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Muscle diseases: mimics and chameleons
  1. R Jon Walters
  1. Correspondence to Dr R Jon Walters, Department of Neurology, Morriston Hospital, Morriston, Swansea, Wales SA6 6NL, UK; Richard.walters{at}wales.nhs.uk or rjonwalters{at}msn.com

Abstract

Muscle diseases are not as common as headaches and funny turns in our general neurology clinics, but most of us will encounter them. We all pride ourselves on a methodical approach to clinical problems—discovering the where and what in neurological parlance—but any diagnostic process can unravel, particularly if one condition resembles another. Before we settle on a diagnosis, we need to ask ourselves, whether the ‘ducks all line up’ to avoid cases of mistaken identity.

  • MUSCLE DISEASE

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Introduction

In medical school, we learned that myopathies present with proximal and axial weakness, and often a raised serum creatine kinase. Many muscle diseases do indeed present in just this fashion, and figure 1 highlights some of these. However, after practising neurology for some time, we encounter exceptions to this rule. The distribution of weakness in some myopathies may be distal—a pattern more suggesting neuropathy—and some patients have proximal weakness not caused by a myopathy.

Figure 1

Causes proximal weakness.

Muscle disease generally presents with weakness but sometimes first manifests with cardiac or respiratory problems, muscle pain (myalgia) or stiffness; myotonic dystrophy type 1 (DM1) shows still more diverse presentations.1

Inevitably, since muscle diseases cause weakness, one is easily mistaken for another. Often this does not matter greatly, but distinguishing genetic from acquired myopathy is important to avoid potential iatrogenic harm. In my experience, certain signs and symptoms may prompt rather perfunctory conclusions; for example, scapular winging can too easily suggest facioscapulohumeral dystrophy (FSHD), or recurrent rhabdomyolysis can lead only to a metabolic work-up. I will highlight some useful rules of thumb to prevent us falling into such traps.

There is a great wealth of potentially expensive and time-consuming tests, many of which are recherché fields in their own right. I have been on many a ‘wild goose chase’ with pages of negative results, a red face and a frustrated patient frowning at me. The essential first step is, therefore, still the clinical assessment.

Sometimes muscle disease may be the unexpected culprit, sometimes it is wrongly implicated, and sometimes we need a little nudge to get the diagnosis spot on (figure 2). Remember not to assume that you and the patient mean the same thing when using words like weakness, numbness and fatigue.2

Figure 2

Do the ducks line-up?

Chameleon presentations

Distal weakness that is actually myopathic

Our neurological instincts tell us that distal weakness is neurogenic (a neuropathy or motor neurone disease). However, some myopathies cause distal weakness in the forearm and tibial muscles (especially anterior but less commonly posterior); anterior tibial weakness causes the common problem of foot drop, and gastrocnemius weakness causes difficulties with climbing stairs and with the ‘push-off’ stage of walking. A powerful clinical clue is that the small muscles of the hands and feet may be prominently weak and wasted in neurogenic disorders, but spared in most distal myopathic conditions (figures 3 and 4).

Figure 3

Causes distal weakness.

Figure 4

Examine the extensor digitorum brevis muscle in foot drop: is it atrophied (neurogenic) or preserved/hypertrophied (myopathic more likely)?

Here are some common examples of distal myopathies:

Inclusion body myositis

  • Pattern recognition is crucial. Although patients with inclusion body myositis generally present with falls—reflecting quadriceps weakness—it is often the upper limb distal weakness that provides the tell-tale clue to the diagnosis. There is striking loss of grip strength with forearm finger flexor atrophy that is almost always worse in the non-dominant forearm; people might mention that their watch strap has become loose.3 The thenar and hypothenar muscles are preserved, in contrast with their prominent atrophy and weakness in neurogenic conditions. Patients cannot carry bags normally and may be hook them over their elbows.

  • Inclusion body myositis can also cause foot drop, but it is the quadriceps weakness and wasting, also frequently asymmetric, that causes sudden collapses while walking or standing, leading patients initially to seek medical help. Sometimes this means coming downstairs is more difficult than going up since knee extension is often weaker than hip flexion.

  • Shoulder abductors—despite our medical school memories of myopathic weakness—are spared, as are hip abductors.

  • Facial weakness and dysphagia are common. Patients rarely recognise facial weakness, but dysphagia is a potential presenting problem. Dysphagia precedes dysarthria in inclusion body myositis, whereas, dysarthria precedes dysphagia in motor neurone disease. Inclusion body myositis as a cause of dysphagia is rarely recognised outside neurological circles.

  • Inclusion body myositis, therefore, involves a select group of muscles, something normally associated with genetic muscle disease.4 ,5

  • Although categorised as ‘inflammatory’, the inflammation is probably an epiphenomenon. Immunosuppression does not help and may actually be detrimental.6

  • About 20% of people with inclusion body myositis do not have a ‘full-house’ of muscle biopsy pathological features, so the clinical pattern is important.7 Biopsy still helps, however, occasionally reveals a surprise finding such as granulomatous myositis.8

Myotonic dystrophy type 1

In adult practice, DM1 generally presents in late teenage years with distal weakness, either with foot drop or with finger flexion weakness; thus, finger flexion weakness is prominent in inclusion body myositis and DM1.1 Older neurologists believe that the competence of clinical assessment of foot drop correlates with experience in clinical neurology. There are excellent articles summarising the causes of foot drop, but do remember the rarer myopathic causes, including DM1.9 Foot drop in DM1 can be very asymmetric, and may mimic superadded common peroneal nerve palsy. Patients with DM1 have facial weakness, ptosis and neck flexion weakness, and so have difficulty keeping their head from lolling backwards in an accelerating car. There are an enormous number of other problems and presentations too in this condition; case 1 highlights some other features. Neurophysiology remains useful to assess distal weakness, distinguishing neurogenic, myopathic, myotonic and the occasional myasthenic patient who presents with distal weakness.

Case 1

A 43-year-old man reported hypersomnolence, causing problems at work. He had fallen and fractured his humerus a year earlier and had suffered other falls too. His sister had died in her 40s from a glioma. He worked in a supermarket, pushing trolleys, which he found increasingly difficult. He was in agony with muscle pain by the end of the day. He had facial weakness, very weak finger flexors and mild bilateral foot drop. He had percussion and action myotonia, worse distally and in the cold (as is typical for DM1). EMG confirmed myotonia and genetic tests confirmed DM1 (CTG expansion in myotonic dystrophy protein kinase gene on chromosome 19q). He acknowledged his hypersomnolence and pain, but seemed indifferent to his profound weakness; this phlegmatic reaction is common in DM1. DM1 can also present with other diverse problems, for example, irritable bowel, unexplained falls, cataracts and arrhythmias.

Facioscapulohumeral dystrophy

Some muscle diseases cause foot drop and periscapular weakness (scapuloperoneal syndromes); uncovering such a pattern refines diagnostic possibilities (box 1). FSHD is a common myopathy that falls within this group; it typically presents in teenage years with difficulty reaching to a shelf, with scapular winging that is asymmetric with the dominant side more severely affected (whereas the non-dominant arm is often weaker in inclusion body myositis) (figures 5 and 6).10 It is a relatively common dystrophy (prevalence 1:20 000), and can present in disguise with prominent axial weakness causing a bent spine (camptocormia), minimal or profound facial weakness, or distal weakness causing foot drop.

Box 1

Scapuloperoneal distribution weakness

  • Facioscapulohumeral dystrophy

  • Myofibrillar myopathies

  • Some congenital myopathies

  • Acid maltase deficiency

  • Emery–Dreifuss syndrome

  • Some limb girdle muscle dystrophies (1B, 2A, 2I)

Figure 5

(A) Wasting of forearm flexors muscles, but relatively preserved small muscles of the hand in inclusion body myositis. (B) More wasting and more severe weakness in non-dominant left arm with inability to flex left thumb because of weakness of flexor pollicis longus (note the loose watch strap). (C) In inclusion body myositis, the arm abductors are strong.

Figure 6

Scapular winging that on close inspection may differ according to the cause. (A) A straight medial scapular border of the scapula occurs in LGMD2A. (B) The lower medial border scapular rotates medially in facioscapulohumeral dystrophy (FSHD). (C) and (D) Scapular winging also occurs in alpha sarcoglycanopathy and LGMD1C (also note paraspinal hypertrophy in LGMD1C). (E) Scapular winging in neuralgic amyotrophy. (F) Scapular winging in LGMD2I, which is unusually asymmetric, and more often seen in FSHD (dominant arm often worse).

Some scapuloperoneal syndromes include diseases where early contractures precede weakness. Their presence always warns of potential cardiac problems; these are genetically diverse and include Emery–Dreifuss syndrome (see case 2).

Case 2

A 35-year-old woman had received a diagnosis of Charcot–Marie–Tooth disease. She had struggled since late teenage years, often tripping over her feet. She had no positive sensory features but did have distal numbness to pinprick. There was pes cavus and wasted legs below the knee. She had weakness of ankle dorsiflexion (4/5). On further examination she had tight Achilles tendons, contractures of the elbows and neck, so she could not put her chin on her chest. She was mildly weak proximally in her arms (4+/5). Her anterior tibial muscles were atrophied, but extensor digitorum profundus was enormous and her toe dorsiflexion very strong. She was areflexic. She had an autosomal dominant condition caused by a LMNA mutation, one of the genetic causes of the Emery–Dreifuss phenotype.10 ,11

Chronic progressive external ophthalmoplegia or ptosis that is myopathic and not caused by myasthenia gravis

Ptosis or chronic progressive external ophthalmoplegia (CPEO) are often felt to be secondary to myasthenia, including seronegative myasthenia, which may have been diagnosed solely on an equivocal edrophonium (tensilon) test. Remember your myopathies! In the context of limb weakness, a CPEO or ptosis is also easily overlooked. A useful clue in the history to myopathic forms of CPEO is lack of diplopia.

Consider:

  • Mitochondrial disease (figure 7) with a blood test looking for DNA polymerase-gamma gene (POLG) mutation, as well as a blood or urine sample for the 3243 ‘MELAS’ mutation, a common cause of late-onset CPEO without other features of MELAS. If these are negative, then a muscle biopsy is the next step in pursuing a mitochondrial explanation.12

  • Oculopharyngeal muscular dystrophy (PABPN1 gene test) presents in middle age with ptosis and/or dysphagia; the ptosis is often asymmetric and the progressive external ophthalmoplegia typically develops late in the natural history of oculopharyngeal muscular dystrophy, and is milder than in mitochondrial disease.10 ,13 This condition is often forgotten: I remember one patient treated by plasma exchange for supposed seronegative myasthenia.

  • Ptosis without CPEO occurs in congenital myopathies (eg, nemaline, central core) and desminopathy (a type of myofibrillar myopathy). DM1 causes ptosis but the facial weakness is often far more striking.

Figure 7

Ptosis (and external ophthalmoplegia) with compensatory overaction of frontalis in mitochondrial disease. The patient has also had ptosis surgery.

Attacks of weakness that are muscular in origin but are mistaken for functional, Guillain–Barré syndrome or neuromuscular junctional disease

It is important not to overlook potassium (and other electrolytes) as a cause of muscle weakness. I have seen hypokalaemia in two young women, one with Sjögren's syndrome and consequent renal tubular acidosis and another after self-induced vomiting, whose low potassium was measured but not noticed; both patients’ weakness was regarded as functional (remember vomiting is also a potential cause of Wernicke's). It is important to measure the potassium (and phosphate) in patients presenting with weakness, but also to remember to look at the results: glory was painfully snatched away when we initially missed thyrotoxic periodic paralysis, mistaking it for Guillain–Barré syndrome, because we did not look at the potassium result before the patient arrived in the high-dependency unit.

  • The primary periodic paralyses are autosomal dominant genetic channelopathies that cause paroxysmal attacks of weakness; unlike myasthenia, they spare extraocular, bulbar and respiratory muscles.14 We will all see hypokalaemic periodic paralysis (incidence 1:100 000), attacks, beginning before 20 years of age. Weakness is often restricted to one limb with discomfort or stiffness, provoked by a carbohydrate meal (insulin translocates potassium as well as glucose). Prolonged, generalised attacks of weakness also occur, at which time there is areflexia (useful to refute a functional label) and sometimes a swollen sensation in muscles.14

  • Hyperkalaemic periodic paralysis is a sodium channelopathy and is less common.14

Case 3

A father and son worked as bakers in the family business and would occasionally develop focal discomfort in their forearms, and difficulty lifting bags of flour. Neither had suffered a severe attack of generalised weakness, and both could work their way gently through the symptoms, which would improve through the day. Their attacks could be provoked by stress or take-away pizza the night before, which they continued to enjoy despite recognising the pattern. Both found a little help from acetazolamide. This family had a sodium channelopathy that accounts for 10–20% of hypokalaemic periodic paralysis and that tends to cause later onset, milder attacks often with more pain compared with the more common calcium channelopathy.14

  • Thyrotoxic hypokalaemic periodic paralysis presents between 20 and 50 years of age, often in people of Asian descent; other features suggesting thyrotoxicosis can be very subtle particularly in non-Asians. It affects approximately 2% of thyrotoxic patients from any cause (these people may have abnormalities of potassium inward rectifying channels).15

  • Andersen–Tawil syndrome. If you think you have made a diagnosis of periodic paralysis, do not rest on your laurels: look for syndactyly, low-set ears, wide-spaced eyes or small chin. These features occur in Andersen–Tawil syndrome, which presents with periodic paralysis, and patients risk sudden cardiac death (often with a mutation in the potassium channel gene, KCNJ2).16

Pain or myalgia caused by muscle diseases

Myalgia is common, but its assessment is not simple; although often referred to neurology with a potential myopathy, it is more often rheumatological or orthopaedic in origin. If there is no accompanying weakness, then it is unusual to find a clear myopathic condition. Watching a person walk on their toes, heels, hop, squat or ascend a flight of stairs in clinic is more useful than simply a couch-based assessment, since pain often inhibits such an examination. Language is important—ensure you and the patient mean the same thing—‘pain’ can mean weakness, stiffness or cramping. It helps to differentiate pain at rest from pain with exercise (see below) and it is vital to look at the medications and alcohol history. Here are some other useful features:

  • Becker's muscular dystrophy in young men can present with myalgia and exercise-induced cramps. Although exercise-induced muscle pain (and sometimes rhabdomyolysis) often raise the spectre of a metabolic myopathy (see below), this presentation can develop in Becker's and other limb girdle muscle dystrophies, for example LGMD2I. If your metabolic work-up is negative, remember to look for limb girdle muscle dystrophies.11

  • DM2 or proximal myotonic myopathy (PROMM) causes stiffness and thigh pain, sometimes asymmetrically, with proximal weakness and sometimes calf pseudohypertrophy.1 Percussion of distal or proximal muscles (eg, trapezius) sometimes but not invariably elicits myotonia; there may be very little myotonia, even electrophysiologically.1 Like DM1, it is autosomal dominant (CCTG expansion in an intron of the zinc finger protein-9 gene), and there are systemic complications such as early cataracts.

  • Other muscle conditions that may present principally with myalgia include acid maltase deficiency (see below) and FSHD.

  • Myositis does not cause severe pain—the worse the pain the less likely myositis. Passive movement is painful in arthritis or synovitis, for example polymyalgia rheumatica, but causes mild discomfort at most in myositis, although pain can be very unpleasant during rhabdomyolysis. The following illustrates just such a misadventure—a case solved by a colleague.

Case 4

An elderly man was admitted with shoulder pain and proximal arm weakness, including pain on gentle passive movement (odd for muscle disease), a sore inflamed tongue and raised ESR. We considered giant cell arteritis and polymyositis as likely explanations. A shoulder X-ray, however, showed bilateral posterior shoulder dislocations and a fractured humerus, all secondary to an initially unrecognised nocturnal seizure with tongue bite (with consequent high serum creatine kinase).

  • Parkinsonism. Take care not to miss the small, steady trickle of parkinsonian patients with prominent myalgia who have been assumed to have a myopathy. It is easy to be hoodwinked, led astray by the referral—so do not miss something that seems will seem obvious in wonderful hindsight.

  • Hypothyroidism. Ensure the thyroid function has been done and reviewed, since hypothyroidism is common in the elderly and causes myalgia, proximal weakness and raised serum creatine kinase. Thyroid function is frequently checked at the time of referral, but not invariably. Similarly, electrolyte disorders cause myalgia, including hypokalaemia.

  • Metabolic myopathy. It is worth distinguishing pain at rest from pain or cramp that accompanies or follows exercise; pain after exercise raises the possibility of a metabolic myopathy (but remember limb girdle muscle dystrophies). Generally, people with metabolic myopathies (see below) are recognisable, describing vividly the awful discomfort that arises from their muscles:

    • Glycogenolysis disorders (usually McArdle's disease) cause prolonged muscle cramps, or ‘contractures’ a few minutes into exercise, particularly vigorous isometric muscle contraction, such as carrying an old-fashioned television across a car park.17 Serum creatine kinase is invariably raised.

    • Fatty acid disorders (usually carnitine palmitoyltransferase II) cause pain, often with rhabdomyolysis, following prolonged exercise or stress, such as infection; this often occurs 6–24 h after such stress. One memorable man only suffered ‘full-blown’ rhabdomyolysis after a complete marathon rather than his habitual half marathon, provoking temporarily port-coloured urine that he had dismissed as normal. Serum creatine kinase is normal between attacks.10

    • Mitochondrial myopathy without CPEO can cause exercise-induced myalgia sometimes with nausea, breathlessness, tachycardia or sweatiness and headache and episodes that often started during childhood.12 ,18

  • Amyloid. Vascular claudication is the commonest reason for exercise-induced muscle pain and we also all encounter neurogenic claudication. However, another muscle disease, amyloid myopathy, can precisely mimic lower limb claudication. Amyloid is perhaps an under-recognised cause of myopathy and sometimes misdiagnosed as polymyositis.19 ,20

Stiffness caused by muscle disease

Experienced neurologists can diagnose myotonia correctly on the history alone, particularly if patients describe their hands as feeling stiff in the cold. We tend to equate stiffness with upper motor neurone problems, but it is important to remember myotonia and myotonic syndromes:

  • Myotonia congenita (chloride channelopathy) may present with patients reporting an awkward first few paces, sometimes a fall, or locking and reduced dexterity in the hands. It improves (‘warms up’) with exercise.

  • Potassium aggravated myotonia and paramyotonia congenita. These sodium channelopathies cause myotonia that worsens with exercise (hence paradoxical myotonia); the myotonia may be painful and prominent in periorbital muscles. Paramyotonia congenita also causes episodes of weakness, provoked by the cold or stress.14

  • Hypothyroid myopathy can present with stiffness and myoedema, a brief mounding of muscle when gently percussed.21 Myoedema also occurs in electrolyte disorders, and intriguingly, in some cases of dumb rabies.22

  • ‘Rippling muscle disease’, where a muscle ripples vividly after percussing it, is caused by genetic (LGMD 1c) as well as acquired disease (autoimmune myasthenia). The name is easily remembered, but like ‘painful legs moving toes’, lacks a certain intellectual punch to impress neurosurgeons.

  • Brody's disease. CaATPase deficiency in sarcoplasmic reticulum prevents calcium reuptake after contraction, causing stiffness that worsens with exercise and in the cold, presenting in childhood or adolescence and often mistaken for paramyotonia.23

  • Neuromyotonia, caused by peripheral nerve hyperexcitability, differs from myotonia clinically as it causes action but not percussion myotonia.

EMG shows the distinct abnormalities seen and heard in myotonia and neuromyotonia; equally useful is the electrical silence that accompanies the contractions in McArdle's disease, Brody's disease, myoedema and rippling muscles.

Cardiorespiratory presentations secondary to myopathy

Fulminant respiratory failure may be the first presentation of DM1 after anaesthetic or sedative exposure; similarly, respiratory failure after an infection or drug exposure can be a presentation of mitochondrial disease.24 ,25 Indolent respiratory failure may produce odd presentations, including delirium or headache with fatigue; the first myopathy to consider in this circumstance is acid maltase deficiency.26 Similarly, some myopathies may present with or have early problems with cardiac difficulties (see boxes 2 and 3).

Box 2

Myopathies with respiratory muscle involvement

  • Limb girdle muscle dystrophy, for example, LGMD2I

  • Myotonic dystrophy type 1 (DM1*)

  • Emery–Dreifuss syndrome

  • Myofibrillar myopathies

  • Congenital myopathy, for example, nemaline*, centronuclear*

  • Inflammatory myositis

  • Mitochondrial diseases

  • Metabolic, for example, acid maltase*, debrancher deficiency

  • Critical illness myopathy*

*Denotes conditions that may present in respiratory failure.

Box 3

Myopathies with potential cardiac manifestations

Myopathies with cardiomyopathy

  • Dystrophinopathies: Becker's and Duchenne's muscular dystrophy

  • Emery–Dreifuss syndrome

  • Mitochondrial disease

  • Alcohol myopathy

  • Amyloid myopathy

  • Endocrinopathies, for example, acromegaly

  • Some limb girdle muscle dystrophies, for example, LGMD2I

  • Myofibrillar myopathies

Muscle diseases complicated with arrhythmias

  • Myotonic dystrophy type 1 (DM1)

  • Emery–Dreifuss syndrome

  • Mitochondrial disease

  • Andersen–Tawil syndrome

  • Myofibrillar myopathies

  • Inflammatory myositis

Case 5

A 64-year-old woman had been admitted with confusion on a few occasions over the previous year. She had a history of ‘polymyositis’ in her forties, which had never responded well to corticosteroids, leaving her generally weak and with muscle pain; she had been lost to follow-up years ago. Her observation charts, always an essential part of our examination, revealed mild hypoxia, often 93–94%, and blood gas analysis showed type 2 respiratory failure. She had marked lumbar lordosis despite her age, and a winged scapula with weak limbs proximally, mainly her hip flexion. She could walk slowly, but had been unable to clamber on to a bus since her late forties because leg weakness prevented her negotiating the step. Her serum creatine kinase was approximately 1500 U/L (24–170). Her vital capacity standing was 1.1 L, but lying down was 0.5 L. Vital capacity may be reduced in several pathologies, including respiratory conditions, but if it falls by 10% or more when someone lies down it indicates diaphragm weakness. Patients describe orthopnoea, mimicking cardiac symptoms, caused by the abdominal contents splinting the weak diaphragm and causing breathlessness when supine. EMG of her paraspinal muscles found myotonic-type changes, and the acid α-glucosidase activity in her leucocytes was decreased, confirming acid maltase deficiency (genetically confirmed too). It is worth emphasising that there is now a dried blood spot test to quantify acid α-glucosidase enzyme activity available, providing a simple quick screening test. This condition can cause prominent respiratory weakness at presentation; histological changes are not always evident on biopsy (as in her case when she had been biopsied in her forties). ECG may show Wolff–Parkinson–White syndrome.27 ,28 She is now on a non-invasive ventilator overnight with no recurrence of her confusion.

There is an understandable emphasis upon acid maltase deficiency and its tendency to cause respiratory muscle weakness, but it is equally important to acknowledge that two-thirds of patients present with proximal lower limb weakness, particularly hip flexion, often with myalgia and lumbar hyperlordosis. It is important in these circumstances to consider the diagnosis in such patients, often aged 30–50 years, and to engage the neurophysiologist to look specifically for myotonic discharges in paraspinal muscles, since there is now enzyme replacement available which appears to stabilise respiratory function and improve walking after 18 months follow-up.29

Mimics: look like muscle disease but are something else

Spinal muscular atrophies

The spinal muscular atrophies can mimic myopathies, clinically and sometimes with ‘myopathic’ features on biopsy (fibre splitting, increased endomyseal connective tissue and central nuclei).

Spinal muscular atrophy type 3 is the commonest form with onset after 18 months, usually between 5 and 15 years of age, and it can closely resemble a myopathy, particularly Becker's muscle dystrophy; there is proximal weakness, a serum creatine kinase of approximately 1000 U/L (24–170), and often seemingly enlarged calf muscles.11 The triceps are weak, whereas in Becker's, there is often weakness of biceps too; similarly in the lower limbs, the hip flexors are weak, whereas in Becker's, hip flexion as well as extension are weak. EMG also helps in distinguishing, and a mutation in the SMN1 gene confirms the diagnosis as spinal muscular atrophy.

The distinction between spinal muscular atrophy and Becker's muscular dystrophy is important for prognosis, particularly potential cardiac complications, and for genetic counselling—remember approximately 8% of woman will have manifest weakness in X-linked Becker's muscle dystrophy—the implications for potential offspring of these women is very different if the diagnosis is spinal muscular atrophy as opposed to Becker's muscular dystrophy. Case 6 illustrates another mistaken identity.

Case 6

A 45-year-old man had become unable to carry on coaching his son's junior rugby team because of worsening weakness. His problem began approximately 10 years before and initially he had noticed difficulty running. He had accommodated his weakness by fixing his knees with bandages and swivelling his hips to generate speed during training sessions but even this had become unsuccessful and he was falling. His arms had become weak, so passing the ball had become difficult and there was wasting in the small muscles of his hand. He developed problems chewing meat or toffee. On examination, he had fasciculations in his arms and in his chin. His serum creatine kinase was 4300 U/L (24–195); he had small sensory action potentials. He was areflexic and had a tremor.

The high serum creatine kinase raised the suspicion of a myopathic process—but beware, since many neurogenic disorders have serum creatine kinase levels up to 1000 U/L (including motor neurone disease) and two common myopathies, DM1 and FSHD, often have serum creatine kinase values that are raised to the same sort of values as neurogenic disorders.

Involvement of the small muscles of his hand and fasciculations favoured a neurogenic problem, and areflexia and tremor also more suggested spinal muscular atrophy. This man had Kennedy's disease (X-linked bulbospinal muscular atrophy); very high serum creatine kinase values may sometimes occur in this condition (although more usually 500–1500 U/L).30

Lambert–Eaton myasthenic syndrome

Lambert–Eaton myasthenic syndrome is notoriously easily overlooked, clinically and electrophysiologically. It causes proximal leg weakness and in approximately one-third there is some myalgia as well as areflexia (classically, but not invariably, reflexes return after repetitive muscle contractions) and a dry mouth. Half the cases are associated with cancer, usually small-cell lung cancer, and symptoms generally begin 10 months before tumour recognition. There are usually antibodies to voltage-gated calcium channels.31

Congenital myasthenic syndromes

Congenital myasthenic syndromes can resemble congenital myopathies and are important to uncover as they are treatable. Many cause ophthalmoplegia, and are therefore more likely to be confused with seronegative myasthenia, but some, for example, downstream of kinase-7 (DOK7), may cause confusion with early onset limb girdle and facial weakness, small muscles, normal or slightly raised serum creatine kinase, ptosis but no ophthalmoplegia. There is usually fatigability on examination and in the history, even if fluctuations occur over long periods, for example from week to week in DOK7. Neurophysiology shows decrement on repetitive stimulation and jitter on single-fibre EMG, but the investigations can be challenging, often with myopathic features electrophysiologically and on muscle biopsy.32 ,33

Other causes of proximal weakness encountered that are not myopathic

Other conditions with proximal weakness that may be wrongly suspected to have had a myopathy include diabetic amyotrophy, other plexopathies such as Parsonage–Turner syndrome, myelopathies, variants of motor neurone disease and chronic inflammatory demyelinating polyneuropathies. However, generally these are recognised in the neurology clinic by the presence of appropriate upper motor neurone signs or sensory symptoms. I have, however, seen a couple of patients with subacute proximal lower limb weakness (coming on over 4–8 weeks) diagnosed as having a myopathy, when actually the diagnosis was neoplastic meningitis, confirmed on CSF examination. Both had a history of cancer (adenocarcinoma lung and breast), and although neoplastic meningitis tends to present with ataxia, headache and cognitive problems, in these two instances there were few clues other than the known history of cancer and asymmetric dropped lower limb reflexes.34 ,35 The acute hepatic porphyrias may initially cause confusion in the acute setting with proximal weakness, myalgia and urine discolouration, leading to an erroneous conclusion of acute myositis with myoglobinuria; the EMG can also be myopathic early on and the ankle reflexes are often preserved. The other features, including abdominal pain, dysautonomia, hyponatraemia, seizures, unusual proximal sensory loss and psychiatric problems as well as a normal serum creatine kinase steer one away from a myopathy although the correct diagnosis often remains notoriously elusive.36

It is a myopathy but not polymyositis…

Distinguishing genetic from acquired inflammatory myopathies is important to avoid unnecessary immunosuppression and potential iatrogenic harm. Becker's muscle dystrophy, other limb girdle muscle dystrophies, particularly LGMD2b (dysferlinopathy) and acid maltase deficiency (case 5) have all been mistaken for polymyositis. Confusion arises as the serum creatine kinase is high, there is proximal weakness, and EMG may show spontaneous activity and even the muscle biopsy can show inflammation in some dystrophies, particularly LGMD 2a, 2b and FSHD.

Clinical features that favour a genetic over an acquired myopathy:11 ,37

  • Indolent onset over years, not acute (less than 4 weeks) or subacute (4–8 weeks) but chronic, often with a story stretching back years. A subacute myopathy is often inflammatory, endocrine, or drug or toxin related. Note that alcohol causes an acute and chronic myopathy.

  • Positive family history—but you may need to dig—did someone have droopy eyes or die young from a cardiac problem, or was there someone in the family who was ‘lame’ or ‘cloff’ (in west Wales)? A negative family history obviously does not exclude a genetic condition.

  • Scapular winging, noting that it does not always mean FSHD (figure 6).

  • Fluctuating history of weakness favours a channelopathy or neuromuscular disorder over polymyositis.

  • Differential involvement of adjacent muscles, for example, normal strength in hip abduction but very weak hip adductors.

  • Differential involvement of parts of the same muscle, for example, only distal biceps atrophied with the proximal portion intact; or differences within the quadriceps. (figures 8).

  • Skeletal deformities suggest chronic genetic causes: for example, a high-arched palate, scoliosis or history of congenital hip dislocation.

  • Pseudohypertrophy, a tough enlarged muscle that feels rubbery and hard, commonly a calf muscle but other muscles can also be affected, for example, macroglossia in LGMD2I (figure 9) or paraspinal muscles in LGMD1C (figure 6D). Pseudohypertrophy develops in some acquired myopathies, for example, amyloid, hypothyroid, and rarely in the calf in S1 radiculopathies, but not in polymyositis.

  • Marked proximal weakness with no distal involvement often indicates a dystrophy; in myositis some distal spread is expected if there is profound proximal weakness.

Figure 8

Genetic as opposed to acquired myopathies. (A) Selective atrophy distal biceps in dysferlinopathy and (B) selective hypertrophy lateral quadriceps and atrophy medial part in a person with alpha sarcoglycanopathy both favour genetic aetiologies.

Figure 9

Macroglossia in LGMD2I.

There are several other circumstances when our neurological bones should grumble before accepting a diagnosis of polymyositis:

  • Inflammatory changes produced in muscle by the EMG needle. It is worth ensuring that the muscle biopsied is not one examined extensively by a neurophysiologist—I have seen a patient with motor neurone disease treated as polymyositis because of this.

  • Remember inclusion body myositis and its tell-tale pattern of weakness—not all patients with this condition have a full-house of pathological findings, some will have inflammation and cytochrome oxidase-negative fibres without inclusion bodies. Could this person with polymyositis actually have inclusion body myositis?38

Conclusion

I hope that having shared with you some of the dilemmas around the diagnosis of muscle disease I have encountered that I will not repeat my errors (famous last words), and you will carry on avoiding them too.

Acknowledgments

Dr Tom Hughes is the neurologist fond of asking, ‘Do the ducks line up?’; Dr Claire Hirst is the colleague who solved the case of the unrecognised seizure in the night, and Dr Ffion Thomas told me about the Welsh word for lame.

References

View Abstract

Footnotes

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by David Hilton-Jones, Oxford, UK.

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