To better help clinicians diagnose and treat periodic paralysis,Â Neurology TimesÂ asked Jacob Levitt, MD, FAAD, to share his insights and expertise in this two-part series.
Dr Levitt is the President and Medical Director to the Periodic Paralysis Association. His interest in PPP is not just a professional one, as he was diagnosed at 13 years old with primary hypokalemic periodic paralysis. Currently, he is the Vice Chairman of the Department of Dermatology at Mount Sinai Medical Center, NY.
In this installment, Dr Levitt explores the importance of developing a comprehensive treatment approach. In the next article, Dr Levitt shares insights on patient education and partnering with patients to achieve best outcomes and quality of life.
Neurology Times: What are the issues in diagnosing PPP that may impact the development of an appropriate and comprehensive treatment plan?
Dr Levitt:Â Treatment for periodic paralysis first rests on the appropriate diagnosis, which may be straight forward or elusive. Often patients are treated empirically on a presumed diagnosis and, if the therapy works, clinicians stick with that plan.
The three disorders that comprise periodic paralysis are hypokalemic periodic paralysis (hypoPP), hyperkalemic periodic paralysis (hyperPP) (which can occur with or without paramyotonia congenita), and Andersen-Tawil Syndrome (ATS). Related diseases of ion channels that are often discussed and sometimes misdiagnosed as periodic paralysis (and vice versa) include potassium-aggravated myotonia, myotonia congenita, and episodic ataxia, among others.
Obtaining an accurate diagnosis entails obtaining a serum potassium level during an attack. High values suggest hyperPP and low values suggest hypoPP, but normal values do not rule out the diagnosis.
Genetic testing is a simple next step. Currently, Invitae, sponsored by Strongbridge Biopharma, provides genetic testing as a free service. Short or long exercise EMG (modified McManis protocol) is helpful. Similar episodes in family members is supportive of the diagnosis. It also is important to rule out hyperthyroidism in cases of hypoPP.
Most importantly, however, is patient history. Triggers of rest after exercise, cold or illness can suggest hypoPP or hyperPP. Improvement with oral potassium suggests hypoPP, and improvement with high carbohydrate substances suggests hyperPP. Triggers of high carbohydrate meals or high salt foods suggest hypoPP. Andersen-Tawil Syndrome is another variant of periodic paralysis, usually hypoPP, associated with skeletal deformities (eg, clinodactyly, mandibular hypoplasia, low set ears, etc) and long QT syndrome.
The nature of attacks themselves may cause diagnostic confusion. Classically, attacks of hypokalemic periodic paralysis are described as weakness or flaccid paralysis with areflexia. However, some patients with mutation-negative periodic paralysis have weakness associated with myoclonus or jerking and what looks like seizure activity. These patients may respond well to potassium, but they are not labeled as having periodic paralysis since they do not fit in a neat diagnostic box.
NT: What are the considerations for addressing acute attacks? Are there specific strategies that have proved to be effective?
Dr Levitt:Treating periodic paralysis outside of a hospital setting must take into account three factors: medical therapy of acute attacks, medical therapy to prevent attacks, and behavioral modification (both physical and dietary).
For acute attacks of hypoPP, therapy includes one of a variety of potassium ion preparations. In the acute attack, most patients benefit from relatively high doses of aqueous potassium. For example, 60mEq K+Â is a reasonable first dose in 250mL to 500mL water. If the attack does not resolve in approximately 15 minutes, another 20 mEq to 60 mEq may be given. Under-dosing potassium in fear of causing fatal hyperkalemia is a common therapeutic error. Fatal hyperkalemia rarely, if ever, happens at the potassium dose levels that are required to abort an attack. Allowing patients leeway to experiment with dosages is important. Therefore, providing larger quantities of monthly prescriptions for potassium packets or tablets can be life-saving.
Unfortunately, this may become expensive for patients. A single packet of potassium chloride 20mEq costs $7 out of pocket, and insurers often limit the amount to be dispensed. Furthermore, arbitrary stop alerts on electronic medical record prescribing protocols often prevent the appropriate amounts of potassium to be dispensed.
Avoiding popular sports drinks (eg, Gatorade) that are high in sugar is important and a commonly overlooked by novice patients and caregivers.
For acute attacks of hyperPP, therapy includes eating sugar (in the form of a candy bar or a cola). The consumed sugar stimulates insulin to drive potassium from the blood into the muscle. Additionally, one to two puffs of Ventolin HFA may be helpful, as it drives potassium from the blood into muscle. In severe attacks, cardiac monitoring for peaked T-waves is helpful, and calcium may be given to stabilize the myocardium from fatal arrhythmia.
For ATS, therapy should be guided by the associated periodic paralysis. Consultation with a cardiologist for long term management is also strongly advised.NT: Preventing attacks must be a key component of a comprehensive treatment plan. What should clinicians consider? What are some common agents that might prevent attacks?
Dr Levitt: Potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene, amiloride) and carbonic anhydrase inhibitors are a mainstay of therapy in preventing attacks in hypoPP. Often, one may start with acetazolamide at 250 mg po once daily and titrate up or down based on perceived benefit by the patient. Dose is typically limited by intolerable paresthesias, mental cloudiness, or nephrolithiasis. Clinicians may consider switching patients to dichlorphenamide, which is more potent than acetazolamide, or change class to eplerenone. Spironolactone is a poor choice for men due to risk for gynecomastia. Occasionally, a carbonic anhydrase inhibitor is successful combined with a potassium sparing diuretic. Less frequently used are amiloride or triamterene.
If there is comorbid high blood pressure, the potassium-sparing properties of ACE inhibitors may be leveraged; toxic hyperkalemia is unlikely to occur in these patients. That said, monitoring serum potassium is warranted in the early phases of therapy to determine how each individual responds to these agents.
Finally, sustained release potassium preparations before bed have a role for patients who tend to wake up paralyzed in the early morning hours.
To prevent attacks in hyperPP, potassium-wasting diuretics are employed, specifically carbonic anhydrase inhibitors or hydrochlorothiazide. Anecdotally, I have found dichlorphenamide to be particularly effective in hyperPP with PMC. The role of newer potassium-sequestration agents approved for renal failure patients is an emerging area of interest for study as chronic therapy for hyperPP patients.
NT: What about behavioral modifications and triggers?
Dr Levitt:Behavioral management in periodic paralysis revolves around the identification and avoidance of triggers. As in diabetes, this may be more difficult than it sounds. For hypoPP patients, salty, high carbohydrate snacks are ubiquitous, cheap, more readily available than healthier options, and they can be hard to resist.
Planning also proves to be useful. For instance, pre-medicating with sufficient doses of potassium chloride can prevent attacks of weakness associated with intense exercise; a second dose hours after the exercise may be necessary. (Heavy exercise is a double whammyâthe exercise itself is a trigger, plus the immediately subsequent increased caloric intake predisposes to next morning weakness.) Doses used to prevent attacks are similar to those used to treat attacks. Remind patients that having pre-mixed potassium by the bedside is useful, as it may be life-saving if they wake up paralyzed and cannot call for help.
For hyperPP, a candy bar by the bedside and on one’s person at all times can be helpful. Keeping a warm environment if cold is a trigger is important. For any form of periodic paralysis, having a “Life Alert” type device is helpful, as is making a buddy system with someone to check-in routinely, especially when the disease is not yet well-managed.
It is important to note that even though exercise is a trigger, exercise should not be avoided. Exercise activity that focuses less on resistance and more on cardio-oriented activity is considered a better option, but this hypothesis needs to be verified via studies. Most patients who can exercise report feeling better and report they are less prone to attacks when they are physically fit.
NT:Â Please look for the next installment, Patient Education and Periodic Paralysis: Tips for Empowering Patients and Improving Quality of Life, for further clinical information on period paralysis.