First, a simplified blurb on normal physiology:

Nerves are like electric wires that transmit signals from the brain to the muscles. Muscle cells have potassium and sodium on the inside and outside of their cell membranes. Muscle cells respond to nerve signals by letting ions change location from the inside to the outside and from the outside to the inside of their cell membranes. The ions cross the muscle membrane through ION CHANNELS. Each ion (i.e. sodium, potassium, calcium, and chloride) has its own channel.

Now….
Periodic paralysis and the non-dystrophic myotonias are diseases where people get muscle weakness and/or muscle stiffness. This happens because the ION CHANNELS in the muscle membrane are faulty. The faulty ion channels prevent the potassium and sodium from being where they need to be. The misplaced ions cause the ion channels to shut off inappropriately, causing weakness, or not to shut off inappropriately, causing stiffness.

Of the periodic paralyses and non-dystrophic myotonias, there are several different disease types that have been identified. A brief description of each disease follows. Please be aware that there are many people with overlapping symptoms (for example, they experience paralysis AND myotonia), there are a wide variety of symptoms that are not listed below, and that many people do not fit the exact mold of the classifications below (for example, acetazolamide does not help all patients with hypokalemic periodic paralysis and indeed can make some patients worse).

There are 6 subtypes:

Hypokalemic Periodic Paralysis:

Genes: Sodium channel, Potassium Channel, Calcium channel
Secondary: Thyroid over-activity
Endocrine or renal problems: Certain substances and medications
Main Symptoms: weakness, low serum potassium; permanent muscle weakness
Main Triggers: carbohydrates, salt, rest after exercise, stress, cold, insulin
Things that Alleviate Attacks Acutely: potassium
Things that Prevent Attacks Chronically: acetazolamide, dichlorphenamide, spironolactone, triamterene, amiloride, proper diet, avoidance of triggers

Hyperkalemic Periodic Paralysis:

Genes: Sodium channel
Secondary: Renal problems
Main Symptoms: weakness, usually less duration than in hypokalemic periodic paralysis, myotonia (muscle stiffness that can be alleviated by exercise), high serum potassium; permanent muscle weakness
Main Triggers: potassium intake, rest after exercise, stress, hunger, cold
Things that Alleviate Attacks Acutely: Carbohydrates (simple sugars), insulin, albuterol, calcium injection
Things that Prevent Attacks Chronically: acetazolamide, dichlorphenamide, other potassium-wasting diuretics (e.g. hydrochlorothiazide), proper diet, avoidance of triggers

Andersen-Tawil Syndrome (ATS):

Gene: potassium channel
Definition: Periodic Paralysis (hyper or hypo), long QT syndrome, and skeletal abnormalities (wide spaced eyes, low-set ears, webbed fingers or toes)
Main Symptoms: weakness, palpitations, atypical attacks with muscle twitching (myoclonus); low or high serum potassium (depends on associated periodic paralysis)
Main Triggers: same as that for the type of periodic paralysis they have Things that Alleviate Attacks: same as that for the type of periodic paralysis they have
Things that Prevent Attacks Chronically: same as that for the type of periodic paralysis they have

Myotonia Congenita:

Gene: Chloride channel
Main Symptoms: muscle stiffness
Main Triggers: sudden exercise, sudden noise
Things that Alleviate Attacks Acutely: repeated movement of stiff muscle (warm-up phenomenon)
Things that Prevent Attacks Chronically: mexilitene, acetazolamide, phenytoin, quinine, carbamazepine

Paramyotonia Congenita:

Gene: sodium channel
Definition: muscle stiffness that worsens with exercise (paradoxical myotonia) and with cold
Main Symptoms: muscle stiffness followed by weakness, especially with exercise in cold weather; can be associated with hyperkalemic periodic paralysis; normal serum potassium; no warm-up phenomenon
Main Triggers: same as those for hyperkalemic periodic paralysis; cooling and heavy muscular work
Things that Alleviate Attacks Acutely: warm environment relieves stiffness, no therapy to relieve weakness acutely; same as for hyperkalemic periodic paralysis (if hyperkalemic periodic paralysis is a feature)
Things that Prevent Attacks Chronically: acetazolamide, mexilitene; same as for hyperkalemic periodic paralysis if that is a feature

Potassium-Sensitive Myotonia:

Gene: Sodium channel
Main Symptoms: intermittent, generalized muscle stiffness; no weakness; not worsened by cold
Main Triggers: potassium ingestion; rest after exercise; succinylcholine anesthesia
Things that Alleviate Attacks Acutely: same as for hyperkalemic periodic paralysis
Things that Prevent Attacks Chronically: mexiletine, acetazolamide

Periodic paralysis is a spectrum of neuromuscular disorders all resulting in episodes of weakness and/or paralysis occurring with variable frequency and lasting anywhere from a few minutes to days. There are two major recognized types of periodic paralysis: that with attacks of weakness caused by high blood levels of potassium, termed HYPERkalemic periodic paralysis, and that with attacks of weakness caused by low blood levels of potassium, termed HYPOkalemic periodic paralysis.

Hypokalemic periodic paralysis can have a number of causes:

1. hyperthyroidism, a condition where your thyroid gland makes too much thyroid hormone, can cause hypokalemic periodic paralysis in susceptible patients;
2. conditions where your body excretes (gets rid of) too much potassium for a number of reasons;
3. a mutation in a gene coding for a calcium channel in your cells arises, causing you to have bouts of weakness. The third condition is called familial hypokalemic periodic paralysis and can be passed down from parent to child.

Say you have a family whose members have hypokalemic periodic paralysis. Say the child has it, the mom has it, and mom’s dad has it, and so on. Somebody in the family, way back when, had to be the first one to get the disease. He or she was unfortunate to get a mutation in the gene that causes this illness. Once one person has gotten the mutated gene, he or she can pass on the gene to future generations. So, if you are the first in your family to get the disease, this is possible. One must be aware that some people can carry the mutated gene, but for one reason or another, do not show signs of illness. So, you may not indeed be the first person in your family with the mutated gene. Then again, maybe you are.

Many cases of hypokalemic periodic paralysis have been proven to be caused by a mutation in a certain gene called the “DHP-sensitive calcium channel.” Healthy humans have one set of 23 genes from their mother and a corresponding set of 23 genes from their father. So, for the calcium channel gene, any human has two copies, one from mom and one from dad. When someone has a child, they pass on one of the two copies of a gene to their child, and their partner passes on the other copy to their child.

Now, let the good copy of the gene be labeled “g.” Let the bad copy be labelled “G.” Most humans have “g from mom” and “g from dad”. A hypokalemic periodic paralysis patient generally has “G from one parent” and “g from the other parent.” Now, let’s make a grid (called a Punnet square in the world of genetics): Say Mom has hypokalemic periodic paralysis.

Hypokalemic periodic paralysis patients describe a few triggers that apply to everyone: rest after exercise, high carbohydrate meals (that is, pasta, pizza, cakes, candy, sugar, rice, potatoes, french fries, etc.), and salty foods (that is, table salt, a.k.a. sodium chloride, a.k.a. NaCl).

Other triggers vary from person to person: alcoholic beverages, large meals, Chinese food (perhaps due to MSG), stress, cold weather, high humidity, dehydration, excessive bedrest, accidentally skipping doses of medications, viral illnesses such as the flu, diarrhea, and lack of sleep (this list is not comprehensive).

One method of discovering what triggers your own attacks is to keep a diary. This has proven useful to a number of people with periodic paralysis. You should first establish a grading system for your attacks: for example, mild = 1; moderate = 3; severe = 7; complete = 9.

In general, it is unlikely for there to be a connection between these two diseases. The genetics behind juvenile myoclonic epilepsy is not worked out; however, given that we do not see the two disorders in a large number of patients, it would lead one to believe that they are unrelated. On the other hand, if indeed one has both, it would warrant research into the possibility of a relationship given that they are both so rare. Sorry to hedge on both sides of the fence!!!

I apologize but would need clarification of this question. I presume you mean “brain fog” associated with attacks of periodic paralysis, and possible continual “brain fog” from an attack that just won’t go away. In this case, proper treatment of the attack with appropriate medication would be the best strategy for alleviating the problem. Also, very strict avoidance of triggers, especially dietary triggers, would probably also help.

PP has been associated with nerve conduction defects, but it is not commonly associated with peripheral neuropathy (at least sensory). The lack of muscles more likely could be from permanent muscle weakness due to intrinsic muscle damage from repeated attacks rather than from atrophy due to an injured nerve.

Paramyotonia can occur along with hyperPP or by itself. It is characterized by worsening of the muscle stiffness with exercise, in contrast to myotonia congenita, which exhibits the warm-up phenomenon. Hence the name paramyotonia (short for paradoxical myotonia).

This is an interesting observation, and is an interesting hypothesis. Without proper testing, I could not comment. That said, if it works for you, roll with it!

No, this is not normal. Fatigue can have many causes, from cardiac to endocrine to neuromuscular to poor sleep hygiene to psychiatric. Your doctor should be able to sort it out. It is entirely possible that this is due to periodic paralysis, and one would expect the symptoms to be less with better control of the disease.

Any medication can trigger an attack in anyone. That is, it is a case by case, trial and error type of discovery for each individual. That said, physiologically speaking, I would not expect any of these medications to be a significant trigger for periodic paralysis.

Yes. The dip in potassium is seen only during attacks and is normal the other times.

This would be atypical. However, if someone’s normal baseline is say, 4.8 and they get weak at 4.2 and get strong again after ingesting potassium, then one could make a good argument that the person may be hypoPP.

Awareness is a difficult thing to achieve for a rare disease. It is best to make the individual doctor aware of the disease. I wonder if we couldn’t make a program whereby the PPA sends literature or a physician awareness campaign to a specific physician that a member knows s/he is going to see. If literature comes from the PPA rather than from the patient, it may be better received. That said, the physician may become suspicious or skeptical at the coincidence of receiving literature and then seeing a patient the next week.

The issue is what do you hope to gain from that test? It is typically a diagnostic test rather than a gauge of treatment success. I am sure that if you create a rational case, any reasonable physician would listen.

HyperPP gets worse when given potassium. A better term would be “potassium-sensitive PP”. HypoPP gets better when given potassium. A handful of drugs, specifically the carbonic anhydrase inhibitors – acetazolamide and dichlorphenamide – happen to work for both diseases for unclear reasons. Of course, this causes much confusion with patients and physicians, who prefer conceptualizing diseases and treatments as either “black or white”. (Maybe there is some good sense as to why the PPA logo is gray after all!!!)

In both instances, permanent muscle weakness is characterized by increased sodium content in muscle. By using diuretics to deplete the sodium from the muscle, we hypothesize that muscle strength will improve. In this way, the diuretic strategy would be expected to work for both hypoPP and hyperPP.

This is somewhat of a mystery. There are a variety of theories. One good one is that these diuretics force you to excrete potassium, so this is good for hyperPP. In hypoPP, there are side currents in the calcium and sodium channels that are responsible for the faulty membrane potentials. These drugs appear to block these side currents in hypoPP. All in all, a strange coincidence!

What I believe I said was that if the potassium is abnormal between episodes, it is likely not periodic paralysis but rather a renal or endocrine problem. That potassium is normal between episodes is a hallmark of periodic paralysis, and it is what makes it so difficult to diagnose.

Yes, with appropriate treatment, it can be reversed partially. It really depends on how advanced the permanent weakness is.

As of now, the Na MRI is an investigational tool that has not made it into mainstream practice. We presented it at PPA to show you a cutting edge research. One can demonstrate similar phenomena with a regular MRI. Muscle biopsy and MRI can help in the diagnosis or assessment of the extent of fixed weakness, but typically they are tertiary studies that are often not necessary in the diagnosis of periodic paralysis.

Currently (2015), I am unaware of any center that offers this for clinical use in patients.

This is an interesting observation that has been reported infrequently in the literature, most often with hypoPP patients. That said, one cannot rely on this information to render a diagnosis. We don’t know why that would work.[/expand]

Weight lifting, in theory, tears muscle. As such, it should be avoided in theory. But, not controlled trial has looked at the value or detriment of weight-lifting in periodic paralysis to know for sure if it indeed does any damage at all. There is no reason to believe that patients with periodic paralysis have an impaired muscle repair capability. In general, patients should remain as active as possible. How much exercise they can do depends on what their individual threshold for inducing an attack of periodic paralysis is. If a particular exercise is inducing an attack then they are doing too much. For all patients with muscle disease, it is less desirable to do progressive resistive exercises meant to bulk up. Rather, patients should do more toning/aerobic types of exercises with less weight/resistance and more repetition. Specifically, eccentric contraction should be avoided.

The ion channels do not work that way, but it is a nice thought. Ion channels reverse their states depending on the voltage across the muscle membranes. So, if we could arrange a micro voltage converter for each cell, it would be great. But, I believe it would be science fiction today.

 I would not expect a channelopathy to cause low CO₂ levels. If it did, I would not understand the mechanism. Acetazolamide and dichlorphenamide cause excretion of bicarbonate, resulting in a metabolic acidosis. The body will blow off more CO₂ than usual to accommodate for that change. But this situation applies to treated patients.

Probably not. Certainly we have not found that periodic paralysis affects ACTH levels.

This is a personal question with no routine good answers. Anytime you feel your life is in danger, you should call 911. Respiratory difficulty and trouble swallowing are reasonable reasons for calling 911.

The mutant ion channels are primarily found in skeletal muscle in the case of periodic paralysis. Respirations are controlled by skeletal muscle. I am not sure I understand what you mean by exceptions. We suspect the GI tract can slow down during a paralysis attack. For Andersen-Tawil Syndrome, the mutant potassium channels can also be found in the heart muscle. Electrical disturbances of the heart can occur due to low or high potassium in the blood without having a mutated ion channel located in the heart muscle itself.

One possibility is the swelling of the muscle during a weakness spell that compresses pain-mediating nerve endings in the muscle.

Patients with hyperkalemic periodic paralysis can demonstrate paramyotonia. This is not universal.

For some people with hypokalemic periodic paralysis, acetazolamide cause ill-feelings, usually within a day or two of taking the drug. We don’t know why this occurs. In terms of benefit, for hyperkalemic periodic paralysis, causing potassium-diuresis is felt to be the main mechanism of action. In hypokalemic periodic paralysis, correction of alkalosis is felt to play a role. In both disorders, we suspect there is also some direct effect on the abnormal ion channel currents as well.

Spironolactone is a potassium-sparing diuretic, so it prevents the kidney from excreting potassium. In doing so, blood potassium levels are kept more elevated than they otherwise would be, and this is thought to prevent attacks of weakness. Spironolactone also excretes sodium, which is felt to collect pathologically in affected muscles.

We do not believe there is a connection.

Optimizing therapy is one way of doing so. This entails trial and error with different kinds, doses, and combinations of diruetics, diet, and in the case of hypokalemic periodic paralysis, potassium supplements.

Sleep paralysis is an unrelated disorder, but it often is on the differential diagnosis of periodic paralysis.

Potassium-wasting diuretics cause low potassium and thereby trigger attacks. Medications with glucose in them can also be problematic as glucose causes endogenous insulin secretion, which drives potassium into cells causing hypokalemia and thereby inducing an attack. Epinephrine and related adrenergic agonists (like albuterol) can also drive potassium into cells. Asthmatic and insulin-dependent diabetic patients with periodic paralysis are among the most difficult to manage. Periodic paralysis patients can be triggered by any medication unpredictably on a case-by-case basis.

I am unaware of any correlation between blood pressure control and periodic paralysis. That said, certain blood pressure medications are diuretics (either potassium wasting or potassium sparing) and/or potassium-sparing (i.e., ACE inhibitors). While these medications serve to control blood pressure, they can positively or negatively affect a person’s periodic paralysis depending on which type of disease a person has.

Alcohol is felt to cause electrolyte disturbances and dehydration, especially during recovery from the alcohol in the hours after indulging. Because alcohol is a depressant of inhibitions in small to moderate doses, we may do things we are not aware of during drinking ” like dietary indiscretion or physical activity beyond our normal comfort level. This may play a role.

It is not likely that surgery can cause an ion channel mutation that would mutate all the body’s ion channels in all the muscles cells of the body. This would have to occur in the egg, sperm, or shortly after fertilization. We do not understand why periodic paralysis can become evident in some individuals near birth and in others late in life.

This is a consideration that must be made with your doctor. In general, Amiloride, when given by itself, is labeled for doses between 5-20mg.

In short, probably not. The ion channels involved in periodic paralysis are felt to be necessary for life, such that fully mutated proteins are likely not compatible with life. The mutations we see in periodic paralysis are of one base pair in DNA resulting in one change in the amino acid sequence of the affected ion channel.

This would certainly not be common, and, statistically speaking, it borders on impossible.

It is possible to do so. I would be concerned about elevating serum potassium and causing arrhythmias.

This is always a tricky subject. If the diagnosis is indeed periodic paralysis, then one should think about the disease as: 1) potassium administration makes weakness better (hypokalemic periodic paralysis), or 2) potassium administration makes weakness worse (hyperkalemic periodic paralysis, and a better term might be potassium-sensitive paralysis). That said, hyperkalemic periodic paralysis patients sometimes require potassium. The term normokalemic is confusing and antequated. It has referred to patients that have either hyperkalemic or hypokalemic periodic paralysis whose attacks of weakness correspond with serum potassium measurements in the normal range. Indeed, we suspect that in such cases, there is either a relative hyperkalemia or hypokalemia in the individual, whereby the abnormal value is either lower or higher than the non-weak baseline but still within the normal reference range for potassium. It is difficult to recommend a particular target potassium level in such cases. It is not unreasonable to shoot for a level of 4.5 in a hypokalemic periodic paralysis patient that gets attacks of weakness at 4.0.

Preterm diagnosis for ATS can be achieved. Embryo selection should be possible if the gene is known.

Right now, I don’t believe there is good evidence for one over another. It would require trial and error by an individual to see which is better.

Long-term side effects of Diamox are mainly kidney stones. There is some question as to whether or not it also affects calcium metabolism, but my understanding is that this concern is largely theoretical.

This is a patient-dependent situation. It depends on the nature of the attack.

Doing a blood draw during an attack should clarify the situation in most cases.

Conventional dogma would say that we shouldn’t see these things in periodic paralysis. I would not be able to explain the exceptions to this rule readily.

Kidney stones are a risk only if one takes carbonic anhydrase inhibitors for the PP.

There is no increased risk for shingles with periodic paralysis.

I would not expect an ion channelopathy to affect levels of immunoglobulins.

Yes.

Insofar as muscle weakness occurs (either transiently or permanently), muscle control can be adversely affected.

Yes. We would be happy to provide your doctor with what information we have. If translation is an issue, consider contacting the U.S. Embassy for translation services.

This is a very involved question. Firstly, for which disease? For periodic paralysis, a number of tests can be done some recommended, some not.

a) Genetic testing
b) Muscle biopsy
c) Nerve conduction study ” McMannis protocol
d) Blood levels of potassium during and between attacks
e) Reflex testing and strength testing during and between attacks
f) Provocative testing ” either with potassium, carbohydrates, exercise, and/or insulin ” often in a monitored setting
g) Hormone work-up for thyroid and adrenal gland disorders
h) Renal work up for potassium-wasting disorders
i) MRI of muscle to see fat and water content[spacer height=”20px”]

Therapies depend on the situation. As it stands, that part of the question is too broad to address here.

This discussion would best be had with an expert in periodic paralysis and your anesthesiologist and surgeon. It will depend on what type of periodic paralysis you have. Where possible, depolarizing muscle relaxants should be avoided as well as inhaled anesthetics. Depolarizing muscle relaxants such as succinylcholine are myotoxic. In addition, the membrane might not recover from depolarization and cause or a long-lasting weakness. It is unclear whether or not inhaled anesthetics have to be avoided. As a malignant hyperthermia (MH) crisis has been reported in the literature for a single HypoPP patient (diagnosis genetically never confirmed), we recommend avoidance just to be on the safe side. In a 1990 paper, we have reported equivocal in-vitro contracture test (IVCT) results for HypoPP patients (the IVCT is the gold standard for MH diagnosis); the halothane response was pathologic, the caffeine response normal.

The specifics of your genetic testing is best addressed directly with Dr. Lehmann-Horn and his associates privately.

Currently, use in children is experimental.

The risks depend on the type of periodic paralysis the boys have.

We cannot explain why some people show symptoms later in life and others early in life. If the mutation is known (and by definition has been present since birth), I don’t expect “late-onset” disease to be different from “early-onset”.

I am unaware of such an enzyme. He should clarify with specifics. I would be happy to discuss this theory with him.

Unfortunately, I am unfamiliar with this diet. A diet low in carbohydrates and low in sodium is typically best for hypokalemic periodic paralysis. A diet that avoids high potassium foods is typically best for hyperkalemic periodic paralysis.

Stiffness is a sensation of inability to relax muscles, or of muscle tension. Myotonia is a specific type of stiffness defined by a characteristic reading on an electromyogram (EMG).

We cannot explain twitching and jerks during attacks of periodic paralysis.

This is an excellent question. This would depend on the individual case and the person’s response to medications. Monitoring of muscle strength over time (say, each 6 months to one year) would be one way to gauge whether strength is deteriorating and if medication needs to be adjusted.

While there is little evidence to support preventing permanent weakness by treating attacks, the current thinking is that people with the gene defect should be on some prophylactic medication and that this medication has a better chance at preventing permanent muscle weakness. Avoiding dietary triggers is also helpful ” that is, avoid high quantities of carbohydrates and salt even if they don’t appear to be causing attacks of weakness.

No.

No.

I don’t understand this question. If you feel hormonal fluctuations are causing attacks, it would be possible to work with your endocrinologist to measure levels of hormones at different times during the month and during and between attacks. Perhaps you will find a trend.

Diet Coke is merely one alternative to a low-sugar drink. It is not meant as a therapy for hypokalemic periodic paralysis. Whether or not it causes attacks in an individual is dependent on the individual. Trial and error is worthwhile if Diet Coke is your fancy.

It is possible that the muscle was paralyzed during surgery or that it has permanent muscle weakness. Muscle biopsy would be one way to determine this, or possibly MRI. Neither may be necessary.

Nephrologist claims test did not show excretion in the kidneys.
Potassium can be stored in muscle, and it does not necessarily have to be absorbed. It depends on a person’s total body potassium stores. If the muscles are relatively potassium-depleted, then they can absorb large quantities of potassium.