Permanent weakness and myopathy in hypokalemic periodic paralysis

Hypokalemic periodic paralysis (HypoPP) is a rare disease that consists of attacks of flaccid paralysis that often occur at night or early in the morning. Some patients with HypoPP may develop permanent muscle weakness and permanent  myopathy. Four phenotypes of disease have been described:  1) no symptoms; 2) periodic paralysis and absence of permanent weakness; 3) periodic paralysis and permanent paralysis; 4) permanent weakness and absence of periodic paralysis. Vacuolar alterations are present in the muscles of all patients affected by HypoPP. In general, vacuoles are heterogeneous in size and content.  Vacuoles are present in both fiber types and are not exclusive to any muscle fiber type, age, or phenotype. Generally, vacuoles contain glycogen but may also contain autophagosomes, fibrillar proteins, central nuclei, and myofiber invaginations. Magnetic resonance shows that fat accumulation  of various extension is present  in the muscle of patients with HypoPP. Water accumulation may also be present whereas atrophy is limited. Fat accumulation tends to increase with time together with a decrease of muscle strength. Permanent weakness and myopathy impairs significantly the quality of life. No treatment is available at the moment.

Introduction

Hypokalemic periodic paralysis (HypoPP) is the most common form among the periodic paralyses with an estimated prevalence of approximately 1 in 100,000 individuals. The majority of cases of HypoPP are familial. Familial HypoPP is an autosomal dominant disease with sex-dependent incomplete penetrance, which is more pronounced in women^1-7. Further forms have been described in association with thyrotoxicosis³.

Mutations in the calcium channel gene CACNA1S occur in HypoPP Type 1 (approximately 60-70% of cases) and mutations in the sodium channel gene SCN4A characterize HypoPP Type 2 (20-30% of cases) ^2-4.

Mutations affect positively charged residues, such as arginine, in the S4 segment of the α-subunit of the skeletal muscle ion channel. These mutations determine alterations of the normal flow of electric current through the ion channel with consequent membrane inexcitability. To this, action potential generation fail follows, producing episodes of flaccid paralysis^3-4.

HypoPP consists of attacks of flaccid paralysis⁵ that often occur at night or early in the morning^2,3. The attacks can either occur spontaneously or be provoked by exercise⁶ or an high carbohydrate meal⁷, high salt meal, steroid administration⁸, alcohol use, cold, infection, fever. Until seventies and eighties, patients diagnosed with familial HypoPP⁹ were told that the disease was functional and that their muscles would not be damaged over time. Indeed, since 1934¹⁰, it was known that some patients with HypoPP may develop permanent muscle weakness and permanent myopathy. Since then, numerous studies have confirmed these results and the knowledge about this disease has improved substantially and dramatically in the last decades^11-14.

The aim of the review is to define the characteristics and the outcome of permanent weakness and myopathy in patients affected by HypoPP.

HypoPP is characterized by attacks of flaccid paralysis consisting in episodes of generalized muscle weakness, predominantly affecting the proximal muscles of the lower limbs that often occur at night or early in the morning. Bulbar and respiratory muscles are typically minimally involved or spared^1,2,5. Hyporeflexia or areflexia during the attack is a characteristic finding. The age of the first paralytic attack in affected individuals who develop repetitive attacks, ranges from 2 to 30 years, with a mean age at onset of 14 years. Occasionally, clinical manifestations can be present at birth. One study⁸ has shown that the mean frequency of paralytic attacks was seven per month (2/week), with a range of one attack per day to one attack every four months. In the past, it was assumed that the frequency of attacks decreases with age, but recent studies have shown that only less than one third of patients reported decreased frequency with age¹⁵. The duration of the paralytic attacks is extremely various ranging from few hours to days^2.3.

During the paralytic attacks, the serum levels of potassium are low, ranging between 1.2 mmol/l to 2.3 mmol/l, in the various studies. Triggers of paralytic attacks are strenuous exercise followed by rest⁶, carbohydrates-rich meals⁷ in the evening followed by nocturnal rest, cold, salt intake, anesthesia, stress and anxiety and fear, prolonged immobility, glucocorticoids use⁹. Severity and frequency of acute attacks are normally milder in women compared with men¹⁶. Episodes of tachyarrhythmias, although uncommon, have been reported during the attacks^17-19.

Muscle pathology

It was already known in the 1970s that HypoPP was a vacuolar myopathy²⁰. Vacuolar alterations are present in all patients affected by HypoPP pathogenic variants in CACNA1S gene and in 27% of all muscular fibers. Vacuolar myopathy was also been observed in patients carrying SCN4A pathogenic variants, but not in all muscle samples. In general, vacuoles are heterogeneous in size and content. Vacuoles are present in both fiber types and are not exclusive to any age or phenotype. Generally, vacuoles contain glycogen but may also contain autophagosomes, fibrillar proteins, central nuclei, and myofiber invaginations^21-24. Vacuoles do not contain actin and/or myosin. It seems that alterations in the autophagic processing may lead to the development of vacuolar lesions^20-27. Tubular aggregates, defined as morphological abnormalities characterized by the accumulation of densely packed tubules derived from the sarcoplasmic reticulum in skeletal muscle fibers, are another prominent pathological finding in HypoPP^25-26. Nagasaka et al.²⁵ reported the presence of tubular aggregates in type 2 fibers that were not typical but instead collection of tubular structure in the ultrastructural study. In the study of Bisciglia et al.²⁶, it was reported a family with three individuals affected by HypoPP CACNA1S variant and with marked phenotypic variability and that two subjects underwent muscle biopsy, and both exhibited tubular aggregates, albeit to different extents. In the study of Gold et al.²⁸, electron microscopy disclosed tubular aggregates in about 15% of the fibers. Tengan et al.²⁹ found that 10 of 14 biopsies obtained from 14 HypoPP patients showed tubular aggregates, particularly in patients with frequent crises or permanent weakness.

Muscle imaging

In 1990, a Dutch study first demonstrated the presence of fat accumulation in the muscles of patients with hypoPP¹³. Fat accumulation was graded on a scale of 0 to 4 using CT scans of the muscles of the neck, chest, abdomen, pelvis, and legs. The score ranged from 0.63 to 2.0. A more recent study³⁰ including 15 patients with HypoPP from both gene variants, who underwent MRI (nine patients) or CT (six patients), demonstrated that fatty infiltration was present in 53.3% of patients at the thigh level and in 60% of patients at the calf level. The muscles that most commonly showed fatty infiltration were the soleus and medial gastrocnemius. Another study³¹ published in the same year demonstrated that edema was frequently present in the lateral gastrocnemius, soleus and gastrocnemius muscles. More recently, larger studies have carefully described the appearance and structure of the muscles of patients with hypoPP on MRI, with somewhat conflicting results^14,32. Holm-Yildiz et al.¹⁴ studied 37 patients with CACNA1S variants that cause hypoPP, using whole-body muscle MRI performed on a 3.0-T scanner. They showed a muscle fat fraction ranging from 2% to 79% in several examined muscles. The lowest values were observed in the anterior leg muscles, rectus femoris, gracilis, vastus lateralis, gastrocnemius lateralis, and biceps femoris, while the highest values were observed in the erector spinae, adductor magnus, adductor longus, psoas major, and multifidus. In the study of Vivekanandam et al.³², 45 HypoPP patients and 8 healthy controls underwent T1-weighted and short-tau-inversion-recovery (STIR) MRI imaging of leg muscles. The 17 patients with HypoPP and pathogenic CACNA1S variants had greater fat accumulation than controls (p = 0.01). The Mercuri’s scale score ranged from 0 to 3.28 with a relatively low mean (±SD) value. No significant differences in fat accumulation were observed between calf and thigh muscles. Fat accumulation tended to be greater in older patients, but at the same time, most young patients had fat accumulation. Overall, greatest muscle fat accumulation occurred in patients with higher disability. However, the degree of fibrofatty replacement was more pronounced in patients with pathogenic SCN4A variants. It is important to note that in that study³², CACNA1S patients with the highest degree of fibrofatty replacement were those who presented with progressive myopathy in the absence of paralytic attacks. These conflicting findings may be due to the different MRI techniques used, and/or to the fact that muscle fat replacement in HypoPP can sometimes be focal and not diffuse, and may not be present in surrounding muscles^21,32. Muscle atrophy does not appear to be moderate-severe in these patients, the score ranging from 0 to 0.8 on the 0 to 3 atrophy scale³². Finally, in some cases, muscles may show water deposition. In a scale from 0 to 3 measuring water content that assess the severity and extent of hyperintensity through axial STIR sequences on MRI, the STIR score ranged between 0 and 1.17, the mean value being relatively low³². Typically, water deposition is most frequent and severe in vastus medialis, vastus lateralis, vastus intermedius, and rectus femoris muscles in the thigh, and in the medial gastrocnemius, lateralis gastrocnemius, and soleus muscles in the leg. Water content (STIR hyperintensity) was significantly related to disability and Mercuri score³². Interestingly, some patients showed fat accumulation and/or atrophy in the muscles of the pelvis that play a key role in the movement and stability of the entire human body³².

Pathogenesis of fat accumulation

The cause and the mechanism underlying the fat accumulation are essentially unknown. The observation that there is no correlation between the number and severity of paralytic attacks and the prevalence and grade of fat accumulation has led some authors to hypothesize that in these patients a continuous and unknown mechanism of damage may occur at the muscle cell level^{13, 21,33}. Recently, two studies have shown that, in patients with HypoPP, muscle autophagy is negatively affected suggesting that the long-term effect of such dysfunctional autophagy may be due to a loss of muscle function^26,27. Nakasaka et al.²⁵, studying the morphological alterations of the sarcotubular system in permanent myopathy of patients with the CACNA1S pathogenic variant of HypoPP, suggested that alterations in type 1 calcium channels and the consequent abnormal function of the sarcoplasmic reticulum and the formation of vacuoles by the fused sarcoplasmic reticulum during the repair process, may determine permanent myopathy²⁵.

Clinical aspects

Four phenotypes of the disease have been described: 1) asymptomatic (A); 2) periodic paralysis and absence of permanent weakness (PP); 3) periodic paralysis and permanent paralysis (MW); 4) permanent weakness and absence of periodic paralysis (PW)²¹. In the study of Holm-Yildiz et al.²¹, the prevalence of these phenotypes was 6.3%, 55.8%, 32.4%, and 5.5%, respectively. Unfortunately, the prevalence of the four types is not always reported in all studies with most commonly only the frequency of permanent weakness being shown^{13,22,25,32,34}. Overall, the prevalence of permanent weakness ranges between 48% and 52%^{13,22,29,32,34}.

Interestingly,it has been shown that patients with HypoPP associated with pathogenic SCN4A variants, typically present with earlier onset, more frequent myalgias, and shorter attack duration compared with cases associated to pathogenic CACNA1S variants¹⁶.

The phenotypes can vary within the same family and most families may present with more than one phenotype. Permanent weakness usually occurs after age 30-40, but it can develop earlier. Permanent weakness generally occurs or is more severe in the lower extremities, both in the thigh and calf, and is symmetrical in older patients²¹.

Muscle strength and contractility

In the presence of permanent weakness (MW and PW phenotypes), muscle strength, assessed by dynamometry and/or a manual scale (Medical Research Council [MRC]), is significantly reduced, especially in paraspinal and abdominal muscles, psoas major muscle, and the proximal limb muscles, resulting in impaired trunk flexion, back extension, hip flexion and abduction. Strength of muscles involved in knee flexion and/or extension and dorsiflexion is also reduced, but to a lesser extent^21,32,33.

A weak correlation has been demonstrated between disability and muscle fat accumulation, atrophy and water deposition³². Muscle contractility was found to be significantly reduced in patients with HypoPP when compared to healthy controls³⁵. It is not correlated with fat content in HypoPP caused by pathogenic CACNA1S variants³⁵. Studying the muscles of the lower limbs, it was found that these alterations occur specifically in the thigh muscles, such as the knee extensors and flexors (corresponding to the quadriceps and hamstrings, respectively)³⁵. Other factors may contribute to the reduction in contractility and the role of vacuolar myopathy should be further investigated as stated by the Danish researchers^31,33,35.

Outcome

Little is known about the progression of the myopathy in patients with HypoPP. A 3-year follow-up study³⁶ has shown that muscle strength, assessed through the MRC scale declined in 29.7% of patients with CACNA1S. Strength was reduced in muscles involved in knee extension, knee flexion, hip flexion, and trunk and back extension. Fat accumulation increased in 73% of cases³⁶. Another study of the same group of scientists²¹, that included 37 patients followed for 20 months, demonstrated that fat accumulation increased in 10/21 examined muscles of the thigh, calf, and lumbar zone. Such increase was more severe in the erector spinae, adductor magnus, psoas major, multifidus, semitendinosus, and semimembranosus muscles³³. Furthermore, Danish researchers³³ demonstrated that baseline muscle fat fraction, expressed as a percentage was higher in patients with mixed or permanent weakness and that the increase in fat fraction, during follow-up, was greater in the PP, MW and PW phenotypes. Interestingly, median muscle strength showed no significant differences during the follow-up³³.

Impact on quality of life

Permanent weakness and myopathy significantly deteriorate the quality of life of patients affected by HypoPP. Many patients (85% to 91%) suffer difficulties in daily activities or have difficulties with mild exercise (10%-15%). Half of them use mobility aids³³. Muscle pain is common, constant or only present after the paralysis attack^6,33,34,37. Fatigue is very common being reported in the majority of patients³³ or in half of them³⁴. Fall injuries are common, occurring in two-thirds of patients, and patients typically experience a constant fear of falling throughout their lives. Depression affects about 35% of patients³³. In patients with type 1 HypoPP, caution is required in case of surgical interventions under general anesthesia due to the risk of onset of malignant hyperthermia, therefore inhalation anaesthetics and muscle relaxants such as succinylcholine should be avoided³⁸.

Treatment

The therapeutic armamentarium for the treatment of HypoPP is small³⁹. We must distinguish between therapy for the acute attack and therapy for the prevention of acute attacks. For the treatment of the acute attack, potassium chloride supplementation is indicated at a dose of 0.5-1 mEq/kg of body weight, with a supplemental dose of 0.3 mEq/kg in case of failure to respond³⁹. Attention should be paid to rebound hyperkalemia, as total body potassium is not depleted in HypoPP.

For the prevention of acute attacks, other than oral potassium supplementation, the only drug approved by the US Food & Drug Administration is dichlorphenamide, which has been shown to reduce the frequency and severity of paralytic attacks^40-43. In the study of Sansone et al.⁴¹, most patients with HypoPP patients treated with dichlorphenamide experienced less than one attack per week compared to more than two attacks per week of patients receiving placebo (median attack rate 0.3 vs 2.4, p = 0.02). The mean 9-week change in the Short Form-36 (SF36) Physical Component Summary score was also better in patients treated with dichlorphenamide than in those treated with placebo⁴⁰. Post-hoc analyses extending the results of the original study demonstrated that efficacy was maintained throughout the 61-week study, with no evidence of decline over time⁴². Acetazolamide⁴⁴ has been widely used in patients affected by HypoPP although there is no evidence of prospective, randomized, controlled trials. A retrospective study demonstrated that acetazolamide is effective in nearly 50% of patients and that benefit is more frequent in patients with CACNA1S mutations than in those with pathogenic SCN4A variants⁴⁴. Furthermore, potassium-sparing diuretics such as spironolactone or triamterene have been proposed as a potential option for the chronic treatment of HypoPP³⁸. Finally, verapamil, tested in nine patients with HypoPP in a randomized, cross-over study, showed no benefit compared to controls⁴⁵. Unfortunately, no drug is currently available for the prevention and/or treatment of permanent weakness and myopathy.

Despite the evidence of a single-case report⁴⁶, the role of physiotherapy in improving muscular strength and functional activities needs to be confirmed by adequate, randomized, controlled studies.

Screening and Follow-up of permanent myopathy

Identifying which patients with HypoPP will develop permanent myopathy is a crucial step in treatment. Regular follow-up including clinical examination, quantification of muscle strength and contractility, and personal history, with particular attention to patient-reported motor outcome measures, may be helpful. The progression of permanent myopathy can also be monitored by muscle MRI. A recent study has in fact demonstrated that quantitative MRI can highlight the subclinical progression of permanent myopathy related to HypoPP³³.

Future research and conclusions

In the near future, efforts should be focused on identifying the mechanisms underlying permanent myopathy and muscle fat accumulation in patients with HypoPP. This step is essential for identifying pharmacological treatments and defining personalized therapeutic strategies. Furthermore, randomized, controlled trials are desirable to define the role of physiotherapy in preventing and/or slowing the progression of permanent myopathy.

Funding

None.

Conflicts of interest statement

None.

Author’ contribution

All authors contributed authors have contributed equally to the concept, writing, revision and approval of the manuscript.

History

Received: January 21, 2026

Accepted: March 12, 2026