Periodic Paralysis: Shedding Light on a Rare Neurologic Disorder

Nancy Melville

Disclosures

October 29, 2018

Like many rare disorders, periodic paralysis can go undiagnosed and be easily misinterpreted as a wide variety of neurologic or other disorders. But with increased awareness of the unique symptoms of this disorder and how to manage them, patients and their families can be spared, or at least better prepared for, the harrowing experience of acute attacks.

Key to the understanding of periodic paralyses is that they are specifically neuromuscular disorders, caused in most cases by mutations in skeletal muscle sodium, calcium, and potassium channel genes.

There are three primary subtypes: hypokalemic periodic paralysis (hypoPP), with an estimated prevalence of 1 case per 100,000 persons; hyperkalemic PP (hyperPP), occurring in approximately 1 per 200,000 persons; and Andersen-Tawil syndrome, with only about 1 case per 1 million persons.

The key symptom that the subtypes all share is muscle weakness, which can emerge gradually. In addition, although some triggers differ among the subtypes, periodic paralysis is commonly triggered in all by prolonged rest, explained Rabi N. Tawil, MD, an expert in periodic paralysis for whom the rarer Andersen-Tawil syndrome is partially named.

"This isn't a sudden weakness or paralysis; it tends to develop over time," Tawil, who is co-director of the MDA Neuromuscular Disease Clinic at the University of Rochester, New York, told Medscape.

"Prolonged rest is a common trigger, and it's something that clinicians need to make sure to ask about, because some patients may not have even realized it until you ask," he explained. "They may realize that since they were young, they haven't been able to just jump out of bed in the morning—they're initially weak and can only slowly start moving their arms and legs."

Another typical scenario is the development of a temporary muscle paralysis after a long trip, he added. "The person will have been driving for 3 or 4 hours, and at the end of the trip, they can't get out of the car because their legs are weak," Tawil said.

The paralysis episodes can last anywhere from hours to days, with frequency ranging from daily to monthly intervals.

Onset of PP is typically early in life. With hypoPP, onset is typically in childhood or adolescence, whereas hyperPP can arise earlier, in infancy or early childhood.

Diagnostic Challenges

The somewhat unpredictable nature of the weakness episodes, and the common onset in youth can add to the challenge in making a diagnosis, Tawil noted.

"One of the difficulties in diagnosis is that patients often look very normal when you see them—they will have had this weakness, but then they come in and look normal, and they may have trouble describing what's happening," Tawil said.

He noted that in fact, most patients who are referred to him wind up not having periodic paralysis, underscoring the lack of understanding of the specific symptoms that would exclude a diagnosis.

A review[1] of the diagnosis and treatment of periodic paralysis that Tawil coauthored, published this year in Muscle & Nerve, notes that other symptoms that could suggest alternative diagnoses include pain, prominent sensory symptoms, or autonomic symptoms during attacks, which may instead suggest Guillain-Barré syndrome or spinal cord injury.

In addition, alteration of consciousness or abnormal movements may be more suggestive of a seizure or stroke, and such symptoms as double vision, ptosis, or difficulty swallowing might point to a neuromuscular junction disorder.

"During the attacks, the motor exam should reveal a flaccid paralysis, so preservation of reflexes in a paralyzed limb should raise the possibility of a different cause," the authors said.

Genetic Test Confirmation

In approximately 60%-70% of cases, the diagnosis can be confirmed with genetic testing. For hypoPP, the culprit is CACNA1S in most patients, or SCN4A in some; for hyperPP, the gene is SCN4A; and for Andersen-Tawil syndrome, the gene to look for is KCNJ2.

For the approximately 30% of patients who do not have the genetic mutation, key symptoms include evidence of low (< 3.5 mEq/L) or high (> 5.0 mEq/L) serum potassium levels during the attacks, in addition to the key sign of weakness after prolonged rest or weakness or paralysis after long periods of exercise.

"If someone overexerts themselves and goes and sits on a couch for the next 3 hours and then after that, they can't move, that would be another typical trigger," Tawil said.

Electrodiagnostic testing, including needle electromyography (EMG), can be useful in diagnosing hyperPP. Long exercise testing and measurement of compound muscle action potentials after paralysis is induced by exercise of a single muscle can also help in identifying periodic paralysis.

Because all three forms of periodic paralysis are inherited, having a parent with the disorder can further suggest the diagnosis in the offspring.

Key Differences in Subtypes

Dietary triggers play a key role in differentiating between hypo- and hyperkalemic subtypes and are highly important in helping to manage the condition.

Because hypoPP is associated with low potassium, a leading trigger of weakness is high intake of carbohydrates, which triggers insulin secretion, driving potassium from the blood into muscle. High-sodium meals are another known trigger for many. Dietary strategies for those patients therefore include avoidance of high-carbohydrate and high-salt meals.

Conversely, with hyperPP, fasting or low blood sugar from skipping a meal is a more common trigger. Consumption of a carbohydrate meal, having frequent carbohydrate snacks, and avoiding high-potassium foods are recommended strategies.

Andersen-Tawil syndrome is distinguished by potassium channel mutations that affect multiple tissues and is therefore associated with a highly variable periodic paralysis. The subtype, which is also notable for distinctive facial and skeletal anomalies, has various cardiac manifestations, including ventricular arrhythmias from long QT, that can be fatal.

Treatment Options

In the management of acute hypoPP attacks, the authors of the review[1] note that mild exercise—specifically nonresistant activities, such as walking around a room or shaking the arms at the onset of the attack—may benefit.

Importantly, they note that low serum potassium is in fact not due to low total body potassium but rather "shifts of potassium from the blood compartment into the intracellular muscle compartment."

"Therefore, correction of serum potassium should not be undertaken with the goal of correcting low total body potassium. Oral potassium is recommended for outpatient treatment (and) slow-release formulations usually should be avoided for acute management," they state.[1]

For hyperPP, mild exercise at the attack onset, along with a carbohydrate snack, is recommended, and beta-agonists can be an effective potassium-lowering therapy.

The drug dichlorphenamide (Keveyis®) was recently approved the US Food and Drug Administration for the treatment of periodic paralysis. Randomized controlled trials have shown efficacy in reducing frequency and severity in attacks for patients with hypoPP and those with hyperPP, with doses of 50 mg twice daily for treatment-naive patients. The mean dose at week 9 was 82 mg per day. Because the studies involved adults, dose adjustments would be required for children.

A key caveat—and controversy, as is common drugs for with rare disorders—is the cost of Keveyis, which was set at approximately $15,000 per a box of just 100 pills when acquired by Strongbridge Biopharma.

Some discounts on Keveyis are available, but Tawil said he often tries starting patients on the carbonic anhydrase inhibitor drug acetazolamide (Diamox®).

Acetazolamide has some caveats as well. Studies show approximately 50% of patients respond to the drug, and side effects are common, including tingling in the arms, disorientation, and nephrolithiasis. Small studies have shown the drug in some circumstances to have either no effect or even worsening symptoms in people with hypoPP and the SCN4A mutation.

"Diamox is very cheap, and my approach is to try starting patients on that, and if it fails, then move on to dichlorphenamide," Tawil said.

Importantly, he noted that the treatments aren't cures, and patients will need long-term management. "Periodic paralysis requires lifelong treatment," Tawil said. "It's a defect in a particular muscle membrane channel—potassium or calcium or sodium. These are symptomatic treatments; they don't change the course of the illness."

A 2012 survey[2] underscored the ongoing challenges of periodic paralysis. In this survey of 66 patients with the disorder, permanent muscle weakness was experienced by as many as 68% of patients, muscle pain in 82%, and muscle fatigue in 89%.

First-Hand Experience With HypoPP and Its Challenges

Jacob Levitt, MD, head of the Periodic Paralysis Association, knows of the lifelong challenges of periodic paralysis firsthand. He is also a patient, diagnosed at age 13 with hypoPP, and underscored the difficulties in finding appropriate care for such a rare disorder.

"In general, once a physician gets on board with prescribing, they generally follow through [with management]," Levitt, who is a dermatologist and vice chairman and professor of Dermatology at Mount Sinai Medical Center, New York, New York, told Medscape.

However, "finding such a physician can take many, many iterations of trial and error," he said. "Some folks end up being shunned in their small towns, because all of the few physicians there take a close-minded stance."

Even after proper treatment is found, setbacks are very common, Levitt said, "because most physicians may know of one treatment or another, but not the subtleties of medication dose adjustment or medication combinations."

Those are just a few of multitude of challenges that patients with periodic paralysis face in getting proper care, Levitt added. Others include:

  • Physicians' lack of reaching out to experts. "I offer to speak with patients' providers all the time, and 99% of the time, the offer goes unused," Levitt said.

  • Physicians' refusal to treat, because they do not have experience with this disorder. "Unfortunately, most doctors worldwide do not have experience treating periodic paralysis, so in this case, researching what can be done is incumbent upon any primary doctor or neurologist presented with the disease."

  • For patients with hypoPP, getting their doctor to prescribe sufficient amounts of potassium to get them out of an attack. "This is a challenge, because these doses far exceed the usual potassium replacement requirements for say, chronic use of a loop diuretic for heart failure."

  • Getting physicians to obtain a blood test during an attack to identify serum potassium as high or low.

  • In the case of normokalemic patients, being told the diagnosis cannot be periodic paralysis because the potassium level is normal.

  • Failure to order genetic testing or EMG compound muscle action potential testing to help the patient achieve a diagnosis.

  • Declaring definitively that the patient cannot have periodic paralysis if genetic testing is negative. "There are numerous instances of patients who were seen by world experts at one point in time where the world experts said periodic paralysis is impossible, and then later getting genetically diagnosed as positive with periodic paralysis as new genes or mutations were discovered."

  • Mistreatment to the point of death in acute attack situations, often with hypoPP, because hospital personnel refuse to listen to patients' pleas to avoid D5W intravenously. "There have been deaths due to mismanagement with D5W, which exacerbates the problem," Levitt said. "I am aware of at least two patients who died of this particular mismanagement, one in China and one in Russia. People also die of arrhythmia with Andersen-Tawil syndrome and of severe hyper- or hypokalemia during attacks."

Education of Patient's Community Is Key

A critical factor in helping overcome challenges for patients is educating the people around them to help better understand, and accommodate, any particular needs, Levitt said.

"There is a large need to educate family, schools, and work for a number of reasons," Levitt explained. "For one, gym class can be a source of attack triggers. Absence due to being paralyzed in the morning affects school and work."

Levitt described once having paralysis after "pulling an all-nighter for a physics problem set in college. The professor would not accept the problem set when I handed it in a couple of hours late because I was paralyzed in my room. I couldn't walk it to class. So, I got a zero."

"I did not know about the Americans With Disabilities Act back then, but this law should be leveraged by all patients with periodic paralysis," he said.

Furthermore, simply making sure the patient's family is well-informed about the rare condition is invaluable, Levitt added. "When family members are knowledgeable about the disease, they can accommodate the patient better, making proper food choices and helping to explain to others what the disease is."

A Patient Profile

Levitt says his hypoPP diagnosis at the age of 13 came owing to the good fortune of having a neurologist relative. He notes, however, that more subtle symptoms had already persisted for years.

"I was 13 when I had a major attack in karate class while sitting down to rest between exercises," he said. "I was carried home and my father, a physician, took a blood sample and found low potassium. His cousin, a neurologist, made the diagnosis on the spot."

"However, I recall waking up paralyzed a couple of times when I was younger, and I dismissed it because it didn't occur to me at that age to tell anyone."

"Once, I mentioned it to my dad, who said it was nothing. And I recall getting mentally unclear/fatigued (not paralyzed in the pure sense of the word) after eating sweets when I was a child, but I assumed that happened to everyone."

"So, by right, I had several years of diagnostic delay."

Levitt noted that genetic testing subsequently revealed that his sister and mother indeed had the disease. However, their symptoms were mild enough that they were not diagnosed earlier—resulting in decades of diagnostic delay.

"In retrospect, my sister got paralyzed a couple of times in years past, and my mom was weak as a child," he said.

"Now, my mom has permanent muscle weakness and gets mentally cloudy as manifestations of her regular attacks. My sister suffered from sensitivity to fluorescent lights, what she thought was chronic fatigue, inability to exercise, and what she thought was gluten sensitivity. It turns out that anything with gluten also tends to be a carbohydrate."

The lack of an earlier diagnosis for Levitt's sister took a heavy toll, and underscores the need to identify and treat this disorder. "Periodic paralysis stole her entire adult life from her," Levitt said. "She was not able to date owing to being chronically ill and now is too old to have a biological child."

Levitt says that his symptoms can range from mild to severe and even life-threatening. "My episodes can be as mild as inability to wiggle my toes or just being a bit clumsy owing to lack of fine motor control," he explained. "Or, I can be completely paralyzed to the point of being barely able to speak or breathe."

"I have been hospitalized twice for the condition, requiring intravenous potassium."

Experiences in Treatment

For treatment, Levitt says he started with acetazolamide, but did experience side effects. "The doses gave me paresthesias and, after some years, kidney stones," he said. "So, I have found out how to adjust the dose and frequency of dose to best suit my lifestyle and disease management."

"I still struggle with the fact that taking acetazolamide does not prevent all attacks. I just probably get fewer and less severe attacks than I would off the medication."

Levitt underscored the importance of using potassium powder that dissolves in water rather than sustained-release potassium chloride pills, which can present a serious risk for choking with paralysis.

"The pills would just sit in my stomach," he said. "One time, I was paralyzed and was on my back, and couldn't turn over, and when I burped all the salt granules came up. I could have aspirated; luckily, I did not."

"Some years later, a neurologist I saw mentioned potassium powder dissolved in water, which changed my life. I can now exercise after taking it and can get out of an attack much more quickly and safely."

Predicting Episodes

Levitt says his episodes tend to occur more frequently if he stops working out regularly, and sudden bursts of exercise can be triggers.

"If I stay in shape, I don't get paralyzed as often or profoundly, and I must be very stringent about avoiding carbohydrate triggers—especially pizza," he said.

"My attacks tend to set in within minutes of a triggering exercise event, so if I do, for instance, gentle walking with no particular effort or adrenaline surge, then I can do things without getting paralyzed," he continued. "But the second I, for instance, burst up the stairs, run suddenly, or do push-ups or lift something heavy, that can trigger an attack of weakness once I stop moving."

Levitt said that he has had the experience of waking up paralyzed, but has learned to predict—and try to prevent—such episodes.

"When I have a cold, or if I have exercised a lot during the day or ate a large dinner, I can kind of predict that I will awake paralyzed," he said. "When I have the presence of mind to do so, I will premedicate with potassium chloride before bed to avoid the morning paralysis."

Although his sister and parents were initially reluctant to be tested for periodic paralysis, Levitt said the family has ultimately benefited from their genetic confirmation. "Having the genetic diagnoses for our family has helped everyone cope with their disease better and be more proactive about their treatment," he said.

Drs Tawil and Levitt have disclosed no relevant financial relationships.

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