Polyneuropathies

Notes

Overview

Polyneuropathy refers to damage or dysfunction of multiple nerves of the peripheral nervous system.

Polyneuropathy is a broad term that refers to the involvement of multiple peripheral nerves. It is a type of peripheral neuropathy and the two terms are often used synonymously. However, this is imprecise as there are many different types of peripheral neuropathy (e.g. radiculopathy, mononeuropathy) that simply refers to damage or dysfunction of peripheral nerves.

Polyneuropathies typically lead to symmetrical involvement of distal peripheral nerves in a ‘length-dependent’ manner, meaning the longer nerves of the legs and arms are affected first. Symptoms are usually those of sensory loss, paraesthesia, and/or weakness. There are numerous causes of polyneuropathy and they can be subdivided in many ways:

  • Acute versus chronic: refers to the time of onset
  • Demyelinating versus axonal: refers to the mechanism of nerve damage
  • Sensory versus motor: refers to the primary symptoms

Here, we give an overview of polyneuropathies including some of the most common causes. For more generalised information on the peripheral neuropathies see our Peripheral neuropathy note.

Epidemiology

The actual incidence and prevalence of polyneuropathy depends on the underlying cause.

Determining the epidemiology of polyneuropathy depends on the underlying cause. In one broad cohort looking at an unselected population, the prevalence of chronic polyneuropathy in middle-aged and elderly adults was 4%.

Diabetes mellitus is the most common cause of polyneuropathy in the Western world with an estimated 50% of patients developing the condition during the course of their illness. On the contrary, Guillain-Barré syndrome, which can lead to a life-threatening acute, progressive polyneuropathy, is a rare cause occurring at an incidence of 0.6-1.9 per 100,000 population.

Classification

There are many terms used to describe polyneuropathies that help classify them into groups.

There are numerous types of polyneuropathy that may affect the peripheral nerves in different ways. This can lead to different patterns of presentation. We can broadly classify polyneuropathies by the onset, pathology, clinical presentation, or even based on the size of the nerve fibres.

Onset

A polyneuropathy may present acutely and be rapidly progressive. Alternatively, it may be chronic and slowly worsen over time. The concern with acute polyneuropathies is that they may ascend affecting nerves more proximally that eventually leads to disruption of respiratory function.

  • Acute: Rapid progression from onset to worst clinical features within 4 weeks. Typical examples include Guillain-Barré syndrome, vasculitis, certain toxins, or critical illness.
  • Chronic: This is the stereotypical presentation of polyneuropathy that occurs over many weeks, months or even years. Typical examples include diabetes mellitus, chronic kidney disease, hereditary neuropathies and alcohol excess

NOTE: Occasionally, polyneuropathies may be described as subacute with progression to the worst symptoms over 4-8 weeks.

Pathology

The two main patterns of pathology in polyneuropathies are demyelination and axonal damage. Occasionally, there may be a mixture of these pathologies.

  • Demyelination: refers to damage to the myelin sheath that insulates nerves and improves conduction. Classic causes of demyelinating polyneuropathy are autoimmune diseases, hereditary causes or myeloma
  • Axonal degeneration: refers to damage to the nerve axon that extends from the cell body and transmits electrical conduction. Classic causes of axonal polyneuropathy include systemic diseases (e.g. diabetes mellitus, connective tissue disease, vitamin B12 deficiency)

Beware that while the pattern of pathology can be used to differentiate causes of polyneuropathy, diseases can present in more than one way. For example, diabetes mellitus is usually axonal, but demyelinating forms can occur.

Clinical presentation

There are two main patterns of clinical features that can occur in polyneuropathies, which include motor and sensory. Polyneuropathy may be motor-predominant, sensory-predominant or a mixture of both.

  • Motor: this refers to damage or dysfunction of motor nerves. Predominant features include weakness and atrophy of affected muscles. Classic examples of motor polyneuropathies include chronic demyelinating inflammatory polyneuropathy, Guillain-Barré syndrome and Charcot-Marie-Tooth disease
  • Sensory: this refers to damage or dysfunction of sensory nerves. Symptoms may be ‘negative’ referring to the loss of normal sensation such as touch, proprioception or vibration. Alternatively, symptoms may be ‘positive’ referring to dysregulated function leading to pain, paraesthesia (pins and needles sensation) or burning. Classic examples of sensory polyneuropathies include diabetes mellitus, alcohol excess, chronic kidney disease and paraneoplastic syndromes

Polyneuropathies may also be described as ‘painful’, which relates to a marked painful sensation from damage to peripheral sensory nerves. Typical examples include diabetes mellitus, vasculitis and paraneoplastic syndromes.

Small and large fibre

Peripheral nerves may be described in relation to the diameter of the nerve fibres. Large fibres have bigger axons and are usually myelinated sending signals faster than small fibres.

  • Large fibres: carry information to control movement and important sensory information including touch, vibration and proprioception. These types of polyneuropathies are often painless.
  • Small fibres: carry information about pain and temperature leading to painful polyneuropathies. Autonomic nerves controlling important visceral functions are also small fibre. This means small fibre polyneuropathies may be associated with autonomic dysfunction (e.g. postural hypotension, gastrointestinal dysmotility, erectile dysfunction, or sweating disorders)

Aetiology

In the western world, the most common cause of polyneuropathy is diabetes mellitus.

There are many different causes of polyneuropathy and these may be grouped based on the pattern of pathology (e.g. demyelinating or axonal), typical presentation (e.g. motor, sensory or painful), or even small versus large fibre as we discussed in the previous section.

As there are so many possible causes, it is often easier to consider them as part of a surgical sieve, which is a way of structuring the differential diagnosis into broad categories. There are many useful mnemonics for a surgical sieve (e.g. VITAMIN DC) to help remember the broad categories. The classic causes of polyneuropathy include:

  • Idiopathic: no known cause (commonly a small fibre painful neuropathy)
  • Diabetes mellitus
  • Systemic illness: critical illness polyneuropathy, hypothyroidism, chronic kidney disease, chronic liver disease, amyloidosis
  • Autoimmune: Guillain-Barré syndrome
  • Inflammatory: chronic inflammatory demyelinating polyneuropathy (CIDP)
  • Toxic: Alcohol, chemotherapy, heavy metals
  • Neoplastic: myeloma, paraneoplastic syndrome
  • Hereditary: Charcot-Marie-Tooth
  • Nutritional: Vitamin B12, folate, pyridoxine, vitamin E deficiencies
  • Vasculitis
  • Medications: nitrofurantoin, isoniazid

We discuss some of the more commonly recognised causes of polyneuropathy in more detail below.

Diabetes mellitus

Diabetes is the most common cause of polyneuropathy in the Western world. Diabetes most commonly causes distal, symmetrical, polyneuropathy with predominantly sensory loss. As it progresses, motor function may also be lost. Diabetes mellitus can cause a wide range of peripheral neuropathies including:

  • Distal, symmetrical polyneuropathy
  • Autonomic neuropathy
  • Radiculopathies
  • Mononeuropathies (e.g. upper limb, lower limb, cranial nerves)
  • Mononeuritis multiplex

The pathophysiology of nerve damage in diabetes is complex but there seems to be a predilection for the small distal sensory and autonomic fibres. To keep it simple, nerve damage occurs due to oxidative stress as part of a byproduct of different metabolic pathways that occur due to persistent hyperglycaemia. This, combined with damage to the small blood vessels that supply the nerves known as the vasa nervorum, leads to peripheral nerve damage.

Charcot-Marie-Tooth

Charcot-Marie-Tooth (CMT) refers to a collection of peripheral neuropathies due to an inherited mutation. CMT is actually a collective term that has been retained in the medical nomenclature due to its widespread use for several hereditary sensory and motor polyneuropathies.

They are due to inherited mutations in a number of genes important for myelin, gap junctions, and axonal structures in peripheral nerves. There are various subtypes of CMT due to the different underlying mutations that present at different ages and with varying severity of symptoms. The hallmark is slowly progressive lower limb neurological changes that can include distal calf atrophy, pes cavus (i.e. high arch), clumsy walking, weakness, and reduced sensation. There is usually a family history of lower limb abnormalities and the inheritance is variable depending on the subtype.

Examples include:

  • CMT1A: Due to duplication of the gene PMP22. Autosomal dominant pattern of inheritance. Causes demyelinating polyneuropathy. Typically presents in the first or second decade of life. Characterised by areflexia, pes cavus, distal lower extremity weakness, atrophy and the classic "stork leg deformity” also known as ‘inverted champagne bottle’ due to distal calf atrophy
  • CMT2A: Commonly due to a mutation within gene MFN2. Autosomal dominant pattern of inheritance. Causes axonal polyneuropathy. Typically presents in the second or third decade of life. Characterised by distal weakness, atrophy, sensory loss, decreased deep tendon reflexes, and foot deformity

Many other types and subtypes of CMT exist

Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) is an acute, inflammatory polyneuropathy typically characterised by a progressive, ascending neuropathy resulting in weakness and reduced reflexes. It is a rare neuropathy classically presenting with progressive lower limb weakness following a history of a preceding illness (typically gastroenteritis or flu-like illness).

GBS is an umbrella term that refers to a number of ‘variants’ with unique features and pathophysiology. Acute inflammatory demyelinating polyneuropathy (AIDP) is the most common form accounting for 90% of the disease. In severe cases, GBS may be life-threatening due to autonomic instability and hypoventilation.

For more information see our Guillain-Barré syndrome note.

Chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy, known more commonly as CIDP, is considered an acquired immune-mediated cause of polyneuropathy. As the name suggests, there is demyelination of peripheral nerves leading to the classic presentation of symmetrical sensorimotor polyneuropathy of which motor symptoms predominate in both proximal and distal muscle groups.

The exact cause of CIDP is unknown but there is clear evidence of an abnormal immunological response to peripheral nerves. The clinical onset is typically slowly progressive but acute variants exist and it may also affect nerve roots (i.e. radiculopathies). It is important to recognise because specific treatments may be offered.

Vitamin B12 deficiency

Vitamin B12 deficiency classically causes a distal, symmetrical sensory polyneuropathy. In severe cases, the dorsal columns of the spinal cord may also be affected, which is known as subacute degeneration of the cord. Patients typically present with weakness, ataxia and paraesthesia. Weakness may occur due to additional involvement of lateral columns in the spinal cord.

Subacute degeneration of the cord in combination with polyneuropathy is one of the classic causes of ‘mixed signs’ where there are features of lower motor neurone weakness (e.g. absent ankle reflexes) and upper motor neurone weakness (e.g. upgoing plantars).

Pathophysiology

The two major pathological mechanisms of polyneuropathy are demyelination and axonal degeneration.

Each peripheral nerve is composed of a cell body (soma), dendrites (short branched extensions from the cell body), axon (long threadlike part of the nerve cell), and the myelin sheath that insulates the axon improving conduction. Some smaller peripheral nerve fibres are unmyelinated.

Damage to peripheral nerves usually occurs due to axonal degeneration or demyelination.

  • Demyelination: Degeneration of the myelin sheath is seen. In pure demyelination, there is sparing of the axon. The clinical presentation is more variable. Demyelination is commonly due to inflammatory or autoimmune causes
  • Axonal degeneration: damage to nerve axons. Typically causes a ‘dying-back phenomenon’ that starts distal and progresses proximally. This is because the distal parts of nerves are more vulnerable due to their distance from the cell body that gives metabolic support. Usually causes a symmetrical polyneuropathy with weakness

Clinical features

Polyneuropathies commonly present with a distal, symmetrical neuropathy with paraesthesia, sensory loss, and/or weakness.

The stereotypical presentation of polyneuropathy is a symmetrical, ‘length-dependent’ neuropathy that affects the hands and feet in a ‘glove and stocking’ distribution leading to paraesthesia, sensory loss, and/or weakness.

Polyneuropathies may be ‘motor-predominant’, ‘sensory-predominant’, or ‘mixed’ which is termed sensorimotor. The majority of polyneuropathies are mixed but this may only be detected on clinical examination or through electrodiagnostic testing. In other words, the patients' primary presentation may be of weakness or painful paraesthesia but on testing, other features (e.g. motor or sensory) may be identified.

Sensory features

  • Burning sensation
  • Paraesthesia
  • Sensory loss (touch, pain, temperature)
  • Ataxia (poor coordination)
  • Loss of light touch
  • Loss of vibration
  • Loss of proprioception

Motor features

Polyneuropathy causes a lower motor neurone pattern of weakness (i.e. everything is reduced - low power, tone, reflexes)

  • Weakness
  • Reduced/absent reflexes
  • Hypotonia
  • Fasciculations
  • Muscle atrophy
  • Muscle cramping
  • Deformity (e.g. pes cavus, clawing)

Diagnosis

A formal diagnosis of polyneuropathy is made on electrodiagnostic studies (electromyography and nerve conduction studies).

In a patient presenting with suspected polyneuropathy, the extent of testing depends on the severity of the clinical features and the suspected underlying cause. If the features are mild (e.g. early sensory symptoms) and the aetiology is known (e.g. diabetes mellitus) limited further testing is likely to be required. However, extensive testing may be requested in a patient with severe symptoms or when the diagnosis is unknown.

The key investigations in polyneuropathies are electrodiagnostic tests. This should be completed and interpreted in the context of the clinical presentation.

Electrodiagnostic tests

Electrodiagnostic tests can be used to confirm peripheral neuropathy and these should be requested and interpreted in line with the clinical presentation. The two main tests include electromyography (EMG) and nerve conduction studies (NCS):

  • Electromyography (evaluates muscle units): this refers to an assessment of the electrical activity of muscles. It can assess activity during rest and voluntary contraction. It is important in the assessment and diagnosis of neuromuscular disease. It helps to differentiate between the different types of peripheral neuropathy (e.g. motor mononeuropathies, plexopathy) as well as muscle abnormalities (e.g. neuromuscular junction, myopathy)
  • Nerve conduction studies (evaluates peripheral nerves): this refers to an assessment of individual peripheral nerve function. It essentially involves activating nerves electrically over several points on the skin of the upper/lower limbs and measuring the response. The test involves assessing both the size (i.e. amplitude) and speed (i.e. velocity) of signals through the motor and sensory fibres. These studies can determine the type of injury (e.g. demyelinating, axonal degeneration, or compressive conduction block)

Each test has its own strength and limitations. The combination of both helps to better localise the pathology and narrow down the possible underlying aetiology. The pattern of EMG/NCS results may also guide further investigations. For example, if there is evidence of an axonal polyneuropathy, this would warrant testing for systemic diseases such as diabetes mellitus, hypothyroidism, or vitamin B12 deficiency.

Investigations

Numerous investigations can be requested in the work-up of polyneuropathy depending on the suspected cause.

Investigations may be requested as part of a panel looking for an underlying aetiology. More specialist tests may be requested based on the pattern of polyneuropathy (e.g. axonal, demyelinating, mixed) or if the cause remains unknown after initial investigations.

Blood tests

  • Full blood count
  • Renal function
  • Liver function tests
  • Vitamins: B12, folate, vit E
  • Myeloma screen: protein electrophoresis, serum-free light chains
  • Thyroid function
  • HbA1c
  • Anti-nuclear antigens
  • Viruses: hepatitis B/C, HIV
  • Autoimmune screen: anti-nuclear antigens, Anti-CCP, complement for connective tissue diseases
  • Heavy metals: copper, lead
  • Serology: syphilis, Lyme

Imaging

The routine use of imaging in polyneuropathy is not required. Imaging may be requested if there is suspicion of a compressive pathology, coexisting neurological abnormality (e.g. radiculopathy) or the diagnosis is unclear. Options include US, MRI, and/or CT.

Special tests

Specialist investigations may be required by neurologists if the cause is still not clear based on initial investigations.

  • Nerve biopsy: rarely performed. May be considered if vasculitis or amyloid suspected
  • Skin biopsy: may be performed if a small fibre polyneuropathy is suspected (EMG/NCS can be normal in these cases)
  • Autonomic testing: important in patients with suspected autonomic nerve involvement
  • Genetic testing: may be completed in hereditary forms of polyneuropathy

Management

The management of polyneuropathy depends on the underlying cause.

There are two important components to the management of polyneuropathies:

  • Treat the underlying cause
  • Manage the symptoms

Treat the underlying cause

In general, treatment and prevention of the underlying cause is critical in axonal polyneuropathies. This may be as simple as avoidance of the precipitating drug or toxin (e.g. alcohol). The focus should be on optimisation or treatment of the cause such as blood glucose control in diabetes mellitus, vitamin B12 replacement if deficient, or levothyroxine in hypothyroidism. These measures should help to halt the progression of polyneuropathy.

Demyelinating polyneuropathies can be targeted more with treatments. This is because demyelinating disorders are often related to inflammatory and autoimmune abnormalities that can be targeted with immunosuppressive treatments. The exact treatment for each polyneuropathy is beyond the scope of these notes as it can get complicated.

Manage the symptoms

Clinical features of polyneuropathies can be quite disabling including quite marked sensory paraesthesia and/or pain. This type of neuropathic pain can be treated with neuromodulating drugs such as gabapentin or duloxetine. If weakness is a problem, patients need assessment by the therapy team to see if they need any additional support and ongoing rehabilitation.

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