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History and
examination
Differential
diagnosis
Investigations
Specific
neuropathies
Treatment

The author

DR ROBERT HENDERSON,
director of neurology, Royal
Brisbane & Womens Hospital,
Brisbane, Queensland.

Peripheral
NEUROPATHY
Background
MANY doctors find it difficult to
diagnose and manage peripheral neuropathies. There is rarely a specific
cause found and there is a lack of
targeted treatments available. This
review hopes to answer these three
points and provide an approach to a
complex topic.

The pathology of
peripheral neuropathies
Peripheral neuropathies include all

disorders in which nerve structures

beyond the spinal cord are affected.
Disorders of nerve roots are considered with neuropathies.
It is worth remembering that the
cell body for motor nerves is the
anterior horn cell in the spinal cord,
while the cell body for sensory
nerves is the dorsal root ganglion
usually located near where the nerve
root exits from the cerebrospinal
fluid.

Motor nerve fibres (axons) terminate as terminal branches at the neuromuscular junctions that connect
with muscle fibres (figure 1, page
34). Sensory nerve axons terminate
at freely branching or specialised corpuscular endings at the skin or other
tissues. The axon is surrounded by a
myelin sheath. The signal speed is
greatly increased by jumping along
the nodes of Ranvier.
Neuropathies occur when there is
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dysfunction of the axon or the surrounding protective myelin sheath.

Loss of the myelin sheath causes
slowed conduction and, over time,
damage to the underlying axon.
Unmyelinated nerve fibres are
slower-conducting nerve fibres and
carry autonomic and sensory information.
Most idiopathic and inherited neuropathies are length dependent, with
contd next page

16 May 2008 | Australian Doctor |

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How to treat peripheral neuropathy

from previous page

the neurotransmitter transport

mechanisms failing at the end of
nerves. Transport mechanisms also
appear vulnerable to toxic neuropathies. Recent work supports an
important role for mitochondria in
many disease processes.
When the nerve axon is damaged, either Wallerian degeneration
(degeneration of the axon distal to
the most proximal site of injury)
or a more generalised axonal
degeneration (a dying back phenomenon that affects the nerve
axon back to the cell body) occurs.
A different pathology occurs in
many immune disorders in which
the surrounding, protective myelin
sheath is damaged (segmental
demyelination). Recovery is slow if
regrowth of the axon is needed but
can occur much more rapidly if the
process is demyelination.

Initial presentations of a
peripheral neuropathy
Sensory symptoms

Sensory symptoms are the most

common presentation of a peripheral neuropathy and can be considered as positive (tingling, burning and pain) or negative (loss of
touch and temperature). In general,
most sensory neuropathies are

length-dependent, with feet

involved before hands. Fingers are
often not involved until sensory
symptoms are noted at the mid-calf
level.
Although many patients describe
sensory symptoms as numbness,
it is important to explore what is
meant by this term. It can vary
between positive and negative
symptoms or sometimes even
weakness.
Positive sensory symptoms are
usually associated with uncomfortable sensations. An ordinary stimulus produces an unpleasant,
abnormal sensation (dysaesthesia)
or unpleasant sensations arising
without apparent stimulus (paraesthesia).
Negative sensory symptoms are
sometimes considered less significant but are more worrying in
terms of disability, with balance
problems, ulceration and Charcot
joints often resulting.
Asking the patient direct questions is often useful Can you
feel when something is in your
shoe? Can you feel the temperature
of bathwater? Do you feel discomfort when something rubs against
your skin (allodynia)?. Difficulty
walking at night may represent loss
of the sense of joint position.

Figure 1: The peripheral motor nerve.

Motor symptoms

Motor symptoms such as weakness

are a less common presentation of a
peripheral neuropathy than sensory
symptoms. Most motor symptoms
begin as gait and balance difficulties.
When weakness becomes significant,
a characteristic pattern occurs, with
loss of foot dorsiflexion.
Falling or tripping are important
symptoms to inquire about. Hand
weakness usually occurs later,
when feet are more severely
affected, and manifests as difficulty
with fine motor control such as

turning a key or writing.

Autonomic symptoms

Autonomic symptoms are rarely

considered but are important indicators of involvement of small
nerve fibre pathways. Loss of
sweating is usually not recognised
by patients, but possible autonomic
dysfunction is suggested by:
Absence of odour on socks.
Dry, cracked and ulcerated skin.
Loss of sexual function in males.
Dry mouth or eyes.
Postural lightheadedness.

History and examination

History
HISTORY is the most
important factor in diagnosing a peripheral neuropathy.
The temporal history of
symptoms allows the neuropathy to be categorised
into a time-course of acute,
subacute or chronic.
Coexisting diseases are
often important and, along
with family history, the GP
needs to consider:
Medications (prescribed
and complementary).
Nutritional status (including alcohol consumption).
Travel history.
Occupation
Exposure to toxins.
While the common hereditary neuropathies are usually autosomal dominant, a
lack of family history does
not exclude the possibility of
a sporadic new mutation.
Direct questioning of family
members for sensory symptoms is often required.

Figure 2: Pes cavus and the

distal muscle wasting
characteristic of an inherited
neuropathy.
(Photo courtesy of
Professor Garth Nicholson.)

Examination
When examining for a possible peripheral neuropathy,
the two aims are to establish
if a peripheral neuropathy
exists and to determine if it
is treatable. Certain patterns
exist that make the examination results easier to synthesise.

tion sense, a large-fibre sensory function. This is different from the unsteady stance
with eyes open that often
represents cerebellar or other
central involvement.

Gait

The gait can usually be

quickly assessed when
patients walk into the room,
but Rombergs test is often a
helpful additional step. A
positive Rombergs test (the
ability to stand with the feet
together and eyes open, yet
falling with the eyes closed)
represents loss of joint-posi-

34

Figure 3: Atrophy of the abductor digiti minimi (arrow), indicating ulnar nerve pathology. The
patient is trying to extend the fingers; the inability to do this represents an additional radial
neuropathy.

Limb inspection

Muscle atrophy is a feature

of neuropathies not usually
seen with muscle or CNS
conditions, unless disuse is
prominent. On inspection of
the distal limbs pes cavus
usually represents an inherited neuropathy but cannot
be detected unless the patient

| Australian Doctor | 16 May 2008

removes their shoes. In addition to the high-arch of the

foot, pes cavus is usually
associated with hammertoes (flexion of the second
to fifth toes) and with loss
of the muscle bulk in the
lower part of the lower leg,
described as inverted champagne-bottle legs (figure 2).
Pes cavus occurs as atrophic
weakness of the foots intrinsic muscles allows the long
extensors of the toes to dorsiflex the toes, and the long
flexors to shorten the foot,
heighten the arch and flex
the distal toes.
Atrophy of the first dorsal
interosseous muscle in the
hand is usually easily visible.
Loss of hair and trophic
changes of the skin can be
noted. Fasciculations may be
seen in neuropathies
although they are not usually a prominent feature.
Strength

Loss of muscle strength is

usually a late sign in most
peripheral neuropathies.
Usually only moderate
weakness can be detected

with manual testing of foot

dorsiflexion or plantar flexion. More careful examination of strength requires testing foot inversion and
eversion and toe flexion and
extension.
Weakness of foot dorsiflexion can be examined by
asking a patient to stand on
their heels.
In the upper limb, loss of
finger and thumb abduction
is usually the first sign of an
upper-limb neuropathy,
although other patterns are
helpful to recognise (figure
3).
Reflexes

Reflexes are very helpful in

assessing a neuropathy. As
the ankle reflex has an afferent sensory and efferent
motor component, the ankle
reflex will be absent in both
types of neuropathy.
In most significant neuropathies involving large
fibres, the ankle reflex will
be reduced or absent and
most other reflexes will be
reduced (ie, knee, biceps, triceps and supinator reflexes).

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By contrast, in neuropathies
that only affect small nerve
fibres, the reflexes will be
retained. Easily obtained or
brisk reflexes would suggest
an alternative diagnosis to a
peripheral neuropathy.
Sensation

The sensory examination is

often considered difficult
and time-consuming. In the
most common pattern of
neuropathies, all sensory
modalities (touch-pressure,
pain, temperature, jointposition sense and vibration)
are similarly affected.
A pattern that occurs in
inherited and metabolic neuropathies is preferential
involvement of pain and
temperature. Involvement of
predominantly vibration and
joint-position sense is
uncommon but is the pattern
seen with vitamin B12 deficiency.
A simple method for the
sensory examination is to
use the 128Hz tuning fork
to test both vibration and
temperature. A gentle tap of
the tuning fork and place-

ment over the hallux is usually felt in normal people,

although in those over 60,
loss of vibration over the
hallux is not necessarily
abnormal and the ankle
should be tested in these
cases. Testing a central reference is needed if there is
any confusion as to the
meaning of vibration.
Cold temperature over the
dorsum and underside of the
foot can also be simply tested
using the tuning fork. Temperature is carried by the
same pathways as pain,
which is more difficult to test.
Pain sensation is best tested
using a dressmakers pin or
branded pins such as Neurotips. Testing over the toes
and dorsum of the foot can
be compared with a more
proximal location such as the
thigh. Often repeated pressure of the pin is needed for
patients with a neuropathy to
be sure of sensation. Lighttouch testing using a cotton
ball is subjective and rarely
helpful, but can be tested in a
similar way to pain.
Joint-position sense can be
helpful as an additional
assessment of the vibration
pathways.
General neurological
examination

When assessing a neuropathy it is helpful to examine

for more widespread neurological involvement. For
example, cognitive involvement, visual or hearing
symptoms or signs might
suggest a metabolic process
such as a mitochondrial disorder. A dysmorphic appearance might suggest an
unusual inherited process.

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How to treat peripheral neuropathy

Differential diagnosis
CLASSIFICATION of the
cause of a peripheral neuropathy can be based on whether
motor, sensory and/or autonomic fibres are involved or
whether small and/or large
nerve fibres are involved
(tables 1 and 2). Other classifications are outlined in table
3. My preference is to initially
consider small- and large-fibre
involvement, as the distinction
between these neuropathies
can be made on history and
examination.
Small-fibre neuropathies
(table 1) usually cause pain
and discomfort and are associated with normal ankle
reflexes, normal nerve conduction studies and, with some
exceptions such as diabetes,
are often relatively benign.
Large-fibre neuropathies
(which usually also involve
small fibres) can be divided
into neuropathies that are predominantly motor or sensory
and those that involve both
motor and sensory function.
Occasionally other conditions can mimic a peripheral
neuropathy. It is worth remembering that balance difficulty
can represent sensory loss (loss
of joint-position sense), weakness or more central problems.
Central causes such as multiple sclerosis can cause predominant sensory symptoms.
A clue is the retained or brisk
reflexes, especially the ankle
jerk, in CNS disorders. Spinal
cord or nerve root pathology
can also similarly present with
distal sensory symptoms, for
example, people with bilateral

Table 1: Smallfibre-predominant
neuropathies
Acute
Toxic
Acute form of GuillainBarr syndrome
Porphyria
Chronic
Idiopathic
Diabetes
Hereditary
Amyloid
Paraneoplastic

Table 2: Chronic pure

motor and sensory
large-fibre
neuropathies
Pure motor neuropathies
Multifocal motor neuropathy with conduction block
Progressive muscular
atrophy (peripheral variant
of motor neurone disease)
Chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP)
Diabetes
Inherited
Sensory-predominant
neuropathies
Immune (eg, Sjgrens
syndrome)
Paraneoplastic
Toxic (especially due to
vincristine, cisplatin and
paclitaxel)
CIDP or paraproteinaemic
neuropathy
Idiopathic

L5 and S1 nerve-root compression often notice sensory

symptoms in the feet.

Table 3: Other classifications of peripheral neuropathies

Acute neuropathies (symptoms
progressing over days)
Guillain-Barr syndrome
Toxic
Vasculitis
Rare: porphyria, diphtheria
Toxic neuropathies
Arsenic (subacute sensorimotor)
Lead (prominent motor)
Mercury (sensory)
Thallium (acute sensorimotor)
Hexacarbons
Methyl-n-butyl ketone
Methyl bromide
Ethylene oxide
Vitamin B6 excess
Nitrous oxide
Important causes of multiple
peripheral mononeuropathies
Vasculitis
Diabetes
Sarcoid
Inherited (liable to pressure palsies)
Medications associated with
peripheral neuropathy
Chemotherapy agents (vincristine,
paclitaxel, cisplatin)
Nitrofurantoin
Amiodarone
Statins
Isoniazid
Phenytoin
Chronic use of metronidazole
Thalidomide
Stavudine
(Medications associated with a
neuropathy but now rarely used: ddC,
perhexiline, chloramphenicol,
hydralazine, dapsone)

Important treatable neuropathies

Metabolic
B12 deficiency
Impaired glucose tolerance
Inflammatory
Acute (Guillain-Barr syndrome) and chronic (chronic inflammatory demyelinating
polyneuropathy) demyelinating neuropathies
Paraproteinaemic neuropathy (IgG and IgA)
Sarcoidosis
Neoplastic
Paraneoplastic, usually associated with lung carcinoma, and anti-Hu positive on
testing of paraneoplastic antibodies
Causes of painful neuropathies
Diabetes (painful symmetric neuropathy, diabetic plexopathy, diabetic
thoracoabdominal radiculopathy)
Idiopathic distal small-fibre neuropathy
Vasculitic neuropathy
Toxic neuropathies (due to alcohol, arsenic, thallium, vincristine, cisplatin)
HIV and treatment (dideoxynucleosides)
Amyloid
Paraneoplastic processes
Fabrys disease
Nutritional neuropathies
Alcohol abuse is one of the most common causes of peripheral neuropathies seen in
general practice, although the mechanism is poorly understood. Nutritional factors
such as deficiency of thiamine and other B vitamins are likely important
Nicotinic acid (niacin) deficiency produces pellagra in a triad of GI symptoms, neuropathy and dementia. The neuropathy is usually a distal sensorimotor neuropathy indistinguishable from thiamine deficiency
Pyridoxine (vitamin B6) deficiency of dietary cause is rarely seen but drugs such as
isoniazid, hydralazine and penicillamine may deplete resources, producing a distal
sensorimotor neuropathy
Vitamin B12 deficiency produces a sensory neuropathy; when this is severe, involvement of the posterior columns can produce imbalance and gait difficulties
Vitamin E deficiency occasionally is seen with disorders of fat malabsorption or, rarely,
as an inherited disorder. A multisystem degeneration with sensory ataxia results
Infections directly associated with neuropathy
Hepatitis B and C
HIV
Leprosy
Cytomegalovirus and Epstein-Barr, herpes simplex and varicella zoster viruses
Not seen in Australia Lyme disease, Chagas disease

Investigations
EVEN in the most specialised neuropathy clinics, a cause for peripheral neuropathy will not be found
in 25% of cases. Tests for a peripheral neuropathy should be based
on a rational approach to the individual patients history and examination in association with an
understanding of treatable neuropathies and the rapidity of disease progression and morbidity.

Nerve conduction studies

Nerve conduction studies (NCS) are
the primary investigation used to
confirm a peripheral neuropathy but
are only useful for large-fibre neuropathies. NCS should be considered
as an aid to the clinical examination
and are performed by most clinical
neurologists and occasionally by
rehabilitation specialists.
In NCS, a nerve is stimulated
and the size and speed of a motor
or sensory response is measured
(figures 4 and 5, page 37). There is
minor discomfort with most commonly studied nerves if the tests
are performed carefully.
NCS distinguish demyelinating
neuropathies from axonal neuropathies. They can also assess progression of a neuropathy, determine subclinical involvement of
nerves and guide further investigations such as a sural nerve biopsy.
They are also particularly helpful

36

| Australian Doctor | 16 May 2008

Neuropathy screen

Figure 4: Nerve conduction study of the ulnar motor nerve.

Testing for small-fibre

neuropathy
Testing for small-fibre neuropathies
is less widely available, more subjective and often research based
(most capital cities have one hospital with an interest in this area).
Commercial equipment is available for quantitative sensory testing, which is useful for quantifying the commonly tested sensory
modalities. Quantitative sudomotor axon reflex test (QSART) is
used in some Australasian centres
to quantify sweat loss in response
to an ionic current.
Thermoregulatory sweat testing
is useful to assess patterns of sweating, for example, a length-dependent pattern, but is time-consuming
and not widely available.

The history is the most important

indicator of which investigations will
be useful. Possible investigations
include:
FBC, electrolytes and LFTs
Vitamin B12
Fasting blood sugar
ESR, C-reactive protein
Serum and urine electrophoresis
Antinuclear antibodies, extractable
nuclear antigens
Antinuclear cytoplasmic antibodies
Rheumatoid factor
Hepatitis B and C, HIV
Cryoglobulins
Folate
Paraneoplastic antibodies
Red cell transketolase
Thyroid function tests
Vitamin E
Urinary porphyrins
Urinary heavy metals
Serum mitochondrial deletions

Nerve biopsy
for entrapment neuropathies such
as carpal tunnel syndrome.
NCS are usually performed with
electromyography (EMG), which
involves inserting a small recording electrode directly into muscle.
In most chronic neuropathies, large
motor units are found in distal
muscles on EMG. In active disease,
regular fibrillation potentials are
found. Abnormally large motor
units in proximal muscles on EMG
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might support the diagnosis of a

process at the nerve roots.
NCS/EMG are also helpful for
distinguishing neuropathies from
disorders of the neuromuscular
junction and muscle (myopathies).

Cerebrospinal fluid examination

CSF examination is useful for measuring the level of protein (raised in
inflammatory neuropathies) and
for cytology (malignancy).

Nerve biopsy (figure 6, page 37) is

rarely performed because of the
invasive nature of the test and
the possibility of a residual area
of discomfort. The sural nerve
above the ankle is the only nerve
commonly biopsied, and this is
usually performed by neurosurgeons.
A sural nerve biopsy may be
helpful in diagnosing inflammatory conditions such as vasculitis,
particularly in conditions such as
Churg-Strauss disease, in which

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peripheral nerves are more commonly involved. A

sural nerve biopsy may also be helpful in diagnosing
infiltrative conditions such as amyloidosis, although
a skin or rectal biopsy may obviate the need for the
sural nerve biopsy.

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Figure 5: Information obtained from nerve conduction studies includes size of

responses, conduction velocity and the pattern of the waveforms.

Figure 6: Sural nerve biopsy showing the myelin sheaths

surrounding motor, sensory and autonomic axons.

When to refer to a neurologist

While most neuropathies are managed by the GP, an
initial assessment by a neurologist is often helpful,
particularly if the neurologist has an interest in neuromuscular diseases. In common practice, the GP
has usually performed the tests for benign and treatable neuropathies.
Reasons for urgent referral of a patient to hospital
would include acute progressive presentation (within one week) with ascending sensory or motor
symptoms, or when Guillain-Barr syndrome or a
toxic cause are a clinical concern. Progressive, disabling neuropathies deserve investigation. When
there is a concern about an inherited neuropathy,
investigations and referral to a geneticist may be
helpful.

Specific neuropathies
Inherited neuropathies
RECENT classifications separate inherited neuropathies
into:
Hereditary motor and sensory neuropathy (HMSN).
Hereditary sensory neuropathy (HSN).
Hereditary sensory and autonomic neuropathy (HSAN).
However, the old nomenclature of Charcot-Marie
Tooth (CMT) remains widely
known and useful. Most
(70%) adult-onset hereditary
neuropathies are CMT1A, for
which genetic testing is widely
available. The typical profile
is given in the Authors case
study (Inherited neuropathy?,
page 38).
The gene test for CMT1A
also tests for deletion of the
PMP22 gene on chromosome
17, which is seen in hereditary
neuropathy with liability to
pressure palsy. Genetic testing
is also available in Australia
for connexin 32 mutation,
which is an X-linked neuropathy, and the mitofusin mutation, which causes progressive
distal wasting and weakness
with milder involvement of
sensation.
An important practical
point is that patients with
inherited peripheral neuropathies might be susceptible
to adverse effects on the
peripheral nervous system if
they are exposed to the medications shown in table 3
(Medications associated with
peripheral neuropathy, page
36). There is no proven therapy for hereditary neuropathies, although foot
surgery to correct deformities
may be helpful, particularly in
children.

Demyelinating
neuropathies
Guillain-Barr syndrome is an
acute motor-sensory neuropathy that develops most commonly over 1-3 weeks. It
affects children and adults of
all ages. About half of patients
report a preceding respiratory
or GI illness.
Although the classic description is of an ascending
polyneuropathy often with

patients with IgG and IgA

monoclonal bands.

Impaired glucose tolerance

and diabetic neuropathy

Within a few days, a key finding on

examination in acute Guillain-Barr
syndrome is areflexia.

Although only
about 15% of
patients with
diabetes have
symptoms and
signs of
neuropathy,
subclinical
involvement
may be found
in up to 50%.

prominent sensory symptoms,

proximal muscles may be
involved early and the weakness usually develops rapidly,
so that atrophy is not found.
Within a few days, a key
finding on examination is
areflexia. Lumbar puncture
may show an elevated CSF
protein
level,
often
>1000mg/dL, particularly if
performed after the first
week.
Admission to hospital is
warranted for all but mild
cases, given the potential
progression. Up to 25% of
cases require admission to
an ICU, although in more
than 90% the prognosis is
favourable for a normal
recovery or minimal symptoms.
Occasionally a prolonged
course with axonal degeneration occurs, and morbidity
and mortality may occur in
the severely affected. The
condition responds to IV
immunoglobulin or plasma
exchange.
The chronic form of Guillain-Barr syndrome is called
chronic
inflammatory
demyelinating polyradiculoneuropathy (CIDP). This
form is less common but is
usually slowly progressive
(occasionally relapsingremitting), with motor and
sensory involvement. The

disease is insidious in onset,

usually without an antecedent illness. Areflexia is a
key finding on examination.
The CSF protein level is elevated in most cases, and
NCS show a demyelinating
picture. Occasionally a sural
nerve biopsy is required to
confirm the diagnosis.
Most cases respond
favourably to prednisone, but
long-term steroid-sparing
agents such as azathioprine
and methotrexate are usually
required. Many patients
respond well to plasma
exchange or IV immunoglobulin, although these therapies
are usually reserved for more
severe disease.
A similar neuropathy to
CIDP occurs with serum
paraprotein bands. In most
cases the association is with
monoclonal gammopathy of
unknown
significance
(MGUS), although multiple
myeloma and polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy and skin
changes (POEMS) syndrome
need to be distinguished.
The neuropathy of monoclonal gammopathy usually
affects males from the sixth
and seventh decades, with a
slowly progressive course.
Plasma exchange may be of
benefit, especially for

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Diabetes is associated with different clinical syndromes of

peripheral neuropathy. The
distal,
symmetrical,
sensory-greater-than-motor
neuropathy is the most commonly recognised neuropathy
of diabetes and is associated
with retinopathy.
Other forms of neuropathy
occasionally seen in patients
with diabetes are:
A painful, asymmetric proximal plexopathy (also called
diabetic amyotrophy).
Mononeuritis multiplex.
Pure autonomic neuropathy
(involving
sphincter
function and circulatory
reflexes).
Painful thoracoabdominal
radiculopathy.
Diabetic cranial neuropathies
(usually ophthalmoplegia).
Recently the association of a
predominantly sensory neuropathy with impaired glucose
tolerance has become clearer.
Although only about 15%
of patients with diabetes have
symptoms and signs of a neuropathy, subclinical involvement may be found in up to
50%. Neuropathy is most
commonly found in people
over 50 with diabetes. Good
long-term control of diabetes is
important for preventing progression and strict glucose control may reduce painful neuropathic symptoms.

Common chronic
peripheral entrapment
mononeuropathies
Carpal tunnel syndrome due
to compression of the median
nerve at the wrist results in
characteristic numbness of the
hand at night. This usually
responds well to decompression of the transverse wrist ligament.
Compression of the ulnar
nerve in the cubital tunnel at
the elbow (or less commonly
in Guyons canal at the wrist)
produces sensory change in the
fifth finger and half of the
fourth finger and clawing of

the hand. Surgery is less clearly

of benefit for ulnar nerve compression at the elbow, but
demonstration of a block on
NCS may help predict success
after surgery.
Meralgia paraesthetica
results from compression of
the lateral femoral cutaneous
nerve of the thigh, producing
numbness over the lateral
thigh. Weight loss is of benefit.
Surgery to relieve the compression is rarely helpful.
Posterior interosseous neuropathy (a branch of the radial
nerve) produces a wrist drop.
Most cases are idiopathic
although compression from
the supinator muscle is implicated in some patients.
Foot drop results from
common peroneal (fibular)
nerve entrapment at the head
of the fibula. It needs to be distinguished from more proximal causes such as a L5
radiculopathy. Care is needed
to avoid this neuropathy in
immobilised patients. Rarely
surgical decompression is helpful.

Neuropathy associated
with systemic disease
Besides diabetes, progressive
sensorimotor neuropathies can
be associated with systemic
disease. Carcinomas and lymphomas are associated with
neuropathies either through
direct infiltration or as a paraneoplastic phenomenon.
Vasculitic disorders often
involve the peripheral nervous
system although this varies
with the disease. Neuropathy
is relatively commonly seen in
Churg-Strauss syndrome, polyarteritis nodosa, Sjgrens
syndrome and rheumatoid
arthritis, whereas Wegeners
granulomatosis and SLE are
uncommonly associated with a
neuropathy.
The pattern in vasculitic
neuropathy is classically that
of a mononeuritis multiplex,
but in practice a distal sensorimotor pattern of neuropathy is
not uncommon. Occasionally
a vasculitis can be confined to
the peripheral nerves. A raised
ESR and C-reactive protein
may be a clue.

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How to treat peripheral neuropathy

Treatment and prognosis
NEUROPATHIES are very
rarely curable. CIDP responds
to immunosuppression or
immunomodulation (IV
immunoglobulin or plasma
exchange). Paraproteinaemic
neuropathy and vasculitic
neuropathies respond to
immunosuppression. Vitamin
deficiencies respond to supplementation.
The focus on treatment of
neuropathies is usually on
reducing exposure to the
cause. Peripheral neuropathies
rarely lead to mortality. The
mainstay of treatment is minimising the associated comorbidity.

Most patients require more than

simple analgesics (aspirin,
paracetamol or NSAIDs).

For many, the disability associated with a neuropathy is a

major concern. When foot
drop and difficulty with walking occurs, an ankle-foot
orthotic device can prevent
falls and allow a normal gait.
Assessment by physiotherapists and occupational therapists may help some patients.

Common clinical course

Pain management
Regardless of the underlying
cause, management of neuropathic pain is identical. There
are different approaches to
management of pain but most
approaches rarely provide
complete relief. Most patients
require more than simple
analgesics (aspirin, paracetamol or NSAIDs).
A non-pharmacological
approach to pain management is important. Good
footwear and the use of foot
creams that maintain the
health of skin prevent complications and are a useful
place to start. Management
of infection and ulcers is
important to prevent more
widespread complications.
Physical therapies, TENS,
acupuncture and hypnosis
may reduce the perception of
pain.
Several different pharmacological classes of medication have been shown to be
safe and effective in managing neuropathic pain. An
older therapy is the tricyclic
antidepressants (amitriptyline
[Endep] or nortriptyline [Allegron]) which are often beneficial, particularly if sleep is disrupted by pain. Their use may
be limited by daytime drowsiness or dry mouth. A dose of
10mg at night with 10mg
increments after five days is a
commonly used regimen.
Often two or more weeks are
required for assessment of
pain relief.
Sodium-channel blockers

Disability

are now rarely used for

managing neuropathic pain,
although occasionally carbamazepine 100mg bd is effective. Carbamazepine remains
first line for conditions such
as trigeminal neuralgia.
Mexiletine, structurally
similar to lignocaine, may be
of benefit for sharp lancinating pain. Mexiletine may
exacerbate cardiac arrhythmias and is usually reserved
for use by pain specialists
when other therapies have
failed.
Gabapentin (eg, Neurontin)
and pregabalin (Lyrica) are
newer agents with proven
efficacy in clinical trials, particularly with painful diabetic
neuropathy. The favourable
side effect profile has encouraged their widespread use.
However, neither have PBS
reimbursement for neuropathic pain.
A typical dose regimen for
gabapentin of 300mg tds
costs about $100/month,
although many pain specialists, neurologists and rehabilitation specialists are able to
prescribe these drugs through
the
hospital
system.
Gabapentin is usually started
at 100mg or 300mg daily and
then, for either strength,
increased by one tablet every

three days. The maximum

dose is 3600mg per day in
divided doses.
Weight gain, drowsiness
and GI symptoms are infrequently reported with
gabapentin. Most patients
with idiopathic, painful
peripheral neuropathies
report a modest benefit from
gabapentin or pregabalin.
Tramadol, a non-narcotic
centrally acting analgesic,
appears modestly effective for
some patients with neuropathic pain, with evidence
derived from diabetes studies.
Topical therapies such as
analgesic creams and capsaicin are occasionally helpful. Capsaicin is believed to
produce relief of pain by
depleting substance P in sensory terminals, and is usually
applied 3-4 times a day.
EMLA cream may provide
relief from painful feet or
focal neuropathic pain.
Narcotics are rarely of benefit for managing chronic
pain associated with a neuropathy. However, oxycodone has been shown to be
of benefit for post-herpetic
neuralgia.
Chronic pain leads to
altered illness behaviour and
treatment of associated
depression may be important.

Most chronic, idiopathic sensory-predominant

neuropathies that occur after age
30 run an indolent or slowly
progressive course. For most,
the description of a gloveand-stocking neuropathy
describes the distribution of
symptoms.
While many patients wish
to know the clinical course
and whether they will end
up in a wheelchair, they can
be reassured that this outcome is relatively uncommon.
Often a cause for a progressive neuropathy is identified
and therapy can change the
outcome.

Areas of clinical
controversy
Some clinical entities remain
of uncertain significance. The
tarsal tunnel syndrome, in
which compression of the
tibial nerve occurs at the
medial ankle (similar to the
carpal tunnel syndrome), is
believed to cause burning
pain in the toes and sole of
the foot.
Percussion at the medial
ankle is occasionally able to
reproduce the symptoms, and
NCS may show a block.
However, it is less clear that
surgery is of benefit and many
cases are probably due to
more proximal or distal
causes.
Thoracic outlet syndrome
(compression of the lower
trunk of the brachial plexus
as it passes above a cervical
rib or rudimentary ligament)
very rarely causes a true neurogenic syndrome in which
wasting of the thenar eminence and clawing of the
hand occurs, usually with illdefined numbness along the
medial forearm and hand.

Summary
Peripheral neuropathy describes motor or sensory symptoms
and signs that result from dysfunction of axons or the
surrounding myelin sheath.
While the cause of a neuropathy can often be identified, even
in specialised neuropathy clinics 25% of neuropathies remain
idiopathic.
There are many different classifications of neuropathies,
which are variably helpful for individual patients. One
classification is separation into small- and large-nerve-fibre
disorders, with the latter then divided into those disorders
affecting motor, sensory or both types of nerves.
Neuropathies are rarely curable; the focus is usually on managing pain and the disability that arises.

Evidence-based practice
Acute (Guillain-Barr syndrome), chronic inflammatory
demyelinating polyradiculoneuropathy, and multifocal
motor neuropathy, have evidence of benefit using
immunomodulatory therapy. For many other types of
neuropathy, randomised trials are needed.
There is no effective therapy for hereditary neuropathies
besides surgery to correct deformity.
Surgical treatment of overt carpal tunnel syndrome is more
effective than simple therapies such as splinting. The
evidence is less clearly established for other compressive
neuropathies.
There is level A evidence for the efficacy of tricyclic antidepressants, gabapentin and pregabalin in neuropathic pain.
However, most of the randomised controlled trials of neuropathic pain were limited to patients with postherpetic neuralgia
and diabetic neuropathies. Some conditions, such as HIVassociated polyneuropathy, are recognised as more refractory.

NCS define the lesion and

there is a favourable response
to surgery. Far more commonly encountered is a syndrome of pain along the
medial forearm and hand, for
which surgery is of doubtful
benefit.

Areas of research
controversy
The physiological basis for
many neuropathies remains
unknown. Even the mechanism of many of the diabetic
variants is poorly understood.
The cause of pain in peripheral neuropathies is not clear.
For example, there is no clinicopathological difference
between painful and nonpainful diabetic neuropathy,
and no correlation between
sural nerve biopsy specimens
and pain descriptions.
Besides an association with
autonomic changes, reflex sympathetic dystrophy (or causalgia) remains an unknown
entity, particularly in the
absence of nerve dysfunction.

Authors case studies

Like after you have been at the
dentist
A 58-YEAR-old woman had noticed
loss of sensation in both feet, which
began in the toes. Some discomfort
was present, which she described as
tingling, like the sensation in your
mouth after you have been at the
dentist. There was no weakness or
balance difficulties.
The patient was in otherwise good
health and taking no regular medications. She was unsure of any
family history of neurological symptoms. Her examination showed
normal strength, reflexes and sensory examination, with subjective
diminution/alteration in pin-prick

38

| Australian Doctor | 16 May 2008

and light touch below the ankle level

bilaterally.
Provisional clinical diagnosis was
idiopathic small-fibre neuropathy.
This neuropathy is usually relatively benign, without progressive
disability. Management of pain is
usually the focus of treatment.

Further reading
Dyck PJ, et al (editors).
Peripheral Neuropathy. 2nd
edn. WB Saunders,
Philadelphia, 1993.

Online resources

An inherited neuropathy?
A 22-year-old man complained of
poor balance and difficulties playing
tennis, perhaps increased at night. The
symptoms had been noticed for five
years and were slowly progressing.
On examination, pes cavus was
noted, along with the patients
inability to stand on his heels. There

was loss of vibration at the hallux

and reduced sensation to pin-prick
to the ankle level. On specific questioning, a sister had been investigated
for a neuropathy.
Provisional diagnosis was CharcotMarie-Tooth type I (inherited neuropathy genetic testing is available).
www.australiandoctor.com.au

This is the most common inherited neuropathy and usually gradual

disability occurs over time. Many
patients will not require wheelchair
assistance, in distinction from other
inherited neuropathies. There is no
specific treatment, but there may be
genetic implications.

A useful reference for

inherited neuropathies is
the genetic web site
Online Inheritance in
Man:
www.ncbi.nlm.nih.gov/
Omim

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How to treat peripheral neuropathy

GPs contribution
Case study

DR MATILDA METLEDGE
Sydney, NSW

answer; mild peripheral discomfort less so.

On examination, testing
of the ankle reflexes may
show loss if there is largefibre involvement, but the
description favours predominant involvement of
small-nerve fibres testing
of pain and temperature
may be helpful. Given the
patients age, testing of
vibration may not be reliable. Secondary depression
and the effect on sleep may
be worth considering, as
symptoms are usually not
described as excruciating.

MRS H, 82, complains of

long-term burning in her
feet at night. The burning
wakes her from sleep, is
mainly in the soles and toes,
and when the sheets touch
them it is excruciatingly
painful. At times she has
placed a cold foot bath near
the bed in an attempt to get
some relief. Walking is very
painful if she gets up during
the night.
Besides hypertension and
osteoarthritis she is in reasonably good health. There
are no symptoms during the
day and examination of the
foot is normal.

Questions for the author

These symptoms seem to be
common in the elderly
regardless of diabetic status.
Could you describe your
approach to assessment of
these types of cases?
The severity of symptoms,
degree of disability and an

elderly patients comorbidities guide the approach to

management and need for

How to Treat Quiz

2. Which TWO statements regarding

aetiology and classification of peripheral
neuropathies are correct?
a) The cause of a peripheral neuropathy can be
identified in about 90% of cases
b) Small-fibre neuropathies usually cause pain
and discomfort and are associated with
absent ankle reflexes
c) Large-fibre neuropathies usually also involve
small-nerve fibres
d) Large-fibre neuropathies can be divided into
neuropathies that are predominantly motor or
sensory, and those that involve both motor
and sensory function
3. Which TWO statements regarding
nutritional neuropathies are correct?
a) Alcohol abuse is one of the more common
causes of peripheral neuropathies seen in
general practice
b) Vitamin B12 deficiency produces a sensory

What is your approach to

management of these types
of cases?
Given the patients age,
management may need to
be carefully considered. If
simple therapies and physical care of the feet are
unhelpful, pharmacological
therapy may be required. I
would be cautious of using
amitriptyline because of the
anti-cholinergic side effects,
but 10mg at night might
just improve the neuropathic symptoms and her
sleep. Equally, gabapentin
may well be effective for
this patient.

INSTRUCTIONS
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by post or fax.
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answer.

Peripheral neuropathy
16 May 2008
1. Which TWO statements regarding the
pathophysiology of peripheral neuropathies
are correct?
a) Myelinated nerve fibres are slower-conducting
nerve fibres that carry autonomic and sensory
information
b) Neuropathies occur when there is dysfunction
of the axon or the surrounding protective
myelin sheath
c) Recovery is slower if the pathological process
is demyelination rather than axonal damage
d) Most idiopathic and inherited neuropathies
are length dependent, with neurotransmission
failing at the end of nerves

referral to a neurologist.
Motor symptoms or balance
difficulties require an

Are there specific clues you

would use to differentiate
between vascular and neurological causes?
This clinical picture
favours an idiopathic sensory neuropathy. Occasionally it can be hard to separate these two causes if the
problem is peripheral pain
and overlap does exist, for

example, in diabetes. The

nature of symptoms is
important, as described in
this article, but the examination may also be helpful,
particularly looking for
trophic changes, testing of
the ankle reflex and pain
and temperature pathways
and the peripheral pulses.

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neuropathy
c) Dietary deficiency of pyridoxine (vitamin B6) is
a common cause of peripheral neuropathy
d) Nicotinic acid (niacin) deficiency produces a
distal sensorimotor neuropathy that is easily
distinguishable from the neuropathy of
thiamine deficiency
4. Which TWO statements regarding initial
presentations of peripheral neuropathies are
correct?
a) Motor symptoms are the most common
presentation of a peripheral neuropathy
b) In general, most sensory neuropathies are
length dependent, with feet involved before
hands
c) Most motor symptoms begin as gait and
balance difficulties
d) Loss of sweating due to autonomic
dysfunction is frequently recognised by
patients
5. Which TWO statements regarding
assessment of a patient with a possible
peripheral neuropathy are correct?
a) A sensory pattern commonly found in many
neuropathies is predominant involvement of
vibration and joint-position sense
b) Loss of muscle strength is usually an early
sign in most peripheral neuropathies
c) A positive Rombergs test represents loss of
joint-position sense
d) The ankle reflex may be absent in both
sensory and motor neuropathies
6. Which TWO statements regarding nerve

conduction studies (NCS) are correct?

a) NCS are useful in both large- and small-fibre
neuropathies
b) NCS can be used to assess the size and
speed of sensory, but not motor, responses
c) NCS can distinguish demyelinating
neuropathies from axonal neuropathies
d) In conjunction with electromyography, NCS
may be helpful in distinguishing neuropathies
from disorders of the neuromuscular junction
and muscle
7. Tom, 65, presents with an acute motorsensory neuropathy. After initial assessment
you suspect Guillain-Barr syndrome (GBS).
Which TWO statements about GBS are
correct?
a) About half of patients with GBS report a
preceding respiratory or GI illness
b) Proximal muscle weakness is always a late
sign in acute GBS
c) A key finding on examination in GBS is
areflexia
d) About 25% of cases of acute GBS require
admission to hospital
8. John, 55, has type 1 diabetes. Which TWO
statements regarding diabetic neuropathy
are correct?
a) About 10% of patients with diabetes have
clinical evidence of neuropathy, although
subclinical involvement may be found in up to
25%
b) The most commonly recognised neuropathy
of diabetes is the painful, asymmetric,
proximal plexopathy (diabetic amyotrophy)

c) Patients with diabetes occasionally may have

a pure autonomic neuropathy
d) Good long-term control of diabetes is
important for preventing progression of
diabetic neuropathy
9. Which TWO statements regarding chronic
peripheral entrapment mononeuropathies are
correct?
a) Surgical treatment of carpal tunnel syndrome
is no more effective than splinting
b) Wrist drop occurs as a result of neuropathy of
the posterior interosseous branch of the
median nerve
c) Weight loss may be of benefit in meralgia
paraesthetica (numbness due to compression
of the lateral femoral cutaneous nerve of the
thigh)
d) Foot drop may result from entrapment of the
common peroneal nerve at the head of the
fibula, but needs to be distinguished from
more proximal causes
10. Which TWO statements regarding the
management of peripheral neuropathies are
correct?
a) Neuropathies are rarely curable, so the focus
usually is on managing pain and the disability
that arises
b) A non-pharmacological approach to pain
management is important
c) Most patients with neuropathic pain can be
adequately treated with simple analgesics
(aspirin, paracetamol or NSAIDs)
d) Narcotic analgesics are very useful in the
management of neuropathic pain

CPD QUIZ UPDATE

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can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post
and fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.

HOW TO TREAT Editor: Dr Martine Walker

Co-ordinator: Julian McAllan
Quiz: Dr Wendy Morgan

NEXT WEEK To coincide with the newly released ninth edition of the Australian Immunisation Handbook, next weeks How to Treat presents an aid to help GPs maintain currency with the latest immunisation
guidelines. The authors are Dr Joanne Molloy, GP in Geelong, Victoria; Medical Officer of Health for the City of Greater Geelong; manager of the immunisation program for the GP Association of Geelong;
and member of the Australian Technical Advisory Group on Immunisation (ATAGI), and Professor Terry Nolan, head, Melbourne school of population health, University of Melbourne; head, vaccine and
immunisation research group, Murdoch Childrens Research Institute and MSPH; chair of ATAGI; and general paediatrician at the Royal Childrens Hospital, Melbourne, Victoria.

40

| Australian Doctor | 16 May 2008

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