Quality of life in hypokalemic periodic paralysis – a survey

Primary hypokalemic periodic paralysis (HypoPP) is a skeletal muscle channelopathy most commonly caused by pathogenic variants in the calcium channel gene, CACNA1S. HypoPP can present with attacks of paralysis and/or permanent muscle weakness. Previous studies have shown that patients with HypoPP can have impaired quality of life (QoL). In this cross-sectional study, we aimed to describe the QoL in patients with HypoPP caused by pathogenic variants in CACNA1S using The Individualized Neuromuscular Quality of Life (INQoL) questionnaire, a validated tool to measure the QoL of patients with neuromuscular diseases (higher score, worse QoL). We showed that muscle weakness and fatigue were the symptoms with the greatest impact on participants' lives and that “activities”, in the life domain of the INQoL, was most affected by HypoPP. Furthermore, we showed that the total INQoL score increased with age. Low QoL was primarily driven by progressive permanent muscle weakness and not attacks of paralysis, although half of the participants reported that attacks of paralysis challenged their daily life. The results suggest that special attention should be given to muscle weakness and fatigue in patients with HypoPP.


Introduction
Primary hypokalemic periodic paralysis (HypoPP) is an inherited skeletal muscle channelopathy most commonly caused by pathogenic variants in the calcium channel gene, CACNA1S [1][2][3].HypoPP caused by variants in CACNA1S presents with different phenotypes.Most patients present in adolescence with a phenotype characterized by attacks of paralysis (PP) lasting from hours to a few days.Between attacks, patients with PP have normal muscle strength.However, some patients with a phenotype of PP develop permanent weakness with time, a phenotype of mixed weakness (MW).Furthermore, some patients present with a phenotype of permanent weakness without attacks of paralysis (PW) [ 4 ].Previous studies have shown that some patients with HypoPP suffer from pain and fatigue and that quality of life (QoL) can be impaired [5][6][7][8][9].No large studies of QoL in patients with HypoPP have been published.The Individualized Neuromuscular Quality of Life (INQoL) questionnaire [ 10 ] is a tool to measure the QoL in patients with neuromuscular diseases.INQoL has been validated in English, Italian, Dutch, Japanese, etc., and is further translated into other languages, including Danish [10][11][12][13].
In this cross-sectional survey study, we aimed to describe the QoL in Danish patients with HypoPP caused by pathogenic variants in CACNA1S using the INQoL questionnaire.

Study design
All Danish citizens have a 10-digit civil registration number used to store health data in the Danish National Registry of Patients (DNRP) and most Danish citizens use e-Boks, a digital mailbox, connected to this number to communicate sensitive information securely.In this study, persons ≥18 years registered with the diagnostic code of HypoPP in the DNRP and subscribing to e-Boks were invited to participate in the web-based survey, using the software REDCap (© 2018 Vanderbilt University).The invitation was sent out three times; first, in April 2022, and to non-responders in June 2022 and July 2022.

Quality of life
QoL was rated using the INQoL questionnaire, Version 2 Full.The INQoL is constructed of four main domains: symptoms, life domains, treatment effects, and a total INQoL score.The first three domains are further divided into 14 subdomains.Symptoms are divided into muscle weakness, locking, pain, fatigue, droopy eyelids, double vision, and swallowing difficulties; life domains are divided into activities, independence, social relationships, emotions, and body image, and treatment effects are divided into perceived treatment effects and expected treatment effects.Each subdomain is composed of questions varying from 3 to 10 items, with responses given on a 7-point scale.The total INQoL score is calculated from the life domains assessing how the muscle condition altogether affects participants' lives as an INQoL score representing the global influence of the disease on QoL.Scores from symptoms are not included in the total INQoL score.The results from the four domains are converted to a score of 0-100.Higher values indicate greater symptom impact or worse QoL.It was specified to participants not to rate periodic paralysis, but only permanent weakness in the subdomain muscle weakness in the INQoL questionnaire.

Physical activity level
Participants categorized their leisure time physical activity (PA) using a version of the four-level Saltin Grimby Physical Activity Level Scale (SGPALS) modified by Scnohr et al. [14,15] .SGPALS was first published by Saltin and Grimby in 1968.The scale is widely used and has since its development been used in several modified versions [16][17][18][19][20].We asked the participants to rate their leisure PA during the last year as 1) Mainly sedentary (e.g., reading books, watching television, or going to the cinema) or engaged in light physical activity less than two hours/week); 2) Light physical activity two-four hours/ week (e.g., walking, cycling for pleasure, gardening, housework, light exercise); 3) Ligth physical activity more than four hours/week, or more strenuous activities two-four hours/week (e.g.brisk walking, fast bicycling, heavy gardening, or exercises that cause perspiration or exhaustion); or 4) Vigorous physical activities more than four hours/week, or heavy exercise (e.g.competitive sport) several times a week [14,15] .

Periodic paralysis
Questions on the age of the first symptom of HypoPP, age of diagnosis, current medical treatment related to HypoPP, frequency of follow-up visits at a medical doctor, and presence and frequency of periodic paralysis were included in the survey.Attacks of paralysis were rated during the last year in ranges of frequencies (1-5; 6-10; > 10) and on a 7-point scale-like symptoms in the INQoL questionnaire.Furthermore, participants were asked to rate the difficulties and importance of difficulties caused by attacks of paralysis on the 7-point scale.

Background questions
Questions on age, sex, height, weight, physical activity, current job status, and family status were also included in the survey.

Statistical analyses
Values are mean ± SD unless otherwise stated.Mean differences were calculated using an independent t -test.We evaluated for correlation among variables using the Pearson correlation quotient.We used a one-way analysis of variance to test the association between continuous variables and categorical data.

Results
In total, 175 adults were registered at the DNPR with a diagnostic code of HypoPP and were invited to participate in the survey.Ninety-six persons never responded.Another, two persons contacted the investigator because they were mistakenly registered at the DNPR with a HypoPP diagnosis and were excluded.Seven persons responded incompletely, three persons did not wish to give information on genetics and further 18 persons did not have a confirmed pathogenic variant in CACNA1S and were excluded.Forty-nine persons with a verified pathogenic variant in CACNA1S completed the survey ( Fig 1 ).Twenty-seven men and 22 women were included.Mean age was 49 ± 19.All phenotypes were represented ( Table 1 ).Forty-eight persons were heterozygous for the pathogenic variant p.R1239H (NM_0 0 0 069.2:c.3716G > A) and one person was heterozygous for the pathogenic variant p.R528H (NM_0 0 0 069.2:c.1583G > A).The family relationships between participants are unknown.The results from the INQoL questionnaire showed that muscle weakness and fatigue constituted the two most common symptoms, reported by 30 (61 %), and 24 (49 %) of participants, respectively, followed by pain 17 (35 %), droopy eyelids 7 (14 %) and muscle locking 5 (10 %).No participants reported having double vision or swallowing difficulties.Muscle weakness and fatigue were the symptoms that most participants found severe defined as considerably or worse (5 or more on the 7-point scale), rated by 13 (43 %) and 6 (25 %) participants, respectively, followed by pain 3 (18 %) and muscle locking 1 (20 %).No participants who reported droopy eyelids rated the symptom as severe ( Fig 2 A).Muscle weakness and fatigue were the only symptoms that participants found to cause severe problems, rated by 7 (23 %) and 2 (8 %) participants, respectively ( Fig 2 B).However, the importance of problems caused by symptoms was rated as considerably important (5 or more on the 7-point scale) for muscle weakness 13 (43 %), fatigue 6 (25 %), and pain 4 (24 %) ( Fig 2 C).
The total INQoL score was 19 ± 20, with the worst result obtained for the physical health domain "activities", while the psychosocial domain "social relationships" showed the best results ( Table 2 ).Thirty-eight (78 %) and 28 (57 %) reported that HypoPP affected their ability to do leisure activities and daily activities, respectively.Thirteen (39 %) of the 33 participants with paid employment reported that HypoPP affected their ability to do work activities and three (6 %) participants reported that they did not work due to HypoPP ( Fig 2 D).
Thirty-eight (78 %) participants answered that they had experienced attacks of paralysis.The number of attacks during the last year was reported to be > 10 by ten (26 %) participants, from 6 to 10 by seven (18 %) and from 1 to 5 by 12(32 %).Eight (21 %) participants with attacks of paralysis had not experienced attacks of paralysis during the last year.Four (11 %) participants rated   the severity of the symptom attacks of paralysis as severe defined as considerable or worse (5 or more on the 7-point scale).Of the participants with attacks of paralysis, 25 (66 %) reported that attacks of paralysis caused problems in their life and four (11 %) of them rated the problems as severe.The importance of problems caused by attacks of paralysis was rated as considerably important (5 or more on the 7-point scale) by 4 (11 %) participants.Total INQoL was higher in participants ≥ 50 years old than in younger participants (27 ±23 vs 9 ± 11, p ≤ 0.01) and there was a weak correlation between age and total INQoL score ( r = 0.397, p = 0.005).There was no difference in total INQoL in men and women ( p = 0.867).There was no association between the severity of attacks of paralysis during the last year and total INQoL score ( p = 0.31) but there was an association between the severity of permanent muscle weakness and total INQoL score ( p ≤ 0.01).Furthermore, there was an association between physical activity and total INQoL score ( p ≤ 0.01), and total INQoL was higher in participants with PA ≤ light activity than in participants with PA > Light activity (26 ±22 vs 8 ± 11, p ≤ 0.01).

Discussion
In this cross-sectional survey, we described the QoL of persons with HypoPP-causing mutations in CACNA1S using the INQoL questionnaire.The main findings are that permanent muscle weakness and fatigue were the symptoms with the greatest impact on participants' lives and that the physical health domain" activities" was the subdomain of life areas that was most affected by HypoPP.Other notable findings were that total INQoL scores were found to increase with age and that there was an association between permanent weakness and total INQoL.This is in line with previous studies on HypoPP showing a relationship between age and decline in muscle weakness [ 4 , 21 , 22 ].The total INQoL scores were not found to increase with the severity of attacks of paralysis..However, half of the participants reported that attacks of paralysis challenged their daily life.The total INQoL score was in line with the results from two previous studies published by Sansone, V. A et al. [ 5 ] and Sasaki R et al. [ 6 ] reporting a total INQoL score of 15.0 and 26.7 in 16 and 11 participants with HypoPP, respectively.Furthermore, the total INQoL scores were lower than reported in other neuromuscular disorders such as chronic inflammatory demyelinating neuropathy (CIDP) [ 23 ], spinal muscular atrophy (SMA) [ 24 ], Myotonic dystrophy type 1 (DM1) [ 25 ], Myotonic dystrophy type 2 (DM2 ) [ 26 ] and Duchenne muscular dystrophy, indicating a relatively higher impact of these diseases on QoL [ 27 ].Knowledge of which symptoms or domains that affects quality of life in patients with HypoPP is important since this may lead the way for a focus on treatment strategies that could be important and typically not associated with HypoPP such as treatment of pain.Furthermore, the knowledge is important in the evaluation of new treatments' impact on patients' QoL.It could be interesting in future studies to investigate whether patients with HypoPP can benefit from physical training and improve QoL.
INQoL is a validated tool to assess QoL in patients with neuromuscular disorder.In this survey we only collect data at a single point in time, future studies er needed to determine whether INQoL is sensitive enough to capture changes over time in patients with HypoPP as outcome measures in future treatment trials.Furthermore, attacks of paralysis that has a negative impact on patients with HypoPP, is not included in the INQoL.We suggest a modification of the INQoL questionnaire to include periodic paralysis as a subdomain in the domain for symptoms.
A limitation of our study is the lack of information on comorbidity that could influence the participants responses and QoL.Seven participants reported to have droopy eyelids and five reported to have muscle locking because of HypoPP in the questionnaire.Neither is a symptom associated with HypoPP.Comorbidity could potentially explain the responses, however since droopy eyelids can be a normal part of aging and diseases causing droopy eyelids are rare, the reported droopy eyelids is probably due to aging.Diseases causing myotonia are also rare, and the possibility that five participants should have comorbidity causing myotonia seems unlikely.It is however possible that the participants misunderstood the question on muscle locking -a potential risk when using a survey, especially a web-based survey without the possibility for clarification.Another limitation of our study is the lack of information on invited non-responders.It is possible that more severely affected invited patients were more prone to respond and that this has influenced the results giving higher scores in the INQoL questionnaire.Furthermore, the relationships found in this cross-sectional study should be interpreted with caution as the results may not reflect a causeeffect relationship.

Conclusion
In this cross-sectional study of QoL in patients with HypoPP, we show that permanent muscle weakness and fatigue were the symptoms included in the INQoL questionnaire with the greatest impact on participants' lives and that the physical health domain "activities" was the life area that was most affected by HypoPP.Furthermore, we showed that the total INQoL score increased with age and that there was an association between permanent weakness and total INQoL but not between attacks of paralysis and total INQoL.However, half of the participants did report that attacks of paralysis caused difficulties in their lives.
The results suggest that special attention should be given to muscle weakness and fatigue in health management and treatment trials in patients with HypoPP.

Fig. 1 .
Fig. 1.Flowchart of included and excluded patients.* Including 3 persons who did not wish to give information on pathogenic variant.

Fig. 2 .
Fig. 2. A. Symptoms of HypoPP.Severity of symptoms is rated using the Individualized Neuromuscular Quality of Life questionnaire (INQoL).Specific information on period paralysis (not part of INQoL) were added to the Fig. B: Difficulties causes by HypoPP.Amount of difficulties is rated using the Individualized Neuromuscular Quality of Life questionnaire (INQoL).Specific information on period paralysis (not part of INQoL) were added to the Fig. C: Importance of difficulties causes by HypoPP.Importance of difficulties is rated using the Individualized Neuromuscular Quality of Life questionnaire (INQoL).Specific information on period paralysis (not part of INQoL) were added to the Fig. D: Impact of HypoPP on the life domain "activities" using the Individualized Neuromuscular Quality of Life questionnaire.

Table 1
Characteristics of participants.

Table 2
Results of INQoL questionnaire in patients with HypoPP.Results of the INQoL questionnaire in patients with HypoPP ( n = 49).INQoL scores are shown as mean ±SD.Values range between 0 and 100, with higher values indicating greater symptom impact or worse QoL.