HYPOKALIEMIC PERIODIC PARALYSIS
by Gianluca Sapino
Hypokalemic periodic paralysis is a disorder that involves occasional episodes of muscle weakness
It is one of a group of genetic disorders that includes hyperkaliemic periodic paralysis and thyrotoxic periodic paralysis (In witch people only develop symptoms of periodic paralysis due to hyperthyroidism).
The two distinct forms of muscle involvement observed in hypokalemic periodic paralysis (HOKPP), paralytic episodes and fixed myopathy, may occur separately or together. The pure paralytic episodic form occurs most commonly; the combination of paralytic episodes and a slowly progressive myopathy is less common; the pure myopathic form without paralytic episodes is rare:
Paralytic episodes. The primary symptom consists of attacks of reversible flaccid paralysis with a concomitant hypokalemia that usually leads to paraparesis or tetraparesis but spares the respiratory muscles.
Myopathic form. The myopathic form results in slowly progressive, fixed muscle weakness that begins as exercise intolerance predominantly of the lower limbs; it usually does not lead to severe disability. This fixed weakness must be distinguished from the reversible weakness that exists between attacks in some affected individuals.
Hypokalemic periodic paralysis is due to faulty genes. In most cases, it is passed down through families (inherited) as an autosomal dominant disorder. Occasionally, it occurs randomly in families. It is believed that the disorder is related to problems with the way the body controls sodium and potassium levels in cells.
Unlike other form of periodic paralysis, person with congenital hypokaliemic paralysis have very low blood levels of potassium and normal thyroid functionduring weakness episodes.
Risk factors include a family history of periodic paralysis. The condition occurs in approximately 1 in every 100,000 people. It affects men more often then women. The disorder is slightly higher in asian men who also have thyroid disorder.
The disorder involves attacks of muscle weakness or loss of muscle movement (paralysis) that come and go. There is normal muscle strength between attacks.
Attacks usually begin in childhood or in adolescence. How often the attacks occur varies. Some people have several attacks a day. Attacks typically last only 1 to 2 hours, but can sometimes last as long as a day. They are usually not severe enough to need therapy. Some people have associated myotonia, in which they cannot immediately relax their muscles after use.
The weakness or paralysis:
- Most commonly occurs at the shoulders and hips
- May also involve muscles of the eyes and those that help you breathe and swallow
- Most commonly occurs while resting after activity
- Usually lasts 3 - 12 hours
Then here are a lot of situations that increase the risk of developing an attack. Triggers may include:
- Carbohydrates : The best known trigger of hypokalemic periodic paralysis is eating a large amount of carbohydrates. The most common circumstance is a meal of pasta, which typically contains a large amount of simple carbohydrates that are broken down to sugars and released quickly into the blood. Other common triggers are sugar-containing drinks and large amounts of candy. Once in the blood, the sugars trigger release of insulin, which causes cells to take up the sugars and also take up potassium from the blood. The lowering of potassium triggers the paralysis in hypokalemic periodic paralysis.
- Salt : One of the most potent triggers of hypokalemic periodic paralysis is consumption of sodium chloride. The salt effect is far less known than the carbohydrate trigger, and many articles on hypokalemic periodic paralysis don't even mention this trigger. For many people it is easier to reduce salt than it is to reduce carbohydrates.
- Excitement / fear / epinephrine : Excitement or fear results in the body producing epinephrine, which makes episodes of paralysis more likely in some patients. Epinephrine injected to treat allergic reactions to foods, and epinephrine-like drugs such as albuterol used in asthma inhalers can trigger episodes of paralysis. This appears to be due to the effect of epinephrine in reducing blood potassium . The same pathway is often manipulated therapeutically: medications that block epinephrine effects such as beta-blockers are sometimes used to reduce the effect of epinephrine produced by the body. However, beta-blockers should be used only with caution, since they can produce severe problems in people with low blood pressure, slow heart rate (bradycardia) or asthma.
- Exercise : After strenuous exercise there is increased risk of symptoms of hypokalemic periodic paralysis.
- Cold environment : Muscles exposed to cold can become weak. Re-warming usually recovers muscle strength.
- Anesthesia : During anesthesia there are many changes that can contribute to paralysis, including cooling, glucose, sodium and certain anesthetics such as succinylcholine. It is not clear that people with hypokalemic periodic paralysis are at any increased risk for malignant hyperthermia.
- Alcohol : It is unclear why alcohol sometimes triggers periodic paralysis. It could be from electrolyte imbalance, dehydration, or increased exercise or dietary indiscretion that often accompanies the inebriated state.
Mutations in the following genes can cause hypokalemic periodic paralysis:
- CACNA1S(a voltage-gated calcium channel Cav1.1 found in the transverse tubules of skeletal muscle cells). Locus: 1q32
- SCN4A(a voltage-gated sodium channel Nav1.4 found at the neuromuscular junction). Locus: 17q23.1-q25.3
An association with KCNE3 (voltage-gated potassium channel) has also been described, but is currently disputed,and excluded from the disease definition in OMIM.
Action potentials from the central nervous system cause end-plate potentials at the NMJ which causes sodium ions to enter and depolarise the muscle cells. This depolarisation propagates to the T-tubules where it triggers the entry of calcium ions as well as from the sarcoplasmic reticulum through the associated ryanodine receptor RyR1. This causes contraction (tensing) of the muscle. Depolarisation of the motor end plate causes potassium ions to leave the muscle cells, repolarising the muscle and closing the calcium channels. Calcium is pumped away from the contractile apparatus and the muscle relaxes.
Mutations altering the usual structure and function of these channels therefore disrupts regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in arginine residues making up the voltage sensor of Nav1.4. This voltage sensor comprises the S4 alpha helix of each of the four transmembrane domains (I-IV) of the protein, and contains basic residues that only allow entry of the positive sodium ions at appropriate membrane voltages by blocking or opening the channel pore. In Cav1.1, mutations have also been found in domains II and IV. These mutations are loss-of-function, such that the channels cannot open normally.
In patients with mutations in SCN4A or CACNA1S, therefore, the channel has a reduced excitability and signals from the central nervous system are unable to depolarise the muscle. As a result, the muscle cannot contract efficiently (paralysis). The condition is hypokalemic because a low extracellular potassium ion concentration will cause the muscle to repolarise to the resting potential more quickly, so even if calcium conductance does occur it cannot be sustained. It becomes more difficult to reach the calcium threshold at which the muscle can contract, and even if this is reached then the muscle is more likely to relax. Because of this, the severity would be reduced if potassium ion concentrations are kept high.
In contrast, hyperkalemic periodic paralysis refers to gain-of-function mutations in sodium channels that maintain muscle depolarisation and therefore are aggravated by high potassium ion concentrations.
This condition is inherited in an autosomal dominant pattern (but with a high proportion of sporadic cases), which means one copy of the altered gene in each cell is sufficient to cause the disorder
The health care provider may suspect hypokalemic periodic paralysis based on a family history of the disorder. Other clues to the disorder are muscle weakness symptoms that come and go.
Before an attack, there may be leg stiffness or heaviness in the legs or in the arms
Between attacks, a physical examination shows nothing abnormal. During an attack, muscle reflexes are decreased or absent, and muscles go limp rather than staying stiff. The muscle groups near the body, such as shoulders and hips, are involved more often than the arms and legs.
- An ECG or heart tracing may be abnormal during attacks.
- An EMG or muscle tracing is usually normal between attacks and abnormal during attacks. During an attack, EMG findings are not specific; EMG demonstrates a reduced number of motor units and possibly myopathic abnormalities.
Between attacks, EMG may exhibit myopathic abnormalities in individuals with fixed myopathy.
- A muscle biopsy may show abnormalities.
The health care provider may run additional tests to rule out other causes.
People with hypokaliemic periodic paralysis are often misdiagnosed as having a hysterical paralysis since the weaknees is muscle based and doesn't correspond to nerve or spinal root distribution. The tendence of patient with this disorder to get paralyzed in fight or fly situations further adds to the temptetion to dismiss the disorder as psychiatric.
The goal of treatment is to relieve symptoms and prevent further attacks.
Attacks are seldom severe enough to require emergency treatment. However, weakness can become worse with repeated attacks, so treatment to prevent the attacks should occur as soon as possible.
Potassium that is given during an attack may stop the attack, it is preferred that potassium is given by mouth. Altought it seems that taking potassium supplements will not prevent attacks.
Avoiding alcool and eating a low carbohydrate diet may help.
Acetazolamide or other carbonics anhydrase hynibitor, may help prevent attacks of weakness.
Acetazolamide or dichlorphenamide are capable to activate the calcium-activated K+ channels (BK) at submicromolar concentrations with fiber repolarization. Acetazolamide is also capable to inhibit the monocarboxylate transporter (MCT) reducing the efflux of lactate thereby preventing vacuolar myopathy. This drug also inhibits the membrane bound carbonic anhydrase (CA) enzymes with effects on the extra-/intracellular proton exchange mechanisms. KATP openers activate the ATP-sensitive K+ channels (KATP) at submicromolar concentrations.
Sometimes attacks disappear later in life on their own. However, chronic generally result in progressive muscle weakness that is present even between attacks.
Hypokalemic periodic paralysis responds well to treatment. Treatment may prevent, and may even reverse, progressive muscle weakness.
- Attention deficit disorder (ADD, ADHD)
- Relative insensitivity to the local anesthetic lidocaine
- Kidney stones (a side effect of acetazolamide)
- Heart arrhythmias during attacks (rare, not fatal)
- Difficulty breathing, speaking, or swallowing during attacks (rare)
- Progressive muscle weakness
As we see, acetazolamide prevents attacks in many cases. Thiazide diuretics such as hydrochlorothiazide are also effective and have fewer side effects than acetazolamide. A high potassium, low carbohydrate diet may also help prevent attacks, as may avoiding fasting, strenuous activity, or cold temperatures.
Here we can see a video of a typical hypokaliemic paralysis attack.