Diseases of the peripheral nerves
Clinical categories of neuropathy
Mononeuropathy, multifocal neuropathy, and polyneuropathy
Peripheral neuropathies may be divided into two broad categories depending
upon the distribution of the involvement. The first category comprises lesions of
isolated peripheral nerves or nerve roots termed mononeuropathy or multiple
isolated lesions termed multifocal neuropathy (multiple mononeuropathy or
‘mononeuritis multiplex’). The lesions in a widespread multifocal neuropathy may
summate to produce a symmetrical disturbance, but the history or a careful
examination may indicate the involvement of individual nerves. Isolated or
multiple isolated peripheral nerve lesions arise from conditions that produce
localized damage, such as mechanical injury, nerve entrapment, thermal,
electrical, or radiation injury, vascular causes, granulomatous, neoplastic, or
other infiltrations, and nerve tumours.
Secondly, there may be a diffuse and bilaterally symmetrical disturbance of
function which can be designated polyneuropathy. When such a process affects
the spinal roots, or affects the roots and the peripheral nerve trunks, the terms
polyradiculopathy and polyradiculoneuropathy are sometimes employed. In
general terms, polyneuropathies result from causes that act diffusely on the
peripheral nervous system, such as metabolic disturbances, toxic agents,
deficiency states, and certain instances of immune reaction. Isolated nerve
lesions may sometimes be superimposed upon a symmetrical polyneuropathy,
as a consequence, for example, of pressure lesions in a patient confined to bed.
In certain polyneuropathies, there is an abnormal susceptibility to pressure
lesions.
Symptomatology
Weakness or paralysis may be due either to conduction block in the motor nerve
fibres or to axonal degeneration. Conduction block is related to demyelination
with preservation of axonal continuity (neurapraxia). Recovery may occur by
remyelination and may be rapid and complete. This can be the situation in
localized nerve lesions, for example ‘Saturday night’ paralysis of the radial nerve,
or in more widespread polyneuropathies, such as in acute inflammatory
demyelinating polyneuropathy (Guillain–Barré syndrome). If axonal interruption
takes place, axonal degeneration occurs below the site of interruption. The
muscle weakness is accompanied by denervation atrophy and
electromyographic signs of denervation. In a reversible process, recovery has to
take place by axonal regeneration which is often slow and incomplete. An
important recovery mechanism in conditions in which muscles become partially
denervated is reinnervation of denervated muscle fibres by collateral sprouting
from the remaining intact axons.
In generalized symmetrical polyneuropathies, the muscle weakness and wasting
are commonly peripheral in distribution with an onset in the lower limbs. This
results in bilateral footdroop and a ‘steppage’ gait in which an affected individual
lifts his feet to an abnormal extent to avoid catching his toes against the ground.
Involvement of the upper limbs begins with weakness and wasting of the small
hand muscles and usually weakness of the finger and wrist extensors before the
forearm flexor muscles are affected. At times, a symmetrical involvement of the
proximal musculature in the limbs occurs in polyneuropathies, for example in the
Guillain–Barré syndrome or porphyric neuropathy. Fasciculation due to
spontaneous contraction of isolated motor units is most often a feature of anterior
horn cell disease but may be encountered in peripheral neuropathies, as may
muscle cramps. Postural tremor, mainly affecting the upper limbs and resembling
essential tremor, may be seen in patients with chronic demyelinating
polyneuropathies with slow conduction velocity. This ‘neuropathic tremor’ is most
often encountered in type I hereditary motor and sensory neuropathy, chronic
inflammatory demyelinating polyneuropathy, and IgM paraproteinaemic
neuropathy. A rare manifestation of peripheral neuropathy is the occurrence of
continuous repetitive discharges in motor nerve fibres leading to generalized
muscular rigidity or ‘neuromyotonia’ (Isaacs’ syndrome, continuous motor unit
activity syndrome).
Loss of the tendon reflexes is a frequent accompaniment of a peripheral
neuropathy, and usually first affects the ankle jerks. In assessing the clinical
findings, it is important to remember that the ankle jerks may be lost in later life,
probably as a result of senile changes in the peripheral nerves.
Sensory symptoms and sensory loss in symmetrical polyneuropathies are
usually distal in distribution, giving rise to the ‘glove and stocking’ pattern of
involvement. Only rarely is a proximal pattern encountered. The sensory loss
may affect all modalities or be restricted to certain forms of sensation. If the loss
is restricted, two broad patterns are discernible. In the first, the impairment
predominantly affects the sense of joint position and vibration and touch–
pressure sensibility, corresponding to a predominant loss of function in the larger
myelinated nerve fibres. Sensory ataxia is the salient manifestation in ‘large fibre’
sensory neuropathies. Loss of postural sensibility may lead to sensory ataxia in
the limbs and to ‘pseudoathetosis’, that is, involuntary movements, most often of
the fingers and hands, that occur, for example, when a patient holds their arms
outstretched with their eyes closed. In the second pattern of selective sensory
loss, pain and temperature sensibility are predominantly affected, often
associated with loss of autonomic function, corresponding to a predominant loss
of small myelinated and unmyelinated axons. ‘Trophic changes’ and pain may
complicate such small fibre neuropathies. The most important factor in their
genesis is the loss of the protective effect of pain sensation with the consequent
development of persistent ulceration or more extensive tissue loss, most
commonly in the feet, and neuropathic joint degeneration.
Paraesthesiae are a frequent feature in peripheral neuropathy. These are usually
of a tingling nature (‘pins and needles’), but, especially in ‘small fibre’
neuropathies, may involve thermal sensations, most often with a burning quality.
The paraesthesiae may be aggravated by touching or stroking the skin. Stimuli
that are normally not painful may acquire an unpleasant quality (allodynia) and
painful stimuli may give rise to an excessive or hyperpathic response, in which
the stimulus, for example a pinprick, is abnormally intense. With repeated
stimulation at the same site, the pain that is felt may spread widely and reach an
intolerable intensity. An unusual symptom encountered most often in uraemic
neuropathy is that of ‘restless legs’ (Ekbom’s syndrome). Affected individuals
experience sensations in the feet and legs that they find difficult to describe but
which are temporarily relieved by movement of the feet and legs. ‘Ekbom’s
syndrome’ may also occur in the absence of any detectable disease process.
Spontaneous pains of an aching or lancinating character may complicate a
number of generalized polyneuropathies. Severe paroxysms of lancinating pain
occur in trigeminal neuralgia, but here the responsible lesion may well lie within
the central nervous system. Causalgia constitutes a particularly troublesome
painful syndrome, most often following gunshot wounds injuring the median
nerve, the lower trunk of the brachial plexus, or the tibial nerve. It is a severe
persistent pain, often with a burning quality that is characteristically aggravated
by emotional factors. Sympathectomy relieves a high proportion of such cases.
Disturbances of autonomic function are occasionally the salient abnormality in a
peripheral neuropathy, as in the Riley–Day syndrome, or they may accompany
other manifestations, and can be observed both with localized peripheral nerve
lesions and in generalized neuropathies.
Diagnosis and investigation
The history and physical examination frequently indicate that the disturbance has
affected the peripheral nerves. If confirmation is required, this may usually be
obtained by nerve conduction studies. Conduction may be examined in motor
and sensory nerve fibres, and can give evidence of both localized and
generalized neuropathies. Severely reduced conduction velocity may occur as a
result of segmental demyelination or because of conduction in regenerating
axons of small calibre after axonal degeneration.
Examination of the cerebrospinal fluid is not commonly of value in the diagnosis
of peripheral neuropathies, although the substantially elevated protein content
that often occurs in the Guillain–Barré syndrome may be helpful, as may
inflammatory changes in some neuropathies.
Nerve biopsy is rarely required in establishing the existence of a peripheral
neuropathy, but may be of diagnostic value in establishing the cause of the
neuropathy, particularly in conditions that affect the vasa nervorum or neural
connective tissues, in some ‘storage’ disorders and in inflammatory
demyelinating neuropathies.
Individual nerves
Phrenic nerve (C2–C4)
This nerve innervates the diaphragm. When the diaphragm is totally paralysed,
the normal protrusion of the upper abdomen during inspiration is lost, or is
replaced by retraction (paradoxical movement). Radiographically, paralysis may
be detected by unilateral or bilateral elevation of the diaphragm in a chest
radiograph and its failure to descend on inspiration. The phrenic nerve may be
involved in its course through the neck or thorax by wounds or tumours such as
bronchial carcinoma, and it is sometimes affected in idiopathic brachial plexus
neuropathy (neuralgic amyotrophy).
Nerve to serratus anterior (C5–C7)
The serratus anterior acts as a fixator of the scapula, holding the scapula against
the chest wall when forward pressure is exerted by the arm. It is involved in
forward movement of the shoulder as in a rapier thrust and in elevation of the
arm, when it rotates the scapula. When serratus anterior is paralysed in isolation,
the position of the scapula is normal at rest but if the extended arm is pushed
forwards against resistance, ‘winging’ of the scapula becomes evident. The
vertebral border, particularly in its lower portion, stands away from the chest wall.
The nerve to serratus anterior may be involved in penetrating wounds, but
usually in association with damage to the brachial plexus. It may be injured by
forcible depression of the shoulder. Serratus anterior weakness is a common
component of idiopathic brachial plexus neuropathy (neuralgic amyotrophy) and
it is not infrequently encountered as an isolated and unexplained lesion.
Brachial plexus
The brachial plexus may be affected by penetrating wounds of the neck, in
fractures and dislocations of the shoulder and clavicle, as a result of traction on
the arm, by pressure from an aneurysm or a cervical rib, and by neoplastic
involvement.
Traction lesions
Traction on the arm may result in damage to the plexus itself or may lead to
avulsion of the spinal roots from the cord. If the roots are avulsed, sensory nerve
action potentials will be preserved if recorded from affected fingers despite total
anaesthesia, and the histamine flare response will be preserved in anaesthetized
skin. This follows from the fact that the nerve fibres are interrupted proximal to
the dorsal root ganglia and therefore the peripheral sensory axons do not
degenerate.
In severe traction lesions, commonly encountered in current medical practice as
a result of motorcycle or aircraft accidents, the whole of the plexus may be
damaged. With forcible downward displacement of the shoulder, as when
someone is thrown forwards and the shoulder strikes against an obstacle, only
the upper part of the plexus, involving the contribution from the fifth and sixth
cervical nerve roots, may be damaged. This may also be encountered as a birth
injury from traction on the head, or on the trunk in a breech presentation (Erb’s
palsy), and rarely in anaesthetized patients during operation or in individuals
carrying heavy rucksacks. Selective injury to the lower part of the plexus
involving the contributions from the eighth cervical and first thoracic nerve roots
occurs as a result of traction with the arm extended, as when an individual falls
from a height and tries to save himself by hanging on to a ledge. It may also
occur as a birth injury following traction with the arm extended (Klumpke’s
paralysis), but is less common than upper plexus damage.
Selective damage to the upper portion of the plexus (C5 and C6 roots or upper
trunk) results in paralysis of deltoid, biceps, brachialis, brachioradialis, and
sometimes supraspinatus, infraspinatus, and subscapularis. If the roots are
avulsed from the cord, the rhomboids, serratus anterior, levator scapulae, and
the scalene muscles will be affected. The arm hangs at the side, internally
rotated at the shoulder, with the elbow extended and the forearm pronated in the
‘waiter’s tip’ position. Abduction at the shoulder and flexion at the elbow are not
possible. The biceps and brachioradialis jerks are lost. Sensory loss affects the
lateral aspect of the shoulder and upper arm and the radial border of the forearm.
Selective paralysis of the lower brachial plexus (C8, T1) results in paralysis of all
the intrinsic hand muscles and a consequent claw-hand deformity, weakness of
the medial finger and wrist flexors, and sensory loss along the medial border of
the forearm and hand and over the medial two fingers. Cervical sympathetic
paralysis, giving rise to Horner’s syndrome, is frequently associated.
When the spinal roots are avulsed from the cord, regeneration is impossible and
intractable spontaneous pain may be a highly troublesome sequel. Where the
injury is distal to the dorsal root ganglia, lesions of the upper portion of the
brachial plexus recover more satisfactorily than lower plexus lesions. The value
of surgical repair is still a controversial issue. In the Erb’s form of birth injury,
weakness of abduction at the shoulder and flexion at the elbow often persist,
although there may be little residual sensory loss. Full recovery takes place in
about a third of the cases. It is less likely to occur with lower plexus injuries or if
the whole plexus is involved. Early recognition and the application of measures
to reduce the risk of joint contractures are important. Surgical treatment is of
limited value.
Thoracic outlet syndromes
The contribution of the eighth cervical and first thoracic roots to the brachial
plexus may be damaged by angulation over an abnormal rib or, more usually, a
fibrous band arising from the seventh cervical vertebra and attached to the first
rib. Although local structures such as the tendon of scalenus anterior may be
involved in the production of symptoms, the isolation of a separate ‘scalenus
anterior syndrome’ or of ‘costoclavicular compression’ is not justified. The
subclavian artery may be affected by cervical ribs giving rise to aneurysmal
dilatation and vascular symptoms such as Raynaud’s syndrome and embolic
phenomena, but the simultaneous occurrence of both neural and vascular
phenomena is rare.
Damage to the lower part of the brachial plexus leads to weakness and wasting
of the small hand muscles, and of the medial forearm wrist and finger flexors.
Occasionally, there is selective wasting of the thenar pad in the hand, mimicking
to some extent the appearances of the carpal tunnel syndrome. Numbness, pain,
and paraesthesiae occur along the inner border of the forearm and hand,
extending into the medial two fingers. The pain tends to be provoked by carrying
heavy articles with the hand on the affected side. Horner’s syndrome may be a
feature. Nerve conduction studies are helpful when there are difficulties in
distinguishing a cervical rib syndrome from a lesion of the ulnar or median nerves
on clinical grounds. Surgical removal of the rib or fibrous band often leads to
abolition of the pain and paraesthesiae, but recovery of power in the small hand
muscles is usually disappointing.
Neoplastic involvement
Tumours may arise locally in the brachial plexus, such as neurofibromata in von
Recklinghausen’s disease (type I neurofibromatosis) or a solitary neurinoma, or
the plexus may be invaded by tumours arising in other structures. In the latter
case the commonest situation is involvement of the lower part of the plexus by
an apical carcinoma of the lung (Pancoast’s syndrome), which gives rise to
wasting and weakness of the small hand muscles and of the medial forearm wrist
and finger flexors, pain and sensory loss affecting the medial border of the
forearm and hand, and cervical sympathetic paralysis. Other tumours that may
invade the brachial plexus include carcinoma of the breast and malignant
lymphomas affecting the lymph glands in the root of the neck.
Neuralgic amyotrophy
This condition was not clearly differentiated from the other painful paralytic
disorders of the shoulder and upper arm, such as root compression from disc
prolapse, until the Second World War. It has been described in a variety of
terms, including ‘idiopathic brachial plexus neuropathy’ and ‘paralytic brachial
neuritis’. It may follow immunizing procedures, in particular the administration of
antitetanus serum or operations, or occur without recognizable antecedent event.
It can occur on a genetic basis as an autosomal dominant disorder, hereditary
neuralgic amyotrophy (HNA), with variable penetrance. This has been mapped to
chromosome 17p.
The disorder develops acutely with intense pain in the shoulder region which
may take some weeks before it subsides completely although generally it ceases
after a few days. Paralysis of the muscles of the shoulder girdle becomes evident
within a day or two of the onset of the pain, sometimes also of the arms or of the
diaphragm. It may be unilateral or bilateral and may be associated with sensory
loss. More distal upper limb muscles may at times be affected, as may the
phrenic nerve, and, occasionally, the recurrent laryngeal nerve. The
cerebrospinal fluid is consistently normal. The affected muscles show
electromyographic evidence of denervation. Recovery is usually ultimately
satisfactory. Not all cases recover fully and recurrences may occur. A
comparable disorder can affect the lumbosacral plexus (idiopathic lumbosacral
plexus neuritis).
The pattern of muscle involvement and sensory disturbances suggests that the
neuralgic myotrophy affects the brachial plexus in a patchy manner. An immune
reaction is assumed but not established. The condition takes the same course
whether or not it follows an immunizing procedure. Corticosteroids do not
influence either the initial pain or the ultimate outcome.
Post-irradiation brachial plexus neuropathy
Brachial plexus damage may occur as a sequel to radiotherapy for breast
carcinoma or tumours in the neck. The onset of symptoms is usually several
years after treatment, but may be within months. It can be difficult to distinguish
from tumour recurrence but is less likely to be painful. Magnetic resonance
imaging may be helpful in diagnosis.
Radial nerve (C5–C8)
The long course of the radial nerve and its position in relation to the humerus
make this nerve unusually susceptible to external compression. It is a
continuation of the posterior cord of the brachial plexus. In the upper arm it
supplies triceps and anconeus and the skin on the back of the arm just above the
elbow through the posterior cutaneous nerve of the arm. The lateral aspect of the
lower part of the upper arm is supplied by the lower lateral brachial cutaneous
branch and the dorsal aspect of the forearm by the posterior cutaneous nerve of
the forearm. Muscular branches of the radial nerve innervate brachioradialis and
extensor carpi radialis longus and brevis. The superficial branch of the nerve is
its continuation. It descends along the radial border of the forearm and supplies
the skin over the dorsum of the hand and the thumb, index, and middle fingers.
The deep branch posterior interosseus nerve winds around the lateral aspect of
the radius, passes through supinator, which it supplies, and innervates extensor
digitorum, extensor digiti minimi, extensor carpi ulnaris, and often extensor carpi
radialis brevis, abductor pollicis longus, extensor pollicis longus and brevis, and
extensor indicis.
The nerve may be injured in wounds of the axilla so that the paralysis includes
triceps, resulting in loss of extension at the elbow. The most frequent type of
injury is compression of the nerve in the middle third of the arm against the
humerus. This is encountered as ‘Saturday night paralysis’ in which an individual
falls asleep when intoxicated with their upper arm over the arm of a chair.
Triceps is spared, but brachioradialis, supinator, and all the forearm extensor
muscles are paralysed. Sensory impairment is limited to the dorsum of the hand.
Commonly the lesion consists of a localized conduction block (neurapraxia) so
that muscle wasting does not occur and a muscle response can be obtained on
electrical stimulation of the nerve below the level of the lesion. Recovery is
complete within a matter of weeks. A cock-up wrist splint may be helpful while
recovery is awaited. At times, there is some associated axonal degeneration so
that electromyographic evidence of denervation is detectable and full recovery is
correspondingly delayed.
Many muscles not supplied by the radial nerve work at a disadvantage when the
wrist and finger extensors are paralysed. These defects must not be mistaken for
signs of injury to other nerves. Owing to the flexed position of the wrist, gripping
is impaired, but if the power of the wrist and finger flexors is tested with the wrist
extended, it can be shown to be normal. The action of the interossei in abducting
and adducting the fingers is also feeble when the wrist is flexed, but full power is
demonstrable if these muscles are tested with the hand resting flat on a table.
A lesion of the posterior interosseus nerve gives rise to weakness confined to
abduction and extension of the thumb and extension of the index finger.
Supinator is spared, together with brachioradialis and the radial wrist extensors,
and there is no sensory loss. The nerve may be compressed under the arcade of
Frohse or during its transit through supinator.
Axillary nerve (C5, C6)
This is a branch of the posterior cord of the brachial plexus. It supplies deltoid
and teres minor and the skin over deltoid through the upper lateral brachial
cutaneous nerve. It may be damaged in injuries to the shoulder and the chief
symptom is an almost complete inability to raise the arm at the shoulder. In the
past, it was sometimes injured by pressure from a crutch (‘crutch palsy’).
Musculocutaneous nerve (C5, C6)
This nerve is rarely damaged alone, but may be involved in injuries to the
brachial plexus. It supplies coracobrachialis, biceps, and brachialis and the skin
over the lateral aspect of the forearm through the lateral cutaneous nerve of the
forearm. Flexion at the elbow is still possible by brachioradialis, but is weak, and
sensation may be impaired along the radial border of the forearm.
Median nerve (C6–C8, T1)
The median nerve arises from the medial and lateral cords of the brachial plexus
and descends with the brachial artery through the upper arm, entering the
forearm deep to the bicipital aponeurosis. It has no muscular branches above the
elbow. It supplies all the muscles in the anterior aspect of the forearm except
flexor carpi ulnaris and the medial half of flexor digitorum profundus. The main
trunk of the nerve supplies pronator teres, flexor carpi radialis, palmaris longus,
and flexor digitorum superficialis. Through the anterior interosseus branch, it also
supplies the lateral aspect of flexor digitorum profundus, flexor pollicis longus,
and pronator quadratus. The main trunk passes deep to the flexor retinaculum of
the wrist and its recurrent muscular branch supplies abductor pollicis brevis,
opponens pollicis, and contributes to the innervation of flexor pollicis brevis. It
also supplies the lateral two lumbrical muscles and the skin of the lateral aspect
of the palm and the lateral three and a half digits over their palmar aspects and
terminal parts of their dorsal aspects.
Lesions in the forearm
The median nerve may be injured in the region of the elbow or compressed at
the level of the pronator teres muscle. Entrapment neuropathies in the upper
forearm, however, are uncommon. Occasionally the anterior interosseus branch
is involved in isolation.
Complete lesions of the median nerve at the elbow give rise to paralysis of
pronator teres, the radial flexor of the wrist, the long finger flexors except the
ulnar half of the deep flexor, most of the muscles of the thenar eminence, and
the two radial lumbricals. In brief, there is an inability to flex the index finger and
the distal phalanx of the thumb, flexion of the middle finger is weak, and
opposition of the thumb is defective. The appearance of the hand has been
described as simian; it shows ulnar deviation, the index and middle fingers are
more extended than normal, and the thumb lies in the same plane as the fingers.
In more detail, pronation is incomplete and defective. The patient attempts to
overcome this by rotating the whole limb at the shoulder. Paralysis of the wrist
flexors is evident when attempts are made to flex against resistance. The tendon
of flexor carpi ulnaris stands out alone and the hand goes into ulnar deviation.
Flexion of the fingers is good in the ulnar two fingers, although weaker than
normal. The index finger cannot be flexed, and the middle finger only
incompletely. Flexion at the metacarpophalangeal joints is possible in all fingers,
including the index, and flexion at these joints with extension at the
interphalangeal joints is accomplished by the interossei and lumbricals. If the
proximal phalanx of the thumb is immobilized, it will be found that flexion of the
terminal phalanx is abolished because of paralysis of flexor pollicis longus.
Paralysis of the thenar muscles gives rise to defective abduction and opposition
of the thumb. By means of the adductor, the thumb can be drawn into the palm,
but as the radial fingers cannot be flexed or the thumb opposed, it is impossible
to place the tip of the thumb on the fingers.
Sensory loss is evident over the lateral three and a half digits and the lateral
aspect of the palm, although individual variations occur. There is almost
complete anaesthesia over the two terminal phalanges of the index and middle
fingers. This degree of sensory loss, combined with the motor deficit, renders the
thumb and index fingers almost useless and makes paralysis of the median the
most serious single nerve lesion in the upper limb.
Vasomotor and trophic changes often ensue. The skin in the distribution of the
median nerve tends to become reddened, dry, and atrophic. The pulp of the
affected fingers becomes atrophic and ulceration occasionally develops in the tip
of the index finger. The nails may become white and atrophic.
After a total transection of the nerve in the region of the elbow, even with a
satisfactory surgical repair, recovery is slow and rarely complete, particularly with
respect to the innervation of the hand.
With partial lesions of the median nerve in the arm or forearm, causalgia may be
a troublesome consequence. This most often follows gunshot wounds. The pain
develops at any time from a few hours to 45 days after the injury. The pain is
severe and unremitting, frequently of a burning or smarting quality. Upon this
may be superimposed severe paroxysms of pain provoked by touching or jarring
the limb or by emotional factors. Vasomotor and sudomotor changes may be
associated. The skin usually becomes dry and scaly, but excessive sweating
may be a feature. The patient adopts a protective attitude towards the limb, so
that fixation of the joints of the fingers and wrist may develop, together with
atrophic changes in the skin and subcutaneous tissue. About 80 per cent of
cases of true causalgia are relieved by sympathectomy. Untreated, the pain
gradually subsides over months or years.
Lesions at the wrist
The superficial situation of the median nerve at the wrist renders it liable to injury
in lacerations sustained by falling against a window with the hand outstretched or
in suicidal attempts. It may also be damaged as an occupational hazard by
individuals who exert repeated pressure on the butt of the hand.
Much the most common lesion at this site is the carpal tunnel syndrome, in which
the median nerve is compressed as it passes deep to the flexor retinaculum. The
usual presentation is with acroparaesthesiae. These consist of numbness,
tingling, and burning sensations felt in the hand and fingers, the pain sometimes
radiating up the forearm as far as the elbow or even as high as the shoulder or
root of the neck. The paraesthesiae are sometimes restricted to the radial
fingers, but may affect all the digits as some fibres from the median nerve are
distributed to the fifth finger through a communication with the ulnar nerve in the
palm. The attacks of pain and paraesthesiae are most common at night and
often wake the patient from sleep. They are then relieved by shaking the hand.
The hand tends to feel numb and useless on waking in the morning but recovers
after it has been used for some minutes. The symptoms may recur during the
day following use, or at times if the patient sits with the hands immobile. Such
symptoms of acroparaesthesiae may persist for many years without the
appearance of symptoms of median nerve damage. In other patients, weakness
of the thenar muscles develops, particularly of abduction of the thumb, and is
associated with atrophy of the lateral aspect of the thenar eminence (Fig. 1).
Sensory loss may appear over the tips of the median innervated fingers.
Occasionally patients present with symptoms of median nerve deficit in the hand
without attacks of acroparaesthesiae having occurred, or motor and sensory
signs may be discovered incidentally in the absence of symptoms, particularly in
older individuals.
The symptoms are usually characteristic. If confirmation is required in atypical
cases, this can generally be obtained by nerve conduction studies. In patients
who are experiencing frequent attacks of acroparaesthesiae, the symptoms may
be reproduced by inflating a sphygmomanometer cuff around the arm above
arterial pressure for 2 min. At times percussion over the carpal tunnel may elicit a
Tinel’s sign, or symptoms may be provoked by hyperextension of the wrist or
sustained flexion (Phalen’s sign).
The majority of cases occur in middle-aged and often obese housewives. In
younger women it is commonly associated with excessive use of the hands, and
it may develop in males after unaccustomed use of the hands, such as in house
painting or fly fishing. In these instances, tenosynovitis of the flexor tendons is
responsible. It may also be caused by tuberculous tenosynovitis at the wrist or
involvement of the wrist joint in rheumatoid arthritis. It may develop as a
consequence of osteoarthritis of the carpus, perhaps related to an old fracture.
Other predisposing causes are pregnancy, myxoedema, acromegaly, and
infiltration of the flexor retinaculum in primary and hereditary amyloidosis.
In cases in which muscle weakness and wasting, or sensory loss, are present
when the patient is first seen, treatment should be decompression of the nerve
by section of the flexor retinaculum. In patients with acroparaesthesiae alone and
in which the cause is probably tenosynovitis at the wrist, reduction in the amount
of activity engaged in with the hands may be sufficient to allow the symptoms to
subside. Injection of the carpal tunnel with a long-acting corticosteroid
preparation may give temporary relief. Splinting of the wrist to reduce movement
during the day may also be useful. If the symptoms persist despite conservative
measures, decompression is then advisable.
The majority of patients with acroparaesthesiae are relieved by decompression.
In patients with sensory impairment and cutaneous hyperaesthesia, such
symptoms may persist for prolonged periods despite decompression. If
denervation of the thenar muscles has been present for a long time, full recovery
may not occur.
Ulnar nerve (C7, C8, T1)
This nerve arises from the medial cord of the plexus, usually with a contribution
from the lateral cord. It descends in the medial side of the upper arm, passes
around the elbow in the ulnar groove, and enters the forearm under an
aponeurotic band between the humeral and ulnar heads of flexor carpi ulnaris. It
then runs superficial to flexor digitorum profundus to the wrist and enters the
hand between the pisiform bone and the hook of the hamate, superficial to the
flexor retinaculum. After penetrating the hypothenar muscles, its deep branch
crosses the palm and ends in flexor pollicis brevis.
In the upper arm, branches arise that supply flexor carpi ulnaris and the medial
part of flexor digitorum profundus. In the forearm, the dorsal branch arises that
winds around the ulna and supplies the skin over the dorsal aspect of the hand
and the medial one and a half fingers. In the hand, a superficial branch supplies
palmaris brevis and the skin over the medial aspect of the palm and the medial
one and half fingers. The deep branch, after supplying the hypothenar muscles,
innervates the interossei, the third and fourth lumbricals, adductor pollicis, and
part of flexor pollicis brevis.
Lesions at the elbow
Total paralysis from lesions at this level, including the branches to flexor carpi
ulnaris and flexor digitorum profundus, gives rise to wasting along the medial
side of the forearm flexor mass. There is weakness of flexion of the fourth and
fifth fingers. If the proximal portions of these fingers are held immobilized, flexion
of the terminal phalanges is not possible. When the hand is flexed to the ulnar
side against resistance, the tendon of flexor carpi ulnaris is not palpable.
Paralysis of the hypothenar muscles abolishes abduction of the fifth finger.
Paralysis of the interossei and the medial two lumbricals gives rise to the ‘claw
hand’ deformity (Fig. 2). The action of these muscles is to flex the fingers at the
metacarpophalangeal joints with the fingers extended at the interphalangeal
joints. In the claw hand, the posture of the fingers is opposite to this, namely,
extension of the metacarpophalangeal joints with flexion at the interphalangeal
joints. Although all the interossei are paralysed, the defect is seen mainly in the
ulnar fingers since the radial lumbricals supplied by the median nerve are still
active. The long extensors of the fingers, being unopposed, overextend the
proximal joints, and the flexor digitorum superficialis flexes the proximal
interphalangeal joints.
In the hand, there is wasting of the hypothenar muscles, of the interossei, and of
the medial part of the thenar eminence. Movements of abduction and adduction
of the fingers are weak, as is adduction to the extended thumb against the palm.
Sensory loss affects the dorsal and palmar aspects of the medial side of the
hand and the medial one and a half fingers.
The ulnar nerve may be damaged by dislocations or fracture dislocations at the
elbow and is sometimes compressed in individuals who habitually lean on their
elbows. Entrapment may occur in the cubital tunnel as the nerve underlies the
aponeurotic band between the two heads of the flexor carpi ulnaris. This is most
likely to occur in those performing heavy manual work or if there is an excessive
carrying angle at the elbow, as may occur following a previous malunited
supracondylar fracture of the humerus (‘tardy ulnar palsy’). The medial wall of the
cubital tunnel is formed by the elbow joint; osteoarthritis of the elbow can lead to
osteophytic encroachment on the tunnel and compression of the ulnar nerve. In
the cubital tunnel syndrome, the ulnar nerve is often palpably enlarged in the
ulnar groove and for a short distance proximally. Ulnar nerve lesions are not
infrequent in leprosy. Here the enlargement of the nerve tends to be maximal at
a little distance above the elbow.
When it is suspected that the nerve has been subjected to repeated compression
at the elbow, surgical transposition to the front of the medial epicondyle should
be considered. If the nerve is compressed in the cubital tunnel, decompression
by slitting the aponeurosis may suffice.
Lesions at the wrist or in the hand
Damage to the nerve at the wrist will spare the dorsal branch, so that cutaneous
sensation over the dorsum of the hand and fingers is spared. A lesion just
proximal to the wrist will give rise to sensory impairment on the palmar aspect of
the hand and fingers alone, and weakness of all the ulnar-innervated intrinsic
hand muscles. A slightly more distal lesion spares the superficial branch of the
nerve and therefore produces no sensory deficit. Finally, damage to the deep
palmar branch spares the hypothenar muscles, but causes weakness of the
other ulnar-innervated small hand muscles. Lesions at the wrist or in the hand
are usually the result of compression by ganglia or by repeated occupational
trauma. Damage to the deep palmar branch, for example, may be caused by firm
pressure in the palm from a screwdriver or drill. If occupational pressure is the
cause, recovery follows cessation of the precipitating cause. Should
improvement fail to occur after an appropriate interval, surgical exploration to
establish whether a ganglion is present is merited.
It is not always easy on clinical grounds to decide whether the lesion is at the
elbow or the wrist. Compression of the nerve in the cubital tunnel, for example,
may spare the branches to the flexor carpi ulnaris and flexor digitorum
profundus. In these circumstances, nerve conduction studies may be helpful, as
they may in distinguishing between lesions of the ulnar nerve and damage to the
eighth cervical and first thoracic spinal roots.
Lumbosacral plexus
Lesions of the lumbosacral plexus are not common. The plexus may be involved
in pelvic malignancy, such as from carcinoma of the uterine cervix, bladder,
prostate, or rectum, or be the site of a local neural tumour. It may be compressed
by a haematoma in patients receiving anticoagulant therapy or suffering from
haemophilia, or be involved in fractures of the pelvis. The lumbosacral cord may
be compressed against the rim of the pelvis by the fetal head during parturition,
with consequent weakness of the anterior tibial and peroneal muscles, and
sensory impairment in the distribution of the fourth and fifth lumbar dermatomes.
The superior gluteal nerve may also be affected. Recovery is initially good but
may not be complete. The plexus may be affected in diabetic amyotrophy. Rare
instances of idiopathic lumbosacral plexus neuropathy are encountered,
comparable to the corresponding disorder that affects the brachial plexus.
Femoral nerve (L2–L4)
This nerve arises from the lumbar plexus, crosses the iliac fossa between the
psoas and iliacus muscles, and enters the thigh deep to the middle of the
inguinal ligament. In the iliac fossa it supplies the iliacus, and in the thigh,
pectineus, sartorius, and quadriceps femoris, and anterior cutaneous branches to
the front of the thigh. The continuation of the femoral nerve is the saphenous
which supplies the skin over the medial aspect of the lower leg as far as the
medial malleolus.
Damage to the femoral nerve causes weakness of knee extension, wasting of
quadriceps, loss of the knee jerk, and sensory impairment over the front of the
thigh and in the distribution of the saphenous nerve. With a proximal lesion, there
may also be weakness of hip flexion from paralysis of iliacus.
The femoral nerve may be injured in fractures of the pelvis or femur, in
dislocations of the hip, and at times during operations on the hip. It may be
involved by psoas abscesses, tumours, or implicated in wounds of the thigh. It is
commonly involved in large psoas muscle haematomas in haemophiliacs (see
Section 22) and in diabetic amyotrophy. Owing to the rapid dispersion of the
branches in the thigh, partial lesions are common from wounds at this site. The
nerve to quadriceps is most often injured. The resulting paralysis causes
considerable difficulty in walking as the knee cannot be locked in extension and
gives way, especially when descending stairs. The saphenous nerve is
sometimes damaged in operations for the treatment of varicose veins.
Obturator nerve (L2–L4)
The nerve emerges from the lateral border of psoas, crosses the lateral wall of
the pelvis, and enters the thigh through the obturator foramen where it supplies
gracilis, adductor longus and brevis, adductor magnus, obturator externus, and
sometimes also pectineus, and the skin over the lower medial aspect of the
thigh.
Damage to the obturator nerve results in weakness of adduction and internal
rotation at the hip, pain in the groin, and sensory impairment on the medial part
of the thigh. The nerve may be involved in neoplastic infiltration in the pelvis and
can be damaged by the fetal head or by forceps during parturition.
Lateral cutaneous nerve of the thigh (L2, L3)
This nerve arises from the lumbar plexus, passes obliquely across iliacus and
enters the thigh under the lateral part of the inguinal ligament. It supplies the skin
over the anterolateral aspect of the thigh.
Meralgia paraesthetica is an entrapment neuropathy resulting from compression
of this nerve as it passes under the inguinal ligament. It is more common in men,
who are often obese, and may be unilateral or bilateral. The symptoms consist of
numbness in the territory of the nerve combined with tingling or burning
paraesthesiae provoked by prolonged standing, or following excessive walking.
Weight loss may be helpful, and in many instances the condition subsides
spontaneously. Decompression of the nerve is rarely necessary.
Sciatic nerve (L4, L5, S1–S3)
The sciatic nerve enters the thigh through the sciatic notch. It is composed of the
tibial and peroneal divisions which are usually bound together within a common
sheath, the tibial division lying medially. It descends through the posterior aspect
of the thigh, initially deep to gluteus maximus, and supplies semitendinosus,
semimembranosus, and the long head of biceps through its peroneal division. It
separates into the tibial and common peroneal nerves in the lower thigh, which
supply all the muscles below the knee, and both nerves contribute to the
formation of the sural nerve.
Total interruption of the sciatic nerve gives rise to foot drop. Walking is possible,
but the patient cannot stand on the toes or the heel of the affected foot and the
ankle is unstable. All movement below the knee is paralysed. If the injury is in the
upper thigh, flexion of the knee is also weak. The skin is completely
anaesthetized over the entire foot except for the medial border which is supplied
by the saphenous nerve. Pressure sores may develop. The anaesthesia extends
upwards on the posterolateral aspect of the calf in its lower two-thirds. The sense
of joint position is abolished in the foot and toes. Beyond this area of complete
anaesthesia, there is a wide zone in which sensibility may be diminished.
Sweating is absent on the sole and dorsum of the foot, but is preserved on the
medial side. The ankle jerk is lost but the knee jerk is retained.
The sciatic nerve may be involved in pelvic tumours and can be injured by
fractures of the pelvis or femur or during hip replacement operations. After the
radial and ulnar, it is implicated in gunshot wounds more frequently than any
other nerve. Partial injury of the tibial division may be followed by causalgia.
Incomplete lesions of the nerve may be caused by pressure of the nerve against
the hard edge of a chair in individuals who fall asleep while intoxicated. Similar
lesions may occur in diabetic subjects, in whom the peripheral nerves are more
susceptible to pressure neuropathy.
The syndrome of root pain and sciatica is considered in Chapter 24.3.11.
Tibial nerve (L4, L5, S1–S3)
After separating from the peroneal division of the sciatic nerve in the lower thigh,
this nerve passes through the popliteal fossa and enters the calf deep to
gastrocnemius through the fibrous arch of soleus. It descends through the calf to
the medial side of the ankle, passes beneath the flexor retinaculum, and divides
into the medial and lateral plantar nerves. It supplies popliteus, all the muscles of
the calf, and, through the plantar nerves, the small muscles of the sole of the foot
and sensation to the sole.
When the nerve is interrupted, the patient is unable to plantarflex or invert the
foot, to flex the toes, or to stand on the ball of the foot. Paralysis of the interossei
leads to a claw-like deformity of the toes. Sensation is lost over the sole.
Causalgia may arise after partial lesions. Injury to the distal portion of the nerve
by a penetrating injury or deep wound of the calf gives rise to paralysis of the
intrinsic muscles of the foot but spares the muscles acting at the ankle.
Sensation is lost on the sole of the foot and this may be accompanied by pain. If
the injury is distal to the origin of the branches to flexor hallucis longus and flexor
digitorum longus, the lesion may escape detection since paralysis of the small
foot muscles and sensory loss over the sole may be overlooked.
The tibial nerve is occasionally compressed under the flexor retinaculum (tarsal
tunnel syndrome), usually precipitated by osteoarthritis or post-traumatic
deformities at the ankle or by tenosynovitis. Burning pain and tingling
paraesthesiae occur in the sole, usually following prolonged standing or walking.
The condition is generally unilateral. Careful examination may demonstrate
wasting of the intrinsic muscles in the medial aspect of the foot, and sensory
impairment over the sole. Nerve conduction studies may be helpful
diagnostically. Treatment is by surgical section of the flexor retinaculum.
Painful neuromas sometimes develop on the digital branches of the plantar
nerves. These give rise to the syndrome of Morton’s metatarsalgia in which pain
occurs in the anterior part of the foot on standing. A localized area of tenderness
is detectable on palpation. The condition is relieved by excision of the neuroma.
Common peroneal nerve (L4, L5, S1, S2)
After separating from the tibial division of the sciatic nerve in the lower part of the
thigh, this nerve descends through the popliteal fossa, winds around the neck of
the fibula, and divides into its superficial and deep branches. The superficial
peroneal nerve passes down in front of the fibula, supplies peroneus longus and
brevis, and emerges in the lower leg, supplying the skin on the lateral aspect of
the lower leg. It crosses the extensor retinaculum and supplies the skin on the
dorsum of the foot and the second to the fifth toes. The deep peroneal branch
continues to wind around the fibula, pierces the anterior intermuscular septum,
and descends on the anterior interosseous membrane. It innervates tibialis
anterior, extensor digitorum longus, extensor hallucis longus, and peroneus
tertius. It passes deep to the extensor retinaculum after which it supplies the
extensor digitorum brevis and the skin of the adjacent sides of the first and
second toes.
Damage to the common peroneal nerve is more frequent than injury to its two
branches because of its vulnerable superficial position at the neck of the fibula. It
gives rise to foot drop with paralysis of dorsiflexion and eversion at the ankle and
of toe extension. Cutaneous sensation is impaired over the lateral aspect of the
lower leg and ankle and on the dorsum of the foot.
The common peroneal nerve may be compressed at the neck of the fibula by
habitual sitting with the legs crossed, prolonged squatting, pressure during sleep
or while anaesthetized, and various other events. It can be damaged by traction
caused by fractures of the tibia and fibula and is sometimes damaged by
ischaemia in the anterior tibial compartment syndrome. Paralysis caused by
external pressure frequently gives rise to a local conduction block (neurapraxia)
with satisfactory recovery within a few weeks. If electromyography indicates that
nerve degeneration has taken place a foot drop support should be provided while
axonal regeneration is awaited.
Sural nerve (L5, S1–S2)
This arises from the sciatic nerve and descends to the back of the calf, winds
around to the lateral side of the ankle, and reaches the lateral border of the foot.
It supplies the skin in this distribution. Sensory impairment occasionally results
from pressure on the nerve as it lies in a superficial situation in the back of the
calf.
Generalized neuropathies
Neuropathies related to metabolic and endocrine disorders
Diabetes mellitus
A significant degree of peripheral neuropathy develops in about 15 per cent of
patients with diabetes, although a substantially greater number either have minor
symptoms without signs, or evidence of a subclinical neuropathy either on clinical
examination or on the basis of abnormalities of nerve conduction. In general, the
neuropathies that appear can be divided into symmetrical sensory and
autonomic polyneuropathies on the one hand, and isolated peripheral nerve
lesions or multifocal neuropathies on the other. Mixed syndromes are common.
The commonest form is a symmetrical sensory polyneuropathy, giving rise to
numbness and tingling paraesthesiae in the toes and feet and less often in the
fingers. Aching or lancinating pains in the feet and legs, particularly at night, may
be a troublesome feature. Examination reveals loss of vibration sense in the feet,
depression of the ankle jerks, and distal cutaneous sensory impairment.
Neuropathic plantar ulcers and occasionally Charcot joints are an important
complication. Loss of pain sense results in perforating ulcers on the feet and
neuropathic joint degeneration, particularly in the toes and in the tarsal joints;
impaired postural sense may give rise to an ataxic gait. An acute painful diabetic
neuropathy also occurs that predominantly affects the lower limbs. The onset is
often associated with poor diabetic control and precipitate weight loss (‘diabetic
neuropathic cachexia’).
Autonomic neuropathy frequently accompanies the sensory neuropathy and may
be the salient manifestation. It rarely occurs in isolation. Pupillary disturbances
usually take the form of a reduced response to light. Gustatory facial sweating
provoked by the smell and taste of food can be troublesome. Anhidrosis may
occur distally in the limbs; if it is extensive and also affects the trunk, heat
intolerance may result. Symptoms referable to the alimentary tract include
dysphagia from oesophageal involvement, episodes of vomiting related to gastric
atony, and episodic nocturnal diarrhoea, often alternating with periods of
constipation. Those related to the genitourinary system include impotence,
retrograde ejaculation, and bladder atony with difficulty in voiding and urinary
retention with overflow. Vascular denervation sometimes results in orthostatic
hypotension, and cardiac denervation may be demonstrable by an elevated
resting heart rate and the absence of beat-to-beat variation with respiration. The
risk of diabetic polyneuropathy is reduced by strict glycaemic control.
Isolated nerve lesions tend to occur more commonly in elderly diabetic subjects.
At times they develop insidiously, at others they have an abrupt onset with pain.
Of the cranial nerves, the nerves to the external ocular muscles, particularly the
third and sixth, and also the facial nerve, are the most often affected. In
contradistinction to the effects of compression of the third nerve by a carotid
aneurysm, the pupillary innervation is often spared. In the limbs, the lesions tend
to occur at the common sites of compression or entrapment. It seems likely that
the nerves of diabetics exhibit an excessive vulnerability to damage from
pressure.
Diabetic amyotrophy, or proximal diabetic neuropathy, represents a particular
example of a multifocal neuropathy that develops usually in elderly obese
diabetics. It consists of an asymmetric proximal motor syndrome that affects the
anterior thigh muscles and hip flexors, and sometimes also the anterolateral
muscles of the lower leg. Less commonly it is symmetric. Its onset may be acute
or insidious and is often accompanied by pain, particularly at night. There is
generally little or no associated sensory loss. The knee jerks are usually
depressed or absent. Inflammatory lesions including vasculitis have recently
been demonstrated in peripheral nerves in proximal diabetic neuropathy, leading
to trials of immunomodulatory therapy.
The causation of diabetic neuropathy is uncertain. It tends to occur more often in
poorly controlled diabetics, but the correlation is not close. It may occur for the
first time on initiation of treatment with insulin, or be the presenting symptom in
maturity onset diabetes. There is evidence to suggest that diabetic
microangiopathy is important in the genesis of isolated nerve lesions. Metabolic
factors are probably more important in the origin of the symmetric
polyneuropathies, but their nature is uncertain. An increased concentration of
sorbitol in nerves secondary to hyperglycaemia may be involved in causing nerve
fibre dysfunction.
Focal peripheral nerve lesions and diabetic amyotrophy, if of acute onset, often
recover adequately, as does acute painful diabetic neuropathy when satisfactory
glycaemic control is achieved. Symmetric sensory and autonomic neuropathy,
once established, recovers less satisfactorily, even with good diabetic control.
Correcting the hyperglycaemia by continuous subcutaneous insulin infusion or
pancreatic transplantation will stabilize the neuropathy. Trials of aldose
reductase inhibitors to reduce sorbitol accumulation have, so far, not given clear
evidence of improvement in neuropathy.
Care of the feet is vitally important in diabetic sensory neuropathy, to prevent the
development of chronic ulceration. Pain may sometimes be helped by
carbamazepine, tricyclic antidepressants, phenothiazines, or mexiletine.
Hypotension can be improved by raising the head of the bed at night or by
support bandages to the legs; more severe cases may require treatment with
fludrocortisone. Gastroparesis may respond to metoclopramide, domperidone, or
erythromycin; persistent vomiting may necessitate a Roux-en-Y
gastroenterostomy. Diabetic diarrhoea can be helped by low-dosage tetracycline
or diphenoxylate, loperamide, or codeine phosphate. Diabetic cystopathy can be
managed in the earlier stages by regular voiding and cholinergic treatment with
bethanechol. Urinary tract infections should be treated promptly. Bladder neck
resection can be useful in carefully selected cases. Penile papaverine injections
can be employed for erectile impotence, and sildenafil (Viagra) may be helpful in
early cases. Silicone implants should be avoided because of the risk of infection.
Amyloidosis
The various forms of amyloid disease are described in Section 11.12. The
peripheral nerves may be involved in primary amyloidosis due to a benign
plasma cell dyscrasia and in amyloidosis related to myeloma (light chain
amyloidosis). There are also several dominantly inherited forms of amyloid
neuropathy, the most important of which are due to mutations in the gene for
transthyretin (TTR), including the Portuguese type (see later). Isolated lesions
may occur from the infiltration of amyloid into nerves or from compression of the
median nerve in the carpal tunnel because of deposits in the flexor retinaculum.
More strikingly, a generalized neuropathy may develop. It begins with selective
loss of pain and temperature sensation in the feet and later in the hands. Motor
involvement, loss of tendon reflexes, and impairment of other sensory modalities
occur later. Autonomic involvement is an early feature, causing impotence,
orthostatic hypotension, bladder atony, and disturbances of alimentary function.
Amyloid deposits are present in the peripheral nerve trunks, which may be
enlarged, and in the dorsal root and sympathetic ganglia.
No treatment influences the progress of the neuropathy apart from liver
transplantation in neuropathy due to TTR mutations (see Section 11). The use of
stem cell transplantation is being explored in amyloidosis related to malignant
plasma cell dyscrasias. The spontaneous pains are sometimes improved by
carbamazepine or tricyclic antidepressant drugs. Care must be taken to prevent
damage to the anaesthetic feet, lower legs, and hands. Autonomic symptoms
may require treatment as described for diabetic neuropathy.
Carpal tunnel syndrome is frequent in patients on long-term haemodialysis
related to deposition of amyloid in the flexor retinaculum derived from retained
β2-microglobulin.
Uraemia
Uraemic neuropathy did not become a clinical problem until the advent of
treatment of endstage renal failure by haemodialysis. It occurs in patients with
severe chronic renal failure. It was most often seen in patients under treatment
with periodic haemodialysis but is now much less frequently a problem. The
symptoms are usually predominantly sensory, with numbness and tingling
paraesthesiae in the feet. ‘Restless legs’ (Ekbom’s syndrome) are often a
conspicuous feature (see Section 24.22). A distal motor neuropathy may be
associated and occasional cases are purely motor. The condition is improved by
increased haemodialysis and more effectively by renal transplantation. A
retained metabolite is assumed to be the cause, but this has not so far been
identified.
Myxoedema
Compression of the median nerve in the carpal tunnel in myxoedema has
already been discussed. Rarely a generalized mixed motor and sensory
neuropathy develops. This improves on treatment of the hypothyroidism.
The slow contraction and relaxation observed in the tendon reflexes is not due to
a disturbance of peripheral nerve function, but to an alteration in the contractile
mechanism of the muscle fibres.
Acromegaly (see Section 12)
The occurrence of the carpal tunnel syndrome in acromegaly has also been
mentioned. A rare manifestation of this condition is a sensorimotor
polyneuropathy in which the peripheral nerves are thickened because of an
overgrowth of the neural connective tissues. A similar neuropathy is occasionally
observed in pituitary gigantism.
Critical illness polyneuropathy
A generalized polyneuropathy involving widespread axonal degeneration may be
encountered in patients in intensive care units with sepsis and multiple organ
failure. The neuropathy is discovered when attempts are made to wean them
from the ventilator. The precise cause of this condition which has been termed
critical illness polyneuropathy is unknown. Slow recovery occurs.
Other metabolic disorders
It has been claimed that a generalized peripheral neuropathy may be caused
either by acute or chronic hepatic failure, but this is probably uncommon. A mild
painful sensory neuropathy is occasionally encountered in primary biliary
cirrhosis, sometimes related to xanthomatous deposits in the cutaneous nerve
trunks. A motor neuropathy is a rare sequel to severe recurrent hypoglycaemia.
Toxic neuropathies
Industrial, environmental, and pharmaceutical substances
Acrylamide
This substance is widely employed industrially. The monomer is neurotoxic and
causes peripheral neuropathy with mixed motor and sensory features. Ataxia is
prominent and is possibly the result of concomitant cerebellar damage. Distal
axonal degeneration occurs and slow recovery takes place on cessation of
exposure.
Arsenic
Arsenical poisoning is occasionally seen as a result of accidental or homicidal
ingestion of insecticides containing arsenic, or from indigenous medicines in
India. Gastrointestinal symptoms develop after acute ingestion, followed by a
mixed sensory and motor neuropathy after 1 to 3 weeks. Desquamation of the
skin of the feet and hands takes place after about 6 weeks and white lines
(Mees’ lines) appear in the nails. With ingestion of smaller quantities on a chronic
basis, gastrointestinal symptoms are less obtrusive and a slowly progressive
neuropathy makes its appearance. The skin may become generally pigmented or
show focal ‘raindrop’ pigmentation, and hyperkeratosis of the palms of the hands
and soles of the feet may appear.
Slow recovery in the neuropathy occurs with removal from exposure. Chelating
agents are of value in treating the non-neurological complications, but it is
uncertain whether they are effective for the neuropathy.
Lead
Lead neuropathy is now a rare occurrence in Britain, although it was
encountered as a consequence of the contamination of drinking water by lead
pipes in old buildings. Subclinical neuropathy may be detectable in lead workers.
It remains a hazard in certain parts of the world from the use of lead glazes in
pottery. Lead neuropathy is predominantly motor, typically giving rise to wrist and
foot drop. The ‘lead colic’ that may occur is probably a manifestation of
autonomic involvement. Other features of lead poisoning that may be associated
include a sideroblastic anaemia and a ‘lead line’ on carious teeth. The
neuropathy improves on cessation of lead intake; the utility of treatment with BAL
(dimercaprol), edetate, or penicillamine is uncertain.
Mercury
Exposure to inorganic mercury salts and to organic mercurial compounds may
lead to neurological damage, as in ‘Minamata disease’ which was related to
consumption of fish contaminated by organic mercury. Dementia, cortical
blindness, and ataxia occur, together with sensory changes in the limbs
attributed to a sensory neuropathy, although how far these have a peripheral
origin is uncertain. Historically, a peripheral neuropathy was an important
component of ‘pink disease’ which was caused by the administration of mercurycontaining purgatives.
Thallium
This is present in certain pesticides and rodent poisons and was formerly used
as a depilatory agent. Accidental or homicidal poisoning is occasionally
encountered. Abdominal pain and diarrhoea are followed after 2 or 5 days by the
development of a mixed motor and sensory neuropathy which is often painful.
Evidence of central nervous system damage may be present with behaviour
disorder, optic neuropathy, and choreiform movements. Alopecia develops later,
after about 2 or 3 weeks, and renal damage may be produced.
Diethyldithiocarbamate, which binds thallium, has been employed in treatment.
Triorthocresyl phosphate
This substance is used industrially as a high-temperature lubricant. Outbreaks of
a sensorimotor neuropathy, often accompanied by evidence of damage to the
central nervous system, occur periodically, usually as a consequence of the
contamination of cooking ingredients or utensils. The original description was in
relation to illegal liquor distillation (ginger jake paralysis) in the United States
during the prohibition era. In more recent years, a large outbreak occurred in
Morocco from the use of contaminated cooking oil. Recovery is slow and often
incomplete.
Other industrial substances
Carbon disulphide, used in the manufacture of rayon, occasionally gives rise to a
mild sensory neuropathy. Neuropathy may occur as a result of industrial
exposure to the organic solvents n-hexane and methyl-n-butyl ketone. The
former is also encountered as a consequence of solvent abuse; n-hexane, which
has an intoxicant action, has been used as a solvent in certain glues. Other
industrial agents causing neuropathy are ethylene oxide and methyl bromide.
Trichlorethylene (or an impurity) has caused trigeminal neuropathy.
Iatrogenic
Cisplatin
This platinum derivative (cis-diaminedichloroplatinum) is used in the treatment of
malignancy, including carcinoma of the ovary. A predominantly sensory
neuropathy that recovers poorly may develop after the administration of several
courses. Ototoxicity is more frequent, causing high-tone deafness and tinnitus.
Isoniazid
A mixed motor and sensory neuropathy may be produced by isoniazid and is
more likely to occur in individuals who acetylate the drug slowly. The neuropathy
is related to an interference with pyridoxine metabolism. Axonal degeneration
occurs in the peripheral nerves. The neuropathy recovers slowly on cessation of
administration of the drug and may be prevented by giving pyridoxine, which
does not interfere with the antituberculous action of the isoniazid.
Nitrofurantoin
Excessively high blood levels of this preparation, as may occur in patients with
reduced renal function, can cause a mixed motor and sensory neuropathy.
Vincristine
A neuropathy will occur in all subjects if sufficient amounts of this cytotoxic agent
are administered. Mild sensory symptoms and the loss of tendon reflexes may
have to be accepted if a satisfactory therapeutic effect of the drug is to be
achieved. If the neuropathy advances, bilateral weakness of the extensors of the
wrist and fingers develops, followed by more widespread weakness. The
neuropathy improves satisfactorily if the drug is withdrawn or if the dosage is
reduced.
Other substances
Less important drugs that may give rise to neuropathy are adriamycin,
amiodarone, dapsone, disulfiram, gold, metronidazole, misonidazole, nitrous
oxide (with a myelopathy), suramin, and zimeldine. A mild sensory neuropathy
may develop after prolonged administration of phenytoin, and neuropathy was
one of the complications produced by thalidomide. Pyridoxine, if taken in large
doses, as ‘megavitamin therapy’, causes a sensory neuropathy.
Deficiency neuropathies
Beri beri neuropathy (see also Section 10)
This disorder is predominantly encountered in populations subsisting on diets
composed largely of polished rice, but a similar neuropathy may be observed in
other malnourished communities. Thiamine deficiency is probably involved, but a
deficiency of other vitamins of the B group may also be implicated. A distal motor
and sensory neuropathy develops which is frequently accompanied by
spontaneous aching pain in the extremities, cutaneous hyperaesthesia, and
tenderness of the soles of the feet and calves. Involvement of the recurrent
laryngeal nerves may lead to hoarseness of the voice. The neuropathy may be
associated with a cardiomyopathy (‘wet beri beri’). Thiamine deficiency is
established by the finding of reduced activity of erythrocyte transketolase. This
enzyme requires thiamine as a cofactor.
Distal axonal degeneration occurs in the peripheral nerves and slow recovery
ensues with vitamin replacement.
Strachan’s syndrome
Strachan’s syndrome, originally described in Jamaica but also observed in other
parts of the world under conditions of nutritional deprivation, is characterized by
the combination of a painful sensory neuropathy with amblyopia and at times
deafness, in association with an orogenital dermatitis. It is assumed to be due to
B vitamin deficiency, but the precise deficit has not been identified. It improves
with B vitamin supplementation.
Alcoholic neuropathy
This always occurs on a background of nutritional deficiency. The dietary intake
of the alcoholic is high in carbohydrates and low in vitamins. Moreover,
alcoholics are known to have a reduced capacity to absorb thiamine. A direct
toxic effect of alcohol on peripheral nerves may also be involved. The clinical
features of alcoholic neuropathy are similar to those of beri beri. Other deficiency
states may coexist, such as the Wernicke–Korsakoff syndrome. Improvement
may take place with vitamin replacement and reduced alcohol intake, but it is
beset with the usual difficulties met in treating alcoholic patients.
Pyridoxine deficiency
Attention has already been drawn to the fact that isoniazid neuropathy is related
to an interference with pyridoxine metabolism. Pyridoxine deficiency may
contribute to the neuropathy that occurs in nutritional deficiency states, and
possibly accounts for the mild neuropathy of pellagra.
Pantothenic acid deficiency
Experimental deficiency of pantothenic acid in human volunteers is known to give
rise to a sensory neuropathy, and the administration of pantothenic acid has
been reported to alleviate the ‘burning feet’ syndrome which sometimes develops
in deficiency states.
Vitamin B12 deficiency
Vitamin B12 deficiency, from whatever cause, may be responsible for the
development of a distal sensory neuropathy, with ‘glove and stocking’ sensory
loss and paraesthesiae, and areflexia, either in isolation or in association with a
myelopathy or other central nervous system manifestations. Haematological
changes are not always present. The peripheral neuropathy improves more
satisfactorily with treatment than the central disturbances. This condition is
considered in detail in Chapter 24.3.9.
A peripheral neuropathy is one component of Nigerian ataxic neuropathy, in
which the other features are posterior column degeneration, sensorineural
deafness, and optic atrophy. It has been suggested that an interference with
vitamin B12 metabolism by cyanide derived from cassava in the diet, combined
with nutritional deficiency, may be responsible.
Chronic severe vitamin E deficiency has recently been established as a cause for
peripheral neuropathy in combination with a spinocerebellar degeneration. This
may occur in abetalipoproteinaemia, and isolated vitamin E deficiency, both of
autosomal recessive inheritance, and in congenital biliary atresia, cystic fibrosis,
and occasional adults with chronic intestinal malabsorption.
Inflammatory and post-infective neuropathies
Leprous neuropathy
Peripheral nerve involvement in leprosy is considered in Chapter 7.11.24.
Guillain–Barré syndrome (acute idiopathic inflammatory polyneuropathy)
Guillain–Barré syndrome is characterized by a polyneuropathy that develops
over the course of a few days up to maximum of 4 weeks. Cases that progress
for up to 8 weeks (subacute Guillain–Barré syndrome) are probably distinct. An
identifiable infection may precede the onset of the neuropathy by 1 to 3 weeks.
This is commonly an upper respiratory tract infection or an infection with an
enterovirus, Epstein–Barr virus, or mycoplasma. More recently Campylobacter
jejuni has been recognized as an important cause, as has human
immunodeficiency virus (HIV) infection. Other cases may follow surgical
operations. In approximately 40 per cent of cases no antecedent event is
identifiable.
The neuropathy may be ushered in by severe lumbar or interscapular pain. Motor
involvement usually predominates over sensory loss and may be of a proximal,
distal, or generalized distribution, and in severe cases affects the respiratory
musculature. Distal paraesthesiae in the limbs are common and, if sensory loss
occurs, it tends to affect tactile, vibratory, and postural sensibility. The cranial
nerves may be affected, in particular the facial nerves, but bulbar involvement
also occurs sometimes. A complete ‘locked-in’ state may develop. Autonomic
disturbances may be associated, including bladder atony, ileus, hypertension
(possibly the result of denervation of the carotid sinus), and orthostatic
hypotension. Associated central nervous system involvement is occasionally
encountered, particularly after infectious mononucleosis, and such cases are
sometimes excluded from the Guillain–Barré syndrome as such. Papilloedema
sometimes develops, possibly related to impaired resorption of cerebrospinal
fluid because of the elevated protein content. Further variants are a combination
of an external ophthalmoplegia, ataxia, and tendon areflexia (Miller Fisher
syndrome), as possibly are instances of acute sensory neuropathy or
pandysautonomia.
Nerve conduction studies reveal evidence of demyelination in most cases, but at
times the findings indicate an axonopathy (‘axonal’ Guillain–Barré syndrome), as
is seen in the acute motor axonal neuropathy or motor and sensory axonal
neuropathy that occurs as an annual epidemic in children in northern China.
Cerebrospinal fluid protein is usually raised, often to a substantial degree, but it
may be normal, particularly in the early stages. The cell content is usually
normal, but there may be a mild lymphocytic pleocytosis; this is more likely to
occur in cases related to HIV infection or infectious mononucleosis. The Miller
Fisher syndrome is frequently associated with circulating anti-GQ1b antibodies.
Histologically, the abnormalities are maximal in the spinal roots but also occur
diffusely throughout the peripheral nerves. In the demyelinating form, focal
perivascular accumulations of inflammatory cells are associated with segmental
demyelination of the nerve fibres and relative preservation of axonal continuity.
Recovery occurs by remyelination. The disease probably represents a cellmediated hypersensitivity reaction in which myelin is stripped off the axons by
mononuclear cells. Whether antibody-mediated demyelination is also involved is
not yet established. Severe axonal loss may be a ‘bystander effect’ or represent
direct axonal damage in cases of axonal Guillain–Barré syndrome.
Most cases of Guillain–Barré syndrome recover satisfactorily within weeks or
months. Severely affected patients, particularly those that require assisted
respiration and in whom extensive axonal degeneration occurs, recover slowly
and often show residual muscle weakness. Occasional patients have
recurrences, which are sometimes multiple.
Although widely employed in the past, controlled trials of treatment with
corticosteroids have shown no beneficial effects. Plasma exchange and highdose intravenous human immunoglobulin have both been shown to improve the
rate of recovery if given before the nadir of the disease. Because of significant
morbidity, particularly with plasma exchange, and cost, these forms of treatment
are best reserved for more severe cases. Severely affected patients may require
extensive support in an intensive care unit because of respiratory failure and
autonomic dysfunction.
Chronic inflammatory demyelinating polyneuropathy
Instances of peripheral neuropathy occur that resemble Guillain–Barré syndrome
in that the neurological involvement is predominantly motor and the
cerebrospinal fluid protein level is elevated, but which pursue either a chronic
relapsing or chronic progressive course. They are also associated with
widespread demyelination in the spinal roots and peripheral nerves and with
inflammatory infiltrates. Nerve conduction velocity is usually markedly reduced
and conduction block may be evident. Cases with a purely sensory ataxic
neuropathy also occur, as do others with localized involvement, most often of the
brachial plexus. Both the generalized and focal cases may respond to treatment
with corticosteroids, plasma exchange, or high-dose intravenous human
immunoglobulin. Cytotoxic drugs may be required in refractory cases. The
response is less satisfactory in the chronic progressive cases.
Patients have recently been identified with a chronic multifocal motor neuropathy
with persistent conduction block associated with GM1 ganglioside antibodies.
They probably represent a variant of chronic inflammatory demyelinating
polyneuropathy. They may respond to immunosuppressive therapy or plasma
exchange.
Lyme borreliosis
Lyme borreliosis is a multisystem disease caused by a tick-borne spirochaete
Borrelia burgdorferi (see Chapter 7.11.30). The peripheral nervous system is
frequently affected both during the phase of early disseminated infection and
during the late stage. Cranial neuropathies or an acute or subacute
radiculoneuritis characterize involvement in the early stages, and a mild,
predominantly distal, neuropathy characterizes the late stage. Nerve biopsies
show perivasculitis and nerve fibre degeneration, but spirochaetes are not
identifiable. Laboratory diagnosis is based on the detection of specific antibodies
to B. burgdorferi but seronegative cases occur, as may false positive reactions.
Treatment, which is with doxycycline and amoxicillin, may therefore have to be
given on clinical suspicion of the disease.
Human immunodeficiency virus infection (see Chapter 24.14.4)
A variety of neuropathies may be related to HIV-1 infection, particular types
tending to occur in different phases of the disease. Characteristically, Guillain–
Barré syndrome or chronic inflammatory demyelinating polyneuropathy occur at
the time of seroconversion, when the patient is otherwise well, and a multifocal
vasculitic neuropathy occurs in the early symptomatic stage. A distal, often
predominantly sensory and painful neuropathy occurs mainly in the later AIDS
phase, and an aggressive lumbosacral polyradiculoneuropathy from
cytomegalovirus infection is encountered in advanced cases. Neuropathy may
also occur in patients with human T-cell leukaemia virus (HTLV-I) infection. The
treatment of HIV infection is discussed in Chapter 7.10.21.
Sarcoid neuropathy
Sarcoidosis (see Section 17) may give rise to a multifocal neuropathy with a
particular tendency to involve the facial nerves, or to a generalized neuropathy.
The neuropathy may be restricted to the cranial nerves (polyneuritis cranialis).
Evidence of involvement of other systems is not always present and sarcoid
tissue may or may not be detectable on biopsy.
Diphtheritic neuropathy
The neuropathy of diphtheria (Chapter 7.11.1) is caused by the exotoxin which
produces segmental demyelination by interfering with Schwann cell function,
probably by affecting protein synthesis. The nerves are not invaded by the
bacteria.
Palatal weakness tends to develop after 2 to 3 weeks following pharyngeal
diphtheria, and local muscle paralysis after a similar interval following cutaneous
diphtheria. Paralysis of accommodation and sometimes of the external ocular
muscles appears after an interval of 4 to 5 weeks. A generalized predominantly
motor neuropathy of distal distribution may develop after 5 to 7 weeks. In severe
cases the respiratory muscles are affected, but if death occurs it is usually as a
result of an associated myocarditis.
Neuropathy in autoimmune connective tissue disorders
Peripheral nerve involvement may be encountered in a wide range of the
‘collagen-vascular’ disorders. Polyarteritis nodosa characteristically gives rise to
a multifocal neuropathy, often with considerable pain. Wegener’s granulomatosis
may similarly be associated with a florid neuropathy and, in both instances, the
peripheral nerve damage is related to necrotizing angiitis of the vasa nervorum.
Such changes may also occur in rheumatoid arthritis in association with a florid
multifocal neuropathy; at other times, a less aggressive neuropathy is observed,
either in the form of a distal sensory neuropathy or one restricted to the digital
nerves. Entrapment neuropathies also occur in rheumatoid arthritis, for example
median nerve compression in the carpal tunnel, related to inflammatory changes
in articular synovial tissues or tendon sheaths.
An ataxic sensory neuropathy related to a sensory ganglionitis can complicate
the Sjögren sicca syndrome. A clinical constellation that combines a distal
sensory neuropathy with a trigeminal sensory neuropathy, and myotonic pupils
with the sicca syndrome is particularly characteristic. A multifocal neuropathy can
also be seen in patients with Sjögren’s syndrome.
The neuropathy of polyarteritis nodosa or rheumatoid arthritis may respond to
corticosteroids or cyclophosphamide. The neuropathy of Sjögren’s sicca
syndrome is largely refractory to treatment.
Neoplastic and paraneoplastic neuropathy
Peripheral neuropathy may develop as a non-metastatic complication of
carcinoma, most often bronchial or gastric, or lymphoreticular proliferative
disorders. The precise mechanism of production of the neuropathy is uncertain.
The neuropathy may antedate the discovery of the carcinoma by as much as 2 or
3 years. In relation to carcinoma of the bronchus, the neuropathy may be purely
sensory, either subacute or chronic, often with troublesome distal dysaesthesiae,
or mixed sensory and motor. The sensory neuropathy is associated with
circulating antineuronal Purkinje cell and anti-Hu antibodies. Guillain–Barré
syndrome may be encountered in Hodgkin’s disease and in chronic lymphocytic
leukaemia, and a subacute, mainly motor neuropathy in relation to lymphoma.
Non-metastatic carcinomatous neuropathies may regress following removal of
the underlying tumour, or may remain unaffected.
Direct invasion of cranial nerves or spinal roots may occur in cases of malignant
infiltration of the meninges and of the cervical and lumbosacral plexuses from
local malignancies. Infiltration of peripheral nerve trunks is seen most commonly
from malignant lymphomas.
Paraproteinaemic neuropathy
A sensory or sensorimotor polyneuropathy related to benign monoclonal
paraproteins (monoclonal gammopathies of undetermined significance) has
emerged in recent years as an important cause of late onset neuropathy. The
neuropathy is usually demyelinating, and in some with features similar or
identical to chronic inflammatory demyelinating polyneuropathy. A postural upper
limb tremor is often a prominent feature. The paraprotein is most commonly
immunoglobulin M, less frequently immunoglobulins G or A. The immunoglobulin
M paraproteins can be demonstrated on surviving myelin sheaths in nerve
biopsies, where they are probably acting as demyelinating antibodies.
Neuropathies associated with immunoglobulin G or A paraproteins may respond
to corticosteroids, intravenous immunoglobulin, plasma exchange or
immunosuppressive drugs; the response in immunoglobulin M paraproteinaemic
neuropathy is disappointing. Although a distal sensorimotor and often painful
axonal neuropathy may be associated with myeloma, a demyelinating
neuropathy accompanied by a dermatoendocrine syndrome may be
encountered, referred to as the Crow–Fukase or POEMS syndrome
(Polyneuropathy, Organomegaly, oEdema, M protein, Skin changes). A mixed
sensorimotor neuropathy occurs which may be associated with papilloedema.
The skin changes consist of excessive pigmentation and hypertrichosis.
Peripheral oedema develops. Partial syndromes may occur in which all features
of the syndrome are not present. The disorder is most often related to
osteosclerotic myeloma.
Multifocal, predominantly lower limb, neuropathy may be caused by single or
mixed cryoglobulins in myeloma, lymphoma, systemic lupus erythematosus,
rheumatoid arthritis, or Waldenström’s macroglobulinaemia. They may be the
result of vasculitis produced by the deposition of immune complexes in the walls
of the vasa nervorum, or to intravascular precipitation of cryoglobulin. These
neuropathies occasionally respond to treatment either with immunosuppressive
or cytotoxic drugs, or to repeated plasma exchange.
Genetic neuropathies
Porphyria (see also Section 11)
A predominantly motor neuropathy may complicate acute attacks in the
autosomal dominant disorders of acute intermittent and variegate porphyria and
hereditary coproporphyria, and in the recessively inherited δ-aminolaevulinic acid
dehydratase deficiency. It tends to affect the proximal muscles to a greater
extent. There may be associated sensory loss which, although sometimes distal
in distribution, can affect the trunk and the proximal portions of the limbs. The
tendon reflexes are lost, with occasional paradoxical sparing of the ankle jerks.
Accompanying autonomic features include abdominal pain and vomiting,
tachycardia and hypertension; mental confusion, psychotic behaviour, and
epilepsy.
The explanation of the neurological damage has not been established. Axonal
degeneration occurs in the peripheral nerves so that recovery is slow and often
incomplete.
Attacks may be provoked by a variety of drugs, including barbiturates,
sulphonamides, and the contraceptive pill, and by alcohol, probably by enzyme
induction in the liver (see Section 14).
Treatment with oral or intravenous glucose, or by infusions of laevulose or
haematin, has been shown to reduce the urinary excretion of porphyrin
precursors, but a beneficial effect on the neurological disturbances has not been
established.
Familial amyloid polyneuropathy
A number of inherited amyloid neuropathies have been recognized, the
commonest being those related to point mutations in the gene for transthyretin,
formerly known as prealbumin, which is on chromosome 18. The commonest is
the Portuguese type where there is a substitution of valine for methionine in the
transthyretin molecule. The neuropathy begins with the involvement of small
nerve fibres, leading to a distal loss of pain and temperature sensation and
autonomic failure. Spontaneous pain is often a feature and a mutilating
acropathy frequently develops. The onset is commonly in the fourth or fifth
decades and the disorder is slowly progressive, leading to death within about
10 years. Transthyretin is produced mainly in the liver and liver transplantation
may halt the progression of the disease. In other types of hereditary amyloid
neuropathy with differing clinical features, the amyloid is derived from a variant
apolipoprotein A1 (Iowa form) or plasma gelsolin (Finnish form).
Hereditary motor and sensory neuropathy types I and II and X-linked
(Charcot–Marie–Tooth disease, peroneal muscular atrophy); hereditary
neuropathy with liability to pressure palsies
Hereditary motor and sensory neuropathies type I and II (or Charcot–Marie–
Tooth 1, Charcot–Marie–Tooth 2) usually present during childhood or
adolescence with difficulty in walking or because of foot deformity. The deformity
is most commonly pes cavus associated with clawing of the toes and sometimes
with an equinovarus position of the foot. Muscle weakness tends to affect the
lower leg muscles and may give rise to bilateral foot drop with a ‘steppage’ gait.
The muscle wasting is often restricted to below the knees, producing a ‘stork leg’
appearance (Fig. 3). Weakness and wasting of the small hand muscles may
appear later. The tendon reflexes become depressed or lost, and there is a
variable degree of distal sensory loss. This is the Charcot–Marie–Tooth
phenotype. Progress of the disease is slow and cases with little disability or
which are asymptomatic are common.
In the commoner type I families, there is a diffuse demyelinating neuropathy. The
onset is most frequently in the first decade. Foot deformity and scoliosis occur
more often than in the type II disease. Sensory loss and ataxia tend to be greater
and generalized tendon areflexia is usual. Weakness in the hands appears
earlier. The peripheral nerves may be thickened. Cases with ataxia and upper
limb tremor are sometimes referred to as the Roussy–Lévy syndrome. The onset
in the type II form, which is an axonal neuropathy, is most often in the second
decade but it may be delayed until middle or even late adult life. Inheritance in
both types I and II hereditary motor and sensory neuropathy is usually autosomal
dominant. The disorder in type I hereditary motor and sensory neuropathy is
most often caused by a segmental duplication on chromosome 17p11.2
(hereditary motor and sensory neuropathy HMSN Ia) which includes the gene for
peripheral myelin protein 22 (PMP22). Other cases are related to mutations in
the gene for myelin protein zero (hereditary motor and sensory neuropathy Ib).
X-linked hereditary motor and sensory neuropathy is due to mutations in the
gene for connexin 32. The clinical features resemble hereditary motor and
sensory neuropathy I but female carriers are asymptomatic or only mildly
affected. Several separate loci have so far been identified for hereditary motor
and sensory neuropathy II but the gene products are not known.
Nerve conduction velocity is severely reduced in type I cases, moderately
reduced in the X-linked form, and either normal or only slightly reduced in type II.
Affected individuals may be helped by the use of orthotic appliances and
sometimes by surgical correction of foot deformity or tendon transfer.
Hereditary neuropathy with liability to pressure palsies is an autosomal dominant
disorder in which affected individuals develop recurrent focal peripheral nerve or
brachial plexus lesions produced by compression or stretch injury. It has been
shown usually to be due to a segmental deletion on chromosome 17p11.2, i.e. it
is the reciprocal of hereditary motor and sensory neuropathy Ia. Nerve fibres
show focal regions of myelin thickening (tomacula).
Hereditary motor and sensory neuropathy type III (Dejerine–Sottas disease
and congenital hypomyelination)
The Dejerine–Sottas phenotype consists of a severe slowly progressive mixed
motor and sensory polyneuropathy with an onset in childhood. There is
hypomyelination and extensive demyelination in the peripheral nerves, and there
may be accompanying hypertrophic changes (concentric Schwann cell
proliferation). Striking enlargement of the peripheral nerve trunks may be evident.
These cases are most often due to de novo PMP22 or P zero (P0) mutations.
Some cases result from mutations in the early growth response gene 2 (EGR2).
A severe congenital hypomyelination neuropathy can also result from P0 or
EGR2 mutations.
Refsum’s disease
This is a rare disorder inherited as an autosomal recessive trait that gives rise to
a mixed motor and sensory polyneuropathy accompanied by a variety of other
clinical features, including ataxia, anosmia, pigmentary retinal degeneration,
pupillary abnormalities, deafness, cardiomyopathy, and ichthyosis. The
presentation is usually during adolescence or early adult life and the course may
be steadily progressive or relapsing. The peripheral nerves become thickened
and display hypertrophic changes. Nerve conduction velocity is usually severely
reduced.
The disorder is due to an inability to metabolize phytanic acid, a long-chain fatty
acid, which accumulates in the blood and tissues. Phytanic acid is largely of
dietary origin, and clinical improvement may be achieved with diets low in
phytanic acid. Plasma exchange is effective for acute episodes of deterioration.
Hereditary sensory and autonomic neuropathies
Predominantly sensory neuropathies may occur with either an autosomal
dominant or recessive inheritance. The symptoms in the latter instance are
usually present from birth; in the former they generally develop during the second
or third decades. In both, the sensory loss often leads to a mutilating acropathy,
with neuropathic joint degeneration and chronic cutaneous ulceration, particularly
of the feet (Fig. 4). Autonomic features are dominant in the recessive disorder of
familial dysautonomia (Riley–Day syndrome). A further rare recessive
neuropathy combines congenital insensitivity to pain and anhidrosis. Most cases
of ‘congenital insensitivity to pain’ are probably examples of small-fibre
neuropathies.
Familial dysautonomia
Otherwise known as the Riley–Day syndrome, this recessively inherited disorder
is encountered most often in Jewish populations. There is an aplasia of
peripheral autonomic neurones that leads to a variety of symptoms, including
absence of tears, unexplained pyrexia, cutaneous blotching, and episodic
sweating attacks. These symptoms are present at birth and are accompanied by
congenital insensitivity to pain related to an associated sensory neuropathy. In
early infancy there is usually difficulty in feeding because of poor sucking, and
repeated episodes of aspiration pneumonia. Later, stunted growth and often
kyphoscoliosis become evident. The disorder has been mapped to chromosome
9.
Other hereditary neuropathies (see also Section 11)
Peripheral nerve involvement occurs in metachromatic and globoid cell
leucodystrophy, adrenomyeloneuropathy, Fabry’s disease, hereditary highdensity lipoprotein deficiency (Tangier disease), hereditary
abetalipoproteinaemia, and cholestanolosis. Giant axonal neuropathy is a rare
autosomal recessive disorder with an onset in childhood, characterized by
segmental axonal enlargements containing accumulations of neurofilaments.
Affected children usually have abnormally curly hair and may have enlarged
tangerine-coloured tonsils.
Cryptogenic neuropathy
Despite extensive investigation, the cause of a substantial number of peripheral
neuropathies remains unknown. This applies in particular to examples of chronic
progressive axonopathies, some of which may be instances of late onset type II
hereditary motor and sensory neuropathy. A careful family history in such cases
may reveal evidence of undetected neuropathy in relatives. Prolonged follow-up
in other cases may disclose underlying malignancy.