Peripheral neuropathy

At the top of any UK/US list of causes must be diabetes and alcohol, worldwide think leprosy

About

• Also see Length Dependent Polyneuropathy for more information
• Disease of the peripheral nerves which is a manifestation of many primary neurological diseases and systemic diseases
• Many different clinical patterns - patchy or symmetrical, distal or proximal, motor or sensory or autonomic

Aetiology

• Peripheral nerves can be crudely divided into large myelinated ones and small unmyelinated ones.
• Smaller ones carry pain and temperature and autonomic
• Large ones carry motor and sensory (vibration and proprioception).

Different forms	Comments
Wallerian Degeneration	The nerve for one reason or other is transected. There is both a myelin and axonal type neuropathy. The nerve distal to the injury dies off and must regrow proximal to distal usually with variable success
Axonal degeneration	Usually toxic, metabolic, nutritional. The largest and longest nerves are the most vulnerable. Tends to the affected distal nerve first and the nerve dies back. Consider diabetes as the commonest cause or toxins.
Demyelination	Loss of myelin with preservation of the axon. Can be patchy with the early loss of reflexes. Can be due to Schwann cell damage or an attack on the myelin sheath. Examples include GBS and CIDP.
Neuronal cell body disease	Anterior horn cell e.g. Polio Motor weakness or motor neuron disease or some paraneoplastic syndromes
Dorsal root ganglion	sensory loss affected in paraneoplastic disease and Sjogren's syndrome

Different patterns	Comments
Polyneuropathy	often synonymous with peripheral neuropathy with a distal glove and stocking sensory and/or distal motor loss. These can be axonal like Diabetes where the neuronal cell body is intact. Alternatively, there are diseases where the primary pathology is demyelination. In some, the cell body is affected e.g. Polio and MND. The commonest causes are diabetes and pre-diabetes, B12/folate deficiency, alcohol, Lyme disease. Comprehensive list.
Mononeuropathy	single nerve affected. Diphtheria and Diabetes and nerve compression
Mononeuritis multiplex	several different nerves affected simultaneously or sequentially. Vasculitis
Autonomic neuropathy	affects the non-voluntary, non-sensory nerves. Diabetes, Amyloidosis, Porphyria, Paraneoplastic neuropathy, Lymphoma, Heavy metals, Thiamine deficiency Vincristine toxicity, GBS, Alcoholic neuropathy Acute pandysautonomia
Abrupt onset	Ischaemic neuropathies, PAN, RA, Diabetes (Cranial and amyotrophy), Nerve compression, HIV/AIDS
Cranial nerves	Often bilateral LMN VII : Diabetes mellitus GBS, HIV/AIDS, Lyme disease, Sarcoidosis, Neoplastic invasion of skull base or meninges, Diphtheria

Causes of Peripheral neuropathy	Comments
Diabetes Mellitus (axonal)	Symmetrical distal sensory loss, Autonomic
Alcohol	Distal, symmetric axonal sensorimotor neuropathy. May be painful.
Rheumatoid arthritis	Distal motor and sensory symmetrical neuropathy
Systemic Lupus erythematosus	Distal motor and sensory symmetrical neuropathy
Paraneoplastic (axonal)	Lymphoma, Pure sensory neuropathies, autonomic, Motor neuropathy
B12 deficiency (axonal)	Mainly proprioceptive loss and loss of ankle jerks, Symmetrical distal sensory loss
Vasculitis (axonal)	Distal motor and sensory symmetrical neuropathy
Uraemia	Often in those on renal replacement therapy
Cisplatinum	Symmetrical distal loss
Guillain-Barré Syndrome	Distal motor and sensory symmetrical neuropathy, autonomic, Bilateral LMN VIIth. Elevated CSF protein
CIDP (demyelinating)	Distal motor and sensory symmetrical neuropathy, Bilateral LMN VIIth. Elevated CSF protein
HMSN 1 (demyelinating) and HMSN 2 (axonal)
Amyloid	Autonomic, Distal sensorimotor
Paraprotein related	Screen for myeloma, MGUS or other haematological malignancies
B1 deficiency	Pure sensory neuropathies
Folate deficiency	Pure sensory neuropathies
B6 deficiency and excess
Porphyria	Autonomic
Lead
Isoniazid
Vincristine	Pure sensory neuropathies
Toxins (axonal)
Diphtheria
Sarcoid
CMT	Distal symmetrical senory and motor
Lyme disease	Bilateral LMN VIIth
Leprosy (axonal)	Nerve thickening
HIV (demyelinating/axonal)	Symmetrical distal. Medications used to treat HIV infection also cause a distal symmetric axonal sensorimotor neuropathy.
MMN
Motor neurone disease	Asymmetrical LMN motor weakness

Clinical

• Distal symmetrical sensorimotor axonal neuropathy leads to altered sensation which can be reduced or unpleasant: terms used include paraesthesia, dysasthesia (unpleasant tingling), allodynia (painful to touch or stroke), hyperaesthesia when there is heightened sensitivity and lastly neuropathic pain. Hypoaesthesia can lead to a feeling of walking on cotton wool. Distal loss of pain and temperature and pain can lead to injuries. The distal proprioceptive loss will lead to an ataxic gait. The loss often starts distally and moves proximally in what has often termed a glove and stocking distribution. A positive Romberg's test may be seen with marked sensory ataxia and suggests large fibre disease affecting proprioception.
• Distal weakness which is lower motor neurone by definition and so there is loss of distal reflexes and over time progressing to even a dropped footnoted with a compensatory high steppage gait. Usually, the feet are affected significantly before the upper limb. In severe cases, the ascending disease can lead to weakness of the intercostal and diaphragm and require assisted ventilation as is seen with Guillain Barre syndrome most classically.
• Autonomic nerve involvement can give postural hypotension, bowel, bladder and erectile difficulties.
• Hereditary causes are often associated with long-standing deformities such as pes cavus and pes planus and clawing of the foot. Motor symptoms are commoner with hereditary causes. Sensory symptoms are more associated with the acquired disease.
• Nerve thickening e.g. ulnar nerve, the sural nerve may rarely be seen but has a list of memorable causes - leprosy, CIDP, Refsum's disease, amyloidosis, Charcot Marie tooth (Types I and III) and Hereditary neuropathy with pressure palsies

Rate of onset

• Days : GBS, Vasculitis
• Weeks : CIDP
• Months/Years: Diabetes, Alcohol

Differentiating clues

• Speed of onset
• Alcohol abuse or Diabetic
• Cranial nerves involved or autonomic
• Sensory or Motor predominates
• Sensory : Pain/Temp (small fibre) loss or Vibration/Proprioception (large fibre)
• Family history : CMT

First line Investigations

• FBC (anaemia ↑ MCV)
• ↑ ESR and CRP: Malignancy, Vasculitis
• ↑ GGT, LFT : Alcohol
• ↑ Urea or creatinine: uraemia ↑ Ca: Malignancy
• ↑ Glucose ↑ HBa1c : Diabetes
• ↓ B12 ↓ Folate, TFTS
• ANA, dsDNA, ENA : Vasculitis
• CXR : Sarcoid, Malignancy, TB, Churg-Strauss syndrome
• EMG and nerve conduction studies are often indicated in the evaluation of a patient with peripheral neuropathy. They confirm the presence of neuropathy and provide information as to the type of fibres involved (motor, sensory, or both), the pathophysiology (axonal loss versus demyelination) and a symmetric versus asymmetric or multifocal pattern of involvement.

Selective tests

• CSF : GBS, CIDP ↑ protein
• ↑ ACE - sarcoid
• ANCA : Vasculitis/Churg Strauss
• Hepatitis B and C serology
• Cryoglobulins
• Complement C3 and C4
• Lyme and HIV serology
• Genetic studies
• Anti GQ1b : Miller Fisher syndrome
• Anti GM1 : MMN + CB
• Anti MAG : IgM Paraproteinaemic neuropathy
• Nerve biopsy usually of the sural nerve. Used for difficult cases.

Management

• See under specific cause