History

Fact Explanation
Weakness Normokalaemic periodic paralysis (NormoKPP) is thought to be a variant of hyperkalaemic periodic paralysis (HyperKPP) though at time, it is treated as a separate disease entity. NormKPP is an autosomal dominant mutation of the gene SCN4A that codes for the protein Nav1.4 which is an important part of the sodium channel. This channelopathy results in uncontrolled influx of the sodium ions in to the muscle during excitation. As sodium ions enter, muscle sustains the depolarization for a while and become unable to accept further action potentials which ultimately leads to weakness/ paralysis. Over influx of sodium ions is not well opposed by the efflux of potassium ions in some patients as does in most of the cases of HyperKPP. This causes normal serum potassium levels during the attack. Episodic/ periodic paralysis along with normokalaemia make a distinct form of periodic paralysis called NormoKPP. The clinical presentation of the disease is more or less similar to HyperKPP. Initially, patients complain of a heaviness in the affected limbs. This is followed by a paralysis.Weakness is mild to severe and the proximal muscle groups of the upper limbs and lower limbs are frequently affected. The neck area may be affected as well. Rarely, patients may present with generalized muscle weakness. A typical mild episode is painless and usually lasts for few hours before patient recovers spontaneously. The severe attacks began in the morning and lasted from 2 hours to 7 days. [1,2,3,4,5]
Lid lagging Lagging of upper eyelid can be the initial symptom, specially in children. Mothers may complain of upper eye lid being unable to follow the eye movements, specially on downward gaze. [2,3,4]
Difficulty of walking Most patients with moderate to severe disease present as the are unable to walk as the lower limbs are affected with the weakness. [1,3,5]
Triggers Fasting, rigorous exercises, exposure to cold, consuming potassium-rich foods or taking medicines that contain potassium, certain pollutants such as cigarette smoke can induce an paralytic attack. [3,4,5]
Past history of similar events 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. [1,2,3]
At risk population Normokalaemic periodic paralysis is an autosomal dominantly inherited disease. So, positive family history can be present. Disease is more common among male sex. And individuals at any age can be affected. [1,2,4]
References
  1. VENANCE SL, CANNON SC, FIALHO D, FONTAINE B, HANNA MG, PTACEK LJ, TRISTANI-FIROUZI M, TAWIL R, GRIGGS RC, CINCH INVESTIGATORS. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain [online] 2006 Jan, 129(Pt 1):8-17 [viewed 22 September 2014] Available from: doi:10.1093/brain/awh639
  2. HAN JY, KIM JB. Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A. Korean J Pediatr [online] 2011 Nov, 54(11):470-2 [viewed 14 September 2014] Available from: doi:10.3345/kjp.2011.54.11.470
  3. JURKAT-ROTT K, LEHMANN-HORN F, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hyperkalemic Periodic Paralysis Type 1 [online] 1993 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301669
  4. KIM JB. Channelopathies. Korean J Pediatr [online] 2014 Jan, 57(1):1-18 [viewed 14 September 2014] Available from: doi:10.3345/kjp.2014.57.1.1
  5. SOKOLOV S, SCHEUER T, CATTERALL WA. Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis. Proc Natl Acad Sci U S A [online] 2008 Dec 16, 105(50):19980-5 [viewed 22 September 2014] Available from: doi:10.1073/pnas.0810562105

Examination

Fact Explanation
Lid lag Infants may have a lid lag during the downward gazing. [1,2]
Muscle weakness Muscle weakness can be demonstrated specially in the limbs. Hips and shoulders are commonly affected. The proximal weakness is far more common than the involvement of the distal parts. [1,3]
Hypotonia As the incoming action potentials cannot be effectively converted in to the contractions, normal resting muscle tone cannot be maintained. So the muscles appear to be heavy and less in tonicity. [1,2,3]
Important negative findings The sensation of any sort is not affected in the periodical paralysis. [1,2,3]
References
  1. KIM JB. Channelopathies. Korean J Pediatr [online] 2014 Jan, 57(1):1-18 [viewed 14 September 2014] Available from: doi:10.3345/kjp.2014.57.1.1
  2. LEHMANN-HORN F, JURKAT-ROTT K. Voltage-gated ion channels and hereditary disease. Physiol Rev [online] 1999 Oct, 79(4):1317-72 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10508236
  3. SOKOLOV S, SCHEUER T, CATTERALL WA. Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis. Proc Natl Acad Sci U S A [online] 2008 Dec 16, 105(50):19980-5 [viewed 22 September 2014] Available from: doi:10.1073/pnas.0810562105

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 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]
Hypokalaemic periodic paralysis 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. [8]
Thyrotoxic periodic paralysis Thyrotoxic periodic paralysis is the periodic muscle paralysis/ weakness that is associated with some degree of hypokalaemia and thyrotoxicosis. High-carbohydrate meal exercise, steroid, and stress can trigger these attacks. The lower extremities are commonly affected. The transient paralysis is more pronounced in the proximal parts of the limbs. [9]
Hyperkalaemic Periodic paralysis Hyperkalemic periodic paralysis is a rare form of autosomal dominant mutation of the gene SCN4A which codes protein Nav1.4. This results in a channelopathy in the of the sodium channels that encourage the uncontrolled influx of sodium ions. The muscle sustains the depolarization for a while and become unable to accept further action potentials which ultimately leads to weakness/ paralysis. The degree of severity varies. Patients usually experience weakness in the proximal parts of the limbs such as hips and shoulder areas. At early stage, however the weakness is limited to the lower limbs. Later on it may spread to the upper limbs and neck. The less common severe forms of disease present with generalized weakness/ complete paralysis. The attack is usually painless and lasts for hours before regress spontaneously in many cases. [10]
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
  8. 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
  9. VIJAYAKUMAR ABHISHEK, ASHWATH GIRIDHAR, THIMMAPPA DURGANNA. Thyrotoxic Periodic Paralysis: Clinical Challenges. Journal of Thyroid Research [online] 2014 December, 2014:1-6 [viewed 18 September 2014] Available from: doi:10.1155/2014/649502
  10. HAN JY, KIM JB. Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A. Korean J Pediatr [online] 2011 Nov, 54(11):470-2 [viewed 14 September 2014] Available from: doi:10.3345/kjp.2011.54.11.470

Investigations - for Diagnosis

Fact Explanation
Serum potassium level Serum potassium level is usually normal during the attack. [1,2,3]
Creatine phosphokinase (CPK) level CPK levels are elevated in most of the cases. [2,3,4]
Nerve conduction studies Reduced amplitude of action potential is seen during the attack. Sensory nerve conduction study findings are normal. [3,4,5]
Genetic studies SCN4A mutation is commonly found in these patients. [1,3,5]
References
  1. VENANCE SL, CANNON SC, FIALHO D, FONTAINE B, HANNA MG, PTACEK LJ, TRISTANI-FIROUZI M, TAWIL R, GRIGGS RC, CINCH INVESTIGATORS. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain [online] 2006 Jan, 129(Pt 1):8-17 [viewed 22 September 2014] Available from: doi:10.1093/brain/awh639
  2. HAN JY, KIM JB. Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A. Korean J Pediatr [online] 2011 Nov, 54(11):470-2 [viewed 14 September 2014] Available from: doi:10.3345/kjp.2011.54.11.470
  3. JURKAT-ROTT K, LEHMANN-HORN F, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hyperkalemic Periodic Paralysis Type 1 [online] 1993 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301669
  4. KIM JB. Channelopathies. Korean J Pediatr [online] 2014 Jan, 57(1):1-18 [viewed 14 September 2014] Available from: doi:10.3345/kjp.2014.57.1.1
  5. SOKOLOV S, SCHEUER T, CATTERALL WA. Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis. Proc Natl Acad Sci U S A [online] 2008 Dec 16, 105(50):19980-5 [viewed 22 September 2014] Available from: doi:10.1073/pnas.0810562105

Management - General Measures

Fact Explanation
Patient/ parent education Parents/ patients should be educated regarding the disease and its good prognosis. Triggering factors such as fasting, sleep deprivation, certain medications, strenuous exercises and stressful situations should be best avoided. Infections should be treated promptly. Though the disease can not be cured fully, Patients regain full range of function after few hours. 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. [1,2,3,4,5]
Prophylaxis Carbonic acid anhydrase inhibitors such as dichlorphenamide or acetazolamide are thought to be effective. [1,3,5]
Dietary modifications Patients should be encouraged to have meals with a high content of carbohydrate components and less potassium. [2,3,4]
References
  1. VENANCE SL, CANNON SC, FIALHO D, FONTAINE B, HANNA MG, PTACEK LJ, TRISTANI-FIROUZI M, TAWIL R, GRIGGS RC, CINCH INVESTIGATORS. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain [online] 2006 Jan, 129(Pt 1):8-17 [viewed 22 September 2014] Available from: doi:10.1093/brain/awh639
  2. KIM JB. Channelopathies. Korean J Pediatr [online] 2014 Jan, 57(1):1-18 [viewed 14 September 2014] Available from: doi:10.3345/kjp.2014.57.1.1
  3. JURKAT-ROTT K, LEHMANN-HORN F, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Hyperkalemic Periodic Paralysis Type 1 [online] 1993 [viewed 14 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301669
  4. SOKOLOV S, SCHEUER T, CATTERALL WA. Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis. Proc Natl Acad Sci U S A [online] 2008 Dec 16, 105(50):19980-5 [viewed 22 September 2014] Available from: doi:10.1073/pnas.0810562105
  5. HAN JY, KIM JB. Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A. Korean J Pediatr [online] 2011 Nov, 54(11):470-2 [viewed 14 September 2014] Available from: doi:10.3345/kjp.2011.54.11.470