Hypokalemic Periodic Paralysis
Hypokalemic periodic paralysis (HypoKPP) is one of the primary forms of periodic paralysis, caused by one or more mutations in the calcium, sodium or potassium ion channels in muscle membrane.
Features of Hypokalemic Periodic Paralysis
There are two forms of HypoKPP, a paralytic form and a myopathic form.
The paralytic form is more common, causing randomly spaced attacks (or episodes) of weakness which range from mild (which feels like fatigue) to flaccid (rag-doll-type) paralysis triggered by a fall in serum potassium. Attacks usually last at least several hours but sometimes can last for several days. Some patients have only one episode in a lifetime; but more often attacks occur repeatedly; daily, weekly, or once or twice a year.
The major triggering factors are sweets, starchy or salty foods, sleep and rest after exercise or an unusual level of exertion. Patients also report that attacks can be triggered by becoming chilled or overheated, or by strong emotion. Attacks usually begin between one and 20 years of age. Paralytic attacks are more common during the ages of 15-40 in most patients, then begin to decrease, and may be replaced by what are called abortive attacks. Abortive attacks are long-lasting attacks of fluctuating weakness which never progress to paralysis. These attacks can be more disruptive than paralytic attacks, which are over and done with in hours when you are young. Recent studies reveal that 65% of patients continue to have paralytic attacks into their 60s and 70s 56.
More than 74% of older patients develop myopathy, or permanent muscle weakness (PMW). In a study of patients over the age of 40 significant muscle pain was reported by 86% and muscle fatigue by 87% 56. Myopathy can begin as exercise intolerance of the legs at any age (even in childhood) and becomes recognizable as PMW by middle age. In some young patients exercise intolerance may be the only symptom of HypoKPP, i.e. these patients may never experience episodic weakness or attacks of paralysis.15, 32. Patients who have only myopathy can find getting a diagnosis extremely difficult, even when they have family members who have been diagnosed with HypoKPP.
All these varying patterns of weakness can produce an extremely complex clinical picture. A patient of 60 years, who has lost perhaps 40% of their muscle function, may have paralytic attacks during which their muscles function at perhaps 10-15% of their remaining 60% capacity. And/or they may have abortive attacks which reduce their strength to from 20-70% of the 60%, varying from hour to hour and day to day. Many a physician looks at a pattern like this and does not know what to think - which puts them in the same position as the patient. Answers are not always easy to come by.
Genetics and Inheritance
The disease is inherited as an autosomal dominant trait. About 1/3 of cases are sporadic or occur in those without any known family history. The most common mutations are found in the Calcium channel on chromosome 1. ---- Calcium Channel: Voltage-Dependent, L Type, Skeletal Muscle Dihydropyridine-Sensitive, Alpha-1 Subunit; CACNA1S Gene map locus 1q32; Mutations described to Date: ARG1239HIS 1, ARG528HIS 2 ARG528GLY 33, ARG1239GLY 3, ARG1086CYS & ARG1086HIS 19, ARG897SER50, Arg900Gly52, His916Gln (which appears to cause symptoms only in males)53 . Sodium Channel: Voltage-Gated, Type IV, Alpha Subunit; SCN4A; Gene map locus 17q23.1-q25.3; Six mutations described to date: ARG669HIS 24, ARG672HIS, ARG672GLY 27,28, ARG672SER 30, DIII-S4 ARG1132Q 32
Heat and Cold Sensitive Myotonic Form: It was believed that HypoKPP and myotonia could not occur in the same individual, but a family has been reported which experiences cold-induced hypokalemic paralysis (serum K+ 2.6) and myotonia, occurring when serum K+ levels are in the normal range (4.0). The mutation responsible is in alpha subunit, between 4th/5th transmembrane segments, domain III SCN4A, Pro1158Ser.26, 31, 34, 35, 36
Potassium Channel: In 2010-2011 research teams identified a previously unreported gene which they called KCNJ18 in which were located mutations responsible for the susceptibility to Thyrotoxic HypoKPP in Kir2.6 a skeletal muscle specific-inwardly rectifying K+ channel; 47, 48 Building on this knowledge mutations R43C, V168M and A200P were identified in HypoKPP patients with no recognized family history of the disorder and normal thyroid function. All three mutations exert dominant-negative inhibition on wild type Kir2.6 and Kir2.1. It is now theorized malfunctions of inwardly rectifying K+ channel decrease outward K+ current and predispose the sarcolemma to hypokalemia-induced paradoxical depolarization during attacks, which in turn leads to Na+ channel inactivation and inexcitability of muscles.48
Diagnosis may be based on patient history and confirmed by evaluation of serum electrolytes and transtubular potassium concentration gradient during an attack 42,43,44,45,46, by the CMAP amplitude test (Exercise EMG)30 or by DNA analysis…5. Negative DNA testing is not conclusive. Knowledge of the gene is thus far incomplete and commercial labs only screen for identified mutations. "It is important to consider that many individuals with HypoKPP will not have one of the identified mutations."6
About 60% of patients are affected before the age of 16 years, but attacks may be recognized at any age. Johnsen's 1981 study found a male patient with onset at age 60, and a female with onset at age 70. 7,8,17 Attacks initially tend to be infrequent but eventually may occur daily. Diurnal fluctuations in strength may then appear, with greater weakness in the night or early morning with improvement in strength as the day passes.10,11 Attacks vary in both severity and frequency. They can last from less than an hour to days. Weakness can be localized or generalized. Deep tendon reflexes are diminished or lost during paralytic attack. Muscle fibers become unresponsive to electrical stimulation. Patients often describe a prodrome of heaviness or aching in the legs or back. Attacks usually begin in proximal muscles and then spread to distal ones. The diagnosis of HypoKPP should not be excluded by abnormal results of sensory nerve conduction studies.25 Oliguria or anuria may develop during attacks. Respiratory and cranial muscles tend to be spared but may also be paralyzed ...bulbar and respiratory weakness can be fatal. Paralysis may resolve quickly once attack ends but there is often residual weakness that is slower to clear. Permanent weakness may ensue.7, 12,13 Because the disorder is associated with a shift in potassium, provocative factors include intense exercise followed by a period of sleep or rest, a carbohydrate load, or any other cause of increased insulin secretion, Epinephrine is a well-recognized provocative factor of attacks and should be avoided. 7,12
Associated with CACNA1S mutations: R528H; R1086C; R1086H; R1239G; R1239H; Provoked by anesthesia, drugs, alcohol, hypokalemia, intense exercise or fasting, worsens with age; causes fatigue & muscle pain and tenderness, damage to muscle sarcolemma, failure of energy supply within muscle cell, swelling. Watch for renal signs: "tea-colored" urine, high CK, low GFR, fever; Complications include: compartment syndrome, renal failure.49 Suxamethonium in combination with hypokalemia may provoke rhabdomyolysis or respiratory insufficiency during anaesthesia. It is hence essential that the use of depolarising relaxants is avoided and that body temperature and serum potassium are kept constant throughout anaesthesia. 51
During an attack, there is urinary retention of sodium, potassium, chloride and water. There is a fall in serum potassium preceding weakness, but in some patients the level may never fall below normal. 54 Johnsen's series of provocative studies recorded an episode of weakness of 11 hours duration provoked by a 0.3 mmol/L fall in the serum K, and an episode of total paralysis of 19½ hours duration provoked by a one point drop.5, 8, 14 Dr. Ingrid Gamstorp campaigned vigorously for the rejection of the terms "hypo" and "hyper" kalemic, hypopotassemia, and hyperpotassemia. She urged use of the terms "decreasing" and "increasing" serum potassium, as weakness in these disorders occurs in connection with fluctuations in serum potassium level, and is not directly related to the serum potassium level. She stated that . . ."It is likely that the severity of symptoms are better related to the quotient between the intra and extracellular potassium than to the extracellular level alone."13
Sinus bradycardia and electrocardiographic (ECG) signs of hypokalemia (U waves in leads II, V-2, V-3, and V-4, progressive flattening of T waves and depression of ST segment) may appear when the serum potassium falls below normal. Prolongation of the PR and QT intervals and T-wave flattening are associated with prominent U-waves. Johnsen's study of 106 Danish patients with HypoKPP revealed two patients who developed transient diastolic murmurs during paralysis and another who developed a transient, partial a-v block. He also describes patients who developed bradycardia and unspecified arrhythmias during episodes.7, 8, 14 Some patients do not exhibit cardiac signs even when serum K+ is very low, and others may exhibit profound cardiac signs of hypokalemia and an EKG which is markedly abnormal while serum potassium are within normal range. 5, 13, 14, 16
Serum Creatine Kinase in HypoKPP
Patients with HypoKPP may have higher than normal levels of serum myoglobin and/or serum creatine kinase, either chronically or following episodes, in the absence of myocardial necrosis. The rise in plasma K+ which accompanies recovery from an attack of HypoKPP may be associated with a simultaneous rise in serum Mb, followed by a rise in serum CK. It is postulated that hypokalemia causes muscle ischaemia, resulting in an accumulation of free fatty acids (FFA) within muscle cells. High concentrations of FFA may induce molecular changes and increase the permeability of the sarcolemma. Higher than normal levels of these enzymes have been used to identify non-symptomatic carriers in families where CK is elevated chronically.39,40,41
If the patient presents with total paralysis of the extremities but is still able to swallow and breathe adequately, oral sips of KCl solution can be given, 15 to 30 mmol (in children 10 to 15 mmol) in 30 to 60 minute intervals. The release from KCl tablets is too slow. If no improvement is apparent after four to five oral doses, or if nausea or diarrhea occurs after oral KCl intake, IV administration of KCl is necessary. This also is preferable in patients with acute attacks of paralysis, cardiac distress or ischemia, arrhythmias, difficulties in swallowing and impaired respiration. Using a peripheral vein, the preferred dose for intravenous K+ is 15 mEq (15 mmol) over 15 minutes then 10 mEq/hr (10 mmol/hr) in 500 ml of dilutant. Many HypoKPP patients are sodium sensitive. Serum K+ may fall if saline solution is used to administer K+ IV. Five percent Mannitol is the solution of choice for IV administration of K+, though half-strength saline may also be used to avoid the brisk diuresis induced by mannitol. Glucose must never be used. Infusion must be continued until serum K+ is normal and the patient's strength returns. Cardiac function must be continuously monitored during IV administration of potassium.15,16,17
Management and Therapy
Management includes a diet low in sodium and simple carbohydrates. (Note: Experience with many patients has taught us that sodium intake is best limited to one gram daily if at all possible. Increased sodium intake is reported to cause muscle pain.) Patients should avoid chilling and over-exertion, and take supplemental potassium. . . The dosage must be adjusted according to attack frequency and severity. Because severely affected patients may awaken paralyzed, a dose may have to be taken at two a.m. The goal is to maintain serum potassium at 5.0 mmol, but it should not exceed 6.0 mmol during therapy. Acetazolamide (Diamox) (125 to 1000 mg/day divided qd to bid) is highly effective in preventing paralytic attacks. Acetazolamide causes K+ excretion, some patients require K+ supplementation in order to achieve control of episodes. 5, 12 Average potassium intake varies from 25 mEq to 150 mEq daily. The potassium citrate or bicarbonate formulas (K-Lyte and Klor-Con EF) are better tolerated and absorbed than potassium chloride tablets (like Slow-K). Acetazolamide is most successfully started at a low dose (125 mg daily) then gradually increased over a period of some weeks. Patients should be careful to maintain adequate fluid intake, to avoid renal calculi.5, 8, 12, 19
Patients who respond poorly to Diamox, or who have adapted to the drug after long usage were once moved to dichlorphenamide (50-200 mg daily), which for most patients was the most effective treatment. Unfortunately dichlorphenamide has been discontinued by the manufacturer but another of the carbonic anhydrase inhibitors, methazolamide, can be substituted. Some patients have difficult side effects. Patients who fail to respond to carbonic anhydrase inhibitors, may respond well to the K+ sparing diuretics triamterene (Dyrenium 50-150 mg daily) or spironolactone (Aldactone). Aldactone may be poorly tolerated because of adrogenic side effects, and a newer drug, epleronone (Inspra) is a novel aldosterone antagonist that causes fewer hormonal issues while retaining its potassium-sparing properties. It is also FDA Pregnancy Category B. As such, this should be tried before spironolactone. It is safe to take potassium supplementation and be on an aldosterone antagonist in the case of hypokalemic periodic paralysis. Either can be used in addition to acetazolamide or methazolamide. 55 The serum K+ of patients receiving diuretic therapy and K+ supplements should be monitored and should remain below 6 mmol. 7, 18 Physicians should also be alert to the possibility of Thyrotoxic Hypokalemic Periodic Paralysis, especially in patients with Grave's Disease and Asian male patients 7, 8. Patients with TPP usually suffer weight loss and very low K+ levels during episodes (below 2.0).
In patients with hypokalemic periodic paralysis (HypoPP), hypothermia, hypokalemia, sodium chloride and glucose infusions as well as myotoxic substances like succinylcholine in the operating room often lead to flaccid muscle weakness and respiratory distress in the recovery room [Siler and Discavage 1975, Melnick et al. 1983, Rollman and Dickson 1985, Lema et al. 1991]. The hypokalemia is induced by operation-induced stress that leads to K+ uptake into muscle via release of catecholamines, insulin, and other hormones. Keeping the patients warm and serum K+ at high level and avoiding hyperglycemia are essential measures in preventing such attacks [Lema et al. 1991].
Typical anesthetic events in HypoPP patients are characterized by hypothermia and hypokalemia-induced flaccid weakness including ventilatory muscles and no signs of hypermetabolism in contrast to malignant hyperthermia which is characterized by a hypermetabolic reaction associated with hyperthermia and hypercontracted stiff muscles. Patients with all types of periodic paralysis often become paralyzed during or after surgery, from stress, chilling in the OR and the use of IV solutions which contain sodium and/or glucose. Patients report long periods of increased weakness after surgical anesthesia, and may experience paralysis or significant reduction of muscle strength in the days following surgery. There is a increased risk of falls and embolus in the days following surgery, if a post-surgical attack is not treated. 20, 21
Andersen-Tawil Syndrome (ATS)
Andersen-Tawil Syndrome is a distinct periodic paralysis, occurring in the setting of either hyper- or hypokalemia, with cardiac involvement (LQT) and skeletal abnormalities. Every patient with periodic paralysis should be screened for ATS. Partial manifestations are common and the subtle nature of the cardiac and dysmorphic features may delay diagnosis but clinical identification is vital given the predisposition for dysrhythmias. Cardiac evaluations using serial ECGs with measurements of the QTc interval are essential and should be performed on all patients undergoing workup for periodic paralysis.23, 24, 25
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