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Peripheral neuropathies

Updated: May 8, 2022


Prevalence of peripheral neuropathy in the general population is 2.4%

Increases with age to an estimated 8% in those older than 55 years

Peripheral neuropathy is more common in patients with diabetes, HIV and dysproteinemic disorders, and those receiving chemotherapy.

For diabetic neuropathy, length-dependent sensorimotor peripheral neuropathy is evident in 8% at the time of diagnosis but increases in frequency with disease duration to 30% to 66%

The combination of history (including family history), examination, ancillary testing, and serologic evaluation yields the etiology of a length-dependent peripheral neuropathy in 74% to 82% of cases.

Importantly, although the etiology of 20% to 25% of these neuropathies remains uncertain, the natural history of these idiopathic neuropathies is that they progress slowly and are unlikely to cause severe physical disability


Damage can occur at different parts of the nerve:

  • Damage to the axon itself (axonopathy)

  • Disruption of the axons with death of axon and myelin sheathe beyond (Wallerian degen)

  • Distal axon with loss of myelin sheath (usually in toxic settings - 'die back' or length dependent neuropathy

Neuronopathies is damage at the motor neuron or dorsal root ganglion with loss of both central and peripheral processes

Myelinopathies occur at the level of the myelin sheath and can be inflammatory or hereditary.

  • In acquired demyelinating neuropathies, the injury is often patchy or segmental. Because the axons are relatively spared, recovery is often rapid (weeks to months) and complete.

  • Hereditary abnormalities of myelin are usually diffuse, with a slowly progressive course.

Definition of a small fibre neuropathy:

A small fiber neuropathy occurs when damage to the peripheral nerves predominantly or entirely affects the small myelinated (Aδ) fibers or unmyelinated C fibers. The specific fiber types involved in this process include both small somatic and autonomic fibers. The sensory functions of these fibers include thermal perception and nociception. These fibers also are involved in a number of autonomic and enteric functions.

Anatomically, the small nerve fibers may be damaged or destroyed in these conditions, resulting in a loss of small nerve fibers and/or abnormal nerve fiber morphology. However, the pathogenesis of injury to small nerve fibers is not well understood. Small nerve fiber neuropathies can occur without large nerve fiber involvement, but in some cases they occur concomitantly or progress to involve large nerve fibers.

Presentation (general)

Sensory symptoms (eg, numbness, tingling), weakness, autonomic symptoms (eg, early satiety, impotence, orthostatic hypotension, sweat abnormalities), or neuropathic (burning, stabbing, electrical) pain may suggest the presence of a peripheral neuropathy.

Presentation (length-dependent)

The most common pattern of clinical involvement is that of a length-dependent peripheral neuropathy. This form of neuropathy is symmetric, and symptoms begin in the longest nerves at their terminals (ie, distal foot).

Positive (prickling, tingling, burning) or negative symptoms (lack of feeling) sensory symptoms usually precede motor weakness. The symptoms ascend insidiously up the leg, with hand symptoms often becoming evident around the time leg symptoms approach the knee. Upper limb involvement may never occur.

Atypical for a diabetic length-dependent neuropathy to occur in upper and lower limbs at the same time, and may indicate coexisting carpal tunnel syndrome or an alternative cause of neuropathy (eg, a toxic etiology).

Proprioception is spared relative to other sensory modalities in mild to moderate length-dependent neuropathies and only becomes affected as the neuropathy severity progresses.

Patients with notable early proprioceptive deficits (gait ataxia, imbalance with eyes closed) require further evaluation for posterior column disease (eg, vitamin B12 deficiency) or for sensory cell body dysfunction (a sensory ganglionopathy as seen in Sjögren syndrome or a paraneoplastic disorder).

In length-dependent neuropathies, as the sensory signs and symptoms progress, weakness and reflex abnormalities develop distally.

The majority of peripheral neuropathies are length dependent, sensory predominant, and clinically mild to moderate in severity without major functional limitations.

The combination of history (including family history), examination, ancillary testing, and serologic evaluation yields the etiology of a length-dependent peripheral neuropathy in 74% to 82% of cases

Clinical reasoning suggestions:

Work out the pattern first - is it focal, multifocal, or symmetric?

As examples:

Focal - Entrapment, compressions, trauma, ischaemia

Multifocal - Diabetes, Vasculitis, Sarcoidosis, HIV

Symmetric DISTAL = Endocrine (diabetes, hypothyroidism), nutritional (alcohol, B12 deficiency, Folate defn etc), Connective tissue disorders (e.g. RA, SLE, PAD), AIDS, Toxic chemicals, Drugs (e.g. chemo)

Symmetric PROXIMAL = RARE = GBS, CIDP, MGUS etc.


One of the hallmarks of a pure small fiber neuropathy is a normal or near normal physical and neurologic examination. The coordination, motor, and reflex examinations will be normal. Light touch, vibratory sensation, and proprioception also may be normal, resulting in diagnostic confusion in some situations. Patients may have decreased pinprick, decreased thermal sensation, or hyperalgesia in the affected region. There may be mildly decreased vibratory sensation in some individuals. Associated skin changes in affected areas may include dry, cracked, or shiny skin, with decreased moisture on the surface of these affected areas as well.

Investigations (length-dependent)

The highest-yield testing includes screens for diabetes mellitus, vitamin B12 with methylmalonic acid, and serum protein immunofixation electrophoresis (SPIEP)

Presentation - (length-independent or multifocal)

These are suspected when sensory and motor signs are more diffuse, length independent (e.g. proximal and distal limbs). These can be sensory dominant, but motor features are more readily appreciable than length-dependent neuropathies.

Reflexes are often reduced or absent

The differential diagnoses for these polyradiculopathies and multifocal neuropathies is quite different to length-dependent neuropathies.

Consider: Sarcoidosis, amyloidosis, neoplastic, paraneoplastic, vasculitic, infectious and inflammatory immune-mediated (eg. CIDP)

Examination (general)

Office screening for neuropathy have utilized light touch perception to a 10-g Semmes-Weinstein monofilament, vibration testing with a 128-Hz tuning fork, superficial pain (pinprick) perception, or testing of ankle deep tendon reflexes.

It is important to note that because peripheral neuropathies may affect different types of nerve fibers to different degrees, single-modality testing may miss 25% to 50% of those with diabetic neuropathy

In diabetic cohorts, combination testing of vibration plus 10-g monofilament testing provides the best balance of an efficient (less than 2-minute), sensitive (90%), and specific (85%-89%) screen for diabetic peripheral neuropathy and correlates with the development of diabetic foot ulcers.

Light touch with a cotton swab is often substituted for monofilament testing in clinical practice, although its effect on sensitivity and specificity is unknown.

However, be aware that there is an age-related decline in vibration sensation. 1/4 of those aged 65 years and 1/3rd > 75 years have absent vibration sensation on clinical examination.

Importantly, although the etiology of 20% to 25% of these neuropathies remains uncertain, the natural history of these idiopathic neuropathies is that they progress slowly and are unlikely to cause severe physical disability.

The highest-yield testing includes screens for diabetes mellitus, vitamin B12with methylmalonic acid, and serum protein immunofixation electrophoresis (SPIEP).

19 A practical evaluation for chronic, length-dependent peripheral neuropathy is presented in Table 2.


Diabetic neuropathy

Most common cause of peripheral neuropathy in Western societies

Prevalence of up to 30% to 66% depending on criteria used

10% to 15% of patients with diabetic neuropathy are neurologically symptomatic (from motor, sensory, or autonomic dysfunction) and 11% to 26% are limited by associated neuropathic pain

Asymptomatic patients are still at risk due to insensate feet.

All patients presenting with signs or symptoms of peripheral neuropathy should be screened for diabetes mellitus with fasting glucose and/or hemoglobin A1c measurements

The risk of diabetic neuropathy, and other late microvascular complications of diabetes mellitus, can be reduced with tight glycemic control.

It usually occurs with other late microvascular complications of diabetes mellitus, namely retinopathy and nephropathy. This association is so strong that if there is no clinical evidence of retinopathy or nephropathy in a patient with suspected diabetic distal symmetric neuropathy, alternative nondiabetic etiologies should be considered.

In up to 10% of diabetic patients, neurologic deficits can be attributed to an alternative cause.

8 Inherited neuropathy is one of the common alternative causes. Although diabetes is the likely cause in diabetic patients presenting with a length-dependent peripheral neuropathy, a limited screening laboratory evaluation (eg, serum protein immunofixation electrophoresis, vitamin B12 with methylmalonic acid, thyroid studies) for other treatable metabolic disorders is reasonable before attributing the neuropathy to diabetes.

Diabetes can cause other patterns of neuropathy including mononeuropathies, thoracic radiculopathy, a length-independent polyradiculoneuropathy, and diabetic lumbosacral radiculoplexus neuropathy (also known as diabetic amyotrophy), so called because of its pathologic predilection toward the lumbosacral segments (although thoracic or cervical involvement is possible) at the root (“radiculo”), plexus, and peripheral nerve (“neuropathy”) levels. Diabetic radiculoplexus neuropathy is a unique subacute neuropathy that affects 1% of patients with diabetes.

8 It begins with severe pain, often involving the proximal aspect of the thigh and mimicking a radiculopathy. Weakness follows and may remain localized or progress multifocally within the limb or to other limbs. Weight loss often precedes the onset of symptoms

IGT on its own is an unlikely cause of clinically significant peripheral neuropathy

Vitamin B12 Deficiency

In the nervous system, vitamin B12 is integral in the initial development of and maintenance of myelin.33 Vitamin B12 deficiency can cause classic subacute combined degeneration or an isolated peripheral neuropathy without central nervous system involvement.34 In patients presenting with a length-dependent peripheral neuropathy, the serum B12 level should be measured. Among patients with low-normal serum B12 levels (200-500 pg/mL [to convert to pmol/L, multiply by 0.7378]), 5% to 10% will have elevated serum methylmalonic acid concentrations indicating cellular B12deficiency.19 Adding methylmalonic acid (with or without homocysteine) to a screen of serum B12level improves the yield of identifying cellular B12 deficiency as a cause of neuropathy from 2% to 8%


Up to 10% of peripheral neuropathies are associated with dysproteinemias (a 6-fold increase over the general population), with the majority being a monoclonal gammopathy of undetermined significance (MGUS).36Evaluation by SPIEP is more sensitive in identifying a monoclonal protein than serum protein electrophoresis (SPEP); SPEP misses 17% of all monoclonal proteins identified with immunofixation and 30% of all IgM monoclonal gammopathies.37 The most common monoclonal protein associated with peripheral neuropathy is IgM. For the evaluation of patients presenting with peripheral neuropathy, SPIEP is recommended over SPEP

The finding of a monoclonal protein necessitates further evaluation, and possible hematologic evaluation, to exclude disorders such as amyloidosis, multiple myeloma, osteosclerotic myeloma (POEMS [polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin abnormalities] syndrome), lymphoma, Waldenström macroglobulinemia, or cryoglobulinemia.

Most MGUS neuropathies occur in the setting of IgM, IgG, or IgA paraproteinemias (IgM being the most common) and usually cause axonal, length-dependent sensorimotor neuropathies (although polyradiculoneuropathies can also occur). Most IgM paraproteinemias are associated with an MGUS; however, some are associated with a distinct demyelinating (distinguishing it from MGUS-associated axonal neuropathies) clinical syndrome with severe symmetric distal sensory-predominant deficits (distal acquired demyelinating symmetric neuropathy).

38, 39 Two-thirds of patients with distal acquired demyelinating symmetric neuropathy have serum antimyelin-associated glycoprotein antibodies.38 This syndrome is important because it may respond to immunomodulatory treatments.40

The peripheral neuropathy associated with POEMS syndrome is typically a uniform mixed demyelinating and axonal length-independent polyradiculoneuropathy in the setting of an IgG or IgA paraproteinemia with a λ light chain.

41POEMS syndrome is associated with osteosclerotic myeloma and increased levels of serum vascular endothelial growth factor.

Electrophysiologic characterization of the neuropathy and neurologic consultation should be considered in patients with non-MGUS paraproteinemias, IgM paraproteinemias, and/or functionally limiting neuropathies.

Toxic neuropathies:

Keys are taking appropriate history and considering these in your patient. For example, chemotherapeutic agents in a patient with cancer

These often have a temporal onset with use of therapeutic, worsening symptoms with higher doses, symptoms onset in both hands and feet at the same time, and improvement when agent is removed

Medication, toxic, and vitamin-related neuropathies (ARTICLE)

Hereditary neuropathies:

Inherited neuropathies are the MOST common inherited neuromuscular condition in the world. These are commonly overlooked.

Charcot-Marie-Tooth disease (type 1 (axonal) and 2 (demyelinating)) (hereditary motor and sensory neuropathy) is the most common form of hereditary neuropathy and can be categorised into axonal and demyelinating forms.

These conditions are autosomal and X-linked dominant

These usually present with an insidious onset of slow progression over years. distal predominant motor > sensory, lack of positive sensory symptoms (dysaesthesias, burning), associated with structural ankle and foot deformities, and a FHx of neuropathy.

Genetic testing may be possible

Charcot-Marie-Tooth (UpToDate 2021)

It is a spectrum of disorders caused by mutations in various genes who protein products are expressed in myelin, gap junctions, and/or axonal structures within peripheral nerves

There are up to 7 different types and an x-linked category

Presents with distal weakness and atrophy with foot drop and pes cavus. Sensory symptoms can occur later - as can foot deformities such as hammertoes. They often develop hand weakness and atrophy following.

Usual testing is an EMG - however could just skip to genetic testing if strong FHx (Though sporadic CMT is common and can happen de novo)

The key reasons to suspect is slowly progressive symptoms, foot deformities, and lack of POSITIVE sensory symptoms despite clear sensory involvement

EMG is the next step in evaluation

NNT's for Peripheral Neuropathy

- TCA 2.5

SNRI 4.5

Gabapentin/pregabalin = 4

Topical lidocaine = 4

Opioids/Tramadol = 4-5


HIV neuropathy: (UpToDate 2021)


This is commonly a distal symmetrical polyneuropathy and varies in prevalence from 9-63% (because of a variation in immunosuppression from disease)

Previous neurotoxic agents were used for HIV (didanosine, stavudine)

Now, issues mainly only occur with advanced immunosuppression or high levels of HIV

Having other risk factors such as diabetes, hypertriglyceridaemia, nutritional deficiencies, substance use etc increase risk


Thought to be a 'dying back' neuropathy with distal fibre loss

Myelinated and demyelinated are lost and it is indistinguishable from other neuropathies

Thought that viral antigens provoke immune activation and create a toxic environment for the nerve.

Different drugs may also contribute to the neuropathy through inhibition of mitochondrial DNA polymerisation leading to mitochondrial dysfunction and less energy availability.

Types of presentation

  • Distal sensory neuropathy

  • Antiretroviral toxic neuropathy (similar presentation to distal sensory neuropathy)

  • Acute/chronic inflammatory demyelinating polyneuropathy

  • Mononeuritis multiples

  • Infectious neuropathy - CMV, HSV, Hep C

  • Other causes

Distal sensory neuropathy - Presents as a bilateral tingling and numbness of the toes. Can spread into the proximal extremities over weeks or months

Exam usually shows loss in all modalities (vibration, pinprick, temp) in a stocking distribution and reflex losses can follow. Weakness can also occur later.

Can be associated conditions such as:

  • Gastrointestinal pain (from infections (candida, clostridium or HIV related cancer))

  • Chest pain (pneumonia, osteomyelitis, malignancies)

  • Arthropathy (HIV associated or reactive arthritis)

  • Osteoporosis

  • Headache - both primary and migraine type, or secondary to infections


Adjust therapy if thought to be contributing (may take 1-6 weeks for drug effect to stop)

Correct any metabolic contributory factors

Pharmacological therapies are the usuals. They recommend gabapentin first line


Hypothyroidism - rare cause of p.neuropathy but treatable

Lyme disease - In the US

Coeliac disease - Sensory predominant usually

Copper deficiency - Can look like B12 deficiency

Vit E Deficiency - Only in malabsorption



Other drugs: Antimicrobials (fluoroquinolone particularly), antiretrovirals, colchicine, phenytoin, disulfiram, amiodarone.


EMG and NCS can be used to confirm suspected diagnoses, exclude mimickers, localise the process (length dependent, length independent, multifocal), confirm modalities affected (motor, sensory), define whether it is from axonal loss, demyelination, or both, and give a guide to the severity.

EMGs and NCSs test large myelinated AB fibres, not small C fibres or Adelta. So, normal findings do not rule out a small fibre peripheral neuropathy (that usually has more pain, sensory loss, and dysautonomia).

Tests for these small fibres includes: Autonomic reflex screen, QST, testing of sweat function, and epidermal biopsy for nerve fibre density.


Nerve conduction studies

Symptomatic Management

Ideally - find the ethology and treat that

Though, even if you find the cause, the already caused damage may persist

Cease any contributory medications

Foot cares - Critically important

Neuropathic pain - Remember comorbid depression/anxiety

- a2delta ligand blockers of calcium channels

- TCAs


- Topicals

- Tramadol

- Lastly opioids

Lamotrigine in a small trial of 227 people - showed some efficacy (more for antiretroviral PN)

8% Capsaicin patch can also help



2. Poncelet, A. N. (1998). An algorithm for the evaluation of peripheral neuropathy. American family physician, 57(4), 755.

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