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Hypokalemic Periodic Paralysis

Genetic disorders account for hypokalemic periodic paralysis, a condition of repeated episodes of reduced potassium levels and severe muscle weakness.


Presentation

The majority of HPP patients first present in adolescence. Severe cases may manifest in early childhood, mild forms may be related to onset delay until the third decade of life. The frequency of paralytic episodes may increase until the fourth decade of life, some patients experience daily attacks then, but subsequently diminishes until paralysis no longer occurs after reaching the age of 50. A small share of cases associated with vacuolar myopathy causes patients to develop permanent motor deficits when aged 30 years and older [1]. With regards to HPP type 1 and HPP type 2, the former is characterized by an earlier onset and longer lasting paralytic episodes.

Beginning paralysis is often noted in the morning and may be related to physical activity or consumption of great amounts of carbohydrates the day before. Other possible triggers of paralytic episodes are stress, infections and menstruation. Certain drugs, particularly corticosteroids and insulin, interfere with ion channel function and may provoke an attack. Patients who underwent surgery have an increased risk for paralytic episodes [8]. While some patients only claim weakness in isolated parts of their limbs, others describe more generalized paralysis. Also, the time between notion of first symptoms and tetraplegia may vary between minutes and hours. HPP-triggered paralysis is mostly symmetrical, but unilateral weakness has also been reported. Muscle weakness mainly affects the legs, often the arms and sometimes the trunk. Although muscle excitability usually returns after four days at most, isolated cases of paralytic episodes lasting more than one week have been described.

During paralytic episodes, myocytes accumulate water and swell. Urine production is therefore reduced.

Xerostomia
  • The patient, who had xerostomia and xerophthalmia for a long period of time, was diagnosed with primary SS from serologic and histologic findings. The patient recovered by being prescribed potassium replacement therapy.[ncbi.nlm.nih.gov]
  • The patient, who had no xerostomia and xerophthalmia, was diagnosed with primary SS from serologic and histologic findings of minor salivary gland biopsy. The patient recovered after potassium replacement therapy.[ncbi.nlm.nih.gov]
Myopathy
  • PURPOSE: Presenting the case of unusual onset hypokalemic periodic paralysis (HypoPP) where myopathy had developed two years before paralysis occurred.[ncbi.nlm.nih.gov]
  • Acute myopathy associated with thyrotoxicosis has been described in Asian populations, although it seldom affects Caucasians or African-Americans. It can be difficult to recognize in western populations.[ncbi.nlm.nih.gov]
  • In an undefined number of cases, hypoPP may be associated with a vacuolar myopathy resulting in permanent motor deficit occurring during the fourth to fifth decade of life.[orpha.net]
  • Other metabolic etiologies of vacuolar myopathy, such as acid phosphatase (lysosomal) associated acid maltase deficiency (a glycogen storage disease), need to be considered in the differential diagnosis. Copyright 2015 Elsevier Ltd.[ncbi.nlm.nih.gov]
  • Muscle biopsy documented a vacuolar myopathy with tubular aggregates. However, genetic analysis ruled out common mutations of the voltage-gated calcium channel observed in primary HypoPP. Common causes of secondary HypoPP were also ruled out.[ncbi.nlm.nih.gov]
Myalgia
  • Postcritic myalgias were reported in 18 patients with Arg528His and one patient with Arg669His in whom the myalgias could last from several minutes to hours.[dx.doi.org]
  • Case 2 was a retroviral disease patient on treatment presented with myalgia and muscle weakness. On the evaluation, she had typical findings of proximal RTA.[mjdrdypu.org]
  • Moderate hypokalemia, with serum potassium concentrations of 2.5–3 mEq/L (Normal Level: 3.5–5.0 mEq/L), may cause muscle weakness, myalgia, and muscle cramps, and constipation (from disturbed function of smooth muscle).[flipper.diff.org]
  • Matthew Thomas Neame, David Wright and Surendran Chandrasekaran , Persisting fatigue and myalgia as the presenting features in a case of hypokalaemic periodic paralysis , BMJ Case Reports , 10.1136/bcr-2017-219991 , (bcr-2017-219991) , (2017) .[doi.org]
Proximal Muscle Weakness
  • She developed significant proximal muscle weakness within 16 hours after the initial dose. Her serum potassium was 1.6 mEq/L. Oral and parenteral potassium replacement restored her neuromuscular function over several days.[ncbi.nlm.nih.gov]
  • Neurological examination revealed proximal muscle weakness and generalized hyporeflexia. There was no sensory abnormality and bowel or bladder involvement. Other systemic examination was unremarkable except for mild hepatomegaly.[ispub.com]
Flaccid Paralysis
  • Hypokalemia, with associated flaccid paralysis, and signs of hyperthyroidism, are the hallmark. We have reported a case of a 28-yr-old white man with Graves' disease presenting with a 2-wk history of episodic flaccid quadriplegia.[ncbi.nlm.nih.gov]
  • In conclusion, clinicians should have a high index of suspicion, especially among Asians presenting with flaccid paralysis and hypokalemia.[ncbi.nlm.nih.gov]
  • Acute recurrent episodes of flaccid paralysis, symmetrically affecting the proximal muscles of the lower limbs, either following strenuous physical activity or carbohydrate overindulgence, is the usual presentation.[ncbi.nlm.nih.gov]
  • Physical examination showed hypertension, tachycardia, and symmetrical flaccid paralysis of all extremities. The major biochemical abnormality was hypokalemia (K , 2.0 mmol/L) with low urine K excretion.[ncbi.nlm.nih.gov]
  • Familial hypokalemic periodic paralysis is an autosomal-dominant channelopathy that features episodic attacks of flaccid paralysis with concomitant hypokalemia.[ncbi.nlm.nih.gov]
Hyporeflexia
  • Upon exam, his vitals were within normal limits; he had zero out of five strength in his hips, two out of five strength in his knees and shoulders, and normal strength distally with bicipital and patellar hyporeflexia.[academic.oup.com]
  • With more severe hypokalemia, flaccid paralysis and hyporeflexia may result. Respiratory depression from severe impairment of skeletal muscle function is found in many patients. Rabdomyolisis can occur with a profound hypokalemia.[flipper.diff.org]
  • Neurological examination revealed proximal muscle weakness and generalized hyporeflexia. There was no sensory abnormality and bowel or bladder involvement. Other systemic examination was unremarkable except for mild hepatomegaly.[ispub.com]
  • , ATS EMG with myotonia hyperPP, PAM, MC EMG silent during attack of weakness hypoPP, TPP, ATS, PMC, MC Palpitations ATS, hypoPP, hyperPP, TPP, PMC EKG – tachycardia TPP EKG – long QTc and/or ventricular arrhythmia ATS EKG – u waves ATS, hypoPP, TPP Hyporeflexia[doi.org]
Asthenia
  • Patient O.R, aged 19, presented marked asthenia and lower limbs paralysis, following high carbohydrate meal. He declared 10 kg weight loss on hypocaloric diet and mild sweating.[ncbi.nlm.nih.gov]
Headache
  • Figure 1 Figure 1: Vesicular lesions on the trunk suggestive of chickenpox Case 2 A 24 year old male presented to emergency with a three day history of high grade fever associated with headache, severe myalgias and one day history of petechial skin rash[ispub.com]
Fine Tremor
  • Physical examination demonstrated fine tremors. Serum potassium level was 2.2 mEq/L on admission. Gastrointestinal and renal causes of potassium loss were excluded by history and physical examination.[ncbi.nlm.nih.gov]

Workup

The patient's medical history may raise suspicion for periodic paralysis, but does not allow for clarifying its origin.

Clinical examination should be supplemented by an electromyographic test. The long exercise test is particularly recommendable to diagnose HPP [9]. Patients have to realize a few short exercises and will then be monitored for up to an hour. During this time, their compound muscle action potential will be measured. Continuous decreases of this parameter may indicate HPP. Standard electromyographic testing is not sufficient to diagnose HPP unless the patient is suffering from a paralytic episode during examination.

If patients are attended during an attack, blood samples should be obtained and checked for possible hypokalemia. Also, thyroid hormone levels should be revised in order to rule out thyrotoxic periodic paralysis. This disease as an acquired metabolic disorder, but similar to HPP, mutations affecting genes encoding for cation channels may play a role in its pathogenesis. Hyperthyroidism and other conditions leading to thyrotoxicosis may trigger symptoms of thyrotoxic periodic paralysis in predisposed patients. Thyrotoxic periodic paralysis is most commonly observed in Latin American and Asian men.

Genetic testing may confirm the diagnosis, but is rather insensitive since only common mutations in CACN1AS and SCN4A genes will be detected. Indeed, no known mutations can be detected in about 20% of all HPP patients.

Muscle biopsies are usually not necessary. If tissue samples are pathohistologically analyzed, severe myopathy with fatty replacement of muscle tissue can often be observed [1]. This is not the case in patients suffering from conversion disorder or other psychiatric diseases.

Prominent U Wave
  • Due to prolonged repolarization of ventricular Purkinje fibers, a prominent U wave occurs, that is frequently superimposed upon the T wave and therefore produces the appearance of a prolonged QT interval.[flipper.diff.org]
  • U waves; Possible sinus arrest Serum K during attack: Low (2.0 mEq/L) Plasma aldosterone: Normal X-linked Episodic Prolonged Muscle Weakness (EMWX) 1 Chromosome Xp22.3; Recessive Clinical Onset age: 0.5 to 8 years Episodes of weakness # Episodes in individual[neuromuscular.wustl.edu]

Treatment

Dietary adjustments are necessary to reduce the frequency of paralytic episodes. Food rich in carbohydrates should be avoided. Also, salt intake should be limited to less than one gram daily if at all possible. Potassium needs to be supplemented, but exact quantities depend on attack frequency and severity. Potassium supplementation aims at maintaining serum potassium levels above 5.0 mmol but under 6.0 mmol. In most cases, the final daily dose of potassium is 25 to 150 mEq. Potassium citrate or bicarbonate are tolerated best.

The diuretic acetazolamide has been proven to be highly effective for HPP treatment. The recommended dose is 125 to 1,000 mg per day, administered in two to four takings. Patients should initially be treated with low doses which may then be gradually increased. Of note, acetazolamide leads to potassium wasting and dietary supplementation needs to be adjusted to diuretic intake. Also, due to acetazolamide being a diuretic, adequate fluid intake is necessary to avoid renal problems [10]. The condition of patients suffering from HPP type 2 has been reported to worsen under acetazolamide therapy.

If patients do not respond satisfactorily to acetazolamid, carbonic anhydrase inhibitors dichlorphenamide and methazolamide may serve as an alternative. However, such treatment may provoke severe side effects. In these cases, potassium-sparing diuretics such as triamterene, spironolactone and epleronone should be administered instead. Spironolactone or epleronone may also be combined with acetazolamide to treat HPP.

Additionally, patients should be advised to avoid overtraining and hypothermia.

Prognosis

Treatment may help to diminish frequency and intensity of paralytic episodes. However, there are no therapeutic options to cure the underlying genetic disorder. While muscle paralysis does not lead to respiratory failure, the risk for aspiration pneumonia is increased. In this line, mortality due to HPP is most commonly associated with aspiration pneumonia.

Etiology

Distinct types of HPP may be caused by genetic disorders affecting calcium, sodium and potassium channels [3] [4]. While a mutation of calcium voltage-gated channel subunit α1 S (CACNA1S) leads to HPP type 1, mutation of sodium voltage-gated channel type 4 subunit α (SCN4A) may trigger HPP type 2. CACNA1S and SCN4A encode for subunits of skeletal muscle calcium and sodium channels, respectively. Functional impairment of certain potassium channels, particularly mediated by mutations of gene KCNE3, have been classified as HPP type 3, but occur less frequently [5]. Of note, other genetic disorders may trigger similar symptoms. In some cases, HPP is diagnosed based on the clinical picture but neither of the aforementioned mutations can be detected [6].

Epidemiology

Although HPP is a rare disease, it is diagnosed more often than other periodic paralyses, e.g. thyrotoxic periodic paralysis. The prevalence of HPP has been estimated to be about 1 per 100,000 inhabitants [7].

Gene mutations accounting for HPP affect CACNA1S (70%), SCN4A (10%) as well as KCNE3 and other, previously not described genes [2] [5]. Mutations are inherited with an autosomal dominant trait, but genetic penetrance is often incomplete. Penetrance seems to be higher in males and gender distribution of the clinically manifest disease is greater than 3:1.

Sex distribution
Age distribution

Pathophysiology

Skeletal muscle fiber contraction is initiated by acetylcholine release at the neuromuscular end-plate. The neurotransmitter activates post-synaptic nicotinergic acetylcholine receptors which are ionotropic ion channels that mediate membrane depolarization. Upon reaching a threshold potential, voltage-gated sodium channels open and initiate an action potential that spreads along the sarcolemma. Voltage-gated calcium channels located in the transverse tubular membrane react to this action potential and provoke conformational changes in ryanodine receptors expressed in the membrane of the sarcoplasmatic reticulum. This facilitates calcium release from the sarcoplasmatic reticulum into the cytosol and subsequent muscle fiber contraction.

The voltage-gated calcium channel that activates ryanodine receptors is called dihydropyridine receptor and one of its five subunits is α1, encoded by gene CACN1AS. As has been indicated above, this channel contributes significantly to electromechanical coupling. There is no consensus regarding the question if calcium entry via this type of channel is required for electromechanical coupling, but the receptor may mediate slowly inactivating calcium influx. Point mutations in CACN1AS, most frequently leading to amino acid interchange R528H and R1239H, interfere with channel function and cause HPP type 1 [4].

In contrast, SCN4A encodes for voltage-gated sodium channels responsible for action potential generation and spread. If the above described physiological chain of events is interrupted at this point, patients may develop HPP type 2.

In both CACN1AS and SCN4A disorders, voltage sensing and channel inactivation is altered. The precise relation to hypokalemia is not completely understood. It has been speculated that changes in intracellular calcium levels affect potassium channel expression and behavior. Particularly, ATP-sensitive potassium channel might be affected.

Prevention

Genetic testing and reproductive decisions are rarely an option to prevent HPP. Patients diagnosed with HPP should avoid food rich in carbohydrates. Because high salt intake has also been related with the frequency of paralytic episodes, low-salt diets are recommended. Alcohol should be avoided.

Summary

Prolonged episodes of decreased serum potassium levels and muscle weakness characterize hypokalemic periodic paralysis (HPP), a hereditary metabolic disorder [1]. Gene mutations associated with HPP are inherited with an autosomal dominant trait, but penetrance is incomplete. These mutations affect cation channels, mainly calcium and sodium voltage-gated ion channels, but sporadic new mutations are reported from time to time [2]. First symptoms usually manifest in adolescence, although certain forms may delay disease onset until the patient is aged 20 years and older.

HPP patients suffer from irregular paralytic episodes of up to several days. Presumably, such episodes principally occur while resting after physical activity or after consuming food rich in carbohydrates. Patients usually become tetraplegic and if an electromyogram is realized at this time, inexcitable muscles can be identified as the cause of paralysis. Molecular biological diagnostics allow for detection of the above mentioned gene mutations and thus permit verification of the tentative diagnosis of HPP. Although complete cure is unlikely, electrolyte imbalances and frequency of paralytic episodes may be reduced by supplementing potassium or administering diuretics.

Patient Information

Hypokalemic periodic paralysis (HPP) is an inherited metabolic disorder characterized by recurring episodes of severe muscle weakness. The term hypokalemic refers to the condition of low serum potassium levels that can be observed during an attack.

Causes

Genetic disorders account for HPP. Particularly, mutations in genes encoding for voltage-gated sodium and calcium  channels have been identified in the majority of HPP patients. These channels are expressed on the surface of skeletal muscle fibers and contribute significantly to excitation transduction and coupling of excitation and contraction. If a nerve impulse reaches a muscle fiber, sodium ions enter the cell and change its electrical potential. This altered potential can be sensed by other channels, which is why they are called voltage-gated channels, that mediate calcium influx and subsequent muscle contraction. In HPP patients, gene mutations provoke functional impairment of these channels, which leads to paralysis. These mutations are inherited from parents to children.

First symptoms usually manifest in adolescence. They may be triggered by physical exercise or consumption of food rich in carbohydrates.

Symptoms

HPP-triggered muscle weakness preferentially affects the legs, but arms and in severe cases the trunk may also become paralytic. Patients often report to note certain weakness when awakening the day after having realized exercise or consumed the above mentioned food. Muscle weakness may increase during the following hours, but a full-blown attack may also develop within minutes. Paralytic episodes may last several hours to several days.

Patients that experience paralytic episode with trunk involvement may suffer from blunted swallowing and gag reflexes, which augments their risks for swallowing the wrong way. This may lead to aspiration pneumonia, a potentially lethal illness.

The frequency of paralytic attacks varies widely. It has been observed to increase until the age of 30, while episodes of muscle weakness become increasingly rare afterwards and disappear after reaching the sixth decade of life.

Diagnosis

The patient's medical history may point at periodic paralysis, but a precise diagnosis cannot be based on it.

Standard diagnostic measures are electromyographic tests and analyses of blood samples obtained preferentially during an attack. In order to prepare the former, patients have to realize a few minutes of exercise. The physician will then evaluate their muscles' behavior during up to one hour. Excitation of muscles of HPP patients will continuously decrease, while this is not the case in healthy individuals. Blood samples may reveal low levels of potassium, but should not show altered levels of thyroid hormones. If thyroid problems are detected, another type of periodic paralysis may be diagnosed.

Treatment

While the genetic disorder cannot be cured, frequency and severity of attacks can be diminished.

Dietary adjustments are necessary. HPP patients are recommended to avoid food rich in carbohydrates and to limit daily salt intake to minimal levels. Alcohol should be avoided. Potassium is supplemented continuously in form of oral medication. It will be administered intravenously to terminate a current attack.

Acetazolamide, a diuretic drug, is very effective to reduce paralytic episodes. Its dose, as well as that of supplementary potassium, will be adjusted to individual requirements.

References

Article

  1. Links TP, Zwarts MJ, Wilmink JT, Molenaar WM, Oosterhuis HJ. Permanent muscle weakness in familial hypokalaemic periodic paralysis. Clinical, radiological and pathological aspects. Brain. 1990; 113 ( Pt 6):1873-1889.
  2. Sugiura Y, Makita N, Li L, et al. Cold induces shifts of voltage dependence in mutant SCN4A, causing hypokalemic periodic paralysis. Neurology. 2003; 61(7):914-918.
  3. Wang Q, Liu M, Xu C, et al. Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family. J Mol Med (Berl). 2005; 83(3):203-208.
  4. Miller TM, Dias da Silva MR, Miller HA, et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004; 63(9):1647-1655.
  5. Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain. 2006; 129(Pt 1):8-17.
  6. Matthews E, Labrum R, Sweeney MG, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology. 2009; 72(18):1544-1547.
  7. Fontaine B. Periodic paralysis. Adv Genet. 2008; 63:3-23.
  8. Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anaesthesia in neuromuscular disorders. Neuromuscul Disord. 2005; 15(3):195-206.
  9. Fournier E, Arzel M, Sternberg D, et al. Electromyography guides toward subgroups of mutations in muscle channelopathies. Ann Neurol. 2004; 56(5):650-661.
  10. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet. 1997; 60(6):1316-1325.

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Last updated: 2018-06-21 19:05