May 2007: Pinpointing peripheral neuropathies
What are the causes of peripheral neuropathies?
What investigations should be done in primary care?
How should GPs treat peripheral neuropathies?
What are the causes of peripheral neuropathies?
What investigations should be done in primary care?
How should GPs treat peripheral neuropathies?
Peripheral neuropathies are a common cause of disability, manifesting as motor and/or sensory impairment, pain, autonomic symptoms and orthopaedic complications. While the causes of peripheral neuropathy are legion, some neuropathies, such as diabetic neuropathy and carpal tunnel syndrome, are very common.
Peripheral neuropathies are often perceived as difficult to investigate, diagnose and treat, but much can be done in primary care to reduce the need for secondary or tertiary referral. Some neuropathies, however, are life-threatening emergencies, rare or difficult to manage. Many, especially the inflammatory and infectious neuropathies, are treatable.
Peripheral neuropathies are common. Diabetes, alcohol overuse, leprosy and HIV infection are the most common causes worldwide. Prevalence depends upon age and geography, but epidemiological studies estimate that 2.5-8% of the population have
a symptomatic peripheral neuropathy. Diabetic neuropathy is the most common peripheral neuropathy in the UK, with an annual incidence of 54 per 100,000 (compared with 205 per 100,000 for first stroke).1 Charcot-Marie-Tooth (CMT) disease has a prevalence of 1 in 2,500.
Clinical history and examination are the key to diagnosis. Patients with peripheral neuropathy usually present with dysfunction of motor, sensory or autonomic nerves. The typical presentation comprises slowly progressive, distal sensory alterations, weakness and wasting. Identification of the cause depends crucially upon a careful and complete history covering the areas discussed below and then assimilating the findings (table 1, below).
1 Temporal evolution
Acute (days up to 4 weeks, for example Guillain-Barré syndrome, vasculitis)
Subacute, such as vasculitis, paraneoplastic syndromes (4-8 weeks)
Chronic, for example chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (>8 weeks)
2 Which parts of the peripheral nervous system are involved?
Motor involvement: This may be proximal as well as distal if the roots are involved (radiculoneuropathy), as in CIDP. Myopathy and myasthenia are obvious differential diagnoses.
Sensory involvement: Acquired neuropathies often have positive sensory symptoms (pins and needles and/or pain – see table 2, attached). Patients with hereditary neuropathies may not recognise their sensory loss.
Small fibre involvement: This usually manifests as a painful burning or cold sensation which is worse at night.
3 Is the autonomic nervous system involved?
Autonomic dysfunction may cause postural light-headedness, impotence, bladder and bowel symptoms and occurs in diabetes, familial and acquired amyloid neuropathy, Guillain-Barré syndrome and porphyria.
4 Is there cranial nerve involvement?
Cranial nerve involvement, especially the facial nerve, may indicate sarcoidosis, Lyme disease, HIV, CIDP, Sjögren's syndrome, malignant infiltration or familial amyloid neuropathy.
5 Are there clues to a hereditary neuropathy in a detailed family history, symptoms since childhood or on examination?
A detailed family history across at least three generations is essential and often very rewarding. The patient will often have to do some research.
A negative family history does not rule out genetic disease: autosomal recessive, new mutations and non-paternity are all possible.
6 Are there signs or symptoms of coexistent disease?
Almost any disease may be relevant, including diabetes, alcohol overuse and connective tissue disease. Rashes, unexplained weight loss, fever and foreign travel could also be relevant. Occam's razor, often paraphrased as ‘the simplest solution tends to be the best' almost universally applies.
The examination should identify the findings expected following a careful history. The typical signs of advanced neuropathy, namely reduced tone, distal weakness and sensory loss and generalised areflexia, are not always found. Their presence is helpful but their absence does not exclude the diagnosis of a neuropathy. The signs may be focal, subtle or very specific.
The examination should include assessement of gait and involvement of cranial nerves and limbs, as well as a full general examination.2
• A foot drop gait or the inability to stand on toes or heels confirms distal weakness.
• Falling on eye closure (Romberg's sign) indicates large fibre (vibration and proprioceptive) sensory disturbance in the periperal nerves or spinal cord.
• Foot deformities such as pes cavus (see figure 2, below), clawing of the toes and scoliosis may be indicative of a hereditary neuropathy.
• Wasting and fasciculation are clues to axonal pathologies (such as diabetes, toxin exposure, vasculitis and hereditary axonal neuropathies), whereas tremor, weakness out of proportion to the degree of wasting, generalised areflexia and thickened nerves are clues to demyelination (for example CIDP).
• In small fibre neuropathies (for example in some cases of diabetes, HIV, amyloid, toxins and some hereditary neuropathies), damage is restricted to unmyelinated and small myelinated fibres; reflexes may be retained through sparing of the 1a afferent fibres.
• Impaired pupillary responses to light and accommodation and a postural drop in blood pressure after three minutes of standing may indicate autonomic involvement.
History and examination will identify the neuropathy, classify it as acute or chronic, symmetrical, patchy or focal, and pinpoint the peripheral areas involved. With this information, the GP can make decisions about whether to investigate and treat the patient in primary care or hospital.
The acute and multifocal neuropathies, which include Guillain-Barré syndrome and the vasculitides (see table 4, attached, and below), are diagnostic emergencies and usually require immediate or early hospital care.
For chronic neuropathies, investigations can be divided into first line (stage 1), second line (stage 2) and third line (stage 3) (see table 3, attached). All of the first-line investigations and most of the second-line investigations can be performed in primary care. If an initial history, examination and first-line investigations fail to reveal a cause the patient should be referred to a neurologist.
Third-line investigations rely upon the results of neurophysiological testing performed in stage 2. 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 is rapid (>50m/sec). In demyelinating neuropathy the distal motor latency is prolonged and nerve conduction velocity is 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. Neurophysiology may:
• Differentiate demyelinating (20% of neuropathies) from axonal neuropathies (80% of neuropathies)
• Identify features that differentiate hereditary from acquired neuropathy
• Detect clinically asymptomatic abnormalities
• Delineate symmetrical length-dependent neuropathies from asymmetric patchy neuropathies, with the latter suggesting a vasculitic or inflammatory aetiology.
Peripheral neuropathies: common and concerning
Peripheral neuropathies can be divided into acute symmetrical, acute asymmetrical (multifocal) and chronic.
Acute peripheral neuropathies
(a) Guillain-Barré syndrome: This is the most common cause of acute neuromuscular paralysis in the Western world, with an annual incidence of about 1 per 100,000 population in the UK. It can progress rapidly over days and may be fatal.
Gastroenteritis (especially that caused by Campylobacter jejuni), upper respiratory tract infection or non-specific viral illness may precede Guillain-Barré syndrome by 10-14 days in about 40-50% of cases. Patients present with ascending sensory loss and weakness, which progresses to flaccid paralysis over a few days.
Older patients may present following a fall. Reflexes may be retained in the first few days of the illness and some patients are wrongly dismissed as hysterical.
The onset of bulbar, neck or respiratory muscle weakness is a sign of impending respiratory failure.
Guillain-Barré syndrome is an autoimmune process, which in most cases in the Western world results in the destruction of myelin. Treatment in hospital with intravenous immunoglobulin arrests the process and leads to more rapid recovery.3 Plasma exchange is an alternative; steroids do not confer any benefit. Despite treatment, 5-8% of patients die and about one third of patients are left with significant residual disability. Fatigue is a very common and an under-recognised persistent problem.
(b) Vasculitis: Vasculitis most often presents with the sequential involvement of multiple peripheral nerves and is another medical emergency.4 Vasculitic neuropathy can occur in the context of a primary vasculitic condition (for example Churg-Strauss syndrome, polyarteritis nodosa or Wegener's granulomatosis) or connective tissue disease (rheumatoid arthritis, systemic lupus erythematosus) or as an isolated peripheral nerve condition.
Typically patients present with painful mononeuropathies, which may accrue over hours to weeks, sometimes in the context of systemic upset with weight loss, fever and indicators of other organ involvement. Neuropathies are frequently irreversible, and rapid aggressive treatment with high-dose steroids is necessary to prevent further damage. Tissue biopsy (nerve or other organ) to demonstrate the vessel changes is preferable before embarking on immunosuppressive therapy, as prolonged treatment with cyclophosphamide, methotrexate, azathioprine or other agents may be required.
Diabetic lumbosacral plexopathy (the Bruns-Garland syndrome), which presents with rapidly progressive focal wasting of quadriceps muscles in the context of pain, weight loss and poor glycaemic control, is also caused by vasculitis.5
(c) Other acute peripheral neuropathies: The other causes of acute peripheral neuropathy in table 4, above, are rare but need rapid investigation. All patients with acute neuropathies should be referred to hospital for investigation and treatment.
Chronic peripheral neuropathies
Chronic peripheral neuropathies can be divided into acquired and hereditary (CMT) forms. This initial distinction can often be made on the basis of the history and features found at examination alone. The clinical pattern of focal, multifocal or generalised neuropathy and a description of clinical symptoms or signs within the sensory, sensorimotor or motor systems assist in diagnosis. These neuropathies can be subdivided by neurophysiological testing into demyelinating or axonal forms, further aiding identification of the underlying cause (see figure 5, attached).
(a) Hereditary neuropathies (CMT disease): CMT has many forms.6 They may be autosomal dominant or recessive or X-linked. They may be subdivided further into demyelinating, axonal or intermediate on the basis of the electrophysiology. These distinctions assist in the search for the underlying genetic abnormality; currently more than 30 genes are known to cause CMT. Once identified, patients and their families can be informatively counselled about inheritance, phenotypic variation and penetrance and the course and prognosis of their condition.
CMT1a is the most common inherited neuropathy and accounts for the great majority of patients with CMT in the UK and Europe. Inheritance is autosomal dominant. Typically CMT presents in the second or third decade with pes cavus (see figure 2, above), distal weakness and wasting affecting the lower limbs (inverted champagne bottles) more than the upper limbs, and is slowly progressive. The mutation is a duplication of the peripheral myelin protein 22 (PMP22) gene on chromosome 17, deletion of which causes hereditary neuropathy with liability to pressure palsies (HNPP).
CMT2 covers the group of autosomal dominant sensorimotor axonal neuropathies. Until recently few of these neuropathies had an identified underlying genetic abnormality. The group of diseases termed CMT4 are autosomal recessive and are more common in populations with a high degree of familial intermarriage.
Rare hereditary neuropathies affect sensory (HSN), sensory and autonomic (HSAN) and motor (HMN) nerves only.
(b) Chronic acquired neuropathies: The most common types of chronic acquired neuropathies are shown in figure 5, attached. Demyelinating neuropathies are relatively uncommon and encompass CIDP, neuropathies associated with a serum paraprotein, multifocal motor neuropathy with conduction block (MMNCB), early entrapment neuropathies and the demyelinating neuropathy associated with amiodarone. Diabetic neuropathies can sometimes have demyelinating features.
The chronic demyelinating neuropathies are largely treatable. CIDP occurs with a prevalence of at least 2 per 100,000 and is a cause of significant disability. It responds to treatment with steroids, intravenous immunoglobulin, plasma exchange and some other immunomodulatory agents. MMNCB is closely related but responds only to intravenous immunoglobulin.
Entrapment neuropathies (carpal tunnel syndrome, ulnar and peroneal neuropathies and meralgia paraesthetica [see figure 1, above]) respond to reversal of the cause if pressure is implicated, but may need surgical exploration and release.
Although neuropathies caused by toxins (including sugar) are less responsive to intervention, removal or control of the cause may lead to amelioration of some of the symptoms.
The chronic axonal neuropathies constitute a large group of conditions. Identification and removal of the cause may stabilise or reverse the neuropathy, thus full investigation is warranted. In about 25 per cent of cases no cause is found. These chronic idiopathic axonal neuropathies (CIAN) are frequently indolent or static and patients can be reassured that they are unlikely to progress.
Small fibre neuropathies cause considerable morbidity and distress as their main symptom is pain.7 This is frequently described as a painful burning or cold sensation, which is often worse at night and may disturb sleep. The only signs are distal loss of pain and temperature sensation with preserved power and reflexes. In 50% of small fibre neuropathies the cause remains unknown, but an oral glucose tolerance test is essential to rule out impaired glucose tolerance, which can be treated.
Any identified underlying cause of a neuropathy, such as diabetes, vitamin B
12 deficiency, drugs or toxins, should be treated as appropriate. It is particularly important to identify CIDP and MMNCB as they are treatable and usually respond well to intervention. Unfortunately no treatments are available for CIAN. Pain may be difficult to treat but amitriptyline, duloxetine, gabapentin, pregabalin and opioid analgesia alone or in combination have been shown to be effective.8
Where orthopaedic complications exist as a result of hereditary neuropathies, physicians are recommended to seek the advice of expert centres before embarking upon local surgical corrective procedures.
Patients with peripheral neuropathy have a multitude of needs which are unique to each individual. Foot care, weight reduction, sensible shoes, ankle foot orthoses and walking aids may be appropriate, and upper limb devices such as adapted eating utensils, writing implements and wrist splints may be invaluable. Assessments by occupational therapists and physiotherapists, either alone or as part of a multidisciplinary team, can be very useful in identifying needs. Patients should be advised to seek driving advice from the DVLA if limb function is limited, as government assistance is available for those with significant disability.Key points Table 2: Sensory terminology Table 3: Investigations in peripheral neuropathies Figure 5: Diagnosis of chronic peripheral nerve disorders* Peripheral neuropathy table 1 Table 1 Peripheral table 4 Table 4 Author
Dr Michael PT Lunn
consultant neurologist, National Hospital for Neurology and Neurosurgery, London
A distinct ‘pocket-shaped' area of sensory loss appears which may be numb, itch or burn;Figure 1 Figure 2: Pes cavus is common in longstanding generalised foot weakness, as occurs in the hereditary neuropathies. The high lateral arch and clawing of the toes are typical Figure 2