Periodic paralysis (PP) includes a group of less common genetic diseases that manifest as muscle weakness leading to paralysis in response to triggers such as ingesting carbohydrates or salt, high exertion, or exposure to cold.1 Neurology Advisor spoke with Jacob Levitt, MD, vice chairman of dermatology at the Mount Sinai Medical Center in New York, New York, for his unique medical and patient perspectives on PP. Dr Levitt has R672S/SCN4A hypokalemic PP and is president of the Periodic Paralysis Association.
Neurology Advisor: There are many forms of PP. How do clinicians differentiate them?
Dr Levitt: PP is an ion-channelopathy. The most common forms are hypokalemic PP (hypo PP), caused by either sodium or calcium channel defects, and hyperkalemic PP (hyper PP), caused by sodium channel defects. Less common forms include Anderson-Tawil syndrome, caused by potassium channel defects, normokalemic PP, and hyperkalemic PP with paramyotonia congenita von Eulenburg, both caused by sodium channel defects. Thyrotoxic PP is prevalent in Asia. There are also sodium channel defects that cause potassium-aggravated myotonia and chloride channel defects that cause myotonia congenita that don’t fall under the rubric of PP, but are often discussed in the basket of ion-channelopathies of muscle.
Different forms of PP can be defined by the triggers. If carbohydrates induce paralysis with low potassium levels, then it suggests hypo PP. If eating carbohydrates improves weakness during an attack, it suggests hyper PP. In patients with normal potassium levels during episodes, disease may either behave as hyper PP or, less commonly, as hypo PP.
Genetic testing can quickly and easily clarify a diagnosis when a classic variant causing hypo PP or hyper PP is found. Unfortunately, often there are years or even decades of diagnostic delay before the diagnosis is entertained and genetic testing is considered. To complicate matters, only 70% of cases are genetically identifiable, so there are another 30% of patients who carry a definitive clinical diagnosis but come up negative on genetic testing.
Neurology Advisor: Tell us about your experience with PP symptoms prior to your diagnosis.
Dr Levitt: I had onset of frequent, dramatic symptoms at about age 12, when I became paralyzed after sitting down in karate class. On 2 or 3 occasions separated by months or years, I recall waking up paralyzed in the middle of the night alone in my room (as early as 9 years old), but when I told people, it was dismissed.
Neurology Advisor: How frequently do attacks occur? Are there modifications to daily life to help reduce the number of attacks?
Dr Levitt: Attack frequency is higher in hyper PP, occurring sometimes several times per day, typically of short duration (about 15 minutes). Patients with hypo PP tend to have daily mild attacks, while more severe attacks occur less frequently. Paralysis can often last for hours and sometimes continues on and off for days, with frequency determined by the degree that dietary triggers are avoided and medical management is optimized.
Avoidance of triggers (salt and carbohydrates) is the main thing, but it’s also important to recognize physical limitations and make accommodations. Daily activities may sometimes have to be limited, or patient expectations of what they can do must be recalibrated. Some people become wheelchair bound because of permanent muscle weakness (PMW).
Neurology Advisor: What is the role of exercise in both promoting and preventing attacks?
Dr Levitt: Exercise followed by rest is a trigger common to most, if not all, forms of PP, but exercise means different things to different people; walking up stairs slowly may not cause an attack, but running up the stairs might. The same is true for a slow jog vs a fast sprint.
Exercise is a very controversial topic in the PP community because some people can tolerate exercise fairly well, and others absolutely cannot — even the mild exertion associated with physical examination can trigger an attack even before they leave the office. That happens frequently and is very frustrating for the patient.
For me personally, the more I regularly exercise, the less likely I am to get paralyzed. If I can achieve a good equilibrium on my chronic medication of either a carbonic anhydrase inhibitor or potassium sparing diuretic, strictly avoid dietary triggers, and optimize daily potassium requirements, I can establish a good exercise regimen.
Neurology Advisor: How is PP best diagnosed and monitored?
Dr Levitt: Magnetic resonance imaging of the femur (and associated surrounding muscle) without contrast would detect PMW, but its role in establishing a diagnosis has not been explored, and the intervals at which to repeat the test to monitor for change from baseline also have not been established. Clinical monitoring remains the mainstay by which to measure optimal management. When you have a successful response to therapy, there is a dramatic and relatively rapid (within the first week) reduction in the severity and frequency of attacks. The threshold for getting an attack is also much higher — you can sustain more insults before you get an attack on therapy vs off therapy, and that allows you to do more exercise, which also makes you less susceptible to attacks. If a patient with PP is put on the right therapy, he or she can achieve a reasonably normal standard of living.
Neurology Advisor: What are some of the long-term consequences of PP?
Dr Levitt: People with PP are at high risk for falling because they can’t support themselves, either while trying to move during an acute attack, or tripping in the context of PMW of the quadriceps.
I also believe that there is a cumulative effect of repeated attacks. Excess sodium accumulates in the muscle during attacks and causes muscle vacuoles to form, and for some reason that causes fibro fatty degeneration of the muscle. If you perform magnetic resonance imaging on someone in their 70s with PP, most of their thigh will be fibro fatty tissue instead of muscle, relative to a normal person. The hope is that control and, ideally, prevention of attacks will lessen the cumulative damage caused by them and stave off PMW.
Neurology Advisor: Are there any specific disease management tips you’ve learned over time in controlling your own disease?
Dr Levitt: I have learned that it is important to know how much potassium should be taken to premedicate before exertion. If you’re experiencing an attack and take 60 mEq and are still weak, is it dangerous to take more? It is well established that in hypo PP, you can take reasonably high doses of potassium and not be concerned about cardiac arrest.
Neurology Advisor: What can neurologists do to better manage patients with PP?
Dr Levitt: Diagnostically, I think that neurologists have to keep an open mind about the triggers that patients report. Therapeutically, the basic tools for hypo and hyper PP are carbonic anhydrase inhibitors. Thiazide diuretics can also be used for hyper PP, and at doses higher than 25 mg because of greater potassium wasting. Patients can also take albuterol in addition to eating a candy bar, if they have to, during a hyper PP attack. For hypo PP, things like epleronone are good for men because spironolactone can cause gynecomastia. Epleronone also works well for women. Acetazolamide and spironolactone can be combined to give added benefit and allow for lower doses of both.
Acetazolamide or eplerenone have no role in the acute attack, but they do reduce the frequency and severity of attacks over time. If intravenous potassium is needed, avoid giving it with normal saline or D5W.
Clinicians also need to prescribe sufficient doses of potassium in the right vehicle to allow patients to self-manage their disease, especially during an acute attack. When patients are on spironolactone and excessive potassium supplementation, serum potassium levels should be monitored regularly, because even hypo PP can become hyperkalemic.
The Periodic Paralysis Association website offers a lot of information for both patients and clinicians, and we also host conferences every year. We are especially focused on helping connect patients with clinical and genetic researchers to identify better treatments.
For more information, visit the Periodic Paralysis Association website.
Levitt JO. Practical aspects in the management of hypokalemic periodic paralysis. J Transl Med. 2008;6:18.