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 the periodic cardiac review by an experienced cardiologist, with paralyses although some patients do develop a proximal ECG and prolonged Holter monitoring. myopathy. However, if patients are examined during an episode of weakness, as well as reduced strength, THE NON-DYSTROPHIC MYOTONIAS the reflexes are reduced or absent. In someone with Myotonia is usually the presenting problem in both hyperkalaemic periodic paralysis there may be detect- myotonia congenita and paramyotonia congenita. able myotonia. Patients with Andersen-­Tawil syndrome It can be difficult for patients to describe (especially can have dysmorphic features including short stature, before a diagnosis is made) and they may use terms low-set­ ears, micrognathia, clinodactyly, dental abnor- such as muscles cramping, being stiff, stuck, aching, malities.16 Note that any dental abnormalities may or ‘not working’. Myotonia can affect any skeletal have been corrected in childhood, so it is important muscle so although typical patterns of involvement to enquire about dental work, especially extraction for occur—legs more than hands and face in myotonia overcrowding. congenita, hands and face more than legs in paramyo- People with myotonia often have generalised muscle tonia congenita—symptoms affecting the trunk, back hypertrophy, or well-­defined muscles.9 Because they (back pain) and chest muscles (cannot catch breath/ are often young adults at presentation, it is easy to take a deep breath) can all be problematic. Myotonia assume they look this way because they are young and affecting the face can affect the jaw and tongue, fit. Muscle hypertrophy must always be considered in making chewing or swallowing difficult especially with context and clinicians should make a specific enquiry cold food or drink. Cardiac and smooth muscle (bowel as to how active or how many times a week they actu- or bladder) are not affected in the non-­dystrophic ally attend the gym. myotonias. Patients with a myotonic disorder will (nearly Other characteristic pointers towards either always) have evidence of myotonia on examination myotonia congenita or paramyotonia congenita include but this can be easily overlooked in a general neurolog- the warm-­up phenomenon in myotonia congenita ical examination. Patients with myotonia congenita are (myotonia improving with repetitive activity) or para- best diagnosed from the waiting room. They may well doxical myotonia in paramyotonia congenita (worsens have sat for a while waiting to be called. When they with repetition), as well as different forms of episodic first rise, their leg muscle myotonia causes them to be weakness (see table 1). Sodium channel myotonia has slow and to have a stiff gait. By the time they reach features that overlap with both myotonia congenita the clinic room this has become normal. Examination and paramyotonia congenita but this term refers essen- for eyelid closure or hand grip myotonia should be tially to a pure myotonic disorder without episodic repeated. If the patient has paramyotonia congenita weakness, caused by mutations in the SCN4A (sodium the first movements may appear unrestricted and only channel) gene. with repetition will myotonia become evident (para- http://pn.bmj.com/ Myotonia itself is a symptom and/or sign, not a doxical myotonia). Conversely in myotonia congenita, diagnosis. It can be seen or detected during electro- the myotonia may be immediately evident with the first myography (EMG) in other conditions including test but improves or disappears with repetition that is, myotonic dystrophy types 1 and 2, Pompe’s disease12 the warm-­up phenomenon. We usually ask the patient and other myopathies13 (where it may have no overt to grip their hands tightly or to close their eyes ‘as if clinical signs and be detectable only by EMG), or they have soap in them’ for 5 s, then to open the hands/ on September 29, 2021 by guest. Protected copyright. it may be drug induced.14 Nevertheless, by far the eyes as fast as possible. This should be repeated three most common diagnosis in someone with myotonia to five times. Other findings can include contractures, is myotonic dystrophy type 1; this should always be for example, at the elbow and scoliosis, although this considered especially in younger patients who may not is most commonly seen in children and young adults. yet manifest its multisystem involvement. Also DM2, less common than DM1 and with more mild systemic INVESTIGATIONS features (even at older ages), can cause confusion with Investigations performed when considering the possi- non-­dystrophic myotonia. bility of a muscle channelopathy need to be interpreted in light of the overall presentation, as a negative test in PAIN AND FATIGUE isolation does not exclude a channelopathy. Although episodic weakness or myotonia are the dominant clinical symptoms in the skeletal muscle BLOODS TESTS/CREATINE KINASE channelopathies, pain (myalgia) and fatigue are often The main role of blood tests in investigating a skeletal prominent and sometimes are the patient’s main muscle channelopathy is to exclude other diagnoses. concern.5 6 15 It is important to enquire about these and A standard ‘battery’ includes tests of renal function to attempt to treat them as well as addressing weakness (is there renal disease altering the serum potassium?), and myotonia. thyroid function tests (does the patient have thyrotoxic

Matthews E, et al. Pract Neurol 2021;21:196–205. doi:10.1136/practneurol-2020-002576 3 of 10 Review Pract Neurol: first published as 10.1136/practneurol-2020-002576 on 9 February 2021. Downloaded from Yes can be generalised Yes Yes can be generalised Yes Yes calf Characteristically muscle hypertrophy but can be generalised Prolonged weakness (can or paralysis have clinical overlap with hyperkalaemic periodic paralysis). Transient weakness Transient improving with repetition of task Characteristic Characteristic finding Paradoxical Paradoxical myotonia (myotonia with worsens repetition) Episodic weakness Muscle hypertrophy No Can occur Can occur No No Warm up Warm phenomenon (myotonia with improves repetition) Characteristic Characteristic finding Warm environments Warm (although extremes can provoke myotonia) Warm Warm environments Warm environments Warm (although extremes can provoke myotonia) Gentle movement before engaging in activity http://pn.bmj.com/ Prolonged rest or sitting (especially after activity) Activity temperature extremes hot or cold Cold environment Activity rest after activity Prolonged rest or sitting (especially after activity) Temperature extremes hot or cold Symptomatic triggers Relieving factors or face.

on September 29, 2021 by guest. Protected copyright. Either pattern Face and hands>legs Face Muscles most commonly affected Legs>hands Falls are common. Falls ­ dystrophic myotonias Autosomal dominant Autosomal dominant Inheritance pattern Autosomal dominant or recessive SCN4A SCN4A CLCN1 Gene Clinical features of the non-

Table 1 Table Sodium channel myotonia* Paramyotonia Paramyotonia congenita Myotonia congenita acetazolamide responsive myotonia but these were subsequently all shown to myotonia, known many clinical phenotypes were described including potassium aggravated *Before the genetic basis of channelopathies was be due to mutations in the SCN4A gene and are now collectively called sodium channel myotonia.

4 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

Table 2 Differential diagnoses of skeletal muscle channelopathies Diagnosis Comment Myopathies–Pompe’s disease, myofibrillar May have electrical myotonia on EMG. myopathy Myopathies–metabolic, McArdle’s disease, Episodic symptoms, often related to physical exertion, can be confused with periodic paralysis. RYR1 related A specific RYR1/periodic paralysis overlap syndrome has recently been identified. Becker muscular dystrophy Large calves occasionally confused with calf hypertrophy seen in myotonia congenita. Secondary causes of hypokalaemia for example, Profound hypokalaemia can induce muscle weakness in anyone, even without a genetic renal disease, drug induced predisposition. Thyrotoxic periodic paralysis Can present with hypokalaemic periodic paralysis, most commonly seen in Asian males. Essential to check thyroid function tests in all first presentations of hypokalaemic periodic paralysis as treatment of the thyrotoxicosis abolishes the episodes of periodic paralysis. Migraine (hemiplegic migraine) Usually, there is a headache history to guide diagnosis but non-­headache symptoms may predominate. Paroxysmal movement disorders, for example, Patients may use the term ‘weakness’ erroneously when it is difficult to quantify a symptom paroxysmal kinesigenic dyskinesia, GLUT1 deficiency, episodic ataxia Functional disorder Most commonly a functional episodic weakness confused with periodic paralysis EMG, electromyography. periodic paralysis?), white cell enzymes (Pompe’s 5 min period). The postexercise CMAPs are recorded disease) and creatine kinase. Serum creatine kinase in for a 50 min period looking for a 40% or more decline people with skeletal muscle channelopathies typically in amplitude compared with the postexercise peak. A ranges from being within normal limits to being up to positive test indicates a periodic paralysis but not the 1000 IU/L.6 It is a non-specific­ test but an abnormal subtype. In a significant minority of cases, especially in result always helps to support the suspicion of a neuro- those with Andersen-­Tawil syndrome as well as those muscular disorder. However, a normal result does not with rare attacks of weakness, the long exercise test can exclude a skeletal muscle channelopathy. Values above be normal.20 So, a positive test can help but a negative 1000 IU/L can occur and are consistent with a skel- test does not exclude a diagnosis of periodic paralysis. etal muscle channelopathy diagnosis but they are less EMG will determine the presence of myotonia. common17; values this high makes it worth considering However, myotonia is non-­specific and having identi- the whole presentation and asking if this could reflect fied it, the clinician needs to consider all the possible an alternative neuromuscular diagnosis (see table 2). differential diagnoses (table 2). Electrical myotonia There are rare reports of a skeletal muscle channelo- without clinical myotonia is more common in people http://pn.bmj.com/ pathy with a serum creatine kinase above 10 000 IU/L with a myopathic disorder but usually there are other 18 and presentation with rhabdomyolysis. indicators of this, for example, a myopathic EMG, Ictal serum potassium concentrations can help but fixed weakness on examination and persistent func- are not absolute in someone with possible periodic tional disability. A repeat short exercise test can show paralysis. If the weakness is severe enough to cause certain patterns of response that help to indicate the tetraparesis, then the serum potassium will usually be different sub-types­ of non-­dystrophic myotonia21 but on September 29, 2021 by guest. Protected copyright. outside the normal range. However, the key element it is not specific and there is overlap with the patterns associated with weakness is a rise or fall in serum potas- seen in myotonic dystrophy. Now that next-­generation sium concentration; the absolute value is not always sequencing allows genes to be sequenced in parallel, abnormal. This can be especially true if an attack is rather than having to select a ‘first choice’, this test has beginning to subside, or has subsided by the time any less practical value. blood tests are taken.

NEUROPHYSIOLOGY GENETIC TESTING Standard EMG and nerve conduction studies are Next-­generation sequencing means that parallel testing usually normal in the periodic paralyses (except in of all genes relevant to skeletal muscle channelopathies some cases of hyperkalaemic periodic paralysis with is now available in the UK. This is particularly helpful myotonia). The most informative test to diagnose for Andersen-­Tawil syndrome, which may present clin- a periodic paralysis is a long exercise test.19 This ically with a hypokalaemic periodic paralysis picture involves stimulating the ulnar nerve and recording a but an accurate diagnosis can be made only by next-­ series of compound muscle action potentials (CMAP) generation sequencing. This includes analysis of all from abductor digiti minimi before and after ‘exer- three periodic paralysis genes, SCN4A, CACNA1S and cise’ of the muscle (abduction against resistance over a KCNJ2. Due to the cardiac risks of Andersen-­Tawil

Matthews E, et al. Pract Neurol 2021;21:196–205. doi:10.1136/practneurol-2020-002576 5 of 10 Review Pract Neurol: first published as 10.1136/practneurol-2020-002576 on 9 February 2021. Downloaded from syndrome we recommend offering genetic testing to all relatives of a proband, regardless of symptoms. For a possible myotonic disorder, CLCN1 and SCN4A are also analysed in parallel. DM1 and DM2 genetic testing needs to be requested separately and should not be forgotten even if the patient appears ‘only’ to have a myotonic disorder. In terms of inheritance pattern, all skeletal muscle channelopathies are autosomal dominant or de novo, Figure 3 MR scan images (STIR) of both calves in a patient with myotonia congenita, showing the ‘central stripe’ in both except for myotonia congenita, which can be dominant left and right medial gastrocnemius muscles (arrowheads). or recessive. Recessive CLCN1 variants can cosegregate Figure reproduced.26 with an SCN4A variant or an expansion in the DMPK and CNBP genes associated with DM1 and DM2. This can cause diagnostic confusion, for example, if a A muscle biopsy is not necessary or generally infor- proband has a clinical diagnosis of myotonia congenita mative for the diagnosis of typical skeletal muscle chan- but genetic analysis identifies one variant in a family nelopathies. Those performed historically have shown with dominant inheritance of a myotonic disorder, it non-­specific myopathic findings, including a vacuolar may be assumed that this reflects a positive diagnosis; myopathy in periodic paralysis.27 Exceptions to this in fact, the proband may have myotonic dystrophy but include the newer and atypical phenotypes of channel- be a carrier for a recessive CLCN1 variant. This has opathy, for example, RYR1-related­ periodic paralysis 22 clinical implications as the patient may not be moni- where a muscle biopsy can support the diagnosis. tored for cardiac and other systemic complications if diagnosed with myotonia congenita. MANAGEMENT The characteristic phenotypes of the skeletal muscle Skeletal muscle channelopathies are genetic disorders channelopathies have been described for over 100 that currently are not curable but there are numerous years and the genetic basis of these disorders known symptomatic treatments and management approaches since the early 1990s. A significant minority of patients that can significantly impact morbidity. do present with a channelopathy like clinical presenta- tion but have a negative genetic result for these estab- LIFESTYLE AND ACTIVITY lished disease causing genes. Many people with skeletal muscle channelopathies In the last few years, several alternative genetic report some clear symptom triggers, for example, causes of episodic neuromuscular weakness have been foods high in carbohydrate or potassium. Keeping a identified, with expanding phenotypes.22 23 Other food diary can help to identify these and help people neuromuscular conditions can also have episodic or to avoid them or make alternative food choices. fluctuant presentations, for example, metabolic disor- The relationship between symptoms and exercise http://pn.bmj.com/ ders (see table 2); these should be considered if genetic means that many people with these conditions avoid testing for a skeletal muscle channelopathy is negative. exercise and activity, having low levels of physical Also other paroxysmal disorders, especially GLUT1 activity and difficulty maintaining an active lifestyle. deficiency syndrome and paroxysmal kinesigenic However, those people who have managed to develop dyskinesia, can erroneously be referred to a neuromus- ways of staying active do find this helpful. cular clinic.24 There are well-established­ benefits of keeping active, on September 29, 2021 by guest. Protected copyright. in terms of extending health span, and particularly for people with long-­term conditions. There are also OTHER INVESTIGATIONS—MR SCANNING AND well known correlations for the general population MUSCLE BIOPSY between extended periods of inactivity (sedentary MR scanning of muscles, usually of the lower limb behaviour), health outcomes including obesity, cardio- muscles in skeletal muscle channelopathies, can show vascular and metabolic diseases, and an increased risk fatty muscle infiltration in keeping with the clinical of mortality.28 29 development of fixed myopathy25 or T1 STIR hyper- There is little published evidence about activity intensity. In periodic paralysis the STIR hyperintensity specifically in people with skeletal muscle channel- probably reflects disease activity, that is, ongoing recur- opathies, although our personal experience suggests rent episodes of weakness. This can help in guiding a trend for high levels of sedentary behaviour in this symptom treatment and response. Early pattern recog- population, indicating that interventions addressing nition, including a gastrocnemius ‘central stripe’ in this may help improve health outcomes. myotonia congenita26 may be diagnostic pointers Advice on extended periods of warm up and cool (figure 3) but as yet there is no established definitive down, and stretches before and after exercise, can MRI pattern of muscle involvement for skeletal muscle support an individual to transition in and out of, and channelopathies. prepare for exercise, without precipitating symptoms

6 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 and/or in some cases associated muscle pain. Low inten- flecainide are commonly used. The requirement for sity and low resistance exercises, focusing on gradually interventional devices such as an implantable cardiac increasing repetitions and resistance as muscles adjust, defibrillator appears to be more common than previ- can also help to avoid worsening myotonia or precip- ously appreciated, emphasising the importance of itating weakness. Activity monitors or apps can help expert cardiac involvement.11 to measure activity, and to establish a baseline from to set goals for gradually increasing activity and/or to EMERGENCY TREATMENT OF PERIODIC PARALYSIS interrupt extended periods of sedentary behaviour. Among patients with skeletal muscle channelopathies Walking and moving around is often more accessible it is those with hypokalaemic periodic paralysis who than formally working out at the gym. present most commonly to emergency departments, Fatigue may also improve with these approaches due to the extended nature of their attacks. All patients or may require additional referral to a formal fatigue presenting with a first episode of hypokalaemic peri- management programme. odic paralysis should be investigated for secondary causes of hypokalaemia, and especially thyrotoxicosis PHARMACOLOGICAL TREATMENTS (figure 2). Those with a low serum potassium require Some people choose to manage symptoms by adjusting ECG monitoring. Any ECG changes are an indica- triggers as much as possible.7 When medication is tion to use an intravenous rather than oral potassium indicated there are numerous choices. In the periodic replacement. ECG and serum potassium monitoring paralyses, prophylactic treatment aims at controlling must continue during replacement and for several serum potassium, with diuretics that are either potas- hours after its correction to normal. This is because sium sparing (aldosterone antagonists for example, during an attack, potassium is held intracellularly spironolactone, or amiloride) or potassium wasting but the total body potassium is not actually low. As (thiazides). For those with hypokalaemic periodic the attack subsides, potassium returns to the serum. Combining this with exogenous replacement can result paralysis, potassium supplements taken at the onset of 34 an attack can help to abort or minimise symptoms.7 in a rebound hyperkalaemia and iatrogenic death. Other options effective in both forms of periodic paral- PREGNANCY AND LABOUR ysis include carbonic anhydrase inhibitors: acetazol- Most pregnant women with skeletal muscle channel- amide or dichlorphenamide (not currently available opathies report symptom exacerbation during preg- in UK). Long-­term acetazolamide requires an annual nancy,35 36 probably due to both hormonal changes and renal ultrasound scan to monitor for renal calculi. The medication withdrawal. The current recommendation treatment of non-dystrophic­ myotonia of any subtype is to stop medication before and during pregnancy due is with sodium-­channel blockers. Mexiletine is most either to evidence of teratogenicity or a lack of safety widely used and has the greatest available evidence 30–32 data. There are some reports of mexiletine having of efficacy and safety but lamotrigine is increas- been used without major adverse event during preg-

33 http://pn.bmj.com/ ingly popular following a recent clinical trial. Other nancy37 38 and the more recent evidence of lamotrigi- options with more limited or anecdotal data include ne’s efficacy in myotonic disorders33 offers a potential ranolazine, carbamazepine, flecainide, propafenone option for pregnant women. Worsening symptoms can and phenytoin. All options are aimed primarily at be particularly detrimental if they provoke increased treating either episodic weakness or myotonia. There falls. The symptoms may necessitate taking maternity are no studies to indicate the best treatment of pain leave early, with the knock-on­ effect of limiting time on September 29, 2021 by guest. Protected copyright. or myalgia in these conditions. Our experience is that available to spend with baby post-partum.­ acetazolamide, often combined with an anti-myotonic­ Many women with skeletal muscle channelopathies agent such as mexiletine can help in the non-dystrophic­ have spontaneous unassisted vaginal deliveries, and myotonias but that analgesics, including neuropathic this should remain an option when birth planning. agents, often have limited benefit. However, we usually recommend considering the There is some limited evidence that aggressive labour to be relatively high risk, such that delivery control of episodic symptoms might influence the takes place in a facility where there are senior paedi- longer term development of a proximal myopathy that atric, obstetric and anaesthetic staff and facilities avail- can occur in muscle channelopathies. able if required. Symptoms of weakness or myotonia may prolong a labour and delivery with all the inherent CARDIAC MANAGEMENT complications of this, but also a subgroup of infants All patients with Andersen-­Tawil syndrome should have can have life-threatening­ respiratory complications an annual review with a cardiologist. Extended ECG if they have inherited the disorder39 (predominantly recording, for example, 24 or 72 hours Holter moni- those inheriting an SCN4A gene mutation). toring may detect arrhythmias that require treatment even when the patient reports no symptoms. There is ANAESTHETIC CONSIDERATIONS no randomised controlled trial evidence for the most For any patient requiring an anaesthetic (including effective antiarrhythmic regimen but beta-blockers­ or during labour) it is essential the anaesthetist knows

Matthews E, et al. Pract Neurol 2021;21:196–205. doi:10.1136/practneurol-2020-002576 7 of 10 Review Pract Neurol: first published as 10.1136/practneurol-2020-002576 on 9 February 2021. Downloaded from of the diagnosis of a skeletal muscle channelopathy speak or to open the eyes at all is not typical and more beforehand, where feasible. Local or regional anaes- suggestive of functional weakness. In young children thetics are preferred to a general anaesthetic if possible. with hypokalaemic periodic paralysis respiratory If using general anaesthesia, propofol and non-­ muscle weakness can cause respiratory distress and depolarising anaesthetic agents appear to be effective hypoxia. This is much less common in teenagers and and safe.40 Depolarising anaesthetics or suxametho- adults but can occur in severe episodes with tetrapa- nium can precipitate a myotonic crisis with profound resis. Does the patient look dysmorphic? Do they have muscle rigidity, which can mimic a malignant hyper- short stature? Short stature and dysmorphic features thermia type reaction. If the rigidity includes the jaw vary widely in Andersen-­Tawil syndrome but among muscles, intubation may be impossible.41 Suxametho- the most common are micrognathia (small chin), clin- nium can also induce hyperkalaemia and ventricular odactyly (curved digit, usually the little fingers) and arrhythmia, which can be fatal.42 Emergency treat- low-­set ears. Are there any other systemic abnormal- ment for a myotonic crisis is with intravenous sodium ities? Hypertension may accompany secondary causes channel blockers such as lidocaine.40 of hypokalaemia. Tachycardia may suggest thyrotoxi- Note that other peri-­operative factors can also exac- cosis but can occur with hypokalaemia itself, or may erbate symptoms of a skeletal muscle channelopathy just indicate the patient is anxious about being unable for example, prolonged immobility, or a cold oper- to walk. ating theatre/recovery room. In summary skeletal muscle channelopathies are INITIAL INVESTIGATIONS AND MANAGEMENT rare. They can evade diagnosis because the symp- Hypokalaemia with normal acid–base balance is toms are sometimes hard for a patient to describe, the expected in genetic forms of hypokalaemic periodic examination is often normal and investigations may paralysis. Acid–base disturbance should prompt more be normal or negative unless conducted during symp- extensive renal, and endocrine investigations for, for toms. Yet they are extremely treatable and making example, renal tubular acidosis, Gitelman’s syndrome, the appropriate diagnosis and management plan can or hyperaldosteronism. Given that the hypokalaemic be very rewarding for clinicians, and greatly benefit weakness may be the only indicator of thyroid disease patients. we recommend routinely testing all first presenta- tions. Serum creatine kinase can be normal or raised CASE EXAMPLE: A WEAK PATIENT IN THE and is non-­specific to diagnosis but a positive test can EMERGENCY DEPARTMENT WITH A LOW POTASSIUM—IS IT PERIODIC PARALYSIS? Key points HISTORY ► When assessing a myotonic disorder without obvious The age of the patient can be indicative. Drug history ►

systemic involvement, do not forget myotonic http://pn.bmj.com/ may be more pertinent in older patients. Genetic dystrophy. disorders are more likely to present for the first time ► Symptoms of a muscle channelopathy are more than in younger patients, the typical age of onset of hypo- ► just weakness and myotonia: pain and fatigue can be kalaemic periodic paralysis being in the teens. These prominent. are of course pointers only, and age is not an absolute ► Andersen- ­Tawil syndrome requires cardiac monitoring criterion for genetic causes of periodic paralysis. Hypo- ►

regardless of symptoms. on September 29, 2021 by guest. Protected copyright. kalaemia from any systemic, drug-­induced or genetic ► Episodic movement disorders can be confused with a cause can induce muscle weakness. Ask the patient if ► muscle channelopathy and vice versa. they have diarrhoea and vomiting, tachycardia and ► Skeletal muscle channelopathies are treatable palpitations (thyrotoxicosis). Is there a history of renal ► disorders. disease? Take a drug history and family history (is there a known family history of periodic paralysis or relatives with the same symptoms)? Has this happened before or have they had milder symptoms of weakness Further reading that resolved spontaneously without needing to attend ► Cannon SC. Channelopathies of skeletal muscle the Emergency Department? ► excitability.Compr Physiol 2015;5:761–90. ► Jitpimolmard N, Matthews E, Fialho D. Treatment EXAMINATION ► updates forneuromuscular channelopathies. Curr Treat Weakness typically affects the limbs and trunk with Options Neurol 2020;22:34. reduced or absent reflexes. Muscles of the neck and ► Matthews E, Balestrini S, Sisodiya SM, et al. Muscle face are less commonly affected but can be. This may ► and brainsodium channelopathies: genetic causes, cause slurred speech if the lower face and tongue are clinical phenotypes,and management approaches. weak or for there to be eye closure weakness. Extra- Lancet Child Adolesc Health 2020;4:536–47. ocular muscles are not usually weak; an inability to

8 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 help with triaging an onward referral after the acute 12 Kassardjian CD, Engel AG, Sorenson EJ. Electromyographic episode. findings in 37 patients with adult-­onset acid maltase deficiency. Monitor the ECG and serum potassium. There is no Muscle Nerve 2015;51:759–61. absolute value for when to choose oral vs intravenous 13 Milone M, McEvoy KM, Sorenson EJ, et al. Myotonia replacement but a potassium <2.5 mmol/L, severe associated with caveolin-3 mutation. Muscle Nerve 2012;45:897–900. muscle paralysis especially if breathing is impaired, or 14 Miller TM. Differential diagnosis of myotonic disorders. ECG changes of hypokalaemia (flat T waves, u waves, Muscle Nerve 2008;37:293–9. ST segment depression) are indicators for giving intra- 15 Palmio J, Sandell S, Hanna MG, et al. Predominantly myalgic venous potassium. A typical dose of 40 mmol/L potas- phenotype caused by the c.3466G>A p.A1156T mutation in sium chloride in 1 L of 0.9% sodium chloride given at SCN4A gene. Neurology 2017;88:1520–7. a rate of 10 mmol/hour is usually sufficient but local 16 Davies NP, Imbrici P, Fialho D, et al. Andersen-­Tawil guidelines should be consulted. If potassium replace- syndrome: new potassium channel mutations and possible ment is given it is mandatory to monitor the ECG phenotypic variation. Neurology 2005;65:1083–9. throughout and for several hours after normokalaemia 17 Matthews E, Miller JAL, MacLeod MR, et al. Sodium and as there is a risk of rebound hyperkalaemia. chloride channelopathies with myositis: coincidence or connection? Muscle Nerve 2011;44:283–8. Twitter Emma Matthews @EmmaM_Channels 18 Anandan C, Cipriani MA, Laughlin RS, et al. Rhabdomyolysis and fluctuating asymptomatic hyperCKemia Contributors All authors contributed to drafting and editing the manuscript. associated with CACNA1S variant. Eur J Neurol 2018;25:417–9. Funding The authors have not declared a specific grant for this 19 McManis PG, Lambert EH, Daube JR. The exercise test in research from any funding agency in the public, commercial or not-­for-­profit sectors. periodic paralysis. Muscle Nerve 1986;9:704–10. 20 Tan SV, Matthews E, Barber M, et al. Refined exercise testing Competing interests None declared. can aid DNA-based­ diagnosis in muscle channelopathies. Ann Patient consent for publication Not required. Neurol 2011;69:328–40. Provenance and peer review Commissioned: externally 21 Fournier E, Arzel M, Sternberg D, et al. Electromyography reviewed by Jon Walters, Swansea, UK. guides toward subgroups of mutations in muscle ORCID iD channelopathies. Ann Neurol 2004;56:650–61. 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