Review Pract Neurol: first published as 10.1136/practneurol-2020-002576 on 9 February 2021. Downloaded from Skeletal muscle channelopathies: a guide to diagnosis and management Emma Matthews ,1,2 Sarah Holmes,3 Doreen Fialho2,3,4 1Atkinson- Morley ABSTRACT in the case of myotonia may be precipi- Neuromuscular Centre, St Skeletal muscle channelopathies are a group tated by sudden or initial movement, George's University Hospitals NHS Foundation Trust, London, of rare episodic genetic disorders comprising leading to falls and injury. Symptoms are UK the periodic paralyses and the non- dystrophic also exacerbated by prolonged rest, espe- 2 Department of Neuromuscular myotonias. They may cause significant morbidity, cially after preceding physical activity, and Diseases, UCL, Institute of limit vocational opportunities, be socially changes in environmental temperature.4 Neurology, London, UK 3Queen Square Centre for embarrassing, and sometimes are associated Leg muscle myotonia can cause particular Neuromuscular Diseases, with sudden cardiac death. The diagnosis is problems on public transport, with falls National Hospital for Neurology often hampered by symptoms that patients may caused by the vehicle stopping abruptly and Neurosurgery, London, UK 4Department of Clinical find difficult to describe, a normal examination or missing a destination through being Neurophysiology, King's College in the absence of symptoms, and the need unable to rise and exit quickly enough. Hospital NHS Foundation Trust, to interpret numerous tests that may be These difficulties can limit independence, London, UK normal or abnormal. However, the symptoms social activity, choice of employment Correspondence to respond very well to holistic management and (based on ability both to travel to the Dr Emma Matthews, Atkinson- pharmacological treatment, with great benefit to location and to perform certain tasks) and Morley Neuromuscular Centre, quality of life. Here, we review when to suspect are often socially embarrassing. The rela- St George's University Hospitals a muscle channelopathy, how to investigate a NHS Foundation Trust, London, tionship of symptoms with activity often London, UK; e. matthews@ sgul. possible case and the options for therapy once a leads to sedentary behaviour, in turn a ac. uk diagnosis is made. risk factor for comorbidities for example, heart disease or stroke. Muscle chan- Accepted 19 December 2020 Published Online First nelopathies are also frequently painful, 9 February 2021 which together with impaired physical INTRODUCTION ability, significantly impacts on quality of Skeletal muscle channelopathies comprise 5 6 life. a group of rare genetic neuromuscular There are readily available symptomatic disorders caused by dysfunction of sarco- http://pn.bmj.com/ treatments for muscle channelopathies lemmal ion channels that are critical for 1 that can usually successfully ameliorate muscle membrane excitability. In simple 7 the burden of morbidity. More often, the terms, they affect the ability of skeletal biggest barrier to improving a patient’s muscles either to contract, causing muscle quality of life is a lack of diagnosis. weakness, or to relax, causing myotonia. However, the diagnosis is not always Skeletal muscle channelopathies are on September 29, 2021 by guest. Protected copyright. easy, the conditions are rare, and patients divided into the periodic paralyses and may be completely asymptomatic with an the non- dystrophic myotonias, based apparently normal initial physical exam- on whether the predominant clinical ination. The diagnosis hinges on careful symptom is muscle weakness or myotonia. history taking arousing clinical suspicion, The hallmark of a skeletal muscle chan- supported by an accumulation of exam- nelopathy is that symptoms occur in an ination findings (or lack of abnormality) episodic or paroxysmal fashion causing and investigative clues. No single test can acute disability.2 As a group, they affect provide an answer in isolation. approximately 1 in 100 000 people in the 3 © Author(s) (or their UK. employer(s)) 2021. No Myotonia (delayed muscle relaxation CLINICAL HISTORY commercial re- use. See rights after contraction) is often described by Skeletal muscle channelopathies include and permissions. Published by BMJ. patients as muscles ‘locking’, ‘sticking’ or the periodic paralyses and the non- ‘cramping’. Episodic weakness can vary dystrophic myotonias. To cite: Matthews E, Holmes S, Fialho D. significantly from one limb ‘not working ► The periodic paralyses are hypokalaemic Pract Neurol 2021;21:196– or feeling right’ to a tetraparesis. Symp- periodic paralysis, hyperkalaemic periodic 205. toms commonly affect the leg muscles and paralysis and Andersen–Tawil syndrome. Matthews E, et al. Pract Neurol 2021;21:196–205. doi:10.1136/practneurol-2020-002576 1 of 10 Review Pract Neurol: first published as 10.1136/practneurol-2020-002576 on 9 February 2021. Downloaded from When taking a history from someone with possible periodic paralysis, it is important to bear in mind several caveats. Despite being called periodic paral- ysis, not all weakness episodes are this dramatic. The most profound episodes do include tetraparesis and these cases are most likely to present to the emergency department with a deranged (often low) serum potas- sium. However, many patients describe more modest weakness, for example, they can stand but only furni- ture walk, or they can walk on the flat but feel weak and cannot run or climb stairs. Weakness often pres- ents during a period of rest following physical activity. Figure 1 The skeletal muscle channelopathies—causative Patients commonly recall having played with friends genes, dysfunctional ion channel and resultant clinical during school lunch break, returning to sit at a desk symptom. for lessons, and then being unable to stand or walk. Sometimes weakness may seem to be task specific or affecting only one limb, for example, a weak dominant ► The non- dystrophic myotonias are paramyotonia hand after a prolonged writing. In these cases, there congenita, sodium channel myotonia and myotonia is usually a history of more generalised weakness; congenita. however, these may be the only symptoms initially These are genetic disorders, and figure 1 shows the volunteered as they are the most troubling. causative genes and the resultant dysfunctional ion Hypokalaemic periodic paralysis characteristically channels. In most cases, symptoms can be traced back presents in the early teens with episodes of weakness to the first or second decade, highlighting the impor- on waking and lasting several hours. This may result tance of taking an early life history. Sometimes, the in being unable to attend school in the morning but symptom onset is delayed into the 30s or 40s and/ appearing ‘normal’ by the afternoon, and so easily or may only appear during certain life events, for misinterpreted as school avoidance.9 Similar scenarios example, pregnancy. can lead to disciplinary procedures for working adults. The recurring episodes of weakness in periodic THE PERIODIC PARALYSES paralysis are similar but not usually stereotyped. The names of hypokalaemic periodic paralysis and Stereotyped episodes would more suggest a parox- hyperkalaemic periodic paralysis relate to episodes ysmal movement disorder or episodic ataxia, in which of muscle weakness accompanying either high or low 8 patients may erroneously use the term ‘weakness’ serum potassium concentrations. They can be further when struggling to quantify a symptom that is difficult distinguished by the typical pattern and duration of to describe, for example, dyskinesia. http://pn.bmj.com/ attacks and symptom triggers that either drive up the serum potassium (foods high in potassium) or drive it down (carbohydrate meals)—see figure 2. Myotonia ANDERSEN-TAWIL SYNDROME can also develop in hyperkalaemic periodic paral- Andersen- Tawil syndrome is the only skeletal muscle ysis but the usual presenting complaint is episodic channelopathy to affect systems other than skeletal weakness. muscle—namely cardiac muscle and bony develop- ment. The classical syndrome is a triad of periodic on September 29, 2021 by guest. Protected copyright. paralysis (usually mirroring the hypokalaemic peri- odic paralysis variety), cardiac conduction defects and dysmorphic features.10 However, in many cases, the dysmorphic features are subtle and overlooked, and the skeletal or cardiac muscle symptoms may domi- nate the clinical picture obscuring the true breadth of systemic involvement. Patients affected predominantly by periodic paralysis may be misdiagnosed as having hypokalaemic periodic paralysis. This has important implications, as the patient’s cardiac risk and need for subsequent monitoring may be overlooked. Sudden cardiac death may occur in Andersen- Tawil syndrome but is generally considered rare. However, cardiac arrhythmias requiring medical intervention appear relatively common, with 20% of patients requiring 11 Figure 2 Features that distinguish hypokalaemic and an implantable cardiac defibrillator in one series, hyperkalaemic periodic paralysis. and sometimes occurring without prominent cardiac 2 of 10 Matthews E, et al. Pract Neurol 2021;21:196–205. doi:10.1136/practneurol-2020-002576 Review Pract Neurol: first published as 10.1136/practneurol-2020-002576 on 9 February 2021. Downloaded from symptoms. We recommend all patients with Andersen- EXAMINATION FINDINGS Tawil syndrome (regardless of symptoms) have annual The examination is typically normal in