Hyperkalemic Periodic Paralysis
Abstract & Commentary
By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Hyperkalemic periodic paralysis has now been well characterized — clinically, physiologically, and genetically.
Source: Charles G, et al. Characterization of hyperkalemic periodic paralysis: A survey of genetically diagnosed individuals. J Neurology 2013:260:2606-1613.
First described in 1951 and now classified as one of the autosomal dominant, voltage-gated, sodium channelopathies, hyperkalemic periodic paralysis (hyperPP) is a rare disorder (1:200,000 persons) affecting men and women equally, causing episodic, painless muscle weakness. To better define — or refute — previously accepted epidemiological, clinical, diagnostic, and therapeutic aspects of hyperPP, review of a large cohort of genetically confirmed cases was undertaken.
Members of multiple organizations were surveyed, including the Periodic Paralysis Association; the Periodic Paralysis News Desk; and the Universities of Ulm (Germany), Rochester (New York), Southwestern Texas, Pierre et Marie Curie (France), and University College, London, England. Surveys comprised multiple-choice questions, offering abundant space for patients' personal comments, with criteria for inclusion requiring patients ≥ 18 years of age with a genetically confirmed diagnosis of hyperPP. Statistical analysis comprised chi-square computations, with Bonferroni correction as needed.
Among 137 responses, 94 (68.6%) possessed the requisite eligible mutation. Men and women were approximately equally distributed (53.3% vs 46.7%), with an age range of 19-84 years (median 46 years). Thyroid dysfunction was a significantly associated comorbidity (20.2%, P < 0.0001), with a non-significant trend found for cardiac arrhythmias (9.6%, P = 0.04). On average, 19.4 years and four different health care professionals were required until a correct diagnosis was obtained. Although onset in the first decade is usually expected, 25% had their initial attack during their teenage years. Attacks were more often reported in the morning (55.8%), during sleep (45.3%), or on waking (43%), with only 29.1% and 19.8% reporting attacks in the afternoon or evening, respectively. Attack frequency varied from 1-3 per month (29.9%) to weekly (20.7%) to 2-6 per week (24.1%), lasting 2 days (22.2%), 30-60 minutes (21%), or 15-30 minutes (13.6%), with 22.9% stating it lasted over a week. Surprisingly, respiratory symptoms were reported in 26.1%, facial weakness in 62%, inability to speak in 2.2%, and 7 and 2 patients, respectively, reporting bladder or bowel incontinence. Among the 55.8% with myotonia, progressive myopathy was reported in 37.5%, compared to 33.3% of those denying myotonia. HyperPP triggers included cold temperature (75.8%), rest following exercise (67%), fatigue or stress (47.3%), alcohol (45.1%), hunger (42.9%), potassium in food, specific foods or drinks, or changes in humidity (35.2% each), oversleeping (34.1%), pregnancy (27.9% of females), illness (27.5%), menstruation (18.6% of females), medication (16.5%), or potassium supplements (14.3%). Prodromal symptoms the day prior to an attack comprised fatigue, weakness, irritability, or restlessness (38.6%), with sweating, myalgia, stiffness, weakness, restlessness, tingling, and/or numbness more immediately preceding the attack (85.7%), usually by 20 minutes, but occasionally up to several hours. Typically, attacks were described as stiffness followed by weakness, and affected areas included the arms and hands (> 80%) as often as thighs and calves. Most attacks were described as mild (43.3%), but 15.6% were felt to be severe ("cannot speak or call for help"). Following attacks, most reported fatigue, weakness, clumsiness, or irritability, symptoms not previously noted in the literature. Muscle pain was experienced during an attack in 41.3% and in 62% following the episode, with only 26.1% denying muscle pain entirely. Between attacks, most felt well with mild or no symptoms, but 12.4% did report impairment of daily activities. Attacks increased in frequency with aging, more so earlier in life, as did muscle stiffness during attacks prior to adulthood, whereas muscle weakness during attacks tended to decrease in severity. By age 40 years and above, 84.6% reported fixed muscle weakness between attacks. Long-term treatment regimens for most patients included a combination of medication (hydrochlorothiazide, mexiletine, or flecainide), and medium-sized, carbohydrate-rich meals, usually 3-5 per day, with a carbohydrate rich snack every 2-3 hours, comprising candy, sugar, bread, or pasta. Strategies to mitigate acute attacks comprised staying warm, eating sweets, drinking water, or doing gentle exercise, but 36% were only occasionally able to abort an attack, if at all, despite best efforts. Liquid and solid carbohydrates were equally efficacious and usually took effect within an hour.
For the first time, a mitochondrial disorder has now been reported in association with periodic paralysis in a patient with acute episodes of limb weakness, identical to periodic paralysis and responsive to acetazolamide, with no recognized channelopathy mutation, but with mitochondrial DNA mutations previously associated with Leigh syndrome and MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes). (Neurology 2013;81;1-9). In cultured primary fibroblasts and cybrid cells, these mutations resulted in complex V and I defects and in oxidative stress. Understanding the mechanistic link between the ionic disturbance at the cell membrane level and the mitochondrial defect will require further study.