Hypokalemic periodic paralysis (HypoKPP) is a rare disorder characterized by the occurrence of episodic severe muscle weakness, usually triggered by strenuous exercise or high carbohydrate diets. HypoKPP episodes are associated with low serum potassium levels. Most cases of the HypoKPP are hereditary or familial. The familial form of HypoKPP is a rare channelopathy caused by the mutation in either of the calcium or sodium ion channels, primarily affecting the skeletal muscle cells. Acquired cases of HypoKPP are also identified and are associated with hyperthyroidism. Hypokalemic periodic paralysis was first described in 1727 by Musgrave, in 1853 by Cavare and in 1857 by Romberg. The disease-causing mutation in HypoKPP, CACNA1S gene, was identified by Jurkat-Rott et al. in 1994.
Both hereditary or familial and acquired causes of hypokalemic periodic paralysis have been identified. Familial hypokalemic periodic paralysis is caused by a mutation in either of two genes, calcium or sodium ion channel gene mutation. Over the last few decades, various mutations have been identified as a cause of HypoKPP. The most common familial form, type 1 HypoKPP, has a mutation in the dihydropyridine-sensitive, skeletal muscle calcium channel gene, CACNA1S. While the other familial form, type 2 HypoKPP, has mutations in the voltage-sensitive skeletal muscle sodium channel gene, SCN4A. Disease-causing mutations in the gene KCNJ2 and KCNJ18, code for inward rectifier potassium (Kir) channel, have also been identified. Acquired HypoKPP has been associated with thyrotoxicosis. The familial form and thyrotoxic HypoKPP constitute the primary HypoKPP. Periodic muscle weakness can also result from hypokalemia secondary to renal and gastrointestinal potassium loss as in renal tubular acidosis, gastroenteritis, or secondary to endocrine causes.
In general, hypokalemic periodic paralysis is a rare disorder and has an estimated prevalence of 1 in 100,000. Most familial cases have an autosomal dominant inheritance pattern with incomplete penetrance. This disorder has lower clinical expression in females because of the lower penetrance and attack rate compared to males. And also the women tend to have fewer attacks of muscle weakness than men. Many cases are sporadic, which represents new mutations.
Most cases of thyrotoxic HypoKPP have been identified as sporadic and is more prevalent among Asian descents with a male predominance of 9 to 1.
The most common genetic abnormality in HypoKPP is the missense mutation in the positively charged residues, i.e., arginine, in the S4 domain of the alpha subunit (voltage sensor domain) of the skeletal muscle ion channel, most commonly L-type calcium channel (Cav1.1) and less commonly voltage-gated sodium channel (Nav1.4). The final common mechanism for all mutations is the formation of anomalous gating pore current itself through the voltage sensor domain of ion channel that makes sarcolemmal muscle inexcitable, resulting in failure of muscle action potential and occurrence of subsequent attacks of flaccid paralysis. Over the past few decades, several mutations in CACNA1S, SCN4A, and KCNJ2 genes have been identified, which underlie almost 70% to 80% of cases of HypoKPP, while rest remain genetically undetermined. In 90% of identified cases, arginine mutation in the S4 segment remains the primary cause. The other possible HypoKPP mutations are yet to be determined.
The presence of gating pore current is mostly studied and understood in sodium channels. Many experiments demonstrated the presence of anomalous gating pore current in the setting of SCN4A mutation in sodium channels during the resting phase. The anomalous gating pore current results inward nonselective cation leak causing aberrant depolarization, which is sufficient to make the resting potential of the muscle fibers unstable. And when serum potassium level drops below 3.0 mM, the affected fibers paradoxically undergo sustained depolarization making muscle electrically inexcitable, whereas normal fibers undergo hyperpolarization at this level of drop in serum potassium. Normally inward rectifying potassium (Kir) channel and membrane Na-K-ATPase maintains the normal negative resting membrane potential. In the presence of CACNA1S and SCN4A mutations, the depolarization induced by the gating pore current, at the modest drop of serum potassium level to around 3.0 mM, counterbalance the Kir current leading to sustained depolarization.
There are fewer experimental studies to demonstrate the evidence of gating pore current in calcium channels. But as the phenotypic expression of HypoKPP in sodium and calcium channel mutations are similar, it is believed that the gating pore current does exist in calcium channel. While it is still unclear, there are numerous observations from different experimental studies to explain the possible underlying mechanisms behind muscle weakness with underlying calcium channel defects:
Although the genetic abnormality remains throughout the lifespan of an affected individual, the mean age of presentation of attacks is the first or second decade of life, usually the late childhood or teenage years. The frequency of attacks tends to decrease with age. However, in the case of thyrotoxic HypoKPP, the onset is usually after age 20.
Though it is termed as periodic, it can be misleading as attacks don't occur at a regular interval, rather they occur suddenly and are episodic. The most consistent triggering factors are rest following strenuous exercise and consumption of diets rich in carbohydrates. It is postulated that these triggering factors cause a rise in plasma epinephrine level or insulin level, causing an intracellular shift of potassium, resulting in lower serum potassium level, thus triggering the episode of weakness. Additional identified triggering factors, less consistent, are excitement, stress, fear, cold, salt intake, glucocorticoids use, alcohol use, or anesthetic procedures.
Patients usually present with attacks of generalized severe muscle weakness, with proximal muscle involvement more marked than distal and a profound decrease in serum potassium level (serum potassium less than 2.5 mmol/L). Usually, patients go to bed in the normal state of health and wake up in the middle of the night or the morning, experiencing an attack of muscle weakness. Many patients also experience prodromal symptoms like fatigue, paresthesias, behavioral changes a day before an attack of muscle weakness. However, when incomplete, it predominantly involves lower limbs than the upper limbs. Bulbar, ocular, and respiratory muscles are usually spared, but respiratory muscle involvement can prove fatal when involved in severe cases. The pattern of muscle weakness is similar in both familial and thyrotoxic HypoKPP, and signs of hyperthyroidism are clinically obvious in most cases of thyrotoxic HypoKPP but are not always present. And attacks of muscle weakness occur during the state of hyperthyroidism and never when the thyroid function is normal.
The frequency of attacks of weakness is very variable and infrequent. Some patients might get attack only once in a lifetime, while others may get it several times a week. Women tend to have fewer attacks than men. And the duration of each attack also varies, ranging from minutes to days and can last up to several hours before they resolve spontaneously.
Neurological examination of the patient during attack shows generalized muscle weakness, usually proximal muscle involvement more than distal and when incomplete legs are more often involved than arms. Hyporeflexia or areflexia is typical. Neurological examination findings are usually normal between attacks. Myotonia is uncommon, unlike in hyperkalemic periodic paralysis, where myotonic is a common finding.
Some individuals may experience a milder form of muscle weakness between attacks that fluctuates and improves with mild exercise.
In a case series of 71 diagnosed patients of hypokalemic periodic paralysis, patients without mutations, compared to patients with mutations, were found to have disease presentation at old age, absence of diet as a precipitating factor, and muscle biopsy showed no vacuolar myopathy. Phenotypic variations were also noted in patients having mutations in this case series. Patients with sodium channel mutations had attacks of shorter durations, and vacuolar changes were more common on calcium channel mutation, while tubular aggregates were seen more in sodium channel mutations.
Hypokalemic periodic paralysis is suspected when an individual presents with a sudden attack of flaccid muscle weakness involving proximal muscles with decreased or normal deep tendon reflexes following the above mentioned identifiable triggering factors. The suspicion is further raised if there is a positive family history or previous personal history of similar attacks of muscle weakness.
When there is an established family history of hypokalemic periodic paralysis, no further diagnostic investigations are required to confirm the diagnosis of an episode of a paralytic attack. Otherwise, a low serum potassium level during a typical attack of weakness establishes the diagnosis.
Even the diagnosis of HypoKPP is clear other several laboratory investigations are also performed to exclude the secondary causes. These include thyroid function test (TSH, T3, T4 level) to rule out hyperthyroidism, an electrocardiogram (ECG) to look for ECG changes consistent with hypokalemia, and an ECG may also show the feature of Anderson syndrome, long QT interval.
After an attack or between attacks, the diagnosis can be challenging as the serum potassium level usually remains normal in primary HypoKPP. A low serum potassium level between attacks usually represents a secondary cause of hypokalemia, such as in distal renal tubular acidosis. The other diagnostic options include genetic testing, provocative testing, and electromyography (EMG).
The primary goal of treatment is to alleviate the symptoms of acute attacks, prevention and management of immediate complications, and prevention of late complications and future attacks.
The goal is to normalize the serum potassium level by administering oral potassium chloride, which is believed to be more readily absorbed compared to other oral potassium solutions, alleviates the symptoms of muscle weakness. Oral potassium chloride is administered in incremental dose, starting initially with 0.5 to 1 mEq/kg (i.e., 60 to 120 mEq of potassium for a 60 kg individual) is reasonable. If they do not respond to the initial dose, then 30% of the initial dose (i.e., 0.3 mEq/kg) is repeated every 30 min. If the patient requires the addition of more than 100 mEq of oral potassium, then close monitoring of serum potassium is needed, and the total dose of oral potassium should not be more than 200 mEq within the 24 hours of starting of the treatment. The starting dose of oral potassium may vary according to the severity of hypokalemia. Patients should be kept on ECG monitoring, and muscle strength should be examined periodically. Serum potassium level should be monitored for 24 hours after treatment as the posttreatment rise in serum potassium level can have an adverse effect on patients.
IV potassium is not preferred initially and is reserved for arrhythmias due to hypokalemia or if the patient has swallowing difficulties or respiratory muscle paralysis. IV potassium is preferentially administered with the mannitol, not with dextrose or saline as both carbohydrate and salt can itself trigger the muscle paralysis and thus may worsen the weakness. IV potassium therapy requires inpatient, continuous ECG monitoring. 40 mEq/L in 5% of mannitol solution of IV potassium is infused at a rate not more than 20 mEq/hour, not exceeding 200 mEq in 24 hours.
Both pharmacological and nonpharmacological interventions can be used to prevent recurrent future attacks. Nonpharmacological interventions include educating patients about triggering factors and lifestyle modifications to avoid these factors (discussed later). Pharmacologic interventions include medications like chronic potassium supplementation, carbonic anhydrase inhibitors (CAIs), potassium-sparing diuretics that are used when lifestyle modifications become insufficient in reducing attack rates. The favored approach is to add one of the diuretics with the chronic potassium supplementation. The initial choice of diuretics is carbonic anhydrase inhibitor acetazolamide.
Carbonic anhydrase inhibitors seem to be potent in decreasing future attacks of muscle weakness, though the mechanism of CAIs in HypoKPP is still unclear. Carbonic anhydrase inhibitors promote urine potassium loss and non-anion gap metabolic acidosis, which reduce the patient's susceptibility to muscle paralysis. It is also suggested that CAIs increase the opening of the calcium-activated potassium channels. Further, CAIs also reduce intracellular sodium accumulation, thus reducing the cellular toxicity and prevent muscle degeneration, which may be effective in the treatment of permanent weakness. 250 mg twice daily dose of acetazolamide has been effective in lessening the frequency of attacks.
The genetic variation in response to acetazolamide treatment had been reported. Patients with SCN4A mutations show less response compared to patients with CACNA1S mutations. In a study of 74 identified cases of HypoKPP, 56% (31/55) of patients with CACNA1S mutations, and only 16% (3/19) of patients with SCN4A mutations showed a response to acetazolamide therapy. Patients with SCN4A mutations had reported the exacerbation of the HypoKPP with acetazolamide therapy. Overall, almost half of the HypoKPP patients respond to treatment with acetazolamide.
FDA recently approved dichlorphenamide for the treatment of HypoKPP. 50 mg twice daily dose of dichlorphenamide has been more effective than a placebo in reducing the occurrence, severity, and duration of future attacks. Dichlorphenamide can be used as the first choice or as a substitute for patients who do not respond or are refractory to acetazolamide. Some patients also benefitted from the addition of a potassium-sparing diuretic, either spironolactone (100 mg daily) or triamterene (150 mg daily), to carbonic anhydrase inhibitors or when used as monotherapy. Electrolytes need to be monitored regularly in patients who are on diuretics therapy.
A study also reported the improvement in severity and frequency of attacks with topiramate therapy in 11 years old twins with HypoKPP, thus necessitates further study regarding the efficacy of topiramate in HypoKPP.
Surgery and HypoKPP
HypoKPP patients with CACNA1S mutation are susceptible to malignant hyperthermia, as the CACNA1S gene is allelic to the gene that increases susceptibility to malignant hyperthermia. Surgeons and anesthesiologists must be aware of this circumstance while using the inhalational anesthetics and muscle relaxants like succinylcholine during surgery and be ready to deal with it. Further, the cold environment and the use of saline and dextrose during surgery, and stress due to surgery itself can act as a trigger and result in muscle weakness. Potassium monitoring is important in such patients during the peri-surgical period.
During pregnancy, potassium management during the attacks should not differ from the pre-pregnancy state. However, drugs like acetazolamide and dichlorphenamide are FDA pregnancy category C so, their use during pregnancy is quite challenging, and risks and benefits of drug use should be weighed in them. Some pregnant women prefer not to take these medicines during pregnancy.
The differential diagnosis of primary HypoKPP includes:
These conditions are associated with either recurrent episodes of hypokalemia, episodic attacks of muscle weakness, and weakness or stiffness associated with exercise. Thus they should be in the mind of the treating physician as they can mimic hypokalemic periodic paralysis. Nevertheless, they can be differentiated based on their clinical features and laboratory tests findings as they differ in several ways.
1. Normokalemic and Hyperkalemic Periodic Paralysis
They differ from the HypoKPP in following several ways:
Generally, the distinction between HypoKPP and normo/hyperkalemic periodic paralysis can be made by potassium level during attacks, EMG, and genetic testing.
2. Andersen-Tawil Syndrome (ATS)
It is caused by the mutation in the KCNJ2 gene, which codes for inward rectifier potassium (Kir2.1) channel. Mutation in the KNCJ2 gene is identified in about 60% of ATS patients, while the cause in the rest is genetically undetermined. The mutation also affects multiple other tissues producing high phenotypic variation. patients usually present with periodic paralysis, cardiac manifestations, and have distinct facial features and skeletal anomalies because of abnormal skeletal muscle development. The distinct skeletal anomalies include low-set ears, small mandible, widely spaced eyes, fifth-digit clinodactyly, syndactyly, scoliosis, short stature, and a broad forehead. Symptoms manifest early in the life (first or second decade) with either cardiac symptoms or muscle weakness following prolonged rest or rest following strenuous exercise, and associated with elevated, normal or reduced serum potassium level. Affected patients often develop permanent weakness. Ventricular arrhythmias are common, include premature ventricular complexes (PVCs), complex ventricular ectopic beats, ventricular tachycardia (polymorphic and bidirectional); however, syncope and cardiac arrest are rare. ECG shows prolonged QT interval, prominent U waves, ectopic beats, and ventricular tachycardia. EMG response to short exercise tests and long exercise tests are similar to that of HypoKPP; thus, genetic testing remains important for diagnosis.
It is potentially a fatal condition, so careful attention to the identification and treatment of disease is needed. Treatment is needed for episodes of muscle paralysis and cardiac manifestations. Treatment of acute attack of muscle paralysis depends on the level of potassium and thus is individualized. ECG monitoring is needed to look for any arrhythmia. Patients are treated empirically with antiarrhythmics to prevent the occurrence of arrhythmias. Flecainide had been reported to have benefits in preventing arrhythmia in ATS patients.
3. Thyrotoxic Periodic Paralysis
Except for certain clinical features and the hyperthyroidism features, the pattern of muscle weakness is identical to that of familial HypoKPP. Hyperthyroidism is required for the disease to manifest, and hyperthyroidism features are present, sometimes subtle, in affected individuals. But muscle paralysis does not occur in the setting of normal thyroid function. The age of symptoms manifestation is usually late compared to familial HypoKPP. Most of the cases of thyrotoxic periodic paralysis are sporadic, lack positive family history, and most prevalent in Asian males. A case series identified the mutation on inward rectifying potassium (Kir) channels, coded by KCNJ18 in approximately one-third of the patients with TPP. The increase in activity of sodium-potassium ATPase (Na/K-ATPase) is believed to result in the intracellular potassium shift and hypokalemia. EMG response to the short and long exercise tests is usually similar to HypoKPP. Treatment of hyperthyroidism is the mainstay of therapy in TPP, which usually results in remission of muscle paralysis.
4. Paramyotonia Congenita
It is a congenital disorder of muscle weakness and myotonia, induced by cold and aggravated with continued activity. The patients develop prolonged myotonia or weakness in a localized group of muscles, which is not associated with the change in serum potassium level. It mainly affects eyelids, neck, and upper limb muscles. Patients characteristically present in their childhood complaining of inability to open their eyes following rapid, forceful successive closures. Weakness and myotonia last for minutes to hours. Even after the immediate rewarding of the muscles, cold-induced weakness usually persists for several hours. The disease is non-progressive, does not cause muscle wasting or hypertrophy. It is caused by mutations in the sodium channel gene SCN4A that codes for the alpha-subunit of the skeletal muscle sodium channels, i.e., voltage sensor domain. Patients usually live a normal life and do not affect longevity. The serum potassium level is moderately elevated. EMG taken during cooling of a muscle shows profuse myotonic discharges and reduced CAMP amplitudes. The mainstay of therapy is an avoidance of cold exposure and physical overactivity.
5. Secondary Hypokalemia
The most common manifestation of hypokalemia is muscle weakness. The episodes of muscle weakness can occur in chronic hypokalemia secondary to renal, gastrointestinal, endocrine, and iatrogenic causes. Following conditions can cause chronic hypokalemia:
A low potassium level between attacks is a clue to secondary hypokalemia. The patient should be carefully examined to look for the systemic manifestation of the disorders, and a careful interpretation of the patient's blood pressure finding, urine potassium, and blood bicarbonate level should be performed to rule out the possibility of any secondary cause of hypokalemia.
6. Metabolic Myopathies
Patients usually complain of fatigue, exercise intolerance, myalgia rather than muscle weakness. Rhabdomyolysis is common and may result from strenuous exercise, stress, illness, cold exposure. Muscle biopsy is required for the diagnosis of the disorder.
7. Myasthenia Gravis
Weakness is not episodic as in periodic paralysis, rather it is predictable and precipitated by exertion. Extraocular and bulbar muscle involvement is common in myasthenia gravis, which is uncommon in HypoKPP. During the myasthenic crisis, respiratory muscle involvement is common. Patients also complain of fatigue. This usually manifests early in second and third decades with female predominance or later in life in sixth to eighth decades with male dominance.
The first episode of quadriparesis can always be confused with the paralytic attacks of Guillain Barré syndrome (GBS), acute myelopathy, myasthenia crisis, tick paralysis, and botulism. But the presence of low potassium level and absence of other specific clinical features like ocular and bulbar involvement, sensory abnormalities, dysautonomia, history of travel and insect bite, fever, history of recent illness can rule out the other causes of paralysis and narrow the diagnosis to HypoKPP.
The prognosis of HypoKPP varies among individuals. The attacks of muscle weakness respond well to oral potassium administration. The repeated attacks of muscle weakness can cause significant morbidity, increase hospital admissions, and thus can affect the patient's social and professional life. The deaths related due to muscle attacks are rare, but several deaths due to aspiration pneumonia have been reported.
The following immediate life-threatening complications during an attack of muscle weakness can occur:
Hypokalemic periodic paralysis does not involve heart, and cardiac arrhythmias are uncommon but have been reported during attacks of muscle weakness.
Long-lasting Muscle Weakness
Many patients can have muscle weakness during the interictal period (i.e., between paralytic attacks), but its frequency and the risk for long-lasting weakness are unknown. It is believed that it is the result of permanent sodium intake, which results from the cation leak through the gating pore current. This may respond to potassium administration or acetazolamide.
Most patients develop progressive proximal myopathy; however, the frequency is unknown. It usually manifests after age 50, is less fluctuating, and less sensitive to medications, which suggest there is muscle degeneration, a fixed myopathy. It may be evident early on muscle biopsy before manifesting clinically. The myopathy is more profound in pelvic girdle muscles and proximal upper and lower limbs. The severity of myopathy varies among individuals, and some develop only mild weakness, which does not affect normal daily activities, while some may develop severe myopathy enough to make them wheelchair-bound. There is little evidence to support the correlation between the development of myopathy and the frequency or severity of paralytic attacks.
Complication Related to Therapy
Nephrolithiasis is a well-known side effect due to acetazolamide therapy. A report showed an occurrence of renal stones in up to 15% of patients taking acetazolamide for the long term. The treatment of acetazolamide induced renal stones is the removal of stone without stopping acetazolamide therapy.
Patient education is a key factor in the management of hypokalemic periodic paralysis. Educating patients about their disease process and advising them to avoid the triggering factors through lifestyle and behavioral modifications can prevent future attacks, reduce recurrent hospital admissions, decrease patient morbidity, improve quality of life and also help to reduce the financial burden that occurs due to hospital readmissions. The triggering factors may vary among individuals and needs to be identified in them. Following lifestyle changes can be beneficial in preventing attacks: avoiding strenuous exercise, taking frequent small meals to avoid carbohydrate load, less salt intake, avoiding stressful events, keep moving to avoid prolonged immobilization.
The patient should be advised to pay close attention to identify the triggering factors in them as they can vary among individuals. Patients usually get attacks in the morning when they woke up or during midnight, so a safe bedside environment is essential to prevent falls and avoid its consequences. The floor of the room should not be slippery. The bed should be far from the cooler or windows, as patients may not be able to move themselves during the episode of paralysis, and they might become hypothermic during the cold. They should alert someone or call or 911 when they feel like or when they get an attack. Patients should be advised to keep their potassium tablets at multiple places like at bedside, office, pockets, in the car as they can take it when they get an attack.
The interprofessional approach in the management of any case of hypokalemic periodic paralysis can improve patient outcomes on any inpatient floor or even outpatients. The comprehensive goals of the therapy are to identify and avoid triggering factors, treat the manifestations, treat or prevent complications, and reduce the future attacks of muscle weakness. The management involves interprofessional care that includes hospitalists, nursing staff, dieticians, geneticists. Careful identification of the triggering factors and their avoidance is essential in preventing future attacks. The careful monitoring of patients by nursing staff while in the hospital can prevent any life-threatening complications arising from hypokalemia or potassium administration during treatment. The involvement of dieticians to modify the diet can reduce future attacks from consuming large carbohydrate meals. Careful arrangements of surrounding structures inside the room can prevent secondary complications, which can occur from falls during attacks of muscle weakness. Prenatal pregnancy genetic testing can be offered to couples who have a positive family history of hypokalemic periodic paralysis if they prefer to conceive.
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