BMJ 2002;324:466-469 ( 23 February )
Clinical reviewRegular review
Peripheral neuropathy Richard A C Hughes,
professor of neurology. Department of Neuroimmunology,
Guy's Campus, Guy's, King's, and St Thomas's School of Medicine, London SE1 1UL
richard.a.hughes@kcl.ac.uk
Peripheral neuropathy is common, often distressing, and sometimes disabling
or even fatal. The population prevalence is about 2400 per 100 000
(2.4%), rising with age to 8000 per 100 000 (8%).1 In Europe the commonest cause
is diabetes mellitus, which can produce painful neuropathy, disabling
foot ulcers, and death from autonomic neuropathy. Leprosy is still
prevalent in Africa, India, and South East Asia. This review explains
how general practitioners can approach the first level of diagnosis
and warn patients about what lies ahead after referral to a specialist.
Summary
points -
-
Peripheral neuropathy can be into divided into acute and chronic forms, symmetrical
polyneuropathy, and multiple mononeuropathy -
-
Acute neuropathies are diagnostic emergencies -
-
Neuropathy due to diabetes mellitus and alcohol misuse can be diagnosed in primary
care -
-
Neurophysiological tests distinguish
axonal from demyelinating neuropathies -
-
Demyelinating
neuropathies are commonly inflammatory and treatable -
-
Axonal neuropathies have multiple causes -
-
Generic management includes foot care, ankle supports, and treatment of neuropathic
pain |
| Methods | I searched
Medline from January 1991 until September 2001 using the terms "peripheral
neuropathy" and "guideline." The search yielded 11 references,
including useful guidelines for the diagnosis and management of diabetic
peripheral neuropathy,2 but no guidelines on the
diagnosis and management of generic peripheral neuropathy. This article
offers a personal approach to the management of generalised peripheral
neuropathy from the perspective of a neurologist with a special interest
in the topic. The recommendations also take account of reviews published
by authorities in peripheral neuropathy (see educational resources)
and a recent audit of a Dutch departmental guideline that showed the
value of investigating common causes before doing electrophysiological
tests.3
| Diagnosis | Patients
with peripheral neuropathy may present with altered sensation, pain, weakness,
or autonomic symptoms. The clinical features vary widely and may resemble
myelopathy, radiculopathy, muscle disease, or even hyperventilation.
Identifying a neuropathy in patients with coexistent problems can therefore
be difficult. The symptoms usually begin in the toes before the fingers
and spread proximally. The classic picture of advanced
polyneuropathy with distal wasting and weakness, absent tendon reflexes, and glove
and stocking sensory loss should be easy to recognise. The clinical
features allow acute symmetrical peripheral neuropathy, chronic symmetrical
peripheral neuropathy, and multiple mononeuropathy to be distinguished,
each with a different differential diagnosis.
| Acute symmetrical peripheral neuropathy | Acute
symmetrical peripheral neuropathy is rare but important because the commonest
cause is Guillain-Barré syndrome, which can be fatal. The table gives
other causes. Common early symptoms are distal paraesthesiae and proximal
or distal weakness occurring one to two weeks after a respiratory or
gastrointestinal infection. Traditionally, the reflexes are absent,
but their retention during the first hours of the illness has led many
patients to be dismissed as "hysterical." Once a patient loses the
ability to walk and develops facial and bulbar weakness the diagnosis
becomes obvious. The rapid progression of sensory or motor deficit
requires emergency investigation. Patients usually have to be admitted
to hospital because of the danger of respiratory failure. Early treatment
should stop the pathological process before axonal dysfunction becomes
irreversible. Guillain-Barré
syndrome is usually due to acute inflammatory demyelinating polyradiculoneuropathy
caused by an autoimmune response directed against the Schwann cells
or myelin. Some cases are due to acute axonal neuropathy, in which
glycolipid in the axolemma is targeted. In both forms, treatment with
intravenous immunoglobulin hastens recovery and reduces the long term
disability and is more convenient than plasma exchange.4 A recent trial suggests that combination
treatment with steroids is more effective than intravenous immunoglobulin
alone, but the full results are awaited.5
Box
1 : Causes of multiple mononeuropathy -
- Vasculitis
-
- Primary systemic vasculitis:
Polyarteritis nodosa Churg-Strauss
syndrome (vasculitis with blood eosinophilia and asthma) -
- Systemic vasculitis
associated with connective tissue diseases:
Rheumatoid arthritis Sjögren's
syndrome -
- Vasculitis confined to peripheral nerves
-
- Other causes
-
- Sarcoidosis
-
- Lymphoma
-
- Carcinoma
-
- Amyloid
-
- Multiple compression palsies
-
- Associated with metabolic or
toxic neuropathy
-
- Hereditary neuropathy with liability to pressure palsies
| |
| Multiple mononeuropathy | Acute
multiple mononeuropathy is also a neurological emergency because the commonest
cause is vasculitis (box 1). Prompt treatment with steroids may
prevent further irreversible nerve damage. If multiple mononeuropathy
develops in a patient with an established connective tissue disorder
(such as rheumatoid arthritis, systemic lupus erythematosus, polyarteritis
nodosa, or Churg-Strauss syndrome) it is reasonable to conclude that
vasculitis is the cause. Steroids are the main treatment, with cyclophosphamide
being added depending on the severity and general medical condition.
Sometimes peripheral neuropathy is the presenting or sole feature of vasculitis.
In this case, vasculitis can be diagnosed only by nerve biopsy. 6 7 In addition, recent biopsy studies indicate
that diabetic amyotrophy is due to microvasculitis in the lumbosacral
plexus. It presents acutely with pain, weakness, and then wasting in
one or both quadriceps muscles.6-8
| Chronic symmetrical peripheral neuropathy | Most
peripheral neuropathies are chronic and usually develop over several months. Diagnosis
of the underlying cause may require three stages of investigation.
Any history of a general medical disorder could be relevant. Patients
should always be asked about alcohol consumption, toxin exposure (insecticides,
solvents), and drugs. They should also have a full examination, including
breasts and genitalia, to exclude underlying carcinoma.
Box
2 : Stage 1 and 2 investigations of peripheral neuropathy
-
- Stage 1
-
- UrineGlucose, protein
-
- HaematologyFull blood count, erythrocyte sedimentation
rate, vitamin B-12, folate
-
- BiochemistryFasting blood glucose concentration, renal
function, liver function, thyroid stimulating hormone
-
- Stage 2
-
- Neurophysiological testsAssessment of distal
and proximal nerve stimulation
-
- BiochemistrySerum protein electrophoresis, serum angiotensin
converting enzyme
-
- ImmunologyAntinuclear factor, antiextractable nuclear
antigen antibodies (anti-Ro, anti-La), antineutrophil cytoplasmic antigen antibodies
-
- OtherChest radiography
| |
The commonest causes of neuropathy can be identified from the history,
examination, and simple stage 1 investigations (box 2). Sometimes the neuropathy is predominantly sensory and subacute
with ataxia that is worse in the dark because of loss of large fibre
function and postural sensation. This pattern is produced by some drugs
(such as cisplatin), an underlying neoplasm, Sjögren's syndrome, or
idiopathic sensory neuronopathy. If other members of the family have
similar symptoms, pes cavus, or claw toes, the patient may have hereditary
motor and sensory neuropathy or Charcot-Marie-Tooth disease, which
is usually autosomal dominant. Difficulty with walking in childhood
also suggests a hereditary neuropathy. If patients have a clear cause
for their neuropathy and a typical clinical picture, treatmentfor instance, of diabetes
mellitus or alcohol misusecan be started without further
investigation. Second stage investigations If
the cause of the neuropathy is not clear from the stage 1 investigations
or is atypical, the patient should be referred to a neurologist. The
most important stage 2 investigation is neurophysiological testing
(figure). About 80% of symmetrical peripheral neuropathies are axonal
and are due to gradual dying back of the axons. In the remaining 20%
(demyelinating neuropathies) most of the damage is to the myelin, although
axonal degeneration often occurs as the disease advances. The other
second stage investigations (box 2) are simple outpatient tests for the commonest
causes of peripheral neuropathy.
[View Larger Version] | Muscle
action potentials after distal and proximal stimulation of a nerve to a muscle
such as abductor pollicis brevis. The upper trace of each pair is the record after
distal stimulation. In the normal nerve the distal motor latency is short and
nerve conduction velocity rapid (>50m/sec). In demyelinating neuropathy the
distal motor latency is prolonged and nerve conduction velocity slowed to less
than 80% of normal. In axonal neuropathy the action potential is reduced, but
the distal motor latency and nerve conduction velocity are unaffected. Multifocal
abnormalities with normal conduction velocity suggest multiple mononeuropathy
| |
Third stage investigations The choice of
third stage investigation will depend on whether neurophysiological
testing has shown the neuropathy to be demyelinating or axonal. Demyelinating
neuropathy The causes of demyelinating neuropathy are limited
(box 3). If the slowing of nerve conduction affects all
nerves roughly equally the diagnosis is likely to be the demyelinating
form of Charcot-Marie-Tooth disease (type 1). Seventy per cent of
such patients have a duplication of the gene for a 22 kDa peripheral
nerve myelin protein on chromosome 17. The duplication causes
overexpression of the protein. The clinical picture ranges from classic
pes cavus with inverted champagne bottle legs to scarcely detectable
clawing of the toes. Different mutations of the same protein and of
other myelin proteins cause a similar clinical picture. Genetic counselling
and prenatal diagnosis can be offered.
Box
3 : Causes of chronic demyelinating neuropathy -
- Charcot-Marie-Tooth disease type 1
-
- Other forms of Charcot-Marie-Tooth
disease
-
- Hereditary liability to pressure palsies
-
- Other genetic
causesfor example, Refsum's disease, metachromatic
leucodystrophy
-
- Chronic inflammatory demyelinating polyradiculoneuropathy
-
- Multifocal motor neuropathy
-
- Paraproteinaemic demyelinating neuropathy:
Associated
with monoclonal gammopathy of undetermined significance Associated with
solitary myeloma
| |
About 10% of patients with a demyelinating neuropathy have a serum paraprotein.
Although occasionally associated with a solitary plasmacytoma, the
paraprotein is usually benign. The commonest syndrome is a slowly progressive
predominantly sensory neuropathy with an IgM
paraprotein. The paraprotein is an autoantibody directed against the
carbohydrate epitopes on myelin associated glycoprotein. The antibody
is directly responsible for the neuropathy. Chronic inflammatory
demyelinating polyradiculoneuropathy is the commonest form of acquired demyelinating
neuropathy and affects about 2 per 100 000 of the population.9 The disease is usually predominantly
motor, and patients show a proximal as well as distal pattern of weakness;
the condition may be relapsing and remitting. Protein concentrations
in the cerebrospinal fluid are almost always increased. Chronic inflammatory
demyelinating polyradiculoneuropathy is diagnosed by exclusion of the
other causes listed in box 3 and from neurophysiological testing,
which shows multifocal abnormalities with partial conduction block.
This causes the compound muscle action potential following proximal
stimulation to be smaller than that following distal stimulation (see
figure). It is thought to be an autoimmune disease because of the inflammation
in the nerves and response to immunotherapy. There is no diagnostic
immunological test, but antibodies to the 28 kDa P0 myelin glycoprotein
were identified in about a quarter of cases in a recent series and
have been shown to induce experimental demyelination.10 Chronic axonal neuropathy
Axonal polyneuropathy can be sensory or sensory and motor. It has
many causes, which will often be suggested by the history or examination.
The third stage investigations (box 4) should show the less common general medical disorders
and identify cases of diabetes mellitus that were not detected by the
fasting blood glucose test.11 Nerve biopsy should usually be done
only on patients with distressing neuropathy in whom it might lead
to useful treatment.12 In an audit of 50 cases the biopsy confirmed
the diagnosis in 70%, affected management in 60%, and caused persistent
pain in 33% of patients.12 Biopsy should be done in a specialist centre
and only when the diagnosis cannot be made in any other way. Specimens
are usually taken from the sural nerve under local anaesthetic. Vasculitis
is the diagnosis most likely to be found. After exhaustive investigation
no clear cause is found in about 25% of patients. Such chronic idiopathic axonal
neuropathy usually occurs in elderly people and is often indolent,
predominantly sensory, and length dependent. Patients can be reassured
that, although their condition may progress, it will usually do so
only slowly and is unlikely to become seriously disabling.13 Loss of pain and temperature
sensation and spontaneous neuropathic pain, described as burning or pricking,
can be prominent symptoms of axonal neuropathy. They are due to degeneration
of thinly myelinated and unmyelinated nerve fibres. Occasionally
small fibre neuropathy occurs without the thicker myelinated nerve
fibres being affected and the nerve conduction test results remain
normal. The diagnosis in such cases usually relies on the clinical
symptoms and signs alone. Proof of the diagnosis would require skin
biopsy or enumeration of unmyelinated nerve fibres in electron micrographs
of a nerve biopsy specimen.
Box 4 : Stage 3 investigation
of peripheral neuropathy -
- UrineBence-Jones protein
-
- BiochemistryOral glucose tolerance test
-
- Cerebrospinal
fluidCells, protein, immunoglobulin
oligoclonal bands
-
- ImmunologyAnti-HIV antibodies, antineuronal antibodies
(Hu, Yo), antigliadin antibodies, serum angiotensin converting enzyme, antiganglioside
antibodies, antimyelin associated glycoprotein antibodies
-
- Tests for
Sjögren's syndromeSalivary flow rate,
Schirmer's test, Rose Bengal test, labial gland biopsy
-
- Search for
carcinoma, lymphoma, or solitary myelomaSkeletal survey, pelvic ultrasonography, abdominal and
chest computed tomography, mammography, or positron emission tomography
-
- Molecular
genetic testsPeripheral nerve myelin
protein 22 gene duplication (the commonest cause of Charcot-Marie-Tooth disease
type 1) or deletion (hereditary neuropathy with liability to pressure palsies),
connexin 32 mutation (X linked Charcot-Marie-Tooth disease), PO gene mutation
(another cause of Charcot-Marie-Tooth disease type 1), etc
| |
Chronic axonal neuropathy occurs in patients with many multisystem hereditary
disorders. The diagnosis of these conditions is usually suggested by
the other neurological and systemic features. Isolated cases of hereditary
neuropathy such as the axonal form of Charcot-Marie-Tooth disease (type
2) can, however, be difficult to diagnose. 14 15 In this disease the symptoms usually
begin in childhood and are associated with pes cavus and claw toes
but may not come to attention until middle or old age. The family
history may not be evident without examination of the apparently unaffected
relatives. The condition is clinically and genetically heterogeneous,
and several gene loci are involved. Molecular genetic tests are available
for only a tiny proportion of patients.
| Treatment | Any underlying
medical cause of peripheral neuropathy, such as diabetes mellitus or vitamin B-12
deficiency, should be treated. Chronic inflammatory demyelinating polyradiculoneuropathy
is important to recognise because it is treatable. Corticosteroids
are usually used initially as they are the cheapest treatment, but
the condition also responds to intravenous immunoglobulin, plasma exchange,
and some immunosuppressant drugs.9 The uncommon variant, multifocal motor
neuropathy, responds to intravenous immunoglobulin and possibly immunosuppressant
drugs but not to corticosteroids or plasma exchange.16 Unfortunately, no specific treatment
is available for chronic idiopathic axonal polyneuropathy.
| Management | Preventive
and palliative treatments include foot care, weight reduction, and sensible shoes,
boots, or ankle-foot orthoses. Patients with severe leg weakness may
need sticks, crutches, or a walking frame. Physiotherapists are best
placed to prescribe these aids, which may need to be adapted to take
account of weakness of the hands. Simple wrist splints can help weak
wrist extension. More complex splints for weak fingers and hands are
usually cumbersome and rarely used. Disabled patients require help
from a multidisciplinary team including an occupational therapist,
who can advise on special utensils and home adaptations. Some drugs
help. Sildenafil may correct erectile impotence. In the United Kingdom,
the NHS will pay if the neuropathy is due to diabetes mellitus.
Patients with neuropathy may experience pain, which can be severe and out
of proportion to any sensory or motor deficit. Painful neuropathy is
difficult to treat. The most useful drugs are anticonvulsants, especially
gabapentin and carbamazepine, and tricyclic antidepressants, especially
amitriptyline. The opioid-like analgesic tramadol has also been shown
to be useful in randomised controlled trials.17
Additional
educational resources Thomas PK, Ochoa J. Clinical features
and differential diagnosis. In: Dyck PJ et al, eds. Peripheral neuropathy.
Philadelphia: WB Saunders, 1993:749-74. Asbury AK, Thomas PK. The clinical
approach to neuropathy. In: Peripheral nerve disorders Oxford: Butterworth-Heinemann,
1995:1-28. Hughes RAC. Management of chronic peripheral neuropathy. Proc
R Coll Physicians Edinb 2000;30:321-7. Sabin TD. Generalized peripheral
neuropathy: symptoms, signs, and syndromes. In: Cros D, ed. Peripheral neuropathy.
A practical approach to the diagnosis and management. New York: Lippincott,
Williams and Wilkins, 2001: 3-20. Patient information Guillain-Barré
Syndrome Support Group (http://www.gbs.org.uk/) Information
and support for people with Guillain-Barré syndrome, chronic inflammatory demyelinating
polyradiculoneuropathy, and related conditions Peripheral Neuropathy Trust
(http://www.neuropathy-trust.org/) Information
about all forms of neuropathy, especially chronic idiopathic axonal neuropathy CMT
United Kingdom (http://www.cmt.org.uk/) A site maintained
by the UK Charcot-Marie-Tooth disease patient support group |
| Acknowledgments |
I thank David Hughes, Haider Katifi, Michael O'Brien, Mary Reilly, and Wolfgang
Schady for reading the manuscript and Kerry Mills for providing the
figure.
| Footnotes | Competing
interests: RACH is coordinating editor of the Cochrane Neuromuscular Disease Review
Group.
| References |
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BMJ 2002
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