The long exercise test: New insights on an old technique

In 1986, McManis and colleagues reported the diagnostic utility of the long exercise test (LET) in patients with primary and secondary periodic paralysis (PP) evaluated in the interictal period. Initially described in 1965 by Engel et al in a patient with hypokalemic PP, the LET is a physiological method to investigate attacks of postexercise weakness common to all forms of PP. As in the initial study, McManis et al reported changes in the hypothenar compound muscle action potential (CMAP) amplitude before, during, and after a controlled 2to 5-minute isometric muscle contraction. They calculated the percentage decrease from peak amplitude during or just after exercise to its nadir, generally 30 to 40 minutes after exercise, with the decline in amplitude proportional to post-exercise loss of muscle membrane excitability and resulting weakness. In their control group of 14 normal subjects, they found a maximal post-exercise decline in peak to nadir amplitude of 30%. Using a 40% decline as the normal cut-off, they found an abnormal LET in 15 of 21 (71%) patients with clinically definite PP, in 3 of 9 (33%) with possible PP, and 6 of 9 (67%) with secondary PP. They cautioned that some patients with negative initial tests have positive tests subsequently, that the exercise test does not distinguish between the different types of primary PP, and that it cannot discern primary from secondary forms. Still, as a screening test for PP, this was a diagnostic advance over provocative testing which can potentially differentiate the type of PP, but which also results in total body weakness, and typically requires inpatient monitoring. Over the subsequent decades, numerous studies have confirmed the diagnostic utility of the LET, including more recent patient cohorts with genetically proven PP, with only slight modifications from the original description. Some studies have utilized area of the CMAP in addition to amplitude, and others have used the baseline amplitude rather than the post-exercise peak amplitude to calculate decrement, albeit with a lower decrement cut-off value. The cut-offs for the LET have been set for a high specificity of 95% to 100%, but its sensitivity has been variable, ranging from 55% to 100%. Its high specificity results in a high positive predictive value, but its lower sensitivity in most cohorts results in a lower negative predictive value. For example, assuming a sensitivity of 71% as per McManis et al, a specificity of 98%, and a pretest probability of disease of 50%, the positive predictive value of the LET is 97%, whereas the negative predictive value is only 77%. Thus, when the pretest clinical likelihood of PP is equivocal, a positive test greatly increases disease probability, essentially confirming the diagnosis, whereas a negative test only moderately decreases disease probability, making the diagnosis less likely, but by no means excluding it. Put differently, with sensitivity at 71% and specificity at 98%, the only path to a negative predictive value of 97%, essentially excluding the disease, is when pretest probability is already very low at 10%. In this issue of the journal, Ribeiro et al look at the LET from a different angle. Of 67 patients from their muscle channelopathy service with positive genetic testing for PP or a positive LET, 45 (67%) had genetically proven PP due to known CACNA1S, KCNJ2, SCN4A HypoPP, SCN4A HyperPP, and RYR1 mutations. On the LET, and using a genetic “gold standard” for diagnosis, 32 of the 45 had an amplitude decrement greater than 40%, for the same overall sensitivity of 71% found by McManis et al using a clinical gold standard. However, in this report, the authors make the key observation that sensitivity of the LET depends on attack frequency, a measure of disease activity, and not genotype. In 8 patients with frequent daily or weekly attacks, all 8 had a positive LET (sensitivity = 100%), whereas, in 21 patients with 1 to 12 attacks per year, the LET was positive in 16 (sensitivity = 71%), and, in 16 patients with rare or no attacks, the LET was positive in only 9 (sensitivity = 56%). As the authors point out, this finding makes intuitive sense and confirms the findings of Tengan et al, who noted that, in hypokalemic PP patients: 1) the LET amplitude decrement was much higher in the subgroup with attacks within 1 year of the test vs patients with more remote attacks or in asymptomatic carriers; and 2) the sensitivity of the LET was correspondingly much higher in the subgroup with more recent attacks (100%, using an amplitude decrement cut-off of 29%) vs the entire cohort (55%). In addition to providing a potential explanation for the wide range of LET sensitivity reported over the years, the dependence of test sensitivity on disease activity has practical clinical applications. Specifically, in a patient with frequent daily or weekly attacks, a negative LET essentially excludes the disease given its high sensitivity and negative predictive value (approaching 100%). Importantly, however, in patients with infrequent attacks, a negative LET remains inconclusive given its much lower sensitivity and negative predictive value. In their landmark paper, McManis et al concluded that: “The exercise test is useful in confirming the diagnosis of periodic paralysis, but does not distinguish the type or mechanism . Further biochemical testing is needed to distinguish the type of periodic paralysis present. ” The authors were likely referring to provocative testing specific for hypokalemic and hyperkalemic PP and laboratory work-up for secondary PP. However, the major diagnostic advances in PP followed a few years later when the genetic bases for these various diseases were identified and genetic testing became commercially available, and then available free of charge after the successful dichlorphenamide Received: 3 January 2022 Revised: 11 January 2022 Accepted: 15 January 2022