LOCALISED NEUROLOGICAL DISEASE AND ITS MANAGEMENT C. PERIPHERAL NERVE AND MUSCLE

Published on 12/04/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 2677 times

SECTION IV LOCALISED NEUROLOGICAL DISEASE AND ITS MANAGEMENT C. PERIPHERAL NERVE AND MUSCLE

THE POLYNEUROPATHIES – FUNCTIONAL ANATOMY

The function of the peripheral nervous system is to carry impulses to and from the central nervous system. These impulses regulate motor, sensory and autonomic activities.

The peripheral nervous system is comprised of structures that lie outside the pial membrane of the brain stem and spinal cord and can be divided into cranial, spinal and autonomic components.

STRUCTURE OF THE NERVE CELL AND AXON

Each axon represents an elongation of the nerve cell – lying within the central nervous system, e.g. anterior horn cell, or in an outlying ganglion, e.g. dorsal root ganglion. The cell body maintains the viability of the axon, being the centre of all cellular metabolic activity.

Many axons are surrounded by an insulation of myelin, which is enveloped by the Schwann cell membrane. Myelin is a protein–lipid complex. The membrane of the Schwann cell ‘spirals’ around the axon resulting in the formation of a multilayered myelin sheath.

All axons have a cellular sheath – Schwann cell – but not all axons are myelinated.

Schwann cells with associated myelin are 250–1000 μm in length and separated from each other by the node of Ranvier. The axon is bare at this node and, during conduction, impulses jump from one node to the next – saltatory conduction. The rate of conduction in myelinated nerves is markedly increased in comparison with unmyelinated fibres. Myelin thus facilitates fast conduction. In unmyelinated fibres conduction depends upon the diameter of the nerve fibre, this determining the rate of longitudinal current flow.

SPINAL PERIPHERAL NERVOUS SYSTEM

Entry to and exit from the central nervous system is achieved by paired spinal nerve roots (30 in all).

These dorsal and ventral roots lie in the spinal subarachnoid space and come together at the intervertebral foramen to form the spinal nerve.

The dorsal roots contains sensory fibres, arising from specialised sensory receptors in the periphery.

The dorsal root ganglia are collections of sensory cell bodies with axons extending peripherally as well as a central process which passes into the spinal cord in the region of the posterior horn of grey matter and makes appropriate central connections.

Sensation can be divided into:

– Pain and temperature

– Simple touch

– Discriminatory sensation – proprioception, vibration.

These different forms of sensation are carried from the periphery by axons with specific characteristics. The central connections and pathways vary also (see page 200).

The anterior horns of the spinal cord contain cell bodies whose axons pass to the periphery to innervate skeletal muscle – the alpha motor neurons. Smaller cell bodies also project into the anterior root and innervate the intrafusal muscle fibres of muscle spindles – the gamma motor neurons.

Each alpha motor neuron through its peripheral ramifications will innervate a number of muscle fibres. The number of fibres innervated from a single cell varies from less than 20 in the eye muscles to more than 1000 in the large limb muscles (innervation ratio). The alpha motor neuron with its complement of muscle fibres is termed the motor unit.

Function:

Mainly preganglionic autonomic, some pain and temperature.

Conduction velocity: 7–5 metres/second.

TYPE C

< 1 μ m diameter.

Unmyelinated.

Function:

Sensory – pain and temperature.

Conduction velocity: < 2 metres/second.

The structure of the spinal peripheral nervous system has been considered but the arrangement is also important. Spinal nerves, after emerging from the intervertebral foramen pass into the brachial plexus to supply the upper limbs and the lumbosacral plexus to supply the lower limbs.

The thoracic nerves supply skeletal muscles and subserve sensation of the thorax and abdomen.

The Autonomic Nervous System is described on page 457.

PATTERNS OF INJURY

Damage may occur to: axon, myelin sheath, cell body, supporting connective tissue and nutrient blood supply to nerves. Three basic pathological processes occur.

THE POLYNEUROPATHIES – SYMPTOMS

Sensory

Negative phenomena – loss of sensation.

Disease of large myelinated fibres produces loss of touch and joint position perception.

Patients complain of difficulty in discriminating textures. Their hands and feet feel like cotton wool. Gait is unsteady, especially when in darkness where vision cannot compensate for loss of joint position sensation (proprioception).

Disease of small unmyelinated fibres produces loss of pain and temperature appreciation as a consequence of which painless burns/trauma result. Damage to joints without pain results in a ‘neuropathic’ joint (Charcot’s joint) in which traumatic deformity is totally painless.

Positive phenomena

Disease of large myelinated fibres produces paraesthesia – a ‘pins and needles’ sensation with a peripheral distal distribution.

Disease of small unmyelinated fibres produces painful positive phenomena:

International Association for the Study of Pain (IASP) definitions has clarified the following.

– analgesia

absent sensitivity to a painful stimulus

– hyperalgesia

increased sensitivity to a painful stimulus

– hypoalgesia

reduced sensitivity to painful stimulus

– hyperaesthesia

increased sensitivity to any stimulus

– hypoaesthesia

reduced sensitivity to any stimulus

– hyperpathia

increased sensitivity with increasing threshold to repetitive stimulation

– allodynia

pain provoked by a non-painful stimulus

Complex regional pain syndromes (CRPS) were previously termed ‘reflex sympathetic dystrophy’ and ‘causalgia’. These may follow a simple soft tissue injury (CRPS-1) or injury to a large peripheral nerve (CRPS-2). Allodynia and hyperalgesia are associated with local changes in temperature and skin appearance (oedema and discoloration). The pain has a burning, shooting quality. Motor manifestations (weakness or involuntary movements) are common and the pathophysiologic mechanism unknown.

Motor

The patient notices weakness:

– When distal, e.g. difficulty in clearing the kerb when walking

– When proximal, e.g. difficulty in climbing stairs or combing hair

– Cramps may be troublesome

– Twitching of muscles (fasciculation) may be felt.

THE POLYNEUROPATHIES – SIGNS

MOTOR EXAMINATION

Muscle wasting. Evident in axonal but absent in demyelinating neuropathies. Oedema of immobile limbs may mask wasting. The 1st dorsal interosseus muscle in the upper limbs and extensor digitorum brevis in the lower limbs are muscles that commonly first show wasting in the neuropathies, but examine all muscle groups. Look for fasciculations – irregular twitches of groups of muscle fibres due to diseased anterior horn cells, these may be induced by exercise or muscle percussion.

Muscle weakness. Weakness is proportional to the number of affected motor neurons. It develops suddenly or slowly and is generally symmetrical, usually starting distally in the lower limbs and spreading to upper limbs in a similar manner before ascending into proximal muscle groups. This pattern of progression is supposedly due to the ‘dying back’ of axons towards their nerve cells – the longest being the most vulnerable.

Some neuropathies, e.g. Guillain-Barré, chronic inflammatory demyelinating polyneuropathy, may affect proximal muscle groups first.

In severe neuropathies, truncal and respiratory muscle involvement occurs. Respiratory muscle weakness may result in death.

Tendon reflexes

The tendon reflex depends on:

– stretch of the muscle spindle (1),

– activation of spindle afferent fibres (2),

– monosynaptic projections to the alpha motoneurons (3).

The gamma motoneuron fibres, projecting to the spindle (4), ‘modulate’ activity in the reflex loop.

Reflexes commonly tested:

The tendon reflexes are lost when any component of the reflex response is affected by disease. Reflexes are lost early in peripheral neuropathies when power and muscle bulk appear normal. Distal reflexes are generally lost before proximal ones.

THE POLYNEUROPATHIES – CLASSIFICATION

There are several approaches to classification:

by MODE OF ONSET – acute, subacute, chronic

by FUNCTIONAL DISTURBANCE – motor, sensory, autonomic, mixed

by PATHOLOGICAL PROCESS – axonal, demyelinating

by CAUSATION – e.g. infections; carcinomatous, diabetic, inflammatory, vascular

by DISTRIBUTION – e.g. symmetrical, asymmetrical; proximal, distal.

The following table based primarily on mode of onset is for reference. Certain neuropathies will be dealt with separately (see pages 439–444).

CAUSE	FUNCTIONAL DISTURBANCE	PATHOLOGY
ACUTE: days to 4 weeks
Inflammatory (Guillain Barré syndrome)	Predominantly motor	Demyelinative with perivascular lymphocytic infiltration
	Distal or proximal
	Autonomic disturbance
Diphtheria——	Cranial nerve onset	Demyelinative. No inflammatory infiltration.
Diphtheria——	Mixed motor/sensory	Demyelinative. No inflammatory infiltration.
Porphyria——	Motor (may begin in arm).	Axonal
	Autonomic disturbance
	Minimal sensory loss.

SUBACUTE – occasionally CHRONIC: months and years
ASYMETRICAL and MULTIFOCAL
Infections
Leprosy	Sensory neuropathy, often multifocal; associated depigmentation	Spectrum from paucibacillary (few organisms with intense inflammation) to multibacillary (many organisms with little inflammation)
HIV	Range of associated neuropathies
Vasculitic disorders
Polyarteritis nodosa;	Usually presents with mononeuritis multiplex or an asymmetrical sensorimotor neuropathy.	Vasculitis with Wallerian degeneration in distal nerves
Wegner’s granulomatosis;
Churg-Strauss syndrome
	Often painful
Non-systemic vasculitis	As above without systemic features

SUBACUTE and CHRONIC: months and years
SYMMETRICAL
Metabolic and endocrine disorders
Diabetes	Most commonly distal sensorimotor
	But wide range of other forms (see later)
Ureamia	Distal sensorimotor	Axonal degeneration
Hypothyroidism	Distal sensorimotor
Acromegaly	Distal sensorimotor

CAUSE	FUNCTIONAL DISTURBANCE	PATHOLOGY
Nutritional deficiencies
Vitamin B₁ (thiamine)	Predominantly sensory, with burning feet.	Axonal degeneration with segmental demyelination
Includes alcoholic neuropathy	Weakness may develop.
	Autonomic involvement common but mild
B₁₂ deficiency	Predominantly sensory; may be associated spinal cord involvement
Malignant disease
Paraneoplastic	Sensory or sensorimotor	Axonal; may be associated antibodies (anti-Hu)
Infiltrative	Multifocal, often a polyradiculopathy	More common with lymphoma
Paraprotein associated
Monoclonal gammopathy (IgG, IgA, IgM)	Sensorimotor neuropathy	Axonal with segmental demyelination
Chronic inflammatory demyelinating polyneuropathy (CIDP) (see later)
Amyloid
Primary, secondary or familial	Sensorimotor neuropathy often with autonomic involvement	Thickened nerves with amyloid deposition and small fibre neuropathy
	May present as multiple mononeuropathies
Inherited neuropathies
Charcot-Marie-Tooth disease (see below)
Refsum’s disease	Phytanic acid storage disorder. Sensorimotor neuropathy with ichthyosis, retinitis pigmentosa and deafness
Drug induced
Wide range of drugs induce neuropathies including:
Antibiotics	Metronidazole; ethambutol; isoniazid; nitrofurantoin; dapsone
Oncology drugs	Adriamycin; cisplatin; taxanes; vincristine
HIV drugs	Didanosine; stavudine; zalcitabine
Others	Amiodarone; gold; phenytoin
Toxin induced
Solvents
Heavy metals	Lead; arsenic; thallium

Chronic idiopathic axonal neuropathy:

In patients about 20% of patients with a chronic neuropathy no cause is identified. Follow up of cohorts of such patients has found that while their symptoms slowly progress they do not develop significant disability.

INVESTIGATION OF NEUROPATHY

Investigation of a neuropathy will be led by the history and the pattern of the neuropathy. In many patients the diagnosis will be relatively straightforward, for example a typical distal symmetrical neuropathy in a patient with diabetes or with a history of alcoholism. Where the aetiology is known and the neuropathy mild and typical there is often no need for further investigation. However, in many patients the diagnosis is not clear and then the investigations will be led by the pattern of the neuropathy. Unlike the situation for chronic neuropathies (see previous page) the cause of acute or subacute neuropathy can usually be defined.

For a patient with a distal symmetrical sensorimotor neuropathy:

Initial investigations:

Glucose, HbA1C, urea and electrolytes, liver function tests, thyroid, protein electrophoresis, ESR or plasma viscosity, vitamin B12 and folate, chest X-ray and nerve conduction studies (see below).

Further investigations (depending on clinical history):

Glucose tolerance test

Autoantibodies (including extractable antibodies (anti-ro and anti-la), rheumatoid factor, ANCA, tissue transglutaminase antibodies. Angiotensin converting enzyme (ACE) levels.

Anti-neuronal antibodies (anti-Hu or anti-Yo).

Anti-gangioside antibodies, anti-myelin associated glycoprotein (anti-MAG) antibodies.

Genetic studies (see later) – including clinical examination of relatives

Porphyria screen

HIV, lyme

CSF studies (cells, protien glucose)

Screen for primary tumour (CT scanning or PET scanning)

Asymmetrical or multifocal neuropathies are much less common and there are usually clues in the history to direct investigation towards what is most frequently an underlying inflammatory disease, for example vasculitis or a specific inflammatory neuropathy. Inflammatory markers and autoantibodies may be helpful. In such patients nerve conduction studies and nerve biopsy may lead to diagnosis.

SPECIFIC INVESTIGATIONS

Nerve conduction studies (see pages 60–61) are useful to confirm there is a neuropathy and to determine the type and distribution of the pathology.

Nerve conduction studies will distinguish axonal from demyelinating neuropathies. They may be able to demonstrate assymetrical involvement, pointing to a multifocal pathology. They may demonstrate conduction block, an area of focal demyelination, indicative of acquired demyelinating neuropathies.

Nerve biopsy

A biopsy is most likely to aid diagnosis in asymmetric multiple mononeuropathies (vasculitis, amyloidosis, sarcoidosis, etc.). The sural nerve is usually chosen, provided it is involved clinically and neurophysiologically.

THE POLYNEUROPATHIES – SPECIFIC TYPES

GUILLAIN BARRÉ SYNDROME (ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY)

Incidence: 2 per 100 000 population per year. Characteristically it occurs 1–3 weeks after a viral or other infection or immunisation.

CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP)

Pathology: Segmental demyelination with remyelination (onion bulb formation) and sparse mononuclear inflammatory change.

Prevalence – 3% of all neuropathies

Incidence – 5 per million

Age of onset: mean 35 yrs (fluctuating course – younger, progressive – older)

Diagnosis:

Electrophysiology

– conduction velocity < 70% of normal

– conduction block (outwith entrapment sites)

– prolonged distal latencies

Distinguish from

– hereditary neuropathy (CMT type 1, page 444)

– paraprotein and lymphoma associated neuropathy (page 443)

– multifocal motor neuropathy with conduction block (page 443)

– HIV neuropathy (page 516)

About two thirds of patients respond to steroids, PE or IVIG. In moderate/severe cases steroids should be used initially (cost and ease of use) followed, if response unsatisfactory, by IVIG and finally PE. Despite little evidence, immunosuppressive drugs (azathioprine, cyclophosphamide or cyclosporin) are deployed in resistant cases.

Outcome with treatment – 30% symptom free – 45% mild disability – 25% severe disability

DIABETIC NEUROPATHY

This condition is uncommon in childhood and increases with age.

Peripheral nerve damage is related to poor control of diabetes. This is more common in insulin-dependent patients. Damage results from either metabolic disturbance with sorbitol and fructose accumulation in axons and Schwann cells or an occlusion of the nutrient vessels supplying nerves (vasa vasorum). The frequent occurrence of neuropathy with other vascular complications – retinopathy and nephropathy – suggests that the latter is the more usual mechanism. Neurological complications correlate with levels of glycosylated haemoglobin A1C, an indicator of the long-term control of hyperglycaemia.

Classification

Treatment

Improved control of diabetes is essential.

Carbamazepine, gabapentin, pregabalin, tricyclic antidepressants or α-adrenergic blockers, e.g. phenoxybenzene, help control pain.

Drugs which reduce aldose reductase and halt accumulation of sorbitol and fructose in nerves are being evaluated.

Management of autonomic neuropathy – see page 460.

Asymmetrical neuropathies usually spontaneously recover, whereas prognosis for symmetric neuropathies is less certain.

CARCINOMATOUS POLYNEUROPATHY

Sensory or mixed ‘sensorimotor’ neuropathy is often associated with malignant disease, particularly small cell carcinoma of the lung. Neuropathy may also occur with Hodgkin’s disease and lymphomas. The neuropathy is characterised by the presence of antibodies (anti Hu) that are detected in serum. Such antibodies not only recognise antigen in tumours but also bind to peripheral nervous system neurons.

Pathology

The sensory type is characterised by degeneration and inflammatory changes in the dorsal root ganglion. The ventral roots and peripheral nerve motor fibres are spared. In the sensorimotor type, degeneration of the dorsal root ganglion is less marked and axonal and demyelinative changes affect motor and sensory fibres equally.

Clinical features

Symptoms and signs may predate the appearance of causal malignant disease by months or even years.

Sensory neuropathy: Progressive sensory loss often commencing in upper limbs is associated with paraesthesia, unpleasant ‘burning’ dysaesthesia and sensory ataxia.

Sensorimotor neuropathy: The onset is gradual with distal sensory loss and mild motor weakness. Occasionally a more acute, severe neuropathy resembling Guillain-Barré syndrome occurs.

Detection and treatment of the underlying malignancy may lead to recovery of the neuropathy. Alternatively the use of immunosuppressive agents, plasma exchange or intravenous gammaglobulin (IVIG) may help.

MULTIFOCAL MOTOR NEUROPATHY WITH CONDUCTION BLOCK

This presents with asymmetric lower motor neuron weakness and may be mistaken for motor neuron disease. Neurophysiological investigation shows ‘conduction block’ at sites distant from possible entrapment. Antibodies to gangliosides (Anti GM1) are found in serum. Immunosuppressive treatment (cyclophosphamide) or intravenous immunoglobulin (IVIG) when indicated, result in clinical improvement.

NEUROPATHIES ASSOCIATED WITH PARAPROTEINS

Approximately 10% of patients with late onset chronic peripheral neuropathy have a circulating monoclonal paraprotein in the serum. If myeloma, lymphoma, amyloidosis and Waldenström’s macroglobinaemia are excluded, the condition is referred to as a ‘monoclonal gammopathy of uncertain significance’ (MGUS). IgM is reactive, in 50% of cases, against myelin associated glycoprotein, anti-MAG antibodies, which can be demonstrated to bind myelin. Neuropathies may be axonal, demyelinating or mixed and show a variable response to immunotherapy.

PORPHYRIA

Acute intermittent porphyria is a rare autosomal dominant disorder in which symptoms of abdominal pain, psychosis, convulsions and peripheral neuropathy occur.

The metabolic fault occurs in the liver. An increased production of porphobilinogen is reflected by its increased urinary excretion. δ-amino laevulic acid, a porphyrin precursor, is also increased.

Clinical features

The onset is acute and predominantly motor with upper limb and occasional cranial nerve involvement. Respiratory failure occurs in severe cases. Autonomic involvement with tachycardia, blood pressure changes, abdominal pain and vomiting often develop. The neuropathy must be distinguished from Guillain-Barré.

Clinical course is variable. Spontaneous recovery occurs over several weeks. Respiratory failure will require ventilation and carries a poor prognosis. During an attack, a high carbohydrate diet and prevention and treatment of electrolyte disturbances are essential. Chelating agents (EDTA or Penicillamine) are used in severe cases. Recurrent attacks may be anticipated. Certain drugs may precipitate these attacks and must be avoided, e.g. sulphonamides, barbiturates, phenytoin, griseofulvin.

THE POLYNEUROPATHIES – SPECIFIC TYPES – INHERITED NEUROPATHIES

CHARCOT-MARIE-TOOTH DISEASE (previously called hereditary motor and sensory neuropathy (HMSN)

A heterogeneous group of disorders with a prevalence of 1:2500 – the largest category of genetic neurological disease. The characteristic appearance is that of distal wasting, the lower limbs having an ‘inverted wine bottle’ appearance.

Many complex forms of hereditary neuropathies occur and the above classification is far from complete with the genetic basis for many now determined. Some pedigrees show additional features such as – optic atrophy, retinopathy, deafness, ataxia, spasticity and cardiomyopathy. Such ‘extra’ features complicate a simple classification. Treatment is symptomatic with provision of appropriate footwear, splints or orthopaedic procedures to maintain mobility. In adult onset disease, the rate of progression is exceedingly slow. The demonstration of genetic markers and the application of nerve conduction studies allows early and correct diagnosis in those at risk. Nerve biopsy is of no diagnostic value.

Other rare forms of hereditary neuropathy

– Hereditary sensory and autonomic neuropathies

– Autosomal recessive

Childhood onset

Characterised by insensitivity to pain and disordered sweating

– Hereditary neuropathy with liability to pressure palsies (HNPP)

– Autosomal dominant (deletion in PMP 22 gene)

Adult onset

Characterised by recurrent entrapment neuropathies e.g. carpal tunnel syndrome

– Hereditary neuropathy with spinocerebellar degeneration

– e.g. Friedreich’s ataxia (pages 552–3)

– Hereditary neuropathy with metabolic defect

– e.g. Familial amyloid neuropathy – mutation of transthyretin gene

Porphyria – abnormality of hepatic haem biosynthesis

Refsum’s disease – abnormality of phytanic acid metabolism.

PLEXUS SYNDROMES AND MONONEUROPATHIES

Disease of a single peripheral or cranial nerve is termed mononeuropathy. When many single nerves are damaged one by one, this is described as mononeuritis multiplex. Damage to the brachial or lumbosacral plexus may produce widespread limb weakness which does not conform to the distribution of any one peripheral nerve. A knowledge of the anatomy and muscle innervation of the plexuses and peripheral nerves is essential to localise the site of the lesion and thus deduce the possible causes.

Certain systemic illnesses are associated with the development of mononeuropathy or mononeuritis multiplex:

– diabetes mellitus

– sarcoidosis

– vasculitis

– leprosy (worldwide commonest cause)

Entrapment mononeuropathies result from damage to a nerve where it passes through a tight space such as the median nerve under the flexor retinaculum of the wrist. These are often related to conditions such as acromegaly, myxoedema and pregnancy, in which soft tissue swelling occurs. A familial tendency to entrapment neuropathy has been described.

Cranial nerve mononeuropathies have been dealt with separately.

BRACHIAL PLEXUS

The plexus lies in the posterior triangle of the neck between the muscles scalenius anterior and scalenius medius.

At the root of the neck the plexus lies behind the clavicle.

The plexus itself gives off several important motor branches:

1. Nerve to rhomboids

2. Long thoracic nerve – to serratus ant.

3. Pectoral nerves – to pectoralis major

4. Suprascapular nerve – to supraspinatus infraspinatus

BRACHIAL PLEXUS SYNDROMES

UPPER PLEXUS LESION (C5C6)

Traction on the arm at birth (Erb-Duchenne paralysis) or falling on the shoulder (especially motor cyclists) may damage the upper part (C5C6) of the plexus.

When damage to C5C6 is more proximal, nerve to rhomboids and long thoracic nerve may be affected.

POSTERIOR CORD LESION (C5C6C7C8)

LOWER PLEXUS LESION (C8T1)

Forced abduction of the arm at birth (Klumpke’s paralysis) or trauma may produce damage to the lower plexus. This results in paralysis of the intrinsic hand muscles producing a claw hand, C8T1 sensory loss and a Horner’s syndrome (page 145) if the T1 root is involved.

N.B. A combined ulnar and median nerve lesion will produce a similar picture in the hand but with involvement also of flexor carpi ulnaris and pronator teres.

TOTAL BRACHIAL LESION

This results in complete flaccid paralysis and anaesthesia of the arm.

The presence of a Horner’s syndrome indicates proximal T1 nerve root involvement.

N.B. When trauma is the cause of brachial paralysis, early referral to a specialist unit with experience in the surgical repair of plexus injuries is advised.

THORACIC OUTLET SYNDROME

Signs

Sensory loss in a T1 distribution.

Wasting and weakness of thenar and occasionally interosseous muscles.

Signs of vascular compression:

– Unilateral Raynaud’s phenomenon.

– Pallor of limb on elevation.

– Brittle trophic finger nails.

– Loss of radial pulse in arm on abduction and external rotation at the shoulder or on bracing the shoulders – ADSON’s sign.

– Subclavian venous thrombosis may occur, especially after excessive usage of arm.

Investigation

Coronal MRI is the definitive investigation.

Plain radiology of the thoracic outlet may reveal a cervical rib or prolonged transverse process. Nerve conduction/electromyography will distinguish this from other peripheral nerve lesions. Arteriography or venography is occasionally necessary if there are obvious vascular problems.

Treatment

In middle-aged people with poor posture and no evidence of abnormality on plain radiology, neck and postural exercises are helpful.

In younger patients with clinical and electrophysiological changes supporting the radiological abnormalities, exploration and removal of a fibrous band or rib may afford relief.

In this rare disorder the brachial plexus, subclavian artery and subclavian vein may be compressed in the neck by contiguous structures such as a cervical rib or tight fibrous band.

Symptoms

Pain in the neck and shoulder with paraesthesia in the forearm, made worse by carrying a suitcase, shopping bag, etc.

Ensure orthopaedic mimics, rotator cuff injury or shoulder joint contractures, are considered prior to assessment.

BRACHIAL NEURITIS (Neuralgic amyotrophy)

Brachial neuritis is a relatively common disorder sometimes associated with:

– Viral infection (infectious mononucleosis, cytomegalovirus)

– Vaccination (tetanus toxoid, influenza)

– Strenuous exercise

In most cases it develops without any evident precipitating cause.

Clinical features

– Acute onset with preceding shoulder pain.

– Weakness is usually proximal, though the whole arm may be affected.

– Occasionally both arms are affected simultaneously.

– Sensory findings are minor (loss over the outer aspect of the shoulder) and occur in 50%.

– Reflex loss occurs.

– Wasting is apparent after 3–6 weeks.

– Recurrent episodes can occur, especially in the presence of a family history.

Differential diagnosis	Investigation
A painful weak arm. Consider:
– Cervical spondylosis. – Cervical disc lesion. – Brachialgia due to local bursitis. – Polymyalgia rheumatica.

CSF may show a mild protein rise and a pleocytosis.

Nerve conduction studies will show slowing in affected nerves after 7–10 days.

Treatment

Narcotic analgesics may be required if pain is extreme. Corticosteriods are normally given though the value of immunotherapy is uncertain. By 2 yrs – 75% have fully recovered. Brachial neuritis may be familial. Recurrent attacks occur in Hereditary Neuropathy with liability to Pressure Palsies – HNPP (page 444). Autosomal dominant forms of Hereditary Neuralgic Amyotrophy (HNA), both acute and chronic are described, some linked to chromosome 17q.

PANCOAST’S TUMOUR

Involvement of the plexus by apical lung tumour (usually squamous cell carcinoma). The lower cervical and upper thoracic roots are involved.

Clinical features

– Severe pain around the shoulder and down the inside of the arm.

– Weak wasted hand muscles.

– Sensory loss (C8T1).

– Horner’s syndrome (invasion of sympathetic chain and stellate ganglion).

– Rarely medial extension can involve the recurrent laryngeal nerve (hoarseness & bovine cough).

RADIATION PLEXOPATHY

Now infrequently seen after irradiation of axillary nodes in breast Ca. Onset usually 2–4 yrs after exposure to high radiation dose (> 44–50 Gy). Thickening of the vascular endothelium causes ischaemia of the plexus. Symptoms start with paraesthesia in the hand and progress slowly to involve all lower plexus structures with wasting, weakness, reflex & sensory loss.

UPPER LIMB MONONEUROPATHIES

LONG THORACIC NERVE (C5C6C7)

Supplies: Serratus anterior muscle

SUPRASCAPULAR NERVE (C5C6)

Supplies: Supraspinatus and infraspinatus muscles.

AXILLARY NERVE (posterior cord) (C5C6)

Supplies: Deltoid and teres minor muscles.

RADIAL NERVE (Posterior cord) (C6C7C8)

Sensory supply: Dorsum of hand. The nerve descends from the axilla, winding posteriorly around the humerus. The deep branch – the posterior interosseous nerve – lies in the posterior compartment of the forearm behind the interosseous membrane.

Damaged by:

– Fractures of the humerus.

– Prolonged pressure (Saturday night palsy).

– Intramuscular injection.

– Lipoma, fibroma or neuroma.

– Systemic causes.

Results in:

– Weakness and wasting of muscles supplied, characterised by wrist drop with flexed fingers (weak extensors). Sensory loss on dorsum of hand and forearm. Loss of triceps reflex (when lesion lies in the axilla) and supinator reflex.

The posterior interosseous branch of the radial nerve can be compressed at its point of entry into the supinator muscle. The clinical picture is similar to a radial nerve palsy, only brachioradialis and wrist extensors are spared. Examination shows weakness of finger extension with little or no wrist drop.

MEDIAN NERVE (Lateral and medial cords) (C7C8)

Sensory supply:

Palmar surfaces of the radial border of the hand.

The nerve lies close to the brachial artery in the upper arm. It passes under the transverse carpal ligament as it approaches the palm of the hand.

Damaged by:

– Injury in axilla, e.g. dislocation of shoulder, compression in the forearm – anterior interosseous branch, compression at the wrist (carpal tunnel syndrome).

Results in:

– Weakness of abduction and apposition of thumb.

– Weakness of pronation of the forearm.

– Deviation of wrist to ulnar side on wrist flexion.

– Weakness of flexion of distal phalanx of thumb and index finger.

– Wasting of thenar muscles is evident.

– Sensory loss is variable but most marked on index and middle fingers

Carpal tunnel syndrome

The most common entrapment neuropathy, more frequent in women, results from median nerve entrapment under the transverse carpal ligament at the wrist.

Causes:	– Connective tissue thickening, e.g.
	–	Rheumatoid arthritis
	–	Acromegaly
	–	Hypothyroidism.
	–	Infiltration of ligament, e.g. amyloid disease.
	–	Fluid retention, e.g. in pregnancy, weight gain.

Symptoms:

Pain, especially at night, and paraesthesia, eased by shaking the hand or dangling it out of the bed.

Objective findings may follow with cutaneous sensory loss and wasting and weakness of thenar muscles (abductor and opponens pollicis). Percussion on the nerve at the wrist produces heightened paraesthesia (Tinel’s sign).

Nerve conduction studies are helpful in confirming diagnosis by showing slowing of conduction over the wrist.

Treatment: of the cause, weight loss and diuretics. Surgical division of the transverse ligament if symptoms fail to improve produces excellent results (90% symptom free).

ULNAR NERVE (Medial cord) (C7C8)

Sensory supply:

Both palmar and dorsal surfaces of the ulnar border of the hand.

In the upper arm the nerve is closely related to the brachial artery and the median nerve, and passes behind the medial epicondyle of the humerus into the forearm.

In the hand, close to the hamate bone, it divides into deep and superficial branches.

Damaged by:

– Injury at elbow, e.g. dislocation.

– Entrapment at elbow or distal to the medial epicondyle.

– Pressure on the nerve in the palm of the hand damages the deep branch resulting in wasting and weakness without sensory loss.

Results in:

– Weakness and wasting of muscles supplied, with a characteristic posture of the hand – ulnar claw hand – as well as sensory loss. The level of the lesion dictates the extent of the motor paralysis. Nerve conduction studies are helpful in confirming entrapment at the elbow.

Surgical transposition may be necessary in such cases.

LUMBOSACRAL PLEXUS SYNDROMES

Trauma following surgery, e.g. hysterectomy, lumbar sympathectomy or during labour. Compression from an abdominal mass, e.g. aortic aneurysm. Infiltration from pelvic tumour. Radiotherapy.

Symptoms may be unilateral or bilateral, depending upon causation. Weakness, sensory loss and reflex changes are dictated by the location and extent of plexus damage. Pain of a severe burning quality may be present; it may be worsened by coughing, sneezing, etc.

The lumbosacral plexus may be affected in the same way as the brachial plexus in brachial neuritis – lumbosacral neuritis – the association with infection, etc., being similar. Recovery is usually good. Recurrent and familial cases occur. Plexus lesions also occur in diabetes mellitus and vasculitis. In both, the symptoms and signs may be bilateral. Investigate with CT/MR and neurophysiology.

LOWER LIMB MONONEUROPATHIES

COMMON PERONEAL NERVE (L4L5)

The nerve arises from the division of the sciatic nerve in the popliteal fossa. It bears a close relationship with the head of the fibula as it winds anteriorly. It divides into superficial and deep branches as well as giving off a purely sensory branch which, with sensory twigs from the tibial nerve, forms the sural nerve, mediating sensation from the dorsum and lateral aspect of the foot.

Damaged by:

– Trauma to the head of the fibula; pressure here from kneeling, crossing legs.

– Systemic causes of mononeuropathy, e.g. diabetes.

Results in: Weakness of dorsiflexion and eversion of the foot. The patient walks with a ‘foot drop’. Sensory loss involves the dorsum and outer aspect of the foot. Partial common peroneal nerve palsies are common with very selective muscle weakness.

PLANTAR AND SMALL INTERDIGITAL NERVES

Compression of these nerves at the sole of the foot produces localised burning pain. Involvement of interdigital nerves produces pain and analgesia in adjacent halves of neighbouring toes.

AUTONOMIC NERVOUS SYSTEM

The autonomic nervous system maintains the visceral and homeostatic functions essential to life. It is divided into SYMPATHETIC and PARASYMPATHETIC components and contains both motor (efferent) and sensory (afferent) pathways.

Both sympathetic and parasympathetic systems are regulated by the limbic system, hypothalamus and reticular formation. Fibres from these structures descend to synapse with preganglionic neurons in the intermediolateral column T1–T12 (sympathetic) and in the III, VII, IX and X cranial nerve nuclei and S2–S4 segments of the cord (parasympathetic).

PARASYMPATHETIC OUTFLOW

SYMPATHETIC OUTFLOW

AFFERENT AUTONOMIC NERVOUS SYSTEM

Sympathetic

Terminate in spinal cord in intermediate zone of grey matter – in relation to preganglionic neurons.

Function: Important in the appreciation of visceral pain.

Parasympathetic

Afferent fibres from the mouth and pharynx, and respiratory, cardiac and gastrointestinal systems, travelling in the VII, IX and X cranial nerves, terminate in the nucleus of tractus solitarius.

Function: Important in maintaining visceral reflexes.

The sacral afferents end in the S2–S4 region in relation to preganglionic neurons.

NEUROTRANSMITTER SUBSTANCES

TESTS OF AUTONOMIC FUNCTION

BLOOD PRESSURE CONTROL

1. Maintenance of blood pressure with alteration in posture – is normally dependent upon reflex baroreceptor function. A fall in BP occurs with efferent or afferent lesions – postural (orthostatic) hypotension.

2. Exposure to cold induces vasoconstriction and a rise in BP – cold pressor test. Stress will produce a similar pressor response, e.g. ask patient to do mental arithmetic.

Both central and peripheral lesions affect these tests.

3. Valsalva manoeuvre:

The patient exhales against a closed glottis, increases intrathoracic pressure and thus reduces venous return and systemic BP. The heart rate accelerates to maintain BP. On opening the glottis, venous return increases and an overshoot of BP with cardiac slowing occurs. An impaired response occurs with afferent or efferent autonomic lesions.

4. Noradrenaline infusion test:

A postganglionic sympathetic lesion results in ‘supersensitivity’ of denervated smooth muscle to adrenaline, with a marked rise in BP following infusion.

HEART RATE

1. Massage of the carotid sinus should stimulate the baroreceptors, increase vagal parasympathetic discharge and slow the heart rate. Either efferent or afferent lesions abolish this response.

2. Atropine test:

Intravenous atropine ‘blocks’ vagal action and with intact sympathetic innervation results in an increase in heart rate.

SWEATING

A rise in body temperature causes increased sweating, detectable on the skin surface with starch-iodide paper. Any lesion from the central to the postganglionic sympathetic system impairs sweating.

SKIN TEMPERATURE

Skin temperature is a function of the sympathetic supply to blood vessels. With pre- or postganglionic lesions the skin becomes warm and red. With chronic postganglionic lesions the skin may become cold and blue (denervation hypersensitivity) compare the temperature of various regions.

PUPILLARY FUNCTION

Check the response to light and accommodation.

Pharmacological tests are important:

1. Atropine – blocks parasympathetic system – dilates pupil.

2. Cocaine – stimulates adrenergic receptors – dilates pupil.

In highly specialised units detailed neurophysiology (e.g. thermal threshold measurements) and plasma concentrations of neurotransmitters and hormones at rest and in response to baroreceptor stimulation are employed to characterize the site and selectivity of the autonomic lesion.

AUTONOMIC NERVOUS SYSTEM – SPECIFIC DISEASES

Symptoms of autonomic dysfunction occur in many common conditions which affect both the parasympathetic and sympathetic pathways e.g. cerebrovascular disease.

The following are less common disorders which primarily may affect the autonomic nervous system –

IDIOPATHIC ORTHOSTATIC HYPOTENSION

Two types of this condition are recognised:

1. Due to degeneration of sympathetic postganglionic neurons.

2. Due to degeneration of sympathetic preganglionic neurons of the intermediolateral column T1–T12 – Multiple system atrophy (MSA).

In the latter disorder, features of extrapyramidal system involvement are also found.

Both disorders are characterised by: postural hypotension: anhidrosis (absent sweating): impotence: sphincter disturbance: pupillary abnormalities.

The disorders may be separated pharmacologically; the postganglionic disorders shows hypersensitivity (denervation hypersensitivity) to noradrenaline infusion.

Treatment

Drugs such as fludrocortisone increase blood volume and may prevent postural hypotension.

DIABETIC AUTONOMIC NEUROPATHY

Symptoms of autonomic dysfunction are common in long-standing insulin-dependent diabetics:

Impotence/retrograde ejaculation.

Bladder dysfunction – decreased detrusor muscle action – resulting in increased residual volume.

Nocturnal diarrhoea.

GI dysfunction – vomiting from gastroparesis.

Orthostatic hypotension.

These problems arise from damage to both sympathetic and parasympathetic postganglionic neurons.

Treatment

Improve diabetic control and treat symptoms e.g. fludrocortisone for BP control.

GUILLAIN-BARRÉ SYNDROME – Guillain-Barré syndrome (see previous chapter). Autonomic involvement is common and may present major problems in patient management. The lesion may involve the afferent or efferent limbs of the cardiovascular reflexes (baroreceptor reflexes) resulting in postural hypotension, episodes of hypertension and cardiac dysrhythmias.

Occasionally the postinfectious neuropathy is purely autonomic.

HEREDITARY SENSORY & AUTONOMIC NEUROPATHY (HSAN)

This group of rare, generally recessively inherited disorders are characterised by insensitivity to pain, anhidrosis (absence of sweating), orthostatic hypotension and unexplained fevers from birth. Riley-Day syndrome is typical of these though its gene mutation is confined to Ashkenazi Jewish families.

PRIMARY AMYLOIDOSIS

Autonomic involvement with orthostatic hypotension, impotence, diarrhoea and bladder involvement may accompany sensorimotor neuropathy in the primary and hereditary forms. Amyloid infiltration affects autonomic ganglia.

ADIE’S SYNDROME

A tonic pupil (page 144) associated with areflexia and occasionally widespread autonomic dysfunction, e.g. segmental hypohidrosis (absent sweating) and diarrhoea.

AUTONOMIC DYSFUNCTION IN QUADRIPLEGIA (autonomic dysreflexia)

A high cervical lesion which completely severs the spinal cord, e.g. traumatic cervical fracture/dislocation will isolate all but the cranial parasympathetic outflow. As a result, disturbed autonomic function is inevitable but variable.

Autonomic reflexes are retained – Passive movement or tactile stimulation of limbs may result in blood pressure rise, bradycardia, sweating, reflex penile erection (priapism).

AUTONOMIC NERVOUS SYSTEM – BLADDER INNERVATION

Efferent innervation

Afferent innervation

BOWEL AND SEXUAL FUNCTION

DISEASES OF SKELETAL (VOLUNTARY) MUSCLE

Normal skeletal muscle morphology

A skeletal muscle is composed of a large number of muscle fibres separated by connective tissue (endomysium) and arranged in bundles (fasciculi) in which the individual fibres are parallel to each other. Each fasciculus has a connective tissue sheath (perimysium) and the muscle itself is composed of a number of fasciculi bound together and surrounded by a connective tissue sheath (epimysium).

The three envelopes (sheaths) are made up of connective tissue richly endowed with blood vessels and fat cells (lipocytes).

The muscle fibre

Each muscle fibre has its own endplate approximately half way along its length.

The cell also contains mitochondria, endoplasmic reticulum and microsomes – the usual cellular constituents.

Fats, glycogen, enzymes and myoglobin lie within the sarcoplasm and related structures.

The MYOFIBRILS are the contractile components of muscle.

MUSCLE MORPHOLOGY AND FUNCTION

Fibre type

It is possible to distinguish two main types of muscle fibre on pathological and physiological study:

Type I: Slow twitch, fatigue resistant.

Type II: Fast twitch, fatigue dependent.

Characteristics:	Type I	Type II
	ATPase stain: Light	ATPase stain: Dark
	Oxidative metabolism	Glycolytic metabolism
	Abundant mitochondria	High glucogen content

The muscle fibre type is influenced by its innervation that further determines its pattern of use; all muscle fibres innervated by a single motor neuron (the motor unit) have identical physiological and pathological parameters. The distribution of muscle fibre types differ in specific muscles within the body according to function – the muscles of the erector spinae are rich in oxidative, fatigue resistant fibres while the converse is true in triceps.

Neuromuscular junction

Each muscle fibre receives a nerve branch from the motor cell body in the anterior horn of the spinal cord or cranial nerve motor nuclei.

When a nerve fibre reaches the muscle it loses its myelin sheath and its neurilemma then merges with the sarcolemma under which the axon spreads out to form the motor endplate. The axon fibre with its endings and muscle fibres it supplies is called the MOTOR UNIT. The number of muscle fibres in a motor unit varies: in the eye muscles it is small (5–10), whereas in the limb muscles the number is large (in the gastrocnemius about 1800). Each motor unit contains only one type of muscle fibre, i.e. type I or type II. The neuromuscular junction is the point at which neuromuscular transmission is effected. The motor endplate is separate from the sarcoplasm by the synaptic cleft.

Physiology

Muscle contraction results from the following:

1) A depolarisation wave arrives at the axon terminus and opens voltage sensitive Ca²⁺ channels

2) Ca²⁺ entry triggers fusion of synaptic vesicles with the axon membrane which then release acetylcholine into the synaptic cleft

3) Acetylcholine attaches to end-plate receptors with Na⁺ entry into muscle. Post synaptic depolarisation initiates an action potential that spreads along the sarcolemmal membrane.

4) Release of Ca²⁺ from the sarcoplasmic reticulum and the interaction of actin and myosin result in muscle contraction.

The enzyme cholinesterase, found in high concentration at motor endplates, destroys acetylcholine so that normally a single nerve impulse only gives rise to a single muscle contraction.

Biochemistry

Muscle contraction requires adenosine triphosphate (ATP). This may be generated either by carbohydrate breakdown (glycogenolysis and glycolysis,) or lipid breakdown (beta-oxidation). These non-oxygen requiring processes produce only a limited amount of ATP but also generate Acetyl-Co-A which, in the presence of oxygen, is further metabolised through the Krebs cycle within the mitochondria. This process yields even greater quantities of ATP.

The biochemical pathways yielding energy from the Krebs cycle reactions are dependent on proteins coded for by both the nuclear and mitochondrial genome. Mitochondrial DNA (mtDNA) is present in many copies per mitochondrion, with many mitochondria per cell. The usual state is that all an individual’s mtDNA has the same sequence – homoplasmy – but in the mitochondrial disorders mutations are frequently present in only a proportion of the mtDNA – heteroplasmy. The distribution of these populations is not homogeneous across tissues and these features make the diagnosis of disorders associated with abnormalities of mtDNA difficult when the mutation may not be detected in blood but may be present in varying amounts in muscle or other affected tissues (see page 481).

MUSCLE DISEASE – HISTORY, EXAMINATION AND INVESTIGATIONS

History taking

This must include

– A family history paying particular attention to additional features that can be associated with muscle disease (e.g. deafness if a mitochondrial disorder is suspected or diabetes and cataracts with Myotonic Dystrophy).

– Age at onset. Parents describe delay in early motor milestones or a history of poor athletic abilities. Old photographs show long-standing facial weakness or ptosis.

– A full drug and alcohol history.

– Terminology. Patients should be given the opportunity to expand on terms such as ‘weakness’, ‘cramp’ or ‘fatigue’. These are often used to describe symptoms distinct from their strict medical definitions.

– Pattern of weakness. Proximal weakness will produce difficulty in descending stairs or rising from a low chair or drying hair. Distal weakness causes difficulty with latch keys, ascending stairs and scuffing toes.

– Pain and cramp. Their relationship to exercise should be noted. In disorders of glycolysis a cramp develops in the exercising muscle after a minute or so whereas in Carnitine-palmityl transferase deficiency cramp and rhabdomyolysis follows some hours later.

– Fatigability. This occurs in neuromuscular transmission disorders and mitochondrial disease.

Examination

This must assess

– Walking – here a waddling or foot drop gait is noted or other neurological problems such as Parkinsonism identified.

– The distribution of weakness and wasting will distinguish proximal, distal and generalised myopathies. Involvement of anatomically adjacent muscles is a feature of the muscular dystrophies. The face must be carefully examined for minor bilateral facial weakness; mild ptosis and limitation of extraocular movements. Muscle weakness should be graded using a standard scale (Medical Research Council scale – page 19).

– The presence of pseudohypertrophy and contractures (easily missed at hips, ankles and elbows) should be noted.

Investigations

– Creatine kinase (CK): this sarcoplasmic enzyme is released from the damaged muscle membrane. High levels are associated with Muscular Dystrophies and Rhabdomyolysis but normal values do not exclude milder muscle disease (benign recessive dystrophies, mitochondrial and some metabolic disorders).

– Neurophysiology: may differentiate neurogenic from myopathic weakness and provide evidence of muscle membrane damage (e.g. inflammatory myopathies), but normal studies do not exclude muscle disease.

– Muscle biopsy: Routine staining of frozen material identifies some disorders but immunohistochemical analysis and appropriate mutation studies are needed for the diagnosis of others (e.g. Muscular Dystrophies). The choice between needle and open biopsy is difficult – the former is simpler but no less painful; the latter may be preferable to avoid sampling error.

INHERITED MUSCLE DISORDERS

The muscular dystrophies (MD) are genetically determined progressive disorders of muscle characterised by cycles of muscle fibre necrosis, regeneration, eventual fibrosis and replacement with fatty tissue. Originally defined and described on patterns of weakness (e.g. Facio-scapulo-humeral muscular dystrophy) they are now defined on the basis of known gene loci and protein product. This is not yet possible in all dystrophies but a continuing reclassification is taking place. Many disorders are associated with abnormalities in the dystrophin associated glycoprotein complex. Congenital myopathies are associated with morphological muscle abnormalities without necrosis and with a more benign prognosis. The metabolic myopathies present with pain, weakness or fatigue.

Xp2.1 DYSTROPHIES (DUCHENNE & BECKER MUSCULAR DYSTROPHY)

The gene for dystrophin is located at Xp2.1. Point mutations and deletions affecting the terminal domains are more often associated with the severe clinical phenotype of Duchenne, while deletions within the central rod domain are associated with the milder Becker Dystrophy.

DUCHENNE DYSTROPHY

Clinical features

Duchenne MD has an incidence of 1:3500 male births. It is characterised by delayed early motor development usually noted between ages 1 and 3 years, followed by scoliosis, contractures and eventual loss of ambulation at around 12 years of age. Pseudohypertrophy of muscle, in particular the calf, is a characteristic (occurring in 80%) but not a pathognomonic feature.

The child cannot climb stairs or rise from a low chair and when attempting to rise from the ground will ‘climb up him’ – Gower’s sign (not diagnostic of the condition, but indicative of pelvic muscle weakness).

Investigation

Gene testing on serum may establish the diagnosis. The Dystrophin gene is large and many protocols only screen a part of it. A ‘negative test’ therefore does not rule it out and muscle biopsy with immunological testing is necessary. This demonstrates the absence of dystrophin. Female carriers can be detected by PCR.

Creatine kinase (CK) – substantially elevated (several thousand times). The enzyme is raised at birth and elevated in female carriers (in earlier times this formed the basis for counselling).

Electrocardiogram – 80% show conduction disorders, tall precordial R waves and deep left precordial Q waves. Echocardiography should be repeated occasionally to detect developing cardiomyopathy.

Electromyography – shows severe myopathic change.

Life expectancy has risen from late teens to late 20s or early 30s with the use of surgery to correct scoliosis, active control of contractures and non-invasive ventilation. Corticosteroids slow progression and delay onset of disability, though the optimum regimen in still uncertain. Death occurs from respiratory insufficiency and infection or is ‘sudden’ and presumed to be related to cardiac disease. Long term care of affected individuals should be co-ordinated with anticipation rather than reaction to the evolution of disease.

BECKER DYSTROPHY

Abnormalities within the dystrophin gene may be associated with a spectrum of presentations from Duchenne to the milder condition described by Becker. Becker MD is rarer than Duchenne MD – incidence 1:35 000, presenting at a later age usually with limb-girdle involvement and pseudohypertrophy. These later milder presentations may also occur in some female carriers of the mutation. Cardiac involvement may be symptomatic in up to 10% of affected individuals and female carriers and is not related to the mutation or the severity of limb muscle disease.

The diagnosis is established in up to 80% of cases with serum DNA analysis. In the rest a combination of immunohistochemical demonstration of the relative absence of dystrophin, elevated CK, the clinical pattern and pedigree analysis make the diagnosis.

MUSCULAR DYSTROPHIES

DYSTROPHIES WITH PARTICULAR PATTERNS OF WEAKNESS

Facioscapulohumeral (FSH)

An autosomal dominant disorder, variable in severity and associated with a contraction of a series of 3.3 kB repeats at locus 4q35. Incidence 1–2:100 000. The mechanism by which this mutation causes disease is not known.

The clinical features include

– Facial weakness (which may be mild or asymmetrical)

– Periscapular weakness producing winging of the scapula and rising up of the scapulae on attempted abduction

– Weakness of the humeral muscles

– A predominantly proximal lower limb pattern of weakness giving a dromedary or camel-backed gait

Pseudohypertrophy is not a feature.

Severity is variable, ranging from severe childhood forms to later onset disease that may be asymptomatic. CK levels may only be raised to 1.5–2 upper limit or normal. EMG and muscle biopsy will show myopathic abnormalities but have no specific features; although secondary inflammatory change on biopsy may lead to an erroneous diagnosis of Polymyositis. Cardiac involvement is not a feature. High frequency sensorineural hearing loss and exudative retinal telangiectases complicate some early onset cases (Coat’s syndrome). Prognosis is dependent on the degree of respiratory muscle involvement. Some may benefit from ventilatory support.

Scapuloperoneal

A dominant or recessive disorder that involves proximal upper and distal lower limb muscles. Onset is in adulthood with foot drop followed by weakness in scapular deltoid, triceps and biceps muscle groups. Differentiation from spinal muscular atrophy and inflammatory muscle disease is difficult.

Distal

Distal weakness due to primary dystrophies is rare with the exception of Myotonic Dystrophy. Both autosomal dominant and recessive patterns are described and may involve upper or lower limb muscles at onset. Some are associated with vacuolation of muscle fibres.

Emery-Dreifuss

Rare but important because of its cardiac complications. Both X-linked and dominant forms reported (the dominant form is now classified as LGMD type 2). Contractures of the spine produce an appearance of hyperextension. Contractures of elbows and ankles occur early. Weakness may be in a scapuloperoneal distribution. Life threatening cardiac condition defects are virtually universal and ventricular tachyarrythmias occur in a proportion. Patients will require pacing and some have implanted defibrillators. Respiratory muscle weakness may occur.

Oculopharyngeal

This is another very rare pattern of weakness associated with a small GCG trinucleotide expansion in the PABP2 gene on chromosome 14. Inheritance is autosomal dominant. Occurs with a mean age of onset of 50 years with a combination of ptosis, ophthalmoparesis and dysphagia. Limb weakness may occur. Muscle biopsy shows rimmed vacuoles and filamentous intranuclear inclusions.

Limb girdle syndromes and limb girdle muscular dystrophy (LGMD)

Slowly progressing proximal weakness is a common presentation of both primary and secondary myopathies. A large number of proteins with differing functions produce a similar LGMD phenotype. Recessive forms are more common than dominant ones. The differential diagnosis of limb girdle distribution weakness is wide (see table).

CATEGORIES	EXAMPLES	SUGGESTIVE FEATURES
Non-dystrophic genetic myopathies	Desmin myopathy, congenital structural myopathies (nemaline etc.)	Early onset, presence of contractures, often very thin muscles yet only mild weakness
Metabolic myopathies	Acid Maltase deficiency, McArdles disease, mitochondrial disorders	Pain, variability, exercise intolerance
Endocrine	Hypo-and hyperthyroidism, osteomalacic myopathy, Cushing’s syndrome	Diffuse pattern of weakness, endocrine features may not be prominent
Toxic/metabolic	Steroid therapy, alcohol, statins	Should be apparent from history
Inflammatory	Polymyositis	See discussion below
Limb Girdle Muscular Dystrophy (LGMD)	At least 3 dominant and 9 recessive forms. Precise diagnosis requires specialised investigation	Symmetry, focal involvement of individual muscles, cardiac conduction defects, contractures from early stages

MYOTONIC DYSTROPHY (MyD)

Myotonic Dystrophy is an autosomal dominant multisystem disorder caused by an unstable trinucleotide repeat expansion in a non-coding sequence at position 19q13.3. This expansion is thought to be pathogenic because of indirect effects on adjacent gene(s). It may present at any age with an incidence of 5 per 100 000.

Whilst neuromuscular features may not be prominent, the condition is usually characterised by the presence of MYOTONIA – failure of immediate muscle relaxation after contraction has ceased.

It can be demonstrated by:

Clinical features

– Cataracts

– Disorders of smooth muscle; gut motility disorders, constipation, poor bladder emptying.

– Cardiac disease; dilated cardiomyopathy and atrio-ventricular block requiring cardiac pacing

– Respiratory failure; due to intercostals and diaphragmatic weakness, impaired swallowing with risk of aspiration and central sleep apnoea (many patients benefit from nocturnal respiratory support).

– Diabetes; due to insulin resistance

– Testicular atrophy and subfertility

Diagnosis

In classic adult-onset cases, clinical diagnosis is straightforward with demonstration of progressive distal and bulbar dystrophy in the presence of myotonia, with frontal balding, and cataracts. Clinical diagnosis can be more difficult in mild cases, where cataracts may be the only manifestation. Direct analysis, by Southern blotting on peripheral leucocytes, of the size of the CTG repeat permits DNA diagnosis. Normal individuals have 5 to 37 CTG repeats, whereas patients have 50 to several thousand CTG repeats.

The importance of recognition of the disorder lies in the management of complications and genetic advice. The gene defect instability (number of repeats) between generations accounts for the wide clinical variability (phenotype) of MyD. Females are at risk of delivering a severely affected child who, due to respiratory failure, may not survive the neonatal period. Occasionally persons first present, either spontaneously or following anaesthesia, with unexpected respiratory failure or sudden death.

When molecular tests are negative but clinical features suggestive two rare alternative disorders are considered –

1. DYSTROPHIA MYOTONICA 2 (MyD 2)

Genetically distinct form of myotonic dystrophy. Affected family members show remarkable clinical similarity to classic MyD (myotonia, proximal and distal limb weakness, frontal balding, cataracts, and cardiac arrhythmias). Disease locus maps to a 10 cM region of 3q.

2. PROXIMAL MYOTONIC MYOPATHY (PROMM)

This dominant disorder presents with myotonia in 30s–40s and mild proximal weakness in the fifth to seventh decades of life. Muscle biopsy demonstrates a non-specific mild myopathy with hypertrophy of type 2 fibres. Cataracts identical to those found in MyD occur in 15 to 30% of patients. Cardiac symptoms (arrhythmias) are infrequent. The gene causing PROMM is also located on 3q, suggesting that PROMM and MyD 2 are either allelic disorders or caused by closely linked genes.

DYSTROPHIES: GENERAL PRINCIPLES

It may not be possible to diagnose or exclude a specific type of dystrophy but practical issues apply to all:

– Genetics. The implications for the family of differing modes of inheritance are clear. Help should be sought from a clinical geneticist to discuss these even if no molecular diagnosis has been reached but an inherited disorder suspected. Isolated cases of LGMD may represent a new dominant mutation and its phenotype is extremely variable. Both patients and their partners should be made aware of such issues.

– Cardiac disease. This is critically important in the Emery-Dreifuss syndrome where life-threatening conduction defects are inevitable but also occur in Xp2.1 related dystrophies and Polymyositis. In the absence of a proven diagnosis, ECGs should be performed at 12 monthly intervals and echocardiography also if symptoms suggestive of cardiac failure develop.

– Respiratory failure related to diaphragmatic weakness, a prominent feature of Xp2.1, MD, LGMD, other forms of MD and inflammatory muscle disease. Late deterioration in some of the congenital myopathies may also lead to sleep disordered breathing. It is important to be aware of this, as non-invasive nocturnal ventilatory support is frequently beneficial to such patients.

INFLAMMATORY MYOPATHY

Primary inflammatory myopathies are clinically, pathologically and therapeutically distinct entities. Inflammatory changes are probably due to an immune mediated process rather than directly pathogenic. These are acquired as opposed to the inherited dystrophies and are classified as follows:

Dermatomyositis

Inclusion body myositis

Inflammatory myopathy associated with malignant disease

Inflammatory myopathy associated with collagen vascular disorders – e.g. lupus erythematosus, systemic sclerosis, rheumatoid arthritis.

Infective – Viral e.g. coxsackie, echo. Parasitic, e.g. cysticercosis, trichinosis, taenia solium, toxoplasma, toxocara.

Sarcoid myopathy – some with this multi-system disease have granulomas in skeletal muscle.

POLYMYOSITIS/DERMATOMYOSITIS

There are two principal forms of inflammatory myopathy – polymyositis and dermatomyositis – which are separated clinically by the dermatological findings in the latter. All age groups are affected. Annual incidence is 8 per 100 000. These disorders are sporadic though familial cases are described.

An autoimmune basis for these disorders is supported by:

– response to immunosuppressive therapy.

– association with other known immunological disorders, e.g. collagen vascular disorders.

– elevated IgG in blood and presence of circulating autoantibodies, e.g. antinuclear antibody in some cases.

– an increased incidence of certain histocompatibility antigens (HLA antigens) – B₈, DR3.

– the reproduction of a similar disorder in laboratory animals by injection of muscle extract with Freund’s adjuvant.

Humoral and cell mediated immune mechanisms seem responsible for these disorders but the trigger factor(s) remain unknown.

Clinical presentation

Onset is acute or subacute over a period of several weeks and may follow systemic infection.

Systemic symptoms prevail at onset, e.g. lassitude, and are then followed by muscle weakness. Extensive oedema of skin and subcutaneous tissues is common (especially in the periorbital region).

INCLUSION BODY MYOSITIS (IBM)

Recognised now as the commonest inflammatory muscle disorder in the middle aged and elderly (women are less commonly affected and more likely to be younger). Unlike the other inflammatory myopathies symmetrical weakness is painless and distal including foot extensors and finger flexors. May be associated neuropathy. Most patients have a protracted course unaffected by immunosuppressive therapies. Occasionally it is associated with connective tissue disorders such as Sjögren’s syndrome.

Investigations

Diagnosis is supported by the following investigations:

Muscle enzymes	Circulating antibodies
Creatine kinase (CK) is elevated.	e.g. rheumatoid factor, antinuclear factor. Present in 40%.
Released from necrotic muscle, it is an indicator of disease activity and severity
Electromyography	Erythrocyte sedimentation rate (ESR)
Shows a typical myopathic pattern.	Elevated in most patients.

Muscle biopsy shows necrosis of muscle fibres with inflammatory cells – lymphocytes, plasma cells, leucocytes.

The distinguishing features of the common inflammatory myopathies and responses to treatment are summarised as follows:

OUTCOME OF INFLAMMATORY MYOPATHIES

The natural history of these conditions is uncertain; mortality is low though perhaps only a minority recover completely. Inclusion body myositis is slowly and steadily progressive. Polymyositis and dermatomyositis respond in varying degrees to treatment and eventually become inactive. Safe monitoring of treatments and protection against side effects (e.g. steroid induced bone disease) is critical.

POLYMYOSITIS AND DERMATOMYOSITIS ASSOCIATED WITH MALIGNANT DISEASES

Approximately 10% of adults with inflammatory myopathy have underlying neoplasia usually carcinoma. In dermatomyositis, of those over 40 years of age as many as 60% harbour neoplasia. Neoplasia may present before or after the development of inflammatory myopathy.

POLYMYOSITIS AND DERMATOMYOSITIS ASSOCIATED WITH COLLAGEN VASCULAR DISEASES

Approximately 15% of adults with inflammatory myopathy have symptoms and signs of an associated collagen vascular disorder.

In 5–10% of persons with these disorders (systemic lupus erythematosus etc.), inflammatory myopathy develops at some stage in their illness.

In the ‘overlap’ syndromes (mixed collagen vascular diseases) muscle involvement is more common.

ENDOCRINE MYOPATHIES

Unlike inflammatory myopathy the weakness in these conditions is more chronic and is unassociated pathologically with inflammation. Serum CK is usually normal and EMG and biopsy (if performed) show non-specific myopathic changes. Correction of the underlying endocrine disturbance results in recovery. Usually the other features of endocrine dysfunction are more problematical and myopathy is of secondary importance.

Pituitary

Acromegaly

Proximal weakness with fatigue. Entrapment neuropathies, e.g. carpal tunnel syndrome may complicate the clinical picture of myopathy. Other features of growth hormone excess are evident.

Parathyroid

Hyperparathyroidism and osteomalacia.

Weakness of a proximal distribution with muscle tenderness occurs in 50% of patients with osteomalacia but is less common in primary hyperparathyroidism. The legs are mainly affected and a waddling gait results. Pathogenesis of hyperparathyroid myopathy is uncertain; hypercalcaemia, Vitamin D deficiency or chronic phosphate deficiency is implicated, tetany results and the CK may be elevated but weakness is uncommon.

Adrenal

Hyperadrenalism and hypoadrenalism

These may both be associated with proximal myopathy. Muscle weakness, fatigue and cramping are frequent in Addison’s disease with attacks of severe episodic hypokalaemic weakness (periodic paralysis) requiring glucocorticoid and mineral corticoid replacement. Hypokalaemic periodic paralysis is also frequent in hyperaldosteronism. Cushing’s syndrome and exposure to excessive exogenous glucocorticoids commonly results in insidious proximal weakness. Reduction of steroid dosage results in improvement.

Thyroid

Hyperthyroidism

Weakness occurs in 20% of thyrotoxic patients. Shoulder girdle weakness is more marked than pelvic. Reflexes are brisk, fasciculation and atrophy may be present. Distinction must be made from motor neuron disease. There is always clinical evidence of thyrotoxicosis in these patients. Diagnosis is confirmed by thyroid function studies.

Hypothyroidism

Hypothyroidism impairs muscle glycolysis and mitochondrial oxidative capacity. Proximal weakness involves pelvic girdle more than shoulder. Painful cramps and muscle stiffness are common.

Muscle enlargement in limbs and tongue often occur (Hoffman’s syndrome). There is always clinical evidence of hypothyroidism in these patients. Diagnosis is confirmed by thyroid function tests and response to thyroid hormone therapy is excellent.

In chronic proximal weakness, careful clinical history taking, examination and appropriate investigation will separate the various endocrine causes.

CHANNELOPATHIES: PERIODIC PARALYSES AND MYOTONIA

Periodic paralyses and congenital myotonias are associated with defects in ion channels and are grouped together as channelopathies. The primary periodic paralyses are classified into two categories: hypokalaemic and hyperkalaemic (or potassium-sensitive). Hypokalaemic periodic paralysis shows the clearest relationship between episodic weakness and alterations in potassium. Hyperkalaemic periodic paralysis is more accurately a ‘potassium sensitive’ periodic paralysis as weakness can be provoked by potassium administration, whilst serum potassium may rise only marginally during spontaneous attacks. Paramyotonia can be associated with either hypo or hyperkalaemic periodic paralysis.

Importantly episodes of weakness, with alterations in serum potassium, are most commonly secondary to drugs (e.g. diuretics and corticosteroids) or disorders such as alcoholism, renal and endocrine disease. (See page 478.)

Hypokalaemic periodic paralysis	Hyperkalaemic periodic paralysis	Paramyotonia congenita
Autosomal dominant. The gene has been mapped on chromosome 1, mutations resulting in upset of the dihydropyridine receptor, a voltage-gated calcium channel. Onset in second decade. Precipitated by: exercise, carbohydrate load. Commences in proximal lower limb muscles and rapidly becomes generalised. Onset usually in morning on wakening. Attacks last from 4 to 24 hours. Bulbar muscles/respiration unaffected. K⁺ falls as low as 1.5 meq/l. Treatment: Acute – oral KCl. Prophylactic _ acetazolamide; low carbohydrate, high K⁺ diet. With age, attacks become progressively less frequent.

Autosomal dominant or recessive.

Chromosome 17 location.

Na⁺ channel gene defect

Onset in infancy/childhood.

Precipitated by: rest after activity or by cold.

Commences in lower limbs and evolves rapidly.

Attacks are of short duration (less than 60 min).

Myotonia is evident in some patients.

K⁺ rises only slightly.

Treatment:

Acute – intravenous calcium gluconate or sodium chloride.

Prophylactic – Acetazolamide is effective prophylaxis.

Autosomal dominant. Same gene as in hyperkalaemic form. Na⁺ channel defect. Onset in infancy. Precipitated by: rest after exercise, fasting and cooling.

Commences in proximal muscles.

Repetitive muscle contractions produce increasing stiffness.

EMG findings are specific with marked spontaneous activity in limb cooling.

Treatment. Na⁺ channel blockers, Tocainide or Mexiletine.

Normokalaemic periodic paralysis	Thyrotoxic periodic paralysis	Congenital myotonia
There are patients with episodic weakness in whom no alteration in serum potassium can be found. Many are sensitive to the administration of oral potassium salts. Treatment is the same as for the hyperkalaemic form but there is no response to acetazolamide. Muscle biopsy in these patients showed occasional vacuoles and prominent tubular aggregates.	Attacks of paralysis are associated with hypokalaemia and are clinically similar to those of the hypokalaemic form. Mainly occurs in Asians and rarely in non-Asians. The majority of patients experience their first attack in their 30s. There is a marked (20 to 1) male to female predominance.	Dominant form (Thomsen’s disease) and recessive (Becker’s) are both caused by mutation in the chloride channel gene. Myotonia can be triggered by cold, improving with exercise. May have muscle hypertrophy. Treatment with quinine, phenytoin or mexilitene reduces myotonia.

METABOLIC AND TOXIC MYOPATHIES

Metabolic myopathies

A group of genetically determined biochemical disorders of muscle characterised by myalgia, cramps, weakness and fatigue. These are divided into conditions with reduced exercise tolerance and those of static weakness. These complex disorders of muscle carbohydrate and lipid metabolism require specialist evaluation. Diagnosis requires detailed muscle staining to demonstrate enzyme loss critical to specific metabolic pathways.

The following disorders are representative but not comprehensive.

McArdle’s disease – disorder of carbohydrate metabolism – block in glycolytic pathway (phosphorylase deficiency). Muscle phosphorylase deficiency is a phenotypically heterogeneous autosomal recessive disorder. In some patients phosphorylase is absent whilst in others present but defective. The gene defect localises to chromosome 10.

Diagnosis:

Failure of serum lactate to rise following exercise.

Muscle biopsy – absence of phosphorylase activity with appropriate histochemical staining.

Can be diagnosed from leucocyte DNA.

Treatment with oral fructose may help.

Carnitine palmitoyltransferase deficiency – Carnitine palmitoyltransferase (CPT) enzymes transfer fatty acids across the muscle mitochondrial membrane. CPT 1 attaches and CPT 2 detaches these fatty acids.

Infrequent episodes of myalgia and myoglobinuria following fasting or strenuous exercise. Onset is in adolescence, occasionally in adulthood. Though an autosomal recessive disorder, males are more commonly symptomatic. Neurological examination is normal. Serum CK, EMG and muscle biopsy (including histochemistry) are normal between attacks. Patients are advised to take a low fat/high protein and carbohydrate diet and to avoid prolonged exercise or fasting.

Acid maltase deficiency (ADM) – A lysosomal glycogen storage disease with infantile, childhood, and adult types. The casual gene localises to chromosome 17 with different mutations accounting for ages of onset. Treatment is supportive, genetic counselling essential.

Infantile AMD (Pompe’s disease) – progressive muscle weakness, cardiomegaly with congestive heart failure. Death occurs before 1 year. Glycogen accumulates in cardiac, skeletal muscle and in the CNS.

Childhood AMD – slower clinical course, with respiratory muscle weakness developing between 5 and 20 years. Histologically, muscle contains glycogen-filled vacuoles.

Adult AMD – proximal weakness in 3rd or 4th decade mimicking limb-girdle muscular dystrophy or polymyositis. Respiratory muscles are severely affected with risk of death from respiratory failure. Muscle biopsy again shows glycogen-filled vacuoles. Liver, heart and central nervous system are spared.

Carnitine deficiency – Carnitine transports long-chain fatty acids into the mitochondria. Deficiency results in systemic or myopathic features.

Systemic carnitine deficiency – childhood onset weakness with hypoglycaemic encephalopathy, precipitated by fasting and resembling Reye’s syndrome (page 508). Serum and muscle carnitine levels are low. Biopsy shows an excessive number of lipid droplets in type 1 fibres. The liver, kidney, and heart contain excessive lipid. Cardiomyopathy is fatal.

Myopathic carnitine deficiency – muscle weakness, exertional myalgias and myoglobinuria. Onset of symptoms is usually in childhood but can be delayed until adulthood. Some cases are complicated by cardiomyopathy. Muscle biopsy shows excessive lipid droplets, especially in type 1 fibres. Muscle and serum carnitine levels are low.

Toxic myopathies

Necrotising myopathy is the pathological consequence of toxic muscle insult characterised by muscle weakness, pain, and tenderness. Investigations – elevated serum CK, myoglobinuria, myopathic motor units and fibrillation on EMG. Muscle biopsy – necrosis and regeneration. Numerous drugs have been incriminated. Statins are the most common culprits. Other examples include clofibrate in renal failure or hypoalbuminaemia. Epsilon-aminocaproic acid, procainamide, zidovudine (AZT) and phencyclidine. Focal muscle necrosis can be caused by intramuscular injections.

MITOCHONDRIAL DISORDERS

The DNA of the mitochondria (mtDNA) is circular, and while mitochondria themselves reproduce by binary fission, mtDNA replication is controlled by the eukaryotic genome. Mitochondrial disorders are transmitted through the maternal line and not by affected males (mtDNA transmits through the ovum not sperm). The relative proportion of normal to abnormal mtDNA determines the degree of expression (phenotype) for the mutation. As well as muscle involvement, characterised by ragged red muscle fibres on biopsy, many other clinical features are associated with mtDNA mutation syndromes and include:

– Seizures, respiratory insufficiency, weakness and vomiting and failure to thrive in the neonate.

– Developmental delay, ataxia, optic atrophy, progressive external ophthalmoplegia, sensorineural deafness, stroke-like episodes, dementia, exercise intolerance, and short stature.

– Renal failure, diabetes mellitus, cataract and cardiomyopathy.

Certain specific syndromes are recognised though overlap and diversity of phenotype is common.

CPEO (Chronic progressive external ophthalmoplegia)

MERRF (Myoclonic epilepsy with ragged red fibres)

Adolescence/adult onset of ptosis and ophthalmoplegia (without diplopia) often associated with mild proximal myopathy. When associated with heart block and retinopathy – Kearns Sayre syndrome (KSS).

Differentiate from ocular myasthenia (page 152).

Investigations Large deletion in mt DNA in skeletal muscle biopsy and serum.

Prognosis good with very slow progression. Heart block may require pacing.

Adult onset of myoclonus, seizures and ataxia occasionally associated with respiratory failure. Disease expression is variable.

Differentiate from other types of myoclonic epilepsy.

Investigations Elevated lactate i.e. serum and CSF.

‘Ragged red’ fibres in muscle biopsy and point mutation in tRNA Lys gene of mt DNA in skeletal muscle biopsy and serum.

Prognosis is poor in fully expressed disease – death from seizures or respiratory failure.

MELAS (Mitochondrial encephalopathy, lactic acidosis and stroke-like syndrome) LHON (Leber’s hereditary optic neuropathy)

Adult onset of stroke-like episodes (posterior hemisphere) associated with focal seizures and vascular headache. ‘Strokes’ are not in vascular territories and are due to failure to utilise substrates rather than to a lack of them.

Differentiate from other causes of ‘young’ stroke.

Investigations CT/MRT shows posteriorly placed ischaemic changes, elevated lactate in serum and CSF.

‘Ragged red’ fibres on muscle biopsy and two-point mutation in tRNA Leu gene of mt DNA.

Prognosis is variable. Seizures and headache followed by ‘strokes’ and eventual dementia.

Adult subacute onset of loss of central vision, initially unilateral but bilateral in all patients after 1 year.

Visual acuity may be reduced to hand movements only due to marked optic atrophy. Male/female ratio: 3:1.

Differentiate from optic neuritis, alcohol/tobacco amblyopia and anterior ischaemic optic neuropathy.

Investigations Several mt DNA mutations have been detected in serum.

Prognosis for visual recovery varies and depends on the specific mutation, as do other accompanying neurological features. In the majority visual loss is irreversible.

NARP (Neuropathy, ataxia and retinitis pigmentosa) Leigh’s syndrome

Adult onset of sensory/motor neuropathy, ataxia and chronic visual impairment. The rarest mitochondrial syndrome. In some, shares a similar molecular basis as

Leigh’s syndrome and can demonstrate maternal, autosomal recessive or X linked inheritance.

Differentiate from other causes of ataxic neuropathy e.g. Freidreich’s.

Investigations Point mutations mt DNA (ATPase) detected in serum.

Prognosis is uncertain, dementia occurs in time.

Infant or childhood onset of subacute necrotising encephalomyelopathy characterised by psychomotor retardation, ataxia, optic atrophy and ophthalmoplegia.

Differentiate from other causes of progressive encephalopathy of childhood e.g. inborn errors of metabolism.

Investigations CT/MRI brain stem changes, elevated lactate and pyruvate dehydrogenase complex in CSF and serum and various mutations at Xp 22.1 and mt DNA (ATPase).

Prognosis is poor with early death.

There is no proven therapy for these conditions. Co-morbid conditions such as infection, cardiac involvement and diabetes mellitus should be treated conventionally. Pharmacologic therapies that may bypass biochemical defects are worth using e.g. L. Carnitine, Ubiquinone, riboflavin, thiamine and free radical scavengers (Vits C and E).

MYASTHENIA GRAVIS

Myasthenia gravis is a disorder of neuromuscular transmission characterised by:

– Weakness and fatiguing of some or all muscle groups.

– Weakness worsening on sustained or repeated exertion, or towards the end of the day, relieved by rest.

This condition is a consequence of an autoimmune destruction of the NICOTINIC POSTSYNAPTIC RECEPTORS FOR ACETYLCHOLINE.

Myasthenia gravis is rare, with a prevalence of 5 per 100 000. The increased incidence of autoimmune disorders in patients and first degree relatives and the association of the disease with certain histocompatibility antigens (HLA) – B₇, B₈ and DR₂ – suggests an IMMUNOLOGICAL BASIS.

AETIOLOGY

Antibodies bind to the receptor sites resulting in their destruction (complement mediated). These antibodies are referred to as ACETYLCHOLINE RECEPTOR ANTIBODIES (AChR antibodies) and are demonstrated by radioimmunoassay in the serum of 90% of patients.

Human purified IgG (containing AChR antibodies) injected into mice induces myasthenia-like disease in these recipient animals.

In human myasthenia gravis a reduction of acetylcholine receptor sites has been demonstrated in the postsynaptic folds. Reduced receptor synthesis and increased receptor destruction, as well as the blocking of receptor response to acetylcholine, all seem responsible for the disorder.

The rôle of the thymus: Thymic abnormalities occur in 80% of patients. The main function of the thymus is to affect the production of T-cell lymphocytes, which participate in immune responses. Thymus dysfunction is noted in a large number of disorders which may be associated with myasthenia gravis, e.g. systemic lupus erythematosus.

MYASTHENIA GRAVIS – PATHOLOGY

Changes are found in the thymus gland and in muscle.

Muscle biopsy may show abnormalities:

– Lymphocytic infiltration associated with small necrotic foci of muscle fibre damage.

– Muscle fibre atrophy (type I and II or type III alone).

– Diffuse muscle necrosis with inflammatory infiltration (when associated with thymoma).

Motor point biopsy may show abnormal motor endplates. Supravital methylene blue staining reveals abnormally long and irregular terminal nerve branching.

Light and electron microscopy show destruction of ACh receptors with simplification of the secondary folds of the postsynaptic surface.

CLINICAL FEATURES

Up to 90% of patients present in early adult life (<40 years of age). Female:male ratio 2:1. The disorder may be selective, involving specific groups of muscles.

Several clinical subdivisions are recognised:

Approximately 40% of class I will eventually become widespread. The rest remain purely ocular throughout the illness.

Respiratory muscle involvement accompanies severe illness.

Cranial nerve signs and symptoms

– Ocular involvement produces ptosis and muscle paresis.

– Weakness of jaw muscles allows the mouth to hang open.

– Weakness of facial muscles results in expressionless appearance.

– On smiling, buccinator weakness produces a characteristic smile (myasthenic snarl).

Bulbar involvement may result in: – dysarthric dysphonic speech and dysphagia.– nasal regurgitation of fluids – nasal quality to speech.

The demonstration of fatiguing is important in reaching diagnosis and in monitoring the response to treatment:

Fatiguing of other bulbar muscles may be demonstrated by:

– blowing out cheeks against pressure.

– counting as far as possible in one breath, etc.

The tongue occasionally shows the characteristic triple grooved appearance with two lateral and one central furrow.

Limb and trunk signs and symptoms

Weakness of neck muscles may result in lolling of the head. Proximal limb muscles are preferentially affected. Fatigue may be demonstrated by movement against a constant resistance.

Limb reflexes are often hyperactive and fatigue on repeated testing.

Muscle wasting occurs in 15% of cases.

Stress, infection and pregnancy and drugs that alter neuromuscular transmission all exacerbate the weakness

Natural history: (Before treatment became available)	10% of patients entered a period of remission of long duration.
	20% experienced short periods of remission (1 to several months).
	30% progressed to death.
	The remainder showed varying degrees of disability accentuated by exercise.

MYASTHENIA GRAVIS – DIFFERENTIAL DIAGNOSIS

Distinguish from:

– The patient who complains of fatiguing easily – general weakness/debility (e.g. chronic fatigue syndrome) & functional weakness.

– The patient with progressive ophthalmoplegia, e.g. mitochondrial myopathy, oculopharyngeal dystrophy.

– The patient with multiple sclerosis – diplopia, dysarthria and fatigue with a relapsing and remitting course.

– The patient with the Lambert-Eaton myasthenic syndrome (see page 549).

INVESTIGATION

PHARMACOLOGICAL

Anticholinesterase drugs are used to confirm diagnosis.

Tensilon (edrophonium) – short action, 2–4 minutes, given i.v. 2–10 mg slowly, with atropine pretreatment to counter muscarinic side effects (nausea and bradycardia – resuscitation facilities need to be available). This is positive when clear improvement in weakness occurs on objective testing. A control injection of saline and blinded observer can be useful. The Tensilon test may be negative in ocular myasthenia and give a false positive in the Lambert-Eaton syndrome.

SEROLOGICAL

Acetylcholine receptor antibodies (anti-AchR) are detected in 90% of patients and are virtually specific to this disease. In ocular myasthenia, only 60% show antibodies. Magnitude of titres correlates with disease severity. Anti-Muscle specific Kinase (anti-MUSK) antibodies are found in a proportion of anti-AchR negative patients.

Other antibodies e.g. microsomal, colloid, rheumatoid factor, gastric parietal cell antibody – are occasionally found, reflecting the overlap with other autoimmune disorders.

Anti striated muscle antibodies are found in 30% of all patients and in 90% of those with thymoma.

ELECTROPHYSIOLOGICAL

Reduction of the amplitude of the compound muscle action potential evoked by repetitive supramaximal nerve stimulation – ‘the decrementing response’.

Various rates of stimulation; even as low as 3/second may produce a decrementing response.

Single fibre electromyography – measure of ‘Jitter’ – the time interval variability of action potentials from two single muscle fibres of the same motor unit – is a more sensitive index of neuromuscular function and is increased (95% of mild cases are abnormal).

ADDITIONAL

Chest X ray will show a large mediastinal mass but will not exclude a small thymoma. CT of chest should be performed in all newly diagnosed cases.

MYASTHENIA GRAVIS – TREATMENT

In severely ill patients, the first priority is to protect respiration by intubation and, if necessary, ventilation.

Anticholinesterase drugs

This is the longest established form of treatment (1930s).

Anticholinesterase drugs inhibit cholinesterase, the enzyme responsible for the breakdown of acetylcholine, allowing enhanced receptor stimulation. As a result, more acetylcholine is available to effect neuromuscular transmission.

A muscarinic inhibitor, atropine, may be required to counter side effects (nausea, vomiting, diarrhoea, muscle fasciculations and increasing weakness). Anticholinesterases rarely give complete symptomatic relief and large doses can result in a cholinergic crisis

– worsening weakness

– increased sweating, saliva and bronchial secretions

– small pupils (miosis)

– eventual respiratory failure.

Atropine may mask early warning symptoms of this potential life-threatening state.

Steroids

Because this disorder is immune-mediated steroids are a logical choice in generalised and occasionally severe ocular disease. Prednisone 60 mg/day is initially used. Deterioration may briefly occur before improvement. Because of this low-dose regimes are often preferred, increasingly slowly from prednisone 25 mg alternate days. Once a response occurs, dosage is reduced.

Immunosuppressants other than steroids

These drugs (azathioprine and cyclosporine) are considered in patients who do not respond to steroids or who require an unacceptably high steroid maintenance dose.

Thymectomy

There are two indications for this:

1. When thymoma is present

2. When myasthenia is generalised and benefits of surgery outweigh risks.

Trans-sternal is preferred to supra-sternal approach giving better chance of total clearance. Within 5 yrs of surgery 70% of patients are in remission.

Plasmapheresis

Plasma filtration removes antibodies and other circulating factors and has short term benefit (4–6 weeks). A plasma volume of 1.5–2 litres is exchanged 3–5 times over a 6–8 day period. The technique is expensive and carries risks (hypotension, metabolic disturbance and thrombo-embolism). It is used to stabilise refractory cases and prior to thymectomy in severe disease.

Immunoglobulin (IVIG)

May be used in place of plasmapheresis at a dose of 400 mg per kg intravenously daily for 5 days. Mechanism may act by blocking ACh receptors. A positive response (75% of patients) lasts for 2–3 months. Treatment is expensive and long term effects and complications unknown.

SUMMARY OF TREATMENT

Anticholinesterases should not be required throughout the whole illness. When immunological control of the disease is obtained, these drugs may be stopped.

EMERGENCY TREATMENT – MYASTHENIC/CHOLINERGIC CRISES

– Identify and treat precipitating cause, e.g. infection, drug interaction or overdose

– Sit patient at 45°, clear airway, give nasal O₂ and if overt respiratory failure – intubate and ventilate for as long as required.

Myasthenic crisis	Cholinergic crisis
– IV neostigmine 8–12 mg/24 hrs – sc. Atropine 0.5 mg tds – Prednisolone 100 mg daily – Consider plasmapheresis or IVIG – Change IV to oral anticholinesterases when able to swallow