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.

PERIPHERAL NERVES

Peripheral nerves are composed of many axons bound together by connective tissue. A ‘mixed’ nerve contains motor, sensory and autonomic axons.

Nerve fibre type

Axons within the peripheral nerve vary structurally. This is related to function. Three distinct fibre types can be distinguished:

TYPE A	2–20 μm in diameter. Myelinated.
Function:	Motor and sensory (vibration, proprioception). Conduction velocity: 10–70 metres/second.
TYPE B	3 μ m diameter. Thinly myelinated.
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.

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.

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)

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.

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 SYNDROMES

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

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.

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)

– 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.

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

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