Muscles

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16 Muscles

Introduction

Muscle weakness is often automatically thought to reflect muscle disease, but that need not be the case. Weak or wasted muscles may result from a lesion anywhere within the nervous system. This starts from the central nervous system (CNS), which produces a typical upper motor neurone (UMN) distribution of weakness. UMN weakness results in the compensatory ‘spastic’ posturing (see Ch 4) consequent to weakness in the antigravity muscles. Damage to lower motor neurones (LMN) will produce weakness in those muscles innervated by the affected LMNs (see Ch 4).

It is possible to get a combination of UMN and LMN weakness that may be caused by motor neurone disease (MND) or vitamin B₁₂ deficiency, as seen in subacute combined degeneration.

More peripheral involvement as evidenced by diseases affecting the neuro-muscular junction, typified by myasthenia gravis, will produce muscular weakness or fatigability. Diseases affecting muscles themselves also cause muscle weakness and wasting.

Perhaps the best and most obvious example of how a lesion at different points in the ‘nerve-to-muscle’ relationship can result in a similar picture is reflected in the presentation of ptosis. This may be caused by nerve damage (be it 3rd cranial nerve or autonomic nerve damage), damage at the neuromuscular junction (as seen in myasthenia gravis), or long-standing muscle disease (especially with mitochondrial myopathy) (see Table 16.1).

TABLE 16.1 Identification of causes of ptosis

Cause	Features
3rd cranial nerve palsy	Ptosis Enlarged pupil (midriosis) Eye may be deviated down and out (though not always so if only affecting to outer parasympathetic fibres) May have diplopia

Horner’s syndrome (sympathetic chain involvement)

Ptosis

Smaller pupil (myosis)

Lack of sweating (especially forehead of affected side)

No limitation of eye movement

No diplopia

Eye may appear sunken (enophthalmos)

Myasthenia gravis

Ptosis

Equal pupils

Fatiguability of eye movements, may have diplopia

May have other myasthenic muscles

Responds to Tensilon test

Mitochondrial myopathy

Ptosis

Equal pupils

Usually longstanding (can be seen in old photographs)

May need to do lactate levels, possibly from hair or muscle biopsy

Pseudo-ptosis from contralateral upper motor neurone (UMN) lesion

No real ptosis, the upper lid is in the same position bilaterally with respect to the top of the pupil

Pupils are equal

Weakness of facial muscles, especially lower face, contralateral to ‘smaller’ eye

Weak contralateral eye closure compared to suspected eye with pseudo-ptosis

There may even be a pseudo-ptosis produced by contralateral facial weakness, which results in a larger contralateral palpable fissure, making the contralateral eye appear larger than the eye with the ‘pseudo-ptosis’. This gives a false impression of ptosis in which the wrong eye is identified as being smaller, rather than the affected eye recognised as being larger (see Table 16.1).

This chapter will not deal with muscle weakness as a consequence of either UMN or LMN lesions, as these have been discussed elsewhere (see Chs 11 and 14). The focus of this chapter will be on pathology at either the neuromuscular junction or more peripherally within the muscle itself. It will be directed to that which is relevant to general practitioners, with the aim of improving clinical acumen and the enjoyment associated with the practice of medicine.

Neuromuscular Junction

a Myasthenia gravis

Myasthenia gravis ¹ epitomises diseases of the neuromuscular junction, and is an autoimmune disease with antibodies directed against the acetylcholine receptors on skeletal muscles in approximately 90% of those with generalised myasthenia gravis and about half those with ocular myasthenia. Should these antibodies not be identified then the muscle-specific kinase antibodies (MuSK antibodies) are found in about half the remaining patients with myasthenia gravis. Those with MuSK antibodies tend to have a slightly atypical presentation of their myasthenic picture with more oculo-bulbar and neck extensor involvement and more respiratory symptoms.

Myasthenia may occur at any age, with male to female ratio of 1 : 3 with an earlier onset in women and girls (10–40 years) as compared to men (often 50–70 years). After the age of 40 years, the male : female ratio is approximately equal. There is a neonatal form of myasthenia, thought to be secondary to placental transmission of the acetylcholine receptor antibodies. This presents with impaired sucking, weak cry and ‘floppy’ limbs. This presents within the first two days of life. It generally only requires supportive treatment for the lifespan of the antibodies. There is also an autosomal recessive congenital form with infantile onset, and a drug-induced form consequent to the use of D-penicillamine.

The usual presentation of myasthenia gravis is with ptosis (see Table 16.1) together with fatiguable muscle weakness, diplopia and possible dysarthria, dysphagia, dyspnoea or fatiguable proximal limb weakness. Almost any skeletal muscle may be involved, as may be respiratory muscles, and myasthenia gravis may mimic other diseases. Purely ocular myasthenia often presents with ptosis and diplopia without other muscle group involvement.

When examining the patient with suspected myasthenia gravis, fatiguability is demonstrated by asking the patient to look up at a fixed object or spot and to maintain the upward gaze (see Fig 16.1).

FIGURE 16.1 Testing for fatiguable ptosis.

Alternative methods for testing for fatiguability include asking the patient to count aloud to 100, and listening to the quality of articulation to recognise the development of a dysarthric and nasal quality to enunciation as the counting proceeds. Testing muscles of mastication, the patient is asked to bite down on a wooden tongue depressor while at the same time the doctor pulls on the spatula and observes the decline in the strength of the bite. Peripheral muscle fatiguability may be tested by asking the patient to repeatedly perform a muscle task with intervening relaxation, and recording the evolving weakness over time (see Fig 16.2).

FIGURE 16.2 (i) Testing for fatiguability of shoulder abduction; (ii) Testing for fatiguability of wrist dorsiflexion.

What presents as purely ocular myasthenia may often progress to become generalised myasthenia, possibly consequent to an intercurrent infection. As with all neurology, the diagnosis requires a high index of suspicion with the differential diagnosis including: brainstem lesions and other causes of ptosis (see Table 16.1); multiple sclerosis; Graves’ disease (thyrotoxicosis) with ophthalmo-paresis; and other inflammatory myopathies, most of which causes elevation of creatine kinase (CK).

While diagnosis usually relies on specialist involvement, the suspicious general practitioner can start the ball rolling, having ordered acetylcholine receptor antibodies and a chest CT scan, looking for thymoma. Repetitive nerve stimulation or single fibre electromyography are clearly the domain of a neurophysiologist. Double-blind edrophonium (Tensilon) testing is best performed within the hospital setting with cardiac monitor and facility for resuscitation, which is rarely required. The general practitioner may perform an ‘ice test’ in which the application of ice produces strengthening of muscles. This is rarely, if ever, used these days as a referral to the consultant has supplanted such simple testing with Tensilon test. The ‘ice’ test really was only used in ocular myaesthenia.

Patients with myasthenia gravis may have concomitant other organ specific autoimmune diseases with up to 10% having associated thyroid disease, be it hyperthyroidism or hypothyroidism, that may be identified by the astute general practitioner who will treat this in their usual fashion, with possible referral.

Thymectomy is advocated in young patients with myasthenia (below the age of 50 years) and all those with thymoma. It is not usually advocated in those older than 65 years, those with pure ocular myasthenia or with MuSK antibodies.²

Pharmacological treatment of myasthenia is with pyridostigmine (Mestinon®) and/or the use of immunosuppression, be it with steroids or more aggressive, but this is usually the domain of the specialist.

Mestinon® is started at 60 mg b.d. or t.d.s. in mild cases, often complemented with slow release ‘Time Span’ (180 mg) at night. Adverse events may include excess salivation, abdominal cramping and possible diarrhoea; the latter may require anticholinergics. It should be remembered that Mestinon® may exacerbate glaucoma. A cholinergic crisis must be considered in patients with respiratory failure. These patients may also experience dilated pupils, together with the above adverse symptoms plus fasciculations. When this occurs the anticholinesterases should be withdrawn and the patient maintained in an intensive care environment with possible intubation. This represents a medical emergency, which may be provoked following the initiation of Mestinon® therapy.

Steroids, at a dosage of 1.0–1.5 mg/kg/day (usually 60–100 mg per day), may exacerbate weakness in the first one to two weeks so caution must be exercised when starting steroids, particularly in outpatients. Additional treatment with myclophenalate, azathioprine or possibly even cyclosporins has been used as steroid-sparing agents. In more severe cases plasmapheresis or IV immunoglobulin may be required, but this again is the domain of the consultant rather than the general practitioner.

b Lambert-Eaton myasthenic syndrome (LEMS)

This is usually a paraneoplastic, auto-immune, myasthenic condition.³ It is caused by antibodies to calcium channels on the presynaptic nerve terminals of skeletal muscles and autonomic ganglia. The myasthenic syndrome usually precedes the diagnosis of the tumour, which is usually a small cell lung cancer.

The symptoms often start in the proximal leg and shoulder girdle muscles without ocular features. There may be parasympathetic symptoms of dryness, including mouth, constipation, urinary retention and impotence.

The diagnosis relies on neurophysiology with post-exercise potentiation of the compound muscle action potential, but this is definitely the precinct of the specialist. Ultimate treatment is directed towards managing the underlying malignancy, although treatment specific to myasthenia gravis may have limited efficacy.

c Botulism

The toxin produced by Clostridium botulinum blocks the release of acetylcholine from the autonomic and motor nerve endings, causing nausea, vomiting, anorexia, constipation, blurring of vision, diplopia, dysarthria, dysphagia, dyspnoea and limb weakness 12–36 hours after consuming contaminated food.⁴

Diagnosis requires a high index of suspicion plus identifying the toxin in serum. Treatment is the application of appropriate anti-serum, by which stage the patient will usually be in hospital.

Myopathies

As the name implies, ‘myo’ meaning muscle and ‘pathy’ meaning pathology, the focus is now on the end organ, namely the muscles themselves.⁵ Consideration of muscle diseases may adopt the traditional approach to classification, examining congenital and acquired causes (see Table 16.2).

TABLE 16.2 Classification of muscle diseases

Congenital	Acquired
Muscular dystrophies: • Duchenne • Becker • Emery-Dreifuss • fascioscapulohumeral • scapuloperoneal • limb girdle

Inflammatory:

• polymositis

• dermatomyositis

• inclusion body myositis

• inflammatory and myopathies associated with connective tissue disease

Metabolic myopathies:

• McArdle’s disease (myophosphorylase deficiency)

• acid maltase deficiency

• malignant hyperthermia (central core disease carnitine palmitoyl transferase deficiency; dystrophinopathies)

Infective:

• associated with HIV

• trichinosis

Mitochondrial myopathies

Metabolic:

• endocrine (steroid-induced, thyroid disease)

Periodic paralysis

Electrolyte disturbance:

• statins and/or niacin

• penicillamine

This produces a long list of disorders, many of which are quite rare and either will not be encountered or will rarely be encountered by general practitioners. Even if encountered by general practitioners, many of the rarer myopathies will be incorrectly diagnosed or overlooked. In many instances the same may be said for the general neurologist who does not practise within the super-sub-specialised area of muscle diseases.

It follows that a very detailed discussion of all these rare myopathies is unwarranted within an overview specifically for general practitioners. This should not be interpreted as being either patronising or derisive of general practitioners, but rather representing a realistic appreciation of the very great demands placed on the average general practitioner. The same might equally apply for the busy general neurologist, who will likewise rely heavily on the input of some specialised colleagues. It is thus incumbent to offer an overview to the approach, acknowledging that the list provided (see Table 16.2) is far from exhaustive.

The fundamental symptoms and signs of myopathy are muscle weakness, both reported by patients and observed when testing power, with/without pain (myalgia). Proximal muscle weakness is more common than is distal weakness, and acute myopathies are usually associated with inflammatory, systemic diseases or toxic aetiology. Slower onset myopathies include the muscular dystrophies and congenital myopathies, mitochondrial myopathies (also congenital although transmitted down the maternal line), metabolic myopathies and muscle membrane channel defects (as evidenced within periodic paralyses and myotonias) (see Table 16.2).

General practitioners faced with these presentations will have ordered CK levels, which should be elevated, and may also have ordered other simple laboratory tests such as: full blood count; biochemical screen, including calcium, phosphate and electrolyte levels plus renal function; magnesium levels; thyroid function; and other tests of systemic disease such as antinuclear antibody, extractable nuclear antibody, C-reactive protein and an erythrocyte sedimentation rate. Once the diagnostic algorithm has proceeded to electromyography (EMG), specialist involvement will have been organised.

The general practitioner may be aware of a positive family history, especially with the congenital diseases, although often other affected family members may have very subtle disease that could have avoided detection. Some diseases may have specific patterns of presentation, such as prominent finger (especially flexor) and quadriceps weakness, which is associated with inclusion body myositis, or the facioscapulohumeral distribution associated with the dystrophy of the same name.

What follows will be a brief discussion of some of the entities in Table 16.2. There will be no attempt to be exhaustive as early involvement of a consultant neurologist is almost universal. The general practitioner provides supportive measures, social interaction and day-to-day symptomatic relief, especially for longstanding disease. The astute general practitioner may offer the initial diagnostic insight, but works in partnership with the consultant. Muscle biopsy requires an even larger therapeutic team in which the physician will suggest which muscle is to be biopsied, the surgeon—usually a neurosurgeon—will conduct the procedure, and the pathologist, armed with adequate history and clinical features, may provide the diagnostic confirmation of the relevant disease process.

Congenital Myopathies

a Muscular dystrophies

These are hereditary diseases ⁶ of which Duchenne and Becker muscular atrophies are most common. Below is a brief overview of some of the congenital myopathies (see Table 16.2).

b Mitochondrial myopathies

Mitochondrial myopathies ⁷ are inherited via the maternal line and encompass a variety of conditions, including: Kearns-Sayer syndrome (KSS); familial progressive external ophthalmoplegia (PEO); myoclonic epilepsy with ragged red fibres (MERRF); and encephalopathy, lactic acidosis and stroke-like episodes (MELAS) with overlap between the various mitochondrial syndromes. Diagnosis and treatment of the mitochondrial myopathies is usually outside the scope of general practice. They have been touched on here purely to whet the appetite, to encourage enthusiastic general practitioners to read further about a relatively new constellation of myopathies.

c Myotonias

Myotonic dystrophy ⁸ is the most common muscular dystrophy with autosomal dominant, multi-system presentation. It results from a protein kinase gene defect occurring in approximately 1 in 8000 adults. In advanced cases it is often an ‘end-of-the-bed’ diagnosis as it causes obvious wasting of the temporalis muscles, which produces a typical facial appearance (see Fig 16.3).

FIGURE 16.3 Facial features of myotonic dystrophy.

The disease has anticipation, meaning it presents earlier in subsequent generations. Unlike most myopathies, weakness starts more distally and patients may present following unusual accidents, such as a road traffic accident occurring at night due to a loss of night vision with blindness caused by myotonic constriction of the pupils provoked by oncoming headlights. Another classical presentation may be as a motorbike accident because of an inability to release the accelerator hand grip of a motorbike due to grip myotonia.

Features of myotonic dystrophy may include: wasting of the face and neck muscles (particularly temporalis and sternocleidomastoid muscles) (see Fig 16.3); pharyngeal weakness with dysphagia; possible aspiration; conduction cardiac problems (possibly requiring pacemaker); psychological complaints (possibly with impaired intellect, apathy or paranoia); ophthalmic problems with specific cataract formation (in addition to senile cataracts); possible retinal or macular pigmentary degeneration; immunosuppression with low IgG; and hypogonadism (especially in males).

Physical examination may reveal the typical facies (see Fig 16.3) and grip myotonia may be evident when testing hand power—the patient having a problem releasing the tight grip. Often patients with myotonic dystrophy have learnt just how tightly to squeeze before the myotonia is provoked, and may have learned to conceal it. It behoves the clinician to encourage the patient to grip more tightly than the patient initially wants to do, and this may provoke the grip myotonia.

There is also percussion myotonia, elicited by tapping the relaxed thenar eminence with a tendon hammer. The thenar muscles contract with the thumb being kept pointing upwards with a delayed relaxation. Tongue myotonia may be provoked by tapping the protruding tongue with a tendon hammer, but personal preference is to avoid this as it should not really be necessary to make the diagnosis.

Up to a quarter of infants from affected women will have congenital myotonic dystrophy with mental retardation, respiratory distress, and poor sucking and dysphagia. It is important to warn expectant mothers with myotonic dystrophy of this possibility.

Use of anti-epileptic medications, such as phenytoin (Dilantin®) or carbamazepine (Tegretol®) may provide some symptomatic relief against the myotonia.

Acquired Myopathies

a Inflammatory myopathies

While uncommon (occurring in about 1 in 100 000), inflammatory myopathies ⁹ have the potential for reversibility so their recognition is imperative. The most common inflammatory myopathies are polymyositis, dermatomyositis and inclusion body myositis. They present with weakness, usually painless, and high CK levels. An exception to this is polymyalgia rheumatica in which there is pain, but CK is usually normal or only slightly elevated while ESR is high.

Polymyositis

Polymyositis is an inflammatory myopathy in patients usually more than 20 years old. It presents with symmetric painless proximal weakness, developing insidiously over weeks to months, although occasionally it may present acutely. It involved limb girdles, neck flexors and may be associated with dysphagia and, later, respiratory weakness and possibly myocarditis. It may be paraneoplastic and associated with anti-neuronal antibodies, such as Jo-1 nucleoprotein antibody. CK is raised, often greater than ten times normal, and EMG gives a mixed myopathic and neuropathic picture. Muscle biopsy shows muscle necrosis with inflammatory infiltrate with lymphocytes, without the vascular lesions seen in dermatomyositis or with perivascular atrophy.

Treatment is via high-dose steroids, such as prednisolone at 60–100 mg per day, roughly calculated at 1.0–1.5 mg/kilogram/day, with gradual tapering as muscle strength increases. Maintenance therapy is continued for 6 months to 2 years, adopting an alternate day regimen. Azathioprine and methotrexate may be used for steroid-sparing effect. As the patient improves so the CK recedes, but ongoing limb girdle weakness may be confounded by steroid-induced myopathy.

Should this approach with simple immunosuppression fail, then alternatives include mycophenolate, IV immunoglobulin, cyclophosphamide, chlorambucil or lymphoid irradiation. These are well beyond general practitioner involvement.

Dermatomyositis

This presents with a similar picture to polymyositis but is compounded by skin changes, including violaceous heliotrope rash of the eyelids (especially upper eyelids) with erythematous cheeks and malar rash (possibly confused with lupus erythematosus). Knuckles may develop erythematous, scaly macules (grotons papules) with possible further involvement of elbows, knees and upper chest.

There may be an association between dermatomyositis and malignancy (such as adenocarcinoma), especially in patients older than 40 years. CK and EMG mirror polymyositis, while biopsy suggests a more vascular origin with pericapillary inflammation that is less apparent in polymyositis. Treatment mirrors that of polymyositis.

Inclusion body myositis

Inclusion body myositis is an inflammatory myopathy affecting 50+-year-old adults with insidious onset involving quadriceps and upper limb forearm flexor atrophy, causing hand involvement with weakness of finger flexors. There may be association with autoimmune diseases and a familial, autosomal recessive consanguinity factor has been recognised. CK is often normal or only mildly elevated, while EMG may show both myopathic and neuropathic features. Biopsy confirms low-grade inflammation with rimmed vacuoles, cellular inclusions and diagnostic amyloid staining, with Congo red, shows specific inclusion bodies. No treatment is really satisfactory, although it is worth trying steroids or immunosuppressive agents that occasionally are efficacious.

b Metabolic myopathies

These include the array of endocrine myopathies,¹⁰ such as steroid-induced myopathy associated with 50–80% of patients with Cushing’s disease and 2–20% of patients on long-term steroid therapy. This produces proximal weakness, more so involving the lower limbs than the upper limbs, and may be reduced by using alternate day dosage regimen.

In 25–50% of people with adrenal insufficiency (Addison’s disease) there will be generalised muscle weakness, muscle cramps and fatigue, responsive to steroid replacement. This may be compounded by hyperkalemic periodic paralysis.

Thyroid disease, both thyrotoxicosis and hyperthyroidism, may cause myopathy. Both may cause proximal weakness with or without wasting and/or myalgia. Thyrotoxicosis may be associated with periodic paralysis similar to familial hypokalemic periodic paralysis, and bulbar muscles are usually spared. Hypothyroidism may cause myo-oedema with apparent muscle enlargement. While CK is usually normal with hyperthyroidism, it may be elevated in hypothyroidism.

Other endocrine diseases, such as acromegaly (with increased growth hormone), hyperparathyroidism (with elevated calcium levels) and hypoparathyroidism may be associated with various myopathies.