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Peripheral Neuropathy 

Peripheral Neuropathy
Peripheral Neuropathy

James Burke

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date: 20 May 2022

  1. A. Introduction

    1. a. Clinical syndromes. Peripheral neuropathies can be divided into three clinical syndromes:

      1. i. Polyneuropathies present with symmetric abnormalities involving more than one nerve affecting sensation, strength, or both.

      2. ii. Mononeuritis multiplex is an initially asymmetric abnormality in more than one nerve occurring either simultaneously or over days to years.

      3. iii. Mononeuropathies imply focal involvement of a single nerve (e.g., carpal tunnel syndrome) and usually result from local nerve compression, stretch, or injury.

    2. b. Because polyneuropathy is the most common peripheral neuropathy and poses the greatest difficulty in differential diagnosis, it is the focus of this chapter.

  2. B. Clinical Manifestations of Polyneuropathy

    1. a. Sensory abnormalities in the feet are usually the first symptom of polyneuropathy.

      1. i. Hypesthesia (decreased sensation), anesthesia (absent sensation), paresthesia (“pins and needles” sensation without any stimuli), dysesthesia (burning sensation with or without stimuli), hyperesthesia (increased sensation to any stimuli), and allodynia (perceiving typically painless stimuli as painful) may all be noted. Initially, subjective complaints may be unaccompanied by objective findings.

      2. ii. Later, a pan-sensory loss in the feet may occur and progress proximally. Finger involvement often occurs after lower extremity sensory loss progresses to the shins or knees; eventually, the classic “stocking glove” pattern may be seen.

    2. b. Motor abnormalities may also occur, most commonly after sensory findings. The ankle reflex is often diminished early in the course of the disease, and a diminished knee reflex and foot drop are seen with progression.

  3. C. Causes of Polyneuropathy. Polyneuropathies may result from a variety of disorders. The mnemonic, “MOVE, STUPID,” can be used to help you remember the various causes of polyneuropathy.

    • MNEMONIC: Causes of Polyneuropathy (“MOVE, STUPID”)

    • Metabolic disorders (diabetes mellitus)—the most common cause of neuropathy

    • Other (including hereditary/familial disorders such as Charcot-Marie-Tooth)

    • Vasculitis or Vitamin deficiency (vitamin B12, thiamine, pyridoxine, folate)

    • Endocrine disorders (hypothyroidism)

    • Syphilis or Sarcoidosis

    • Tumor-related (i.e., paraneoplastic syndrome)

    • Uremia or liver disease (chronic liver disease, hepatitis B and C)

    • Paraproteinemia/amyloidosis,1Porphyria, Primary biliary cirrhosis, or Polycythemia vera

    • Infections,2 Inflammatory (e.g., acute inflammatory demyelinating polyradiculoneuropathy [AIDP]/Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy [CIDP]), or Idiopathic causes

    • Drugs or toxins (including alcohol, antiretroviral nucleoside analogues)

      Hot Key

      While diabetes is the most common cause of neuropathy, impaired glucose tolerance or fasting glucose can also cause neuropathy.

  4. D. Approach to the Patient. While most disorders that cause polyneuropathies are relatively indolent, some progress rapidly and can even be life-threatening if not appropriately diagnosed and treated. AIDP/Guillain-Barré syndrome is one of the most common rapidly progressive neuropathies. Because the differential diagnosis is extensive and the etiology may or may not be obvious, the evaluation needs to be tailored to the situation. If the diagnosis is not initially apparent, a four-step process may be used to cover most of the possibilities.

    1. a. Take a thorough patient history.

      1. i. Make sure to ask about recent events that may provide a clue to the diagnosis. Specifically, inquire about the occurrence of a recent viral illnesses such as upper respiratory or gastrointestinal syndromes (which may suggest Guillain-Barré), the presence of similar symptoms in family members or coworkers (which may suggest a toxic exposure or hereditary disease), or systemic symptoms (e.g., weight loss), which may raise suspicion for an occult malignancy.

      2. ii. Obtain a medication history. Some drugs that may be responsible for polyneuropathy include vincristine, amiodarone, dapsone, hydralazine, isoniazid, metronidazole, nitrofurantoin, phenytoin, nucleoside reverse transcriptase inhibitors, and high doses of pyridoxine. Recent exposure to these agents, in particular, should be considered in the differential.

      3. iii. Inquire about toxin exposures. The most common toxins leading to neuropathy include heavy metals (e.g., arsenic, lead, mercury, thallium), industrial agents, and pesticides (e.g., organophosphates); diphtheria toxin should also be considered but is quite rare.

        Hot Key

        Common things are common: if diabetes mellitus or uremia is present or the patient is a long-time alcoholic, you may not need to look any further for the cause of neuropathy.

    2. b. Assess the time course. Only a few disorders commonly result in an acute polyneuropathy (i.e., one that occurs over a few days).

      1. i. Acute demyelinating polyneuropathies display a significant decrease in conduction velocities on nerve conduction studies (NCSs), although NCSs can be unremarkable early in the disease course. AIDP/Guillain-Barré syndrome is far more common, but diphtheria and toxic berry (i.e., “buckthorn”) ingestion may also produce similar clinical pictures.

      2. ii. Acute axonal polyneuropathies are relatively rare but can be caused by heavy metal toxins or porphyria. They are characterized by preserved conduction velocities and decreases in amplitude on nerve conduction studies.

      3. iii. Mononeuritis multiplex due to an aggressive cause can be clinically difficult to differentiate from acute polyneuropathies and is most commonly caused by inflammatory or autoimmune conditions such as vasculitis, lupus, and HIV infection.

    3. c. Use the neurologic examination. Acute polyneuropathies typically include early motor involvement. Reflexes are lost relatively early in AIDP/Guillain-Barré syndrome, and patients are areflexic.

    4. d. Perform appropriate laboratory studies if the diagnosis is still not evident. Review the list of possible causes and obtain the laboratory tests that will help shorten the list. Tests that may be requested include:

      1. i. Complete blood count (CBC)

      2. ii. Renal panel with electrolytes

      3. iii. Fasting glucose level and/or 2-hour oral glucose tolerance test

      4. iv. Vitamin B12 level

      5. v. Serum and urine protein electrophoresis and serum immunofixation

      6. vi. Liver function tests

      7. vii. Thyroid function tests

      8. viii. Fluorescent treponemal antibody absorbed (FTA-ABS) test for syphilis

      9. ix. Erythrocyte sedimentation rate (ESR)

    5. e. Consider occult disorders. The laboratory tests outlined may not rule out some of the more occult processes (e.g., tumor, vasculitis, sarcoidosis), but they may provide evidence for or against a possible diagnosis (e.g., a normal ESR makes vasculitis less likely). The following tests may be useful in certain clinical settings:

      1. i. Electrodiagnostic studies may be performed (if they have not been already) to help categorize whether there is primarily axonal degeneration or demyelination and inform the most likely cause.

      2. ii. Additional laboratory studies—antinuclear antibody (ANA), rheumatoid factor (RF), and serum cryoglobulin assessments—may be used in the evaluation of suspected vasculitis (see Chapter 75). Urinary heavy metal and porphobilinogen levels can be used to evaluate the possibility of toxic metal exposures and acute intermittent porphyria, respectively. Lyme titers are only useful when there is a reasonably high pretest probability of the diagnosis because the results lack specificity. Similarly, paraneoplastic syndromes are uncommon causes of neuropathy; thus, they should only be obtained in isolated cases because false positive findings are common.

      3. iii. Cerebrospinal fluid evaluation

        1. 1. Findings include high protein levels and a normal cell count in patients with Guillain-Barré syndrome or CIDP.

        2. 2. In severely immunosuppressed patients with cytomegalovirus polyradiculopathy, findings include neutrophilic pleocytosis, high protein levels, and low glucose levels.

        3. 3. Inflammatory conditions (e.g., vasculitis, sarcoidosis) may result in pleocytosis and high protein levels, particularly if they involve nerve roots (e.g., polyradiculopathy).

        4. 4. CNS lymphoma can directly invade nerve roots, resulting in a neuropathy-like picture and lymphocytic pleocytosis that can at times be diagnosed by cytology.

      4. iv. Radiographic imaging is rarely helpful in the diagnosis of neuropathy.

        1. 1. Chest radiographs may show evidence of sarcoidosis or an occult tumor.

        2. 2. A computed tomography (CT) scan may be performed if an intra-abdominal malignancy is suspected.

        3. 3. Magnetic resonance imaging (MRI) studies should not be performed as part of the neuropathy evaluation. Conversely, MRI of the spine is essential in the diagnosis of myelopathy (typically involving upper motor neuron signs, such as hyperreflexia) or in rare cases of polyradiculopathy mimicking neuropathy.

      5. v. Sural nerve biopsy. The ankle is the easiest place to obtain a cutaneous nerve biopsy.

        1. 1. Nerve biopsy is of low yield in symmetric polyneuropathies but should be considered in patients with suspected mononeuritis multiplex because a vasculitis may be more likely. The yield of biopsy is also increased in patients with suspected vasculitis, amyloidosis, sarcoidosis, or leprosy and in those with palpably thickened nerves.

        2. 2. Because hereditary disorders often present at an early age and have a characteristic histopathology, a sural nerve biopsy can also be considered in children.

  5. E. Treatment is generally aimed at the underlying disorder. Some general measures and specific therapies are discussed here.

    1. a. General measures

      1. i. Relief of neuropathic pain can be challenging. Tricyclic antidepressants (e.g., nortriptyline, amitriptyline, desipramine), the serotonin-norepinephrine reuptake inhibitors duloxetine or venlafaxine, or the anticonvulsants gabapentin or pregabalin are often tried with varying results. Other anticonvulsants (e.g., carbamazepine) and topical capsaicin or lidocaine may also be helpful in some cases.

      2. ii. Ankle-foot orthotics can help prevent Achilles tendon contractures and relieve foot drop.

    2. b. Specific therapies

      1. i. Guillain-Barré syndrome

        1. 1. Most patients require hospitalization for observation and supportive care (e.g., intubation for respiratory failure).

        2. 2. Plasmapheresis or intravenous immunoglobulin (IVIG) is beneficial and can hasten recovery, especially if administered within the first 2 weeks of illness. Steroids are not effective.

        3. 3. Approximately 85% of patients will recover completely or have only mild residual defects. The mortality rate is approximately 3% and is due to respiratory failure or autonomic instability.

      2. ii. CIDP is treated with steroids, immunosuppressants, and IVIG or plasmapheresis if symptoms are disabling.

      3. iii. Isoniazid overdose can be treated with intravenous pyridoxine (1 g for each gram of isoniazid ingested). Dialysis is usually not required because the drug is metabolized by the liver.

      4. iv. Acute intermittent porphyria

        1. 1. Acute treatment. Intravenous glucose and hematin may be needed for acute attacks.

        2. 2. Chronic treatment entails avoiding precipitating factors (e.g., sulfa drugs) and adhering to a high-carbohydrate diet.

Suggested Further Readings

Callaghan BC, Burke JF, Feldman EL. Electrodiagnostic tests in polyneuropathy and radiculopathy. JAMA 2016;315:297–8.Find this resource:

Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132.Find this resource:

Hughes RAC. Peripheral neuropathy. BMJ 2002;324:466–9. (Classic Article.)Find this resource:

Vinik AI. Diabetic sensory and motor neuropathy. N Engl J Med 2016;374:1455–64.Find this resource:


1 Amyloidosis may cause peripheral neuropathy without an accompanying paraproteinemia but is listed with paraproteinemia because these disorders are often considered together.

2 Peripheral neuropathy can be associated with infection (e.g., Lyme disease, leprosy, or AIDS). Patients with AIDS may develop polyradiculopathy with abnormalities on cerebrospinal fluid analysis that may be secondary to cytomegalovirus infection.