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Peripheral neuropathy: clinical features and management

Peripheral neuropathy describes damage to the peripheral nervous system. This article discusses how peripheral neuropathy is assessed and managed.

Peripheral neuropathy describes damage to the peripheral nervous system, which transmits information from the brain and spinal cord to every other part of the body. It is common, particularly among the elderly, with an overall prevalence of approximately 2,400 per 100,000 (2·4 per cent) of the population. In people older than 55 years, the prevalence rises to about 8,000 per 100 000 (eight per cent)1.

Worldwide, leprosy remains the primary cause of treatable neuropathy2. In the developed world, common causes of peripheral neuropathy in the elderly population include diabetes (27 per cent), neoplasms causing a paraneoplastic syndrome (13 per cent) and also Guillain-Barré syndrome (GBS) (11 per cent). No specific cause is identified, however, in 28 per cent of patients3.

Undiagnosed and untreated, neuropathy may contribute to foot pain, ulceration, deformity, and falls. However, the clinical recognition of peripheral neuropathy in the elderly is challenging. This is because the history may be unreliable, particularly in cognitively impaired patients, and because peripheral neurological deficits such as absent ankle jerks are commonly found on routine examination. Also with the absence of symptoms, minor changes in peripheral nervous function may not be clinically significant as these changes are usually detected clinically, anatomically, and electrophysiologically among elderly persons4.

Older patients also often have multiple neurological pathologies that confound the diagnostic process. Common co-existing conditions include Chronic Idiopathic Sensory Axonal Polyneuropathy (CIAP) and cervical spondylotic myelopathy. A structured diagnostic approach can however increase the diagnostic yield. Dyck et al described a methodology based on clinical pattern of neuropathy to help guide investigations. This is called ‘the 10 P’s for characterising peripheral neuropathy’ (Table 1)5. Other authors have suggested the use of algorithms.6

Table 1: The 10 P’s for characterising peripheral neuropathy5

  1. Pattern: anatomic and temporal
  2. Population of neurons
  3. Part of neuron assumed to be the primary site of pathological abnormality
  4. Physiology
  5. Pathology
  6. Prickling
  7. Phenomena: toxic exposures, diseases, or signs
  8. Pedigree
  9. Plasma: laboratory abnormalities
  10. Pharmacology: response to therapies.

Clinical features of peripheral neuropathy

Below are various clinical features that can aid in identifying the cause of peripheral neuropathy.

Time course of symptoms

Neuropathies can be divided according to the time course of symptoms. These are:

  • Acute with an onset over days (up to 28 days) e.g. GBS, vasculitic neuropathy
  • Subacute with an onset over four to eight weeks e.g. paraneoplastic
  • Chronic progression for more than eight weeks e.g. CIDP.


Neuropathy patients present with either positive symptoms such as allodynia, dysaesthesias, hyperaesthesias or paraesthesias (Table 1) or negative symptoms such as numbness. The presence of pain suggests a number of aetiologies. The association of severe pain and dysautonomia raises the possibility of amyloidosis; although other disorders, including diabetes, can produce a similar picture. Altered sensation to pain and temperature (in association with painful dysaesthesias and autonomic dysfunction) are characteristic of small fibre neuropathies. These conditions may have few objective signs on neurological examination. Deep tendon reflexes are often preserved, as are balance and the motor function. In contrast, the neurological examination is typically abnormal in patients with large fibre neuropathies.

Pain may not be reported by older persons with cognitive impairments. Even when elderly patients can indicate pain, they may have difficulty describing its characteristics. A multifaceted approach to pain assessment using a combination of self-report measures, family or caregiver input, and measures of functional impairment, can improve the accuracy of pain assessment7.

Prominent motor symptoms

Few neuropathies have pure motor involvement. The distribution of weakness is helpful in refining the differential diagnosis. Symmetric distal weakness raises the possibility of an inherited aetiology such as Hereditary Motor and Sensory Neuropathy (HMSN); other possibilities include porphyria and less often lead poisoning. Proximal motor involvement usually suggests either plexus or root involvement. GBS, polyradiculoneuropathy, (acute form), acute motor axonal neuropathy and CIDP are the most frequent cause of motor neuropathies. Although CIDP and GBS are usually associated with minor sensory symptoms and signs. The rate of progression can also help distinguish HMSN from demyelinating and toxic neuropathies because the former is slowly progressive, whereas the latter two have a subacute and progressive course.

Asymmetric distal motor weakness suggests Motor Neuron Disease (MND) or Multifocal Motor Neuropathy (MMN). The former is associated with muscle atrophy, fasciculations and brisk deep tendon reflexes, whereas MMN causes asymmetric upper extremity weakness, often without significant atrophy.

Nerve conduction studies (see investigations for further information) in MMN typically reveal partial motor conduction block and/or abnormal temporal dispersion but relatively little denervation. These findings are helpful in differentiating MMN from MND as in MND there is marked denervation without conduction block.

Prominent sensory symptoms

The most common sensory neuropathy in the developing world is leprosy, but pure sensory neuropathies or neuronopathies (ganglionopathy) are uncommon in the UK. The distribution of sensory loss though may be helpful in the differential diagnosis. For example, proximal spread and asymmetric sensory loss suggests inflammatory dorsal root ganglionopathy and narrows the differential diagnosis to paraneoplastic neuropathy, Sjögren’s syndrome, or idiopathic causation. Also, the presence of keratoconjuctivitis sicca and xerostomia associated with a predominantly sensory neuropathy (with or without multifocal features or cranial neuropathies) are considered classical findings of Sjögren’s syndrome. And the Miller Fisher variant of GBS is distinguished from classical GBS by its acute onset, ophthalmoplegia, sensory ataxia and areflexia.

A challenging diagnosis however is the antiHu paraneoplastic syndrome, which is generally associated with small cell lung cancer. Individuals with risk factors for carcinoma of the lung should be screened routinely with chest radiographs and subsequently with computed tomography/positron emission tomography because sensory neuronopathy and the demonstration of anti-Hu antibodies frequently precede the detection of cancer.

In addition, approximately three per cent of the population over 70 years has Monoclonal Gammopathy of Unknown Significance (MGUS) compared with up to 10 per cent of patients with neuropathy8. There is a distinct group of distal demyelinating neuropathies associated with MGUS (e.g. distal acquired demyelinating symmetric neuropathy), which presents with predominantly large fibre sensory neuropathies, sensory ataxia and action tremor of upper limbs. When present, weakness is predominantly distal and develops months to years later than the sensory symptoms.

Proximal and distal mixed sensorimotor neuropathies

Identification of proximal involvement in any sensorimotor neuropathy should generate an element of anticipation from the clinician, and these neuropathies are treatable. Proximal and distal sensorimotor neuropathies may be further subclassified as symmetric or asymmetric. GBS and CIDP generally present symmetrically. The duration of symptoms, the temporal profile, and the electrophysiological findings differentiate these two entities. Asymmetry in a neuropathy should always raise the possibility of an underlying vasculitis.

Autonomic nervous system involvement

This is seen in diabetes, familial and acquired amyloid neuropathy, GBS and porphyria.

Cranial nerve involvement

Involvement of the cranial nerves, particularly the facial nerve, may indicate diabetes, GBS, HIV, Lyme disease/brucellosis or sarcoidosis.

Table 1: Definitions of positive symptoms

  • Allodynia: Pain sensation induced by non-painful stimulus, further classified as dynamic (brush evoked) or static (pressure evoked)
  • Dysaesthesia: An abnormal or unpleasant sensation, whether spontaneous or evoked
  • Hyperaesthesia: An increased pain response to a stimulus which is normally painful
  • Paraesthesia: An abnormal, although not unpleasant sensation, whether spontaneous or evoked.


Clues in the past, family, occupational, and drug histories

It is important to establish whether the neuropathy is an isolated illness of peripheral nerve or if it occurs in the context of systemic disease. Therefore, concomitant systemic diseases should be noted, particularly organ failure, endocrine and connective tissue diseases. Diabetes, and impaired glucose tolerance should always be investigated with an oral glucose tolerance test as a fasting glucose test alone may be insensitive among patients with neuropathy9.

The clinical history is of crucial importance as it helps eliminate or identify potential nutritional disorders, toxic exposure, and hereditary disorders. A history of substantial weight loss, anaemia and fatigue may suggest an underlying malignancy or systemic disease. Taking a detailed family history though can be time-consuming, and toxic exposure in the workplace is now a rare cause of neuropathy in the developed world as the industrial environment has improved. However, a drug history is mandatory, and the list of prescribed medications resulting in neuropathy should be explored (Table 4). Many potential aetiologies can be eliminated based on a careful history and more focused and effective laboratory investigations that may include evaluation of fasting blood sugar, thyroid and renal functions, vitamin B12, serum protein electrophoresis and autoimmune studies.

Electrophysiological studies

Nerve conduction studies are the most informative part of the electrodiagnostic evaluation of peripheral neuropathy. They measure nerve conduction velocity and determine how well individual nerves can transmit electrical signals. Unlike a physical examination, nerve conduction studies require minimal subjective input from the patient. They can evaluate the severity and monitor any progression of a peripheral neuropathy.

Whereas, an electromyogram measures the electrical impulses of muscles at rest and during contraction. Denervation detected by electromyogram is a sensitive measure of motor nerve damage. Occasionally demonstrating a gradient between the tibialis anterior and quadriceps muscles suffices to support a length dependent neuropathy.

Other invasive investigations

Upon conclusion of the clinical and electrodiagnostic evaluation, a specific characterisation of neuropathy should emerge. The differential diagnostic list is relatively short under each type of neuropathy. At this point, a targeted series of laboratory tests may be ordered. cerebrospinal fluid (CSF) analysis may be useful to support CIDP because the CSF protein is frequently raised.

Other specialised studies, including sural nerve biopsy should be considered to exclude vasculitic neuropathy and skin biopsy may be occasionally required to confirm small fibre neuropathy. It is important to appreciate that a significant percentage (perhaps more than 50 per cent) of neuropathies will remain undiagnosed despite an exhaustive evaluation.


Peripheral neuropathy is common among older persons, and its detection is clinically relevant. It is hoped that clinicians will be able to use these findings to evaluate elderly patients more accurately. The related decline in peripheral nerve function is not a barrier to an efficient and rational clinical identification of peripheral neuropathy among older persons.

Dr Jia Haur Tho, Neurologist & Neurophysiologist

Dr Jeff Gawler, Consultant Neurologist, London


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