of strokes that led to his death in 1924. Quincke and Nonne knew that most patients with the combination of papilledema (seen through the ophthalmoscope) and elevated intracranial pressure (measured with the lumbar puncture) had a mass—tumor, abscess, or blood clot—causing these findings. Both men documented patients who had papilledema and elevated intracranial pressure without an obvious cause (no tumor, abscess, or other cause was found). These patients did not die, and in fact many improved over time.
These doctors were working long before CT scans and MRI tests, so there was no way for them to find these masses until autopsy. But Quincke and Nonne noticed that sometimes the improvement in these patients (often younger ones who seemed to have a tumor, but did not) seemed to follow one or more lumbar punctures. Because the patients didn’t actually have tumors, Nonne applied the name pseudotumor cerebri. Although it is clear that some of the cases these men described did not have what we would today call pseudotumor cerebri, many of them did.
The exact mechanism for this condition was unknown to Quincke and Nonne, but they hypothesized that it had to do with the flow of cerebrospinal fluid. Over a century later, doctors still do not precisely know the cause of the problem. More modern names for the condition are idiopathic intracranial hypertension—doctor-speak for increased pressure in the head for reasons that nobody understands—and benign intracranial hypertension, which points to the overall good outcomes. Whatever the cause, and despite these more modern descriptions, Nonne’s nomenclature stuck and remains in common use today.
The large majority of patients with pseudotumor cerebri have the finding of papilledema, but not all of them. Patients usually consult their doctors because of headaches or neck pain. Sometimes they complain of ringing in the ears, double vision, decreased vision, or odd, very transient episodes of obscured vision. Some will also have nausea and vomiting.
The diagnostic criteria for pseudotumor cerebri include symptoms or signs of elevated intracranial pressure, a normal CT scan (or other brain imaging study), normal spinal fluid (other than the pressure being raised), and a normal physical examination (other than some of the eye findings, most notably papilledema). In some definitions, the doctor must have excluded a clot in the veins of the brain, which can sometimes mimic pseudotumor (an association first described by Nonne). Overall, pseudotumor is a rare condition, and many doctors will go through a career seeing only one or two cases. In children it is even less common than in adults. But it is an important diagnosis to make, because the major complication is that it can lead to permanent blindness if untreated. Various treatments, both medical and surgical, exist.
The pattern of patients in which pseudotumor cerebri appears is curious. It is most commonly seen in overweight adult women, typically in the twenty-to-forty age range. In fact, women are affected nearly ten times more frequently than men, and adults are affected much more commonly than children. In children, though, it is seen equally in boys and girls. In all populations, however, the disease is quite rare. In any population, one thing is clear: doctors do not know why it happens. In cases where the patient does not fit the usual epidemiological pattern (obese adult women), there is a long list of conditions that are associated with the development of pseudotumor, but the nature of what causes it is still unknown, even in these cases.
One of these associated conditions is Lyme disease. This is especially true in North American children with Lyme disease, which is common in the northeast. Pseudotumor cerebri is also associated with various antibiotics especially in the tetracycline group, and with vitamin toxicity, especially vitamin A. Other medications, such as lithium, steroids, oral contraceptives, and hormone replacement therapy, have also been reported to be associated with pseudotumor. Still other cases have been described in patients with abnormal thyroid function, Addison’s disease (underactive adrenal glands), lupus, severe anemia, and even cancers. In these instances, simply treating the associated condition will resolve the pseudotumor cerebri.
“So now we had to find the cause of the pseudotumor,” Urion said, shaking his head as he recalls how they made the ultimate diagnosis. “We went back and re-asked about medications. Did she take any meds? Did she have access to other peoples’ medicines in the house? The family took a little umbrage at our repeated questions. Finally the family asked us, ‘What can cause this?’ We gave them the list and one of the things on the list is vitamins. They seemed to stop at ‘vitamins’ on that list. They asked, ‘Could fish oil have these vitamins in them?’”
Fish oils, such as cod liver oil, are nutritional supplements made from the fish parts, particularly livers, containing high levels of omega-3 fatty acids and vitamins A and D. Vitamin A, or retinol, is an important substance for normal vision, bone health, neurological development, and various immune functions. As with all vitamins, the U.S. government sets a recommended daily dose, which in the case of vitamin A is expressed as “retinol activity equivalents” (RAE). The daily RAE is a function of age and sex. For a girl of Luisa’s age, the daily dose is about 1,350 RAE. Most Americans get enough retinol from the diet. A single carrot, for example, which gets its orange color from a pigment called carotene, has over 1,000 RAE by itself. Other orange foods, such as pumpkin, butternut squash, and sweet potatoes, are also high in vitamin A. Cod liver oil contains about 1,350 RAE per teaspoon.
The next day, the grandmother brought in a bottle of Smith’s Fish Emulsion, which contained 100 percent of the adult daily requirement of vitamins A and D in each tablespoon. The directions on the bottle were to take one tablespoon per day, which is what the grandmother dutifully had been giving Luisa. Every other month, for more than a year, this five-year-old child had been getting the recommended daily dose— for an adult—of these vitamins. The vitamin A in the fish oil, of course, was in addition to all that she got in her normal diet.
The oil itself was in some ways a by-product of the North American Free Trade Agreement, which greatly freed up import restrictions, leaving the U.S. pharmaceutical industry manufacturing too much of vitamins A and D for domestic use, and therefore in search of a market for the surplus. It found one in Latin America, where it turned out there was demand for “high-grade,” U.S.-approved, pharmaceutical-quality vita
mins sold over the counter. Eventually these came to be established products for Latin American consumers, and they started to be sold in Latino bodegas back in North America, which is where Luisa’s grandmother found them.
As often happens in unusual cases, there were precedents in the medical literature. One of the first was the remarkable tale of Douglas Mawson and his fellow explorers of Antarctica. In November 1912, Mawson, Belgrave Ninnis, and Xavier Merz set out to map the area near the South Pole. On December 14, disaster struck: Ninnis, along with a huskypulled sled carrying most of their food, fell to his death in a crevasse. Merz and Mawson had to find their way back to the base camp with extremely low rations, and they ended up killing the remaining sled dogs and eating them. They ate not only the meat, but their livers. Merz died on the return, on January 8, 1913. A full month later, remarkably, Mawson crawled back into camp, on February 8. Several who have studied the expedition believe that Merz and Mawson suffered from vitamin A toxicity from the dog livers. Merz and Ninnis are remembered by having two of the large glaciers in Antarctica named in their honor.
Because vitamin A is fat-soluble, large amounts accumulate in the liver, and other pseudotumor cases have been described in people eating too much liver from bear, shark, seal, and cow. Even carrots have been associated with pseudotumor. In one twenty-seven-year-old obese woman with pseudotumor, her symptoms were resolving with a very successful weight-loss program. After about six months, however, her eyes began to once again show signs of papilledema, even though she continued to successfully lose weight. It turned out she had been eating two to three pounds of raw carrots a week for sixteen months. Vitamin A toxicity was diagnosed when her serum retinol was measured at twice the normal value. Eliminating the carrots from her diet cured the problem, and all the findings resolved.
Vitamin A toxicity has been reported with children eating too many vitamins as well. Because the vitamins are flavored and taste good to children, sometimes they eat them like candy. In patients who have pseudotumor cerebri, blood levels of vitamin A have been found to be elevated, although the mechanism and significance of this finding are not clear.
The Deadly Dinner Party: and Other Medical Detective Stories Page 23