COLLAPSING IN THE MALL, PLAYGROUND TROUBLES

"I was 13 or 14 and having ice cream in the mall with friends," says Christine Feigert of Portland, Ore., "when it just came on all of a sudden." Feigert couldn't move a muscle and had to be carried out of the mall on a stretcher.

"It was scary and humiliating," she remembers, especially when no one believed she was truly paralyzed. "The doctors told my parents I was trying to get attention," she says. "One doctor talked to me about being a hypochondriac or something."

Christine Feigert

Daniel DeShon of Bothell, Wash., has similar memories. "It was the first day of school in fifth grade," he recalls, "and we were outside playing kickball. I kicked the ball -- we had been running around -- and then all of a sudden my foot dropped and I couldn't lift it up. It was kind of dragging."

At first, DeShon's parents thought he was "kind of crazy," but when the problem persisted, they took him to an orthopedic surgeon, who operated on the boy.

"He thought I had torn a ligament in my leg," DeShon says, "so I went in for surgery." Oddly, when the doctor opened up his patient's leg, he found nothing wrong with any of the tissues. Puzzled, he applied an electrode to the child's muscle and found it didn't respond at all, a highly unusual occurrence. He admitted his bafflement to DeShon's parents. "When they took the cast off, my foot worked fine," DeShon remembers.

MUSCLES MALFUNCTION WITH CHANGES IN DIET, EXERCISE, STRESS

Neither Feigert nor DeShon has a psychiatric problem, though it's easy to see why some people might have thought so. What both of them have is a muscle disorder known as periodic paralysis, which comes in two main forms. Feigert has the type known as hyperkalemic, meaning high serum potassium, periodic paralysis (hyperKPP), and DeShon has hypokalemic, meaning low serum potassium, periodic paralysis (hypoKPP).

People with these disorders periodically lose function of all or some of their skeletal muscles in response to changes in their diet that alter the amount of potassium circulating in the blood, exercise changes and -- just to confuse the situation -- emotional stress. Facial and respiratory muscles usually aren't affected. Recovery occurs after a short time, a few hours to a day or so, but persistent weakness can develop after many years of such attacks. In the hyperkalemic form, people also often have an inability to relax their muscles -- a condition known as myotonia -- in between attacks of paralysis. In general, people with periodic paralysis attacks only have them about 1 percent of the time. Attacks can come days, weeks, months or years apart.

Daniel DeShon and daughter KayLi.

These disorders aren't difficult to diagnose for an experienced specialist, says MDA grantee Louis Ptacek, a neurologist and neurogeneticist at the University of Utah in Salt Lake City. "The problem," he says, "is that these diseases are very rare, and most doctors have little or no experience with them."

Attacks are typically triggered when a person rests after exercising, Ptacek says, leaving a person vulnerable to charges of malingering. A typical example is the soldier who does fine on a 12-mile hike, then returns to the barracks, sits down and tells his sergeant he can't get up. The child who plays ball during recess and then becomes too weak to get out of his seat in study hall isn't likely to be believed either, Ptacek says.

Feigert, now 31 and a legal secretary, had several more attacks in her teens and 20s, some of which were extremely frightening. On one occasion, she had been out drinking with friends (some types of alcohol are high in potassium) and had come home and gone to bed. In the middle of the night, she awakened, nauseated and completely paralyzed. For some reason, her mother came into the room just in time to save her from vomiting while on her back, which almost certainly would have led to a choking incident, possibly a fatal suffocation.

At one point, her disease was misdiagnosed as polymyositis, an inflammatory muscle problem, and she was treated with the drug prednisone (Deltasone, Orasone). She gained 40 pounds (weight gain is common when prednisone is taken for months or years), but her condition remained otherwise unchanged. "To be that heavy in the 10th grade was just unbelievable," Feigert recalls with some bitterness. At other times, her disease was called panic attacks.

DeShon is now a 40-year-old deli department manager for a Seattle-area supermarket and he, too, has some bad memories. When he was in the seventh grade, he considered himself a fair guitar player and convinced his father to take him guitar shopping. "I can't remember how this came on, but my left hand got real weak and I couldn't hold down the strings. My dad was having me try out all these different guitars, and I felt really embarrassed because I could barely play." When his hand function later returned, the family doctor told his parents the problem was probably a psychosomatic reaction.

A PROBLEM WITH IONS

Dr. Louis Ptacek with grad student Zie Zhang at the University of Utah.

The real problem, Ptacek explains, has to do with the way charged atoms called ions -- often called electrolytes in biological systems -- flow back and forth across the muscle fiber (cell) membrane. Embedded in the membrane are submicroscopic pores known as ion channels, which allow sodium, potassium, chloride and calcium ions to move between the inside of the cell and the fluid around it. These channels exist in all cells, but they're slightly different in different cell types. For example, the ion channels in skeletal muscle, cardiac muscle and nerve cells are unique to those cell types.

In excitable cells, such as muscle and nerve, these ion channels have a specialized role. In muscle, they're a vital link in the chemical chain of events that causes a muscle fiber to either contract or relax.

IN HYPERKPP, SODIUM LEAKS IN TOO LONG

In hyperKPP, the problem lies in the sodium channel, says Ptacek, whose MDA-backed research group identified the gene on chromosome 17 that's defective in this disorder in 1991. The defect affects only the channels in skeletal muscle cells, which explains the lack of direct effects on the heart or other systems in this disorder. (Another MDA-funded group that included Robert Brown of Harvard University and Eric Hoffman of the University of Pittsburgh independently made the same discovery at almost exactly the same time.)

The gene these groups identified codes for a protein that forms the main part of the sodium channel, the so-called alpha subunit, the voltage sensor for the channel. A key function of the sodium channel is to sense voltage changes in the muscle fiber membrane, Ptacek explains. When the voltage becomes sufficiently positive in response to a signal from a connecting nerve fiber (see "Steps to Muscle Contraction"), the channel opens and allows sodium ions from outside the cell to rush in. This inward flow of sodium is an early phase of muscle contraction, lasting only a small fraction of a second.

What happens in people with hyperKPP, Ptacek says, is that a small percentage of these channels fail to close properly. He says to picture a system with two doors. Just as one door is opening, the other door is beginning to swing shut; in the sodium channel, this "inactivation gate" begins to swing shut almost as soon as the first door opens to let sodium into the cell, so that sodium can only enter the cell during the necessary fraction of a second.

In people with hyperKPP, the inactivation gate gets stuck. "It's as if you had a door that's warped," Ptacek says. "If you slam it hard enough, it will close, but if you don't, it won't close completely." At least some of the time, some small percentage of the second doors aren't closing, allowing sodium to keep leaking into the muscle fiber. As long as the second door remains open, the channel can't go into its "inactivated state," a necessary prelude to opening again when the next signal to contract comes down from a nerve fiber. That's when weakness or partial or even complete paralysis occurs.

And how does high serum potassium fit into this picture? "We don't understand that at all," Ptacek admits. In fact, he notes, most people with so-called hyperKPP don't have any elevation of serum potassium most of the time. If they show any high serum potassium level at all, it's at the very beginning of an attack of weakness or paralysis -- hard to catch for a physician, since most patients aren't going to be at precisely this stage when they arrive at the doctor's office.

But potassium, sodium, calcium and other ions are all in careful balance before, during and after each muscle contraction, so changes in any of these ions in the presence of a malfunctioning channel could certainly upset the system -- and apparently do.

In people with hyperKPP, skeletal muscle membranes are "perched between hyperexcitable [too excitable] and hypoexcitable [not excitable enough] all the time," Ptacek says. "Many of them have myotonia [hyperexcitable muscles, which can't relax] all the time, but then something pushes them over the edge to the hypoexcitable side of the fence and they get weak. The precipitating factors are vigorous exercise followed by complete rest, like running four miles and then lying down on the couch; eating high-potassium foods; and stress, for reasons that we don't understand."

Ptacek's MDA-supported group was also responsible for discovering that a disorder that involves persistent inability to relax muscles in cool temperatures, known as paramyotonia congenita, is caused by flaws in the same sodium channel as the one linked to periodic paralysis. However, the particular flaws involved in this disorder differ from those that cause paralysis. The mutations are in the same gene and affect the same voltage-sensing unit, but they're different mutations. Some mutations in the gene appear to cause a combination of both disorders.

One thing is certain: Doctors can cause an attack of hyperKPP by giving such patients a high dose of potassium, usually in the form of an oral potassium preparation. "The disorder is named for our ability to precipitate attacks by administering potassium," Ptacek says, not for any consistently high potassium level in patients. This diagnostic maneuver may not seem important, but it's been a godsend to many people previously accused of being either lazy, manipulative, psychologically disturbed or told they have a disease they don't really have.

IN HYPOKPP, CALCIUM IS THE CULPRIT

HypoKPP, although it may look similar to the observer, is actually an entirely different disorder. Ptacek's group also identified the gene for this disorder, with MDA funding, in 1994. It's a chromosome 1 gene that affects the voltage sensor (alpha subunit) of another ion channel, a calcium channel.

People with hypoKPP have similar attacks of weakness or paralysis, either partial or complete, at widely spaced intervals. Myotonia isn't associated with this disorder, however. Typically, says Ptacek, the person with hypoKPP awakens with severe weakness of the limbs. Attacks can also occur in response to food or drink that lowers serum potassium -- those that contain a lot of sodium or carbohydrate -- and, as in hyperKPP, by rest following exercise. Emotional stress can also cause an attack. For some reason, males are generally more severely affected than females with the same genetic mutation in this form of the disorder.

People with hypoKPP generally have low serum potassium levels during an attack of weakness, Ptacek says, but otherwise their potassium levels are likely to be normal when tested. To diagnose the disorder, doctors can cause an attack by giving patients substances that acutely lower their serum potassium. Usually, this is an intravenous solution of glucose and insulin, which pushes potassium ions from the blood into the cells.

Ptacek says people with hypoKPP are generally very sensitive to decreases in serum potassium that wouldn't bother the average person. Anyone, he says, can be made weak by a drastic lowering of serum potassium, but hypoKPP patients get weak with even a slight fall in potassium level.

The calcium channel is also activated by voltage changes in the muscle fiber membrane. But an inward flow of calcium plays a different part in fiber contraction from that played by the inward rush of sodium ions. When calcium ions come through their channels in response to a voltage shift, some kind of switch is thrown by the channel that releases more calcium from special calcium storage structures inside the fiber. This release of internal calcium stores is the final step in muscle fiber contraction, because it allows the proteins that actually perform the contraction to interact with each other.

In people with hypoKPP, Ptacek says, it can only be surmised that "their calcium channels are somehow working abnormally. Their muscle fiber membranes become inexcitable, so I presume that they're not dumping calcium from their stores. If they were, the muscle should be contracting."

DIAGNOSIS, UNDERSTANDING HAVE IMPROVED

Dr. Robert Griggs

Fortunately, the outlook for people with periodic paralysis is much improved over just a few years ago. Research, especially from the molecular genetics studies of the 1990s, has yielded genetic diagnosis procedures (see "Genetic Testing") and better understanding of the physiology of the disorder.

A genetic counselor can help with decisions about family planning. The periodic paralyses are dominant disorders, meaning a person has to inherit only one flawed gene to show symptoms of these disorders. In many cases, including Feigert's and DeShon's, there's no family history of the disorder and the problem is considered to be a new genetic flaw.

Better understanding of physiology has led to more rational approaches to medications and dietary changes.

DRUGS HELP CONTROL SYMPTOMS

Symptoms can be controlled with medications, in combination with dietary changes, in most people, says Robert Griggs, a neurologist and MDA research grantee at the University of Rochester (N.Y.) Medical Center. Griggs has had recent MDA funding to study treatments for periodic paralysis.

The oldest drug for both forms of the disorder is acetazolamide (Diamox), used since the 1960s, Griggs says. It belongs to a class of drugs known as carbonic anhydrase inhibitors. They block the action of the enzyme carbonic anhydrase and have long been used to treat glaucoma. It isn't clear how they help in periodic paralysis, but they probably change the chemical environment of the fluid that bathes the muscle by changing which ions are excreted by the kidneys.

Griggs, Ptacek and others were part of a recent MDA-funded study that tested another carbonic anhydrase inhibitor on more than 100 people with both forms of periodic paralysis at seven medical centers. They found that the alternative drug dichlorphenamide (Daranide), also used in treating glaucoma, was highly effective for hypoKPP but not effective for hyperKPP. The drug's effectiveness was measured by its ability to prevent attacks of weakness when taken on a continuous basis.

The study doesn't have anything to say about acetazolamide, Griggs says. "We didn't do a head-to-head comparison of dichlorphenamide and acetazolamide." But he adds that, in his experience, dichlorphenamide seems to be the better drug for hypoKPP.

Other drugs are also used to treat both hyper- and hypoKPP. Diuretics, which change which ions the kidneys excrete and which they retain, are frequently used. For hyperKPP, diuretics in the thiazide family, such as chlorothiazide (Diuril, Diuregen) and chlorthalidone (Hygroton), are often prescribed. These drugs increase urinary excretion of potassium.

For the myotonia often associated with hyperKPP, the drug mexiletine (Mexitil) is used. This drug, also used to treat irregular heartbeats, seems to change the way membranes handle sodium.

For hypoKPP, a different type of diuretic, one that causes the kidneys to retain potassium, is used. Triamterene (Dyrenium) and spironolactone (Aldactone) are in this family.

In the future, Griggs says, "We might be able to create designer drugs that would actually modify individual abnormalities of channel function."

CHANGING DIET NECESSARY -- AND SOMETIMES SUFFICIENT

Dietary modifications can also help, Ptacek and Griggs say. "High-carbohydrate meals or high-sodium meals and, occasionally, the carbohydrate in alcoholic beverages will trigger the low potassium and precipitate an attack," Griggs says of hypoKPP.

HyperKPP patients have to be careful about taking in too much potassium at a time, Ptacek notes. "Some patients know they can bring on attacks if they eat three or four bananas or drink orange juice, things that have a lot of potassium."

Potassium seems to show up in a lot of places, sometimes where people don't suspect it. Ptacek tells about a family in England that got attacks of weakness whenever they drank New Castle Brown Ale. A colleague of Ptacek's sent a sample to the lab and found the ale was very high in potassium.

Some other foods very high in potassium are oranges; some melons, such as honeydew and cantaloupe; dried fruits in general; some nuts, especially almonds; and sunflower seeds.

Christine Feigert was started on a low-potassium diet but admits she didn't really follow it because it didn't seem to help her much.

"I think dehydration is the biggest problem for me," she says. Feigert, who's now on a carefully planned exercise schedule, drinks a lot of Gatorade, a sports drink that contains sodium, potassium and carbohydrates and is designed to prevent dehydration and electrolyte imbalance in athletes. She also uses Power Bars, which contain electrolytes, protein and carbohydrates, and takes chlorthalidone. Her attacks are very much under control (she hasn't had a major one since 1992) and rarely affect her work as a legal secretary or her life in general. She's engaged to be married soon and says she and her fiancee will discuss family planning issues when the time comes.

Daniel DeShon has also found his own way. He didn't like taking acetazolamide at all, finding it interfered with the quick thinking he needed on his job as a deli department manager, and took himself off the drug. "I don't think my doctor was real happy with me, but I just decided it had to be," he says. DeShon finds the biggest trigger of attacks for him is sodium in his diet.

His doctor was sympathetic with the idea of dietary control and referred him to a dietitian. With her help and that of his wife, a nurse, DeShon developed a 2,000-milligram sodium diet, which is a fairly stringent restriction in today's world of prepared, frozen and canned foods, most of which are high in sodium.

He's had to give up his favorite packaged blueberry muffins (600 milligrams of sodium each) and has had to make a lot of food at home that he used to eat at restaurants. "We make homemade pizza," he says, "and I make my own sauces." If they do eat out, he says, "you have to be real assertive. You have to say, 'I don't want any salt. How much salt is on this thing? Do you have meat that you don't put salt on?'" (Salt is sodium and chloride.)

DeShon has recently started taking spironolactone and finds he can eat a little more sodium with this medication.

Article continued on next page