The Polyneuropathies

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 brainstem 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-system, e.g. anterior horn cell, 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

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 may vary also

• 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 fibers of muscle spindles- the gamma motor neurons

• Each alpha motor neuron through its peripheral ramifications will innervated 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 (innervations 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

The blood supply to these bundles is by means of small nutrient vessels within the epineurium – the vasa nervorum

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.

The Polyneuropathies – Symptoms

• 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 in which traumatic deformity is totally painless

Positive phenomena

• Disease of large myelinated fibres reduces 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

- 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-I) or injury to a large peripheral nerve (CRPS-2)

• Allodynia and hyperalgesia are associated with local changes in temperature and skin appearance. The pain has a burning, shooting quality. Motor manifestations 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 fasciculation's – irregular twitches of groups of muscle fibres due to diseased anterior horn cells these may be induced by exercise or muscle percussion

The Polyneuropathies – Classification

The Polyneuropathies – Neuropathy Despite extensive investigation, the cause of chronic neuropathy

cannot be identified in 30% of such cases.

The following conditions require exclusion before a chronic neuropathy is classified as idiopathic or of unknown aetiology: diabetes, uraemia, deficiency states, connective tissue disorders, paraproteinaemias, underlying malignancy, drugs and toxins

Hereditary disease can sometimes be excluded by clinical examination and genetic analysis of relatives

The cause of acute or subacute neuropathy can usually be defined.

Here, CSF examination may prove a useful diagnostic investigation, e.g. Guillain-Barre syndrome.

Investigation of Neuropathy

Localised compression of nerve slowing of conduction in region of block, e.g. over the elbow when ulnar nerve is compressed at that site

Conduction block, distant from entrament sites may suggest multifocal motor neuropathy

Electromyography :

A fine needle is inserted into the muscle and the recorded activity displayed on an oscilloscope

Electromyography is primarily of value in muscle disease but can also give indirect evidence of a neuropathic process

The presence of denervation in paraspinal muscles indicates proximal never root disease

If chronic denervation has occurred, reinnervation may be present with long duration high amplitude motor unit potentials

Also, with voluntary efforts, poor recruitment of motor units is seen on the oscilloscope screen

Nerve biopsy :

A biopsy is most likely to aid diagnosis in asymmetric multiple monneuropathies (vasculitis, amyloidosis, sarcoidosis etc)

The sural nerve is usually chosen, provided its sensory conduction is abnormal

The Polyneuropathies – Specific Types

Acute inflammatiory posinfectious polyneuropathy (Guillain-barre syndrome)

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

Aetiology/pathology :

The condition may follow viral infection, e.g. varicella-zoster, mumps and cytomegalovirus. It is also associated with Mycoplasma, campylobacter, infections, immunizations with both live and dead vaccines, anti toxins, trauma, surgery and, rarely, malignant disease and immunodeficiency

Both antibody and cell-mediated reactions to peripheral nerve myelin are involved

Some patients produce antibodies to myelin glycoproteins or gangliosides, others develop a T cell-mediated assault on myelin basic protein

Segmental demyelination results with secondary axonal damage if the process is severe

Perivascular infiltration with lymphocytes occurs within peripheral nerves and nerve roots

Lymphocytes and macrophages release cytotoxic substances (cytokines) which damage Schwann cell/myelin

When axon damage and nerve cell death occur, regeneration cannot take place

Clinical features :

Sensory symptoms predominate at the beginning with paraesthesia of the feet, then hands

Pain, especially back pain, is an occasional initial symptom

Weakness next develops- this may be generalized, proximal in distribution or commence distally and ascend

Tendon reflexes are absent or depressed

In severe cases, respiratory and bulbar involvement occurs

Weakness is maximal three weeks after the onset

Tracheostomy/ventilation is required in 20% of cases

Facial weakness is present to some extent in 50% of cases

Papilloedema may occur when CSF protein is markedly elevated (blocked arachnoid villi?)

Autonomic involvement- tachycardia, fluctuating blood pressure, retention of urine-develops in some cases

Variants are common (20% if cases)

- Acute motor axonal neuropathy (AMAN)

- Acute motor, sensory axonal neuropathy (AMSAN)

Investigations :

CSF protein is elevated in most patients but often not until the second or third week of illness.

Cells are usually absent but in 20% up to 50 cells/mm3 may be found

Nerve conduction studies

When carried out early in the illness, these may be normal.

Findings of multifocal demyelination soon develops with slowing of motor conduction, conduction block and prolonged distal motor latencies

Ancillary investigations

Performed to identify any precipitating infection: e.g. viral and bacterial studies.

Electrolytes are checked for inappropriate secretion of antidiuretic hormone and immune complex glomerulonephritis

Diagnosis is based on clinical history supported by CSF and neurophysiological investigation and exclusion of acute spinal cord disease, porphyria and myasthenia gravis.

Treatment :

Supportive care in HDU/ITU with prevention of respiratory and autonomic complications provides the best chance of a favourable outcome

Signs of impending respiratory failure- forced vital capacity (FVC) below 18 ml/kg, arterial PaCO2 > 6.5kPa and PaO2 < 8 kPa on oxygen – indicate elective intubations for ventilation.

When respiratory assistance is likely to exceed 2 weeks, tracheotomy should be performed

Subcutaneous low molecular weight heparin with support stockings must be given where the degree of immobility makes thromboembolism a possible complication

Both plasma exchange (PE) and intravenous immune globulin (IVIG), 0.4 g/kg – are equally effective at speeding recovery and improving outcome

IVIG is the preferred treatment because of ease of administration but is not without side effects (flu-like symptoms, vasomotor instability, congestive cardiac failure, thrombotic complications –strokes and myocardial ischaemia, transient renal failure and anaphylaxis)

Treatment is generally given to those who can no longer walk and is deferred in milder cases

Steroids are no longer justified, two trials showing no benefit

Outcome :

Mortality – 2%. Of those progressing to respiratory failure, 20% are left severely disabled and 10% moderately disable

In milder cases the outcome is excellent

Recurrence – 3%

Miller Fisher variant of Guillain-Barre :

The Miller Fisher syndrome consists of ophthalmoplegia, are flexia and ataxia without significant limb weakness

Serum IgG antibodies to a specific ganglioside are characteristic

Management is that of Guillian –Barre

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

Treatment :

Improved control of diabetes is essential. Carbamazepine, gabapentin, 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

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 characterized by the presence of antibodies (anti Hu) that are detected in serum

Such antibodies not only recognize antigen in tumours but also bind to peripheral nervous system neurones

Pathology :

The sensory type is characterized 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-Barre 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 GMI) 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 Waldenstr6m'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

IgA and 19B are not. Neuropathies may be axonal, demyelinating or mixed and show a variable response to immunotherapy

Porphyria :

Acute intermittent porphyria is an 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

§-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-Barre

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. sulphonamide , barbiturates, phenytoin, griseofulvin