History

Fact Explanation
Weakness Hypokalemic periodic paralysis is the commonest cause of periodic paralysis, which is caused as a result of a channelopathy. Periodic paralysis is classified as hypokalemic when it occurs in association with low serum potassium levels. The disease has 2 varieties. Type 1, which is the commonest, is caused by the calcium channel mutation. This occurs early in the life. Type 2 variant is caused by a rare mutation of Potassium channels which occur in late life. Defect in a voltage-gated calcium channel is the commonest cause. As a result, the depolarization of the muscle is failed. This inexcitability of the muscle membrane ultimately leads to the flaccidity of certain muscles. The severity ranges from mild to severe. The distribution of the affected muscles are limited. It involves only a group of muscles unilaterally or partially. The commonest sites are legs. The less common severe forms of disease present with generalized weakness/ complete paralysis. They are acute or insidious in onset. The weakness is usually bilateral, and may spread to the proximal parts of the upper limbs, trunk and neck later. Patients waking up with the weakness in the morning is very common. An attack usually last for several hours and resolves spontaneously. There is no associated pain. Other possible but rare outcomes are complete, paralysis and very rarely, death. [1,2,3,4,5,6]
Heaviness of the limbs Flaccid limbs are often heavy. Patients may complain of an unusual heaviness of the lower limbs and this may be the sole complains in the mild disease. [1,2,3,4]
Difficulty on walking Patients initially present with difficulty in extending/flexing the proximal parts of the lower limbs such as hips and knees and the weakness of the thigh or calves. Thus the initial paralysis usually affects the lower limbs making the walking difficult during the attack. [2,4,5]
Reduced urine output Accumulation of the water in the muscle cells results in the reduction of the urinary output during the attacks. [2,3,6]
Difficulty in breathing Difficulty breathing, speaking, or swallowing during attacks are rare presentation and are secondary to the bulbar muscle involvement. [1,2,3,5]
Chest pain This is due to arrythmias owing to the hyperkalaemia. It is an infrequent presentation as that much of decline of serum potassium level does not occur. [1,3,6,7]
Triggers Attacks/ episodes are characteristically provoked during/ minutes to hours after a stressful event, high carbohydrate meals, infection, menstruation, sleep deprivation and certain drugs such as beta-agonists, insulin and corticosteroids. [5,7,8]
Past history of similar events Hypokalaemic periodic paralysis is a recurring disease. patients often have past events with similar characteristics. Patients are usually normal and asymptomatic in between these episodes. Rarely after sometimes, there may be a residual mild weakness following an acute attack. [1,3,5,7]
At risk population Age of onset is variable. It could be either during the childhood or in the third decade of life. Acquired cases of Hypokalaemic periodic paralysis accounts for one third of cases. Hyperthyroidism is the commonest secondary/ acquired cause of Hypokalaemic periodic paralysis. Patients may give details of a disease history or follow up regarding thyroid disorder. Most of the cases are hereditary usually with an autosomal dominant inheritance pattern. Therefore, patients with a family history are also predisposed. The disorder is three to four times more commonly clinically shown in men. [1,3,5,8]
Complications Eye myotonia is a common complication in which the patient is unable to open his/ her eyes for a short period of time. Cardiac arrythmias/ irregular heart beats, difficulty in breathing, speaking, or swallowing and residual muscle weakness that worsens over time are the complications of the disease. Kidney stones can occur as a side effect of acetazolamide, that is used in the treatment. [3,5,6,8]
References
  1. CHENG CJ, KUO E, HUANG CL. Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis. Semin Nephrol [online] 2013 May, 33(3):237-47 [viewed 13 September 2014] Available from: doi:10.1016/j.semnephrol.2013.04.004
  2. MATTHEWS E, PORTARO S, KE Q, SUD R, HAWORTH A, DAVIS MB, GRIGGS RC, HANNA MG. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology [online] 2011 Nov 29, 77(22):1960-4 [viewed 13 September 2014] Available from: doi:10.1212/WNL.0b013e31823a0cb6
  3. ABBAS H, KOTHARI N, BOGRA J. Hypokalemic periodic paralysis. Natl J Maxillofac Surg [online] 2012 Jul, 3(2):220-1 [viewed 13 September 2014] Available from: doi:10.4103/0975-5950.111391
  4. SOULE BR, SIMONE NL. Hypokalemic Periodic Paralysis: a case report and review of the literature. Cases J [online] 2008 Oct 21, 1(1):256 [viewed 13 September 2014] Available from: doi:10.1186/1757-1626-1-256
  5. KAYAL AK, GOSWAMI M, DAS M, JAIN R. Clinical and biochemical spectrum of hypokalemic paralysis in North: East India. Ann Indian Acad Neurol [online] 2013 Apr, 16(2):211-7 [viewed 13 September 2014] Available from: doi:10.4103/0972-2327.112469
  6. WI JK, LEE HJ, KIM EY, CHO JH, CHIN SO, RHEE SY, MOON JY, LEE SH, JEONG KH, IHM CG, LEE TW. Etiology of hypokalemic paralysis in Korea: data from a single center. Electrolyte Blood Press [online] 2012 Dec, 10(1):18-25 [viewed 13 September 2014] Available from: doi:10.5049/EBP.2012.10.1.18
  7. KIM H, HWANG H, CHEONG HI, PARK HW. Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations. Korean J Pediatr [online] 2011 Nov, 54(11):473-6 [viewed 13 September 2014] Available from: doi:10.3345/kjp.2011.54.11.473
  8. TRIFANESCU RA, DANCIULESCU MIULESCU R, CARSOTE M, POIANA C. Hypokalemic periodic paralysis as first sign of thyrotoxicosis. J Med Life [online] 2013 Mar 15, 6(1):72-5 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23599824

Examination

Fact Explanation
Lid lag This is due to extensive disease that is complicated with eye myotonia. Patients may show a difficulty in opening or closing the eye. Sometimes this may be the only clinical signs in hyperkalemic periodic paralysis. [1,2,3,4]
muscle atrophy Progressive muscle atrophy has been described in some patients with hyperkalemic periodic paralysis. Proxiamal muscles of the lower limbs are commonly wasted. This is specially marked when hyperkalemic periodic paralysis is associated with motor neuron degeneration. This is in contrary with the hyperkalaemic paralysis where the affected muscles are tend to be hypertrophied. [1,2,3]
Muscle fasciculation Muscle fasciculation is a rare finding in the hypokalaemic periodic paralysis. Small, local, involuntary muscle contraction and relaxation which may be visible under the skin can be demonstrated in the affected areas such as in calves, and thighs. [2,3,5]
Muscle weakness Patient usually present with heaviness, weakness of a group of muscles localized to proximal lower limbs around the hips and knees. In more generalized severe form, a generalized weakness can be demonstrated involving the upper, lower limbs, and trunk. The proximal weakness is far more common than the involvement of the distal parts. [2,3,4,5]
Hypotonia The causative calcium channel defect results in the inexcitability of the muscle membrane. This result in the failed depolarization and flaccidity. This is commonly manifest in the proximal parts of the lower limb during the initially and more generalized in severe cases. The limbs are unusually heavy and flabby. [2,3,4]
Dyspnea This is very rare and is due to the bulbar muscle involvement in severe cases. [1,2]
Absent stretch reflexes Stretch reflexes such as knee reflex is diminished due to the failed transmission of the action potential in to the muscle contraction. [3,4,5]
Important negative findings The sensation of any sort is not affected in the periodical paralysis. [1,3,5]
References
  1. KIM H, HWANG H, CHEONG HI, PARK HW. Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations. Korean J Pediatr [online] 2011 Nov, 54(11):473-6 [viewed 13 September 2014] Available from: doi:10.3345/kjp.2011.54.11.473
  2. MATTHEWS E, PORTARO S, KE Q, SUD R, HAWORTH A, DAVIS MB, GRIGGS RC, HANNA MG. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology [online] 2011 Nov 29, 77(22):1960-4 [viewed 13 September 2014] Available from: doi:10.1212/WNL.0b013e31823a0cb6
  3. ABBAS H, KOTHARI N, BOGRA J. Hypokalemic periodic paralysis. Natl J Maxillofac Surg [online] 2012 Jul, 3(2):220-1 [viewed 13 September 2014] Available from: doi:10.4103/0975-5950.111391
  4. WI JK, LEE HJ, KIM EY, CHO JH, CHIN SO, RHEE SY, MOON JY, LEE SH, JEONG KH, IHM CG, LEE TW. Etiology of hypokalemic paralysis in Korea: data from a single center. Electrolyte Blood Press [online] 2012 Dec, 10(1):18-25 [viewed 13 September 2014] Available from: doi:10.5049/EBP.2012.10.1.18
  5. KAYAL AK, GOSWAMI M, DAS M, JAIN R. Clinical and biochemical spectrum of hypokalemic paralysis in North: East India. Ann Indian Acad Neurol [online] 2013 Apr, 16(2):211-7 [viewed 13 September 2014] Available from: doi:10.4103/0972-2327.112469

Differential Diagnoses

Fact Explanation
Guillain-Barre Syndrome Guillain-Barré syndrome (GBS) is a autoimmune disease affecting the peripheral nervous system (AIDP - acute inflammatory demyelinating polyradiculoneuropathy). It usually follows an infection. That infection/antigens trigger the production of antibodies. The cross reactivity between neural antigens and those antiganglioside antibodies due to molecular mimicry causes neuronal damage. The primary target is Schwann cell surface causing widespread myelin damage. Macrophage activation creates a variable degree of secondary axonal damage. Pathologically both humoral and cellular immune mechanisms are involved. When the peripheral nervous system is affected, It produces a symmetrical motor weakness which usually starts from the lower limbs and ascends upwards. (Ascending flaccid paralysis). Proximal muscles may involve earlier than the distal ones. Patient may complain of difficulty in rising up from sitting position or climbing stairs. The symptoms are bilateral and reach their peak by the second week. Though the weakness usually affect the lower limbs, it progresses rapidly (usually over periods of hours to days) to affect trunk and bilateral upper limbs too. Therefore severity may range from mild weakness to complete tetraplegia. Patient may complain this as a generalized fatigue. Acute inflammatory demyelinating polyradiculoneuropathy is the most common subtype of GBS.(90%) So, this symptom is the most common one among all others. Descending weakness is a rare but occurs in some sub types such as Miller Fisher syndrome and pharyngeal-cervical-brachial sub type. defined by rapidly progressive oropharyngeal and cervicobrachial weakness associated with areflexia in the upper limbs. Serial nerve conduction studies suggest that PCB represents a localised subtype of Guillain-Barré syndrome characterised by axonal rather than demyelinating neuropathy. [1]
Myasthenia gravis Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatigue. Diplopia, ptosis and bulbar symptoms like dysarthria are other common signs. There is no sensory involvement or proceeding illness. Weakness progress in a descending manner. CSF analysis is normal. [2]
Botulism Botulism is a rare and potentially fatal paralytic illness caused by a toxin produced by Clostridium botulinum. Bilateral symmetrical & descending flaccid paralysis occurs after 12-36 hours of ingestion contaminated food. The classic symptoms of botulism include double vision, blurred vision, drooping eyelids, slurred speech, difficulty swallowing and dry mouth. CSF analysis is normal. [3]
Critical illness polyneuropathy This is characteristically present in critically ill patients who are under intensive medical care. Generalized muscle weakness and neurological abnormalities are common among them. Limb paralysis and associated respiratory paralysis are usually accompanied with the underlying multi organ dysfunction and septicaemia. [4]
Lambert Eaton Myasthenic Syndrome Lambert Eaton Myasthenic Syndrome is an auto immune mediated presynaptic voltage-gated calcium channel disease that is presented with striking predominantly proximal arm and leg weakness. Sometimes bulbar muscle involvement also occurs. Physical exercise and high temperatures can worsen the symptoms. Respiratory paralysis and ataxia can occur in severe forms of disease. [5]
Spinal cord Infarction, Hemorrhage Spinal Cord Infarction or hemorrhages are due to either trauma or arteritis. The spinal cord stroke, either ischemic or hemorrhagic. The patient may present with acute severe pain in the back which radiates caudally which is followed by bilateral weakness, paraesthesia and sensory loss. Sphincter function may also be affected. [6]
Multiple Sclerosis Autoimmune mediated destruction of the myelinated axons in the central nervous system is initially presented with sensory impairment. Later the disease extensively spread to the autonomic and motor dysfunction along with bulbar muscle involvements. Therefore the patient may have difficulties in speaking or swallowing and visual problems such as nystagmus, optic neuritis or double vision. Chronic pain syndromes and psychiatric issues such as depression are not uncommon. [7]
References
  1. WALLING AD, DICKSON G. Guillain-Barré syndrome. Am Fam Physician [online] 2013 Feb 1, 87(3):191-7 [viewed 06 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23418763
  2. SUH J, GOLDSTEIN JM, NOWAK RJ. Clinical characteristics of refractory myasthenia gravis patients. Yale J Biol Med [online] 2013 Jun, 86(2):255-60 [viewed 07 June 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23766745
  3. THANONGSAKSRIKUL J, CHAICUMPA W. Botulinum neurotoxins and botulism: a novel therapeutic approach. Toxins (Basel) [online] 2011 May, 3(5):469-88 [viewed 07 June 2014] Available from: doi:10.3390/toxins3050469
  4. KUKRETI V, SHAMIM M, KHILNANI P. Intensive care unit acquired weakness in children: Critical illness polyneuropathy and myopathy. Indian J Crit Care Med [online] 2014 Feb, 18(2):95-101 [viewed 07 June 2014] Available from: doi:10.4103/0972-5229.126079
  5. TITULAER MJ, LANG B, VERSCHUUREN JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol [online] 2011 Dec, 10(12):1098-107 [viewed 14 September 2014] Available from: doi:10.1016/S1474-4422(11)70245-9
  6. HUGHES JT. SPINAL-CORD INFARCTION DUE TO AORTIC TRAUMA. Br Med J [online] 1964 Aug 8, 2(5405):356 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/14160229
  7. LUBLIN FD, REINGOLD SC, COHEN JA, CUTTER GR, SøRENSEN PS, THOMPSON AJ, WOLINSKY JS, BALCER LJ, BANWELL B, BARKHOF F, BEBO B JR, CALABRESI PA, CLANET M, COMI G, FOX RJ, FREEDMAN MS, GOODMAN AD, INGLESE M, KAPPOS L, KIESEIER BC, LINCOLN JA, LUBETZKI C, MILLER AE, MONTALBAN X, O'CONNOR PW, PETKAU J, POZZILLI C, RUDICK RA, SORMANI MP, STüVE O, WAUBANT E, POLMAN CH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology [online] 2014 Jul 15, 83(3):278-86 [viewed 14 September 2014] Available from: doi:10.1212/WNL.0000000000000560

Investigations - for Diagnosis

Fact Explanation
Serum potassium level Serum potassium level is normal during the attack. The muscle weakness along with this result usually confirm the diagnosis. The serum potassium level does not necessarily below normal in many cases. They are usually borderline. Serum potassium should be meticulously measured during the hospital stay to prevent serious declines that can result in rare, but fatal complications such as arrythmias. [1,2,3,4,5]
Creatine phosphokinase (CPK) level CPK level rises during attacks. The ratio between serum potassium to creatinine distinguished primary hypokalemic paralysis from secondary cases. Values of more than 3.0 mmol/mmol indicated secondary hypokalemic periodic paralysis. [1,3,5,6]
Nerve conduction studies Reduced amplitude of action potential can be observed during the attacks. Sensory nerve conduction study findings are normal. [2,3,5,6]
Electromyography Muscles are electrically silent during the attacks due to the inexcitability of the affected areas. [1,2,3]
Muscle biopsy Results are abnormal, more typically in patients with hypokalemic type paralysis. Single or multiple centrally placed vacuoles are the commonest finding. Tubular aggregates may be seen in some patients. [2,3,4]
Genetic studies Mutations like CALCL1A3 and SCN4A are commonly found in these patients. [1,2]
Oral glucose loading test Oral glucose loading test is a provocative test that is rarely used in the diagnosis. Glucose loading is a triggering factor for appearance of the symptoms. In this test, oral glucose is given in a dosage of 1.5g/kg. Physical examination to assess the muscle strength and serum electrolytes are performed half an hourly. If a weakness is detected within 2-3 hours, it is diagnostic. Intravenous glucose challenge and Intra-arterial epinephrine test are additional provocative investigations that are rarely used nowadays. [1,2,6]
Electrocardiogram Bradycardia, flat T waves, U waves and ST-segment depressions can be detected due to the low serum potassium levels. [2,3,6]
Serum thyroxine This is done to differentiate the hypokalaemic periodic paralysis from thyrotoxic periodic paralysis when the thyroid enzyme levels are abnormally high. [1,4,5]
References
  1. SOULE BR, SIMONE NL. Hypokalemic Periodic Paralysis: a case report and review of the literature. Cases J [online] 2008 Oct 21, 1(1):256 [viewed 13 September 2014] Available from: doi:10.1186/1757-1626-1-256
  2. WI JK, LEE HJ, KIM EY, CHO JH, CHIN SO, RHEE SY, MOON JY, LEE SH, JEONG KH, IHM CG, LEE TW. Etiology of hypokalemic paralysis in Korea: data from a single center. Electrolyte Blood Press [online] 2012 Dec, 10(1):18-25 [viewed 13 September 2014] Available from: doi:10.5049/EBP.2012.10.1.18
  3. KIM H, HWANG H, CHEONG HI, PARK HW. Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations. Korean J Pediatr [online] 2011 Nov, 54(11):473-6 [viewed 13 September 2014] Available from: doi:10.3345/kjp.2011.54.11.473
  4. KAYAL AK, GOSWAMI M, DAS M, JAIN R. Clinical and biochemical spectrum of hypokalemic paralysis in North: East India. Ann Indian Acad Neurol [online] 2013 Apr, 16(2):211-7 [viewed 13 September 2014] Available from: doi:10.4103/0972-2327.112469
  5. ABBAS H, KOTHARI N, BOGRA J. Hypokalemic periodic paralysis. Natl J Maxillofac Surg [online] 2012 Jul, 3(2):220-1 [viewed 13 September 2014] Available from: doi:10.4103/0975-5950.111391
  6. MATTHEWS E, PORTARO S, KE Q, SUD R, HAWORTH A, DAVIS MB, GRIGGS RC, HANNA MG. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology [online] 2011 Nov 29, 77(22):1960-4 [viewed 13 September 2014] Available from: doi:10.1212/WNL.0b013e31823a0cb6

Management - General Measures

Fact Explanation
Patient/ parent education parents/ patients should be educated regarding the disease and its good prognosis. Triggering factors such as heavy carbohydrate diets, sleep deprivation, certain medications and stressful situations should be best avoided. Infections should be treated promptly. Still, hypokalemic periodic paralysis cannot be cured as it can be inherited. However, patients regain full range of function after sometime. Genetic counseling may be advised for couples at risk of the disorder. As the patient encounters some degree of initial weakness/ heaviness of the legs, doing mild exercises is thought to prevent a full-blown attack. [1,2,3,4]
Prophylaxis Acetazolamide, a carbonic anhydrase inhibitor, is the preferred drug that is used as a prophylaxis in prevention of an attack. Acetazolamide produced a mild metabolic acidosis but did not have a demonstrable effect on total body sodium, total body potassium, or thyroid function. Still, it is considered as the most effective drug in prevention. Acetazolamide at a dose of 125-1500 mg/d in divided doses is administered as prophylaxis. Spironolactone is an alternative/ second line option. [2,3,4]
Dietary interventions Low-carbohydrate and low-sodium diet has been proven to reduce the frequency of episodes. Daily oral potassium supplementation are recommended in some patients though the effectiveness is not definite. [1,2,3]
References
  1. TRIFANESCU RA, DANCIULESCU MIULESCU R, CARSOTE M, POIANA C. Hypokalemic periodic paralysis as first sign of thyrotoxicosis. J Med Life [online] 2013 Mar 15, 6(1):72-5 [viewed 13 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23599824
  2. ABBAS H, KOTHARI N, BOGRA J. Hypokalemic periodic paralysis. Natl J Maxillofac Surg [online] 2012 Jul, 3(2):220-1 [viewed 13 September 2014] Available from: doi:10.4103/0975-5950.111391
  3. CHENG CJ, KUO E, HUANG CL. Extracellular potassium homeostasis: insights from hypokalemic periodic paralysis. Semin Nephrol [online] 2013 May, 33(3):237-47 [viewed 13 September 2014] Available from: doi:10.1016/j.semnephrol.2013.04.004
  4. MATTHEWS E, PORTARO S, KE Q, SUD R, HAWORTH A, DAVIS MB, GRIGGS RC, HANNA MG. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology [online] 2011 Nov 29, 77(22):1960-4 [viewed 13 September 2014] Available from: doi:10.1212/WNL.0b013e31823a0cb6

Management - Specific Treatments

Fact Explanation
Oral potassium supplementation Potassium should be given during an acute attack. This may not prevent or suppress further attacks, but may prevent serious complications such as arrythmias. Oral potassium chloride supplementation is preferred over intravenous access in many cases. The initial dose is 60 mEq which increases the serum potassium concentration by 1.0-1.5 mEq/L. According to the response, dose can be raised up to maximum of 200 mEq per day. But close monitoring of serum electrolyte levels is essential. [1,2,3,4,5]
Intravenous potassium supplementation Intravenous potassium chloride is reserved for refractory cases and severe episodes that are comlicated by arrythmias and respiratory compromization. IV potassium chloride 0.05-0.1 mEq/kg body weight is the recommended dosage. 5% mannitol is used as solvent instead of normal saline or dextrose as both sodium and dextrose have a potential to worsen the attack. It is mandatory to titrate and monitor the treatment with continuous ECG monitoring and frequent serum potassium measurements. [1,2,3,5]
References
  1. WI JK, LEE HJ, KIM EY, CHO JH, CHIN SO, RHEE SY, MOON JY, LEE SH, JEONG KH, IHM CG, LEE TW. Etiology of hypokalemic paralysis in Korea: data from a single center. Electrolyte Blood Press [online] 2012 Dec, 10(1):18-25 [viewed 13 September 2014] Available from: doi:10.5049/EBP.2012.10.1.18
  2. SOULE BR, SIMONE NL. Hypokalemic Periodic Paralysis: a case report and review of the literature. Cases J [online] 2008 Oct 21, 1(1):256 [viewed 13 September 2014] Available from: doi:10.1186/1757-1626-1-256
  3. ABBAS H, KOTHARI N, BOGRA J. Hypokalemic periodic paralysis. Natl J Maxillofac Surg [online] 2012 Jul, 3(2):220-1 [viewed 13 September 2014] Available from: doi:10.4103/0975-5950.111391
  4. KAYAL AK, GOSWAMI M, DAS M, JAIN R. Clinical and biochemical spectrum of hypokalemic paralysis in North: East India. Ann Indian Acad Neurol [online] 2013 Apr, 16(2):211-7 [viewed 13 September 2014] Available from: doi:10.4103/0972-2327.112469
  5. KIM H, HWANG H, CHEONG HI, PARK HW. Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations. Korean J Pediatr [online] 2011 Nov, 54(11):473-6 [viewed 13 September 2014] Available from: doi:10.3345/kjp.2011.54.11.473