Normokalemic Periodic Paralysis (NormoKPP)
Normokalemic periodic paralysis (NormoKPP) is similar to hyperkalemic or hypokalemic periodic paralysis, but it’s not quite the same.
Periodic paralysis is a rare genetic disorder that is characterized by temporary attacks of extreme muscle weakness or paralysis.
These attacks can be triggered by a variety of things, with the most common triggers being resting after exercise, cold temperatures, and having too much or too little potassium. There are several types of periodic paralysis. Understanding the different types can be difficult, but we are here to give you guidance.
Periodic paralysis is caused by muscle cells that do not have the right balance of chemicals to work properly. Muscle cells have openings called channels that open and close to let particles such as sodium, potassium, and calcium go in and out. These particles are called ions, and muscle cells can only work if the right kinds of ions enter and exit the cells at the right times. When the channels don’t open and close the way they’re supposed to, the ions become imbalanced, and muscles aren’t able to function normally.
Normokalemic periodic paralysis (NormoPP or NormoKPP) is a rare form of a rare disorder. Scientists are still pinning down exactly what it is and what causes it. In many cases, it is a variant of hyperkalemic periodic paralysis and both disorders are caused by the same sodium channel mutation. However, there are some cases in which it is a variant of hypokalemic periodic paralysis and the cause is a calcium channel mutation. It’s difficult to fully define this unusual disorder, but one key fact about it is that in normokalemic patients, blood potassium levels stay normal during attacks instead of rising (hyperkalemic) or falling (hypokalemic).
The main symptom of normokalemic periodic paralysis is attacks of extreme muscle weakness, stiffness, or paralysis. These attacks usually last from around ten minutes to an hour, but in some cases, they can stretch on for several hours or multiple days. There are many features of the attacks that vary from person to person, so one person’s experience might be different from another person’s even though they both have the same disorder.
Some people have attacks every day, others have them several times per month, while there are others who have them every few months or less often. These kinds of attacks can affect one area of the body or multiple areas. Arms and legs are often affected, but facial muscles can also be affected, making it difficult to make facial expressions or open eyelids. In rare cases, respiratory muscles are affected.
The strength of the attacks isn’t always consistent — sometimes, the patient feels fatigued, but can still move around slowly. Other times, they aren’t able to move at all. When it comes to muscle stiffness or myotonia, sometimes the patient can “work it off” by gradually moving the stiff muscles little by little. Other times, the patient isn’t able to work off the stiff feeling. Sometimes, attacks may come very suddenly and cause the patient to fall, although attacks aren’t always this sudden. There are some patients who experience muscle swelling and cramping before attacks.
If the patient has attacks for many years and they receive little to no treatment, it’s likely they will develop permanent muscle weakness, which is called myopathy. This might happen as the patient reaches their 50s or 60s. Some patients with myopathy use a wheelchair or scooter to help them get around outside the house to ease the strain on their weakened muscles. However, they are still able to have fulfilling lives and do many kinds of activities.
People who have normokalemic periodic paralysis must try to avoid situations that trigger their attacks. A major trigger is being in a cold environment, so going outside in cold weather can cause an attack to happen. Humid weather can sometimes be a trigger, too. Stress is also a major trigger. The more stress a patient feels in their day-to-day life, the more likely it is that they will have an attack. In addition to that, since normokalemic periodic paralysis is often similar to hyperkalemic, eating high-potassium foods might trigger attacks, too.
Rest after strenuous exercise often triggers attacks, although sometimes, attacks happen during exercise, not after. However, even without exercising, it’s possible to have an attack just from not moving for a long period of time, such as when sitting through a movie. Sleep is also a trigger because of the fact that sleeping involves being inactive for a long period of time. Patients often have attacks in the morning when they wake up, making it hard to get out of bed.
Because there are many triggers and different people will have different triggers, it is recommended that patients keep a trigger diary. After you have an attack, you should write down what happened, how you felt, what you were doing before the attack, and how you were able to recover from it. After doing this for a while, you’ll be able to look back on your previous diary entries and notice certain patterns.
Normokalemic periodic paralysis symptoms almost always begin during the childhood or teen years. The frequency of attacks can change throughout the patient’s lifetime. Usually, the attacks start out not being very frequent, but as the patient reaches their 30s, there are more attacks. Then, in their 50s, the patient might have fewer attacks, but their muscles have been permanently weakened (myopathy).
The impact that this disorder can have on a person’s life is determined by how many years went by before they received a correct diagnosis. Because it is such a rare disorder, doctors often mistake it for other more common conditions. This results in patients spending a large portion of their lives with the wrong diagnosis, which means they are not receiving the proper treatment. Getting the right diagnosis makes a big difference!
Giving doctors your family’s health history and your trigger diary can help them come closer to a periodic paralysis diagnosis, and there are other diagnostic tools available, too. Normokalemic periodic paralysis is a genetic disorder, and commercial lab genetic tests can be performed that can detect the disorder in some patients. However, genetic testing is not perfect and does not always detect all cases. A muscle biopsy is sometimes needed for doctors to diagnose periodic paralysis. This means that the doctor must remove and examine a small piece of the patient’s muscle tissue during or after an attack to see if the muscle tissue is abnormal. Another diagnosis method is the Compound Muscle Action Potential test, which measures the electrical activity of muscles. This test can’t always detect periodic paralysis, but it can do so in a lot of cases.
Attacks of normokalemic periodic paralysis can vary in severity. For more mild attacks, it’s possible to do simple things to recover, such as eating or drinking a high-carb food or beverage or slowly making small movements in order to work off muscle stiffness. Medication might be needed if these methods don’t work. KEVEYIS (dichlorphenamide) is the only FDA-approved treatment for periodic paralysis. Albuterol inhalers are another way of possibly treating attacks. Acetazolamide is a drug that might help, as well as potassium-wasting diuretics. Severe attacks might affect the heart or breathing, so patients experiencing a severe attack must receive hospital treatment.
Patients should try their best to live a lifestyle that prioritizes minimizing triggers when possible. Living somewhere with a warm climate can help reduce the chances of an attack happening. Keeping stress levels low is another important way to make attacks less likely to happen. Avoid exercise that is overly intense, because resting after an intense workout is likely to trigger an attack. Planning your diet carefully is necessary to have fewer attacks because it’s crucial to stay away from potassium-rich foods.
Your Next Steps
If you think you may have normokalemic periodic paralysis, please talk with your doctor. Speaking with a doctor about a rare disorder can be intimidating, and many doctors have little to no prior knowledge about periodic paralysis. The PPA has many resources to help you become a better advocate for yourself. Click here to learn about other types of periodic paralysis. You can also submit a question to our Ask the Experts panel. Remember, we are here to support you all the way as you take action to advocate for your health!
Common Characteristics Associated with the Normokalemic Periodic Paralyses
- Attacks may last from minutes to days, and occur sporadically.
- Weakness can be local or generalized.
- The deep tendon reflexes become depressed, diminished, or lost in the course of the attacks.
- The muscle fibers become unresponsive to either direct or indirect electrical stimulation
- The generalized attacks usually begin in proximal muscles and then spread to distal ones.
- Respiratory and cranial muscles tend to be spared but eventually may also be paralyzed.
- Rest after exercise tends to provoke weakness of the muscles that had been exercised, but
continued mild exercise may abort attacks.
- Exercise restricted to a single muscle or a small group of muscles can induce weakness of the
exercised muscles without a detectable change of the potassium level in systemic circulation.
- Exposure to cold may provoke weakness in the primary forms of the disease.
- Complete recovery usually occurs after initial attacks.
- Permanent weakness and irreversible pathological changes in muscle can develop after repeated
- Onset at puberty is common. The reason for this still remains a mystery.
Diagnostic Work Up
Chief Complaint: I had a bout of weakness. I think I have periodic paralysis.
Primary Medical Doctor can do:
- Attack triggers (diet history to exclude licorice, diuretic abuse, laxative abuse).
- Duration of attack.
- Family history.
- Medication history.
- Features of attacks – describe what happens to you.
- Do attacks have periodicity/recurrent.
- The above gives you pre-test probability.
- Suspect hypoPP or hyperPP
- Check serum potassium in an attack (often difficult to catch, may require standby EMS
and/or arrangements with a local emergency room).
- Check serum potassium outside an attack (if normal, speaks less for renal disease).
- CK (skeletal muscle).
- Check serum potassium in an attack (often difficult to catch, may require standby EMS
- Thyroid studies (for hypoPP) – TSH, free T4, and free T3.
- Rarely, rule out RTA IV, licorice use, diuretic abuse, laxative abuse,
renin-aldosterone-angiotensis axis in context of hypokalemia or hyperkalemia (r/o Conn’s syndrome
vs. Addison’s disease). Ask nephrologist about specific tests.
- Neurological investigation – EMG (exclude myotonia) and exercise test (if abnormal then suggestive,
but if normal, does not exclude).
- Routine MRI to judge how much muscle bulk is preserved and presence of edema (should be done before
diuretic therapy); if possible, Na MRI is ideal but only investigational now.
- Genetic testing
- Empiric therapy sequentially with potassium supplementation, and either eplerenone or
- Repeat MRI after 4-6 weeks of empiric therapy looking for a decrease in edema.
- Biopsy if genetic testing is negative.
- Provocative test – dangerous.
- Refer back to PMD once the diagnosis is established for continued management.
CMAP (McMannis Protocol)
McManis EMG protocol to diagnose periodic paralysis:
The Long exercise nerve conduction test:
- This will be performed in accordance with the protocol described by McManis. All nerve conduction testing will be done on the abductor digiti minimi muscle with stimulation of the ulnar nerve at the wrist. Ambient skin temperature should be approximately 31-32 degrees F or 0 degrees C.
- Compound muscle action potentials (CMAPs) are evoked with a single supramaximal stimulus and repeated every minute for 5 minutes to ensure a stable baseline.
- Maximal, voluntary, isometric exercise of the muscle is performed in 10-second intervals
followed by 5 seconds of rest for a total of 5 minutes. CMAP amplitudes are then recorded every
1 minute for 5 minutes then every 5 minutes for 30 minutes.
- A decrement of >40% is highly suggestive of periodic paralysis. It does not differentiate,
however, between the primary and secondary forms of periodic paralysis.
Please see the following link for Genetic Testing.
MRI of muscles looking for fatty degeneration, which is a feature of permanent muscle weakness
The significance of elevated Creatine Phosphokinase (CK or CPK) during or after attacks is unclear, and for now, does not aid in the diagnosis. Further study is warranted given that some patients may present with this lab abnormality. Involve an Endocrinologist to rule out adrenal causes of hypokalemia. Specific studies they might perform to rule in or out hypoPP are: (more information to follow). Involve a Nephrologist to rule out renal disease and to get advice about electrolyte management.
In terms of genetic counseling, the disease is autosomal dominant. A variety of mutations in sodium, calcium, and potassium channel genes in muscle have been reported to cause hypokalemic periodic paralysis. One Lab in the United States, one lab in Germany, one lab in France, and one lab in the U.K.perform the genetic testing. The genetic test has very high specificity but poor sensitivity — that a positive test is confirmatory, but a negative test DOES NOT rule out periodic paralysis.
Currently, there are only limited data to support a certain genotype predicting disease phenotype i.e. severity and likelihood of responding to treatment). So, at this time, genetic testing may be helpful in establishing the diagnosis, for family planning, or for research purposes. There is a 50% chance the patient will give the disorder to his offspring.