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Polyneuropathy refers to pathology affecting multiple peripheral nerves and involves the cell body, axon, myelin sheath, or a combination thereof.  The scope of this article is limited to peripheral, or length-dependent polyneuropathy. Therefore, non-length-dependent pathology affecting the neuronal cell body (e.g., neuronopathy, ganglionopathy, and motor neuron disease) is excluded.


Having diagnosed peripheral polyneuropathy, the astute neuromuscular physician proceeds with a targeted etiologic investigation. The identification of etiology(ies) is paramount to guiding treatment, when available, rather than resigning immediately to palliative care strategies.

The diagnostic workup should be guided by history, examination, and electrodiagnostic findings, given the wide spectrum of etiologic considerations. Much has been published in recent years regarding pattern recognition as a tool for sleuthing out the etiology of peripheral neuropathy.2,3,4,5

Barohn and Amato suggest a 3-6-10 approach, characterized by 3 goals and 6 key questions, leading to 10 phenotypic patterns facilitating a narrowed and refined diagnostic workup.2

3 Goals2

  1. Determine anatomical and physiological locations.
  2. Determine cause.
  3. Determine treatment.

6 Key questions2

  1. What systems are involved?
    • Motor
    • Sensory
    • Autonomic
    • Mixed
  2. What is the distribution of weakness?
    • Distal-only vs. proximal and distal?
    • Focal, asymmetric, or symmetric?
  3. What is the nature of the sensory involvement?
    • Severe pain/burning or stabbing
    • Proprioceptive loss
  4. Is there evidence of upper motor neuron involvement?
    • With sensory loss?
    • Without sensory loss?
  5. What is the temporal evolution?
    • Acute (days to 4 weeks)
    • Subacute (4 to 8 weeks)
    • Chronic (> 8 weeks)
    • Preceding events, drugs, toxins?
  6. Is there evidence for a hereditary neuropathy?
    • Family history
    • Skeletal deformities
    • Signs > symptoms

10 Distinct phenotypic patterns2

The distinct clinical features of each pattern enable the neuromuscular physician to not only recognize the various patterns of presentation, but customize further diagnostic testing to confirm the clinical impression. (Note: although it is less-frequently encountered than Pattern 2, Pattern 1 is listed sequentially first to highlight the importance of not missing the associated conditions since they are often amenable to immunotherapy.)

Pattern 1: Symmetric proximal and distal weakness with sensory loss


  • Inflammatory demyelinating polyneuropathy (GBS/AIDP, CIDP, and variants)
  • Acute arsenic poisoning, vincristine
  • Confirm diagnosis using published clinical criteria and electrodiagnostic criteria for demyelination.6

Pattern 2: Symmetric distal sensory loss with or without distal weakness


  • Cryptogenic (idiopathic) sensory polyneuropathy
  • Metabolic disorders7
    • vitamin deficiencies (B12, folate, thiamine, vitamin E)
    • malabsorption: bariatric and gastric surgeries, inflammatory bowel disease
    • renal disease
    • chronic liver disease
    • metabolic syndrome
  • Drugs4
    • neurologic/psychiatric agents: phenytoin, amitriptyline, lithium
    • antimicrobials: nitrofurantoin, metronidazole, chloramphenicol, tuberculosis therapies, chloroquine, hydroxychloroquine
    • cardiovascular agents: statins, amiodarone, flecainide, hydralazine
    • nitrous oxide
    • antirheumatic agents: colchicine, gold, leflunomide, methotrexate
    • immunomodulators: tacrolimus, interferon-α, ipilimumab, nivolumab, pembrolizumab, bortezomib, others
    • antineoplastic therapies: various chemotherapeutic agents, paclitaxel and other taxanes, vinca alkaloids, platinum analogues, doxorubicin, etoposide, ifosfamide, misonidazole
    • antinucleosides
  • Toxins4
    • alcoholism
    • heavy metal toxicity: lead, arsenic, inorganic mercury, zinc, thallium, gold others
    • herbicides (dichlorophenoxyacetic acid, Agent Orange and other deforestation agents)
    • organophosphate insecticides/pesticides (parathion, dioxin, others)
    • industrial agents: acrylamide, polychlorinated biphenyl, vinyl chloride (used to make polyvinyl chloride (PVC) plastic and vinyl products)
    • solvents: n-hexane (glue sniffing) and other hexacarbons, dry cleaning solvents, carbon disulfide, perchloroethylene, trichloroethylene, triorthocresyl phosphate, ethylene oxide, styrene, toluene, methyl n-butyl ketone, mixed solvents, and others
  • Endocrinopathy7
    • diabetes mellitus
    • thyroid disease
    • acromegaly
  • Hereditary: Charcot-Marie-Tooth (CMT), amyloidosis and others
  • Systemic disorders7
    • peripheral arterial disease
    • monoclonal gammopathy/paraproteinemia
    • amyloidosis
    • POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin abnormalities)
    • sarcoidosis
    • collagen vascular diseases
    • critical illness

Pattern 3: Asymmetric distal weakness with sensory loss

Multiple nerves, consider25

  • Vasculitis (various collagen vascular/connective tissue disorders):7
    • polyarteritis nodosa
    • Churg-Strauss syndrome
    • Wegener’s granulomatosis
    • temporal arteritis
    • rheumatoid arthritis
    • systemic lupus erythematosus
    • Sjogren’s syndrome
    • scleroderma
    • cryoglobulinemia
    • others
  • Hereditary neuropathy with liability to pressure palsies (HNPP)
  • Connective tissue diseases
  • Multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy
  • Infectious (leprosy, Lyme, sarcoid, HIV)

Single nerves/regions, consider25

  • Compressive mononeuropathy
  • Radiculopathy
  • Herpes zoster focal paresis
  • Ischemic lesions
  • Neoplastic infiltration
  • Direct trauma to nerves such as injection, cold exposure, burns, radiation

Pattern 4: Asymmetric proximal and distal weakness with sensory loss

Consider2, 25

  • Polyradiculopathy
  • Radiculopleuxus neuropathy
  • Meningeal carcinomatosis or lymphomatosis
  • Sarcoidosis
  • Amyloidosis
  • Lyme disease
  • Hereditary (HNPP, familial)
  • Idiopathic

Pattern 5: Asymmetric distal weakness without sensory loss

With upper motor neuron findings, consider2

  • Motor neuron disease:
    • amyotrophic lateral sclerosis (ALS)
    • primary lateral sclerosis (PLS)

Without upper motor neuron findings, consider

  • Progressive muscular atrophy (PMA)
  • Multifocal motor neuropathy (MMN)
  • Multifocal acquired motor axonopathy (MAMA)
  • Juvenile monomelic amyotrophy

Pattern 6: Symmetric sensory loss and distal areflexia with UMN findings


  • B12 deficiency
  • Copper deficiency (including Zinc toxicity)
  • Other causes of combined system degeneration with peripheral neuropathy
  • Inherited disorders
    • adrenomyeloneuropathy
    • metachromatic leukodystrophy
    • Friedreich’s ataxia

Pattern 7: Symmetric weakness without sensory loss*

* Some overlap with myopathy and NMJ disorders2

  • Proximal and distal weakness: consider spinal muscular atrophy
  • Distal weakness: consider hereditary motor neuropathy

Pattern 8: Focal midline proximal symmetric weakness*

* Some overlap with myopathy and NMJ disorders.  Consider2

  • Neck extensor weakness
    • isolated neck extensor myopathy
    • axial myopathy
    • ALS
  • Bulbar weakness
    • ALS
    • PLS

Pattern 9: Asymmetric proprioceptive sensory loss without weakness


  • Sensory neuronopathy (ganglionopathy)
    • cancer
    • paraneoplastic syndromes (small cell lung cancer, lymphoma, multiple myeloma, others)
    • Sjögren’s syndrome
    • idiopathic sensory neuronopathy
    • cisplatinum and other analogues
    • vitamin B6 toxicity
    • HIV-related sensory neuronopathy
  • Chronic immune sensory polyradiculopathy (CISP)

Pattern 10: Autonomic symptoms and signs

Consider: neuropathies associated with autonomic dysfunction2

  • Hereditary sensory autonomic neuropathy
  • Diabetes mellitus
  • Amyloidosis (familial and acquired)
  • Guillain-Barré syndrome
  • Vincristine-induced
  • Porphyria
  • HIV-related autonomic neuropathy
  • Idiopathic pandysautonomia

Cryptogenic/idiopathic peripheral neuropathy

For ~25% of patients with a peripheral neuropathy in a referral population, etiology remains elusive despite a careful search.8 After additional workup, a proportion can be attributed to hereditary forms, immunologic causes (acquired demyelinating, e.g., CIDP and variants), paraproteinemia, or undiagnosed medical conditions.2,8,9

Epidemiology including risk factors and primary prevention

Worldwide, the prevalence of peripheral polyneuropathy varies widely and depends largely on the socioeconomic status and age distribution of the study population, but in the general population ranges from 1-3%, and increases to 7% in those over age 50.1 It is expected that this number will continue to grow due to an aging population and increasing disparities in healthcare. Diabetes, specifically, is shown to account for 40% of polyneuropathy cases. Further, those with polyneuropathy are almost four times more likely to have a lower limb amputation than those without polyneuropathy. 20 The lack of existing interventions to delay progression or relieve symptoms of neuropathy is one reason for worsened quality of life in these patients. Common risk factors are mentioned above.


Regardless of the etiology of peripheral neuropathy, pathophysiology devolves into predictable patterns of nerve cell response to injury: demyelination, axonal degeneration, or a combination of both.

Small or large nerve fiber injury may cause symptoms of polyneuropathy. Large nerve fibers regulate motor, sensory, vibratory, and proprioception while small nerve fibers regulate pain, temperature, and autonomic function.

Demyelination can have a focal segmental distribution, such as neurapraxia, when compression is insufficient to damage axons, yet leads to injury involving a focal segment of myelin, resulting in action potential failure (conduction block) or conduction velocity slowing. Typical examples include acute compression and chronic entrapment.  Generalized demyelination results in conduction block and/or temporal dispersion in multiple nerves often asymmetrically and in anatomical locations outside common areas of compression/entrapment.

Axonal (Wallerian) degeneration, represented by axonotmesis and neurotmesis, results from prolonged, focal crush injury or transection resulting in disintegration and removal of axon and myelin distal to injury followed by an alteration of neural properties proximal to injury (so-called ‘dying back’), and ultimately, cell body death. Axonopathy can also be the result of toxic degeneration or a generalized insult to the peripheral nervous system.

Many conditions affect both peripheral nerve myelin and axon, but ultimately, Wallerian axonal degeneration represents the final common pathway of neuronal injury. With significant axonal death, myelin will not remain intact, and in cases of severe demyelination, axonal injury also occurs. In chronic polyneuropathy, this often obscures the initial distinguishing pathophysiologic features that might steer toward a specific underlying etiology, contributing to the diagnostic quandary.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Disease trajectory is variable and hinges upon the course of the underlying etiology. Toxin exposure symptoms may present more rapidly, while medication induced neuropathy may take months to present.Trauma or ischemic conditions typically present acute and severe at onset.25 A minority of the above etiologies are potentially treatable (most notably immune-mediated demyelinating neuropathies), and fewer still are reversible. Acute neuropathies such as GBS may appear suddenly, progress rapidly, and resolve subacutely. Most chronic forms of peripheral polyneuropathy are subtly progressive over many years. Slow, predictable decline can be accelerated by the development of new medical conditions that have neurological manifestations (e.g., multifactorial neuropathy), or exacerbated by various infections, surgeries, or illnesses.

Specific secondary or associated conditions and complications

Loss of sensation and particularly proprioception cause sensory ataxic gait and increase risk of fall, more so when accompanied by leg weakness or foot drop. Loss of protective sensation can result in neuropathic ulceration or Charcot joint deformities. Autonomic neuropathies can cause impaired thermoregulation, gastrointestinal dysmotility, neurogenic bladder, sexual dysfunction, heart rate and blood pressure dysregulation, and exercise intolerance. Peripheral neuropathies associated with peripheral nerve enlargement (CIDP, CMT, HNPP) or deposition (amyloid) may present with entrapment mononeuropathies or even manifest as polyradiculopathy or neurogenic claudication.

Essentials of Assessment


Since the diagnosis of peripheral neuropathy relies heavily on pattern recognition, a thorough history will provide initial clues10

  • Symptoms: onset, timing, character, severity, location/distribution and symmetry, course, exacerbating and relieving factors
  • Preceding illnesses, immunizations, or trauma
  • Associated symptoms: atrophy, fatigue, poor endurance, muscle cramps or stiffness, gait difficulties
  • Functional History: ambulatory distance, falls, transitions from floor to standing, and difficulty with climbing stairs, dressing, operating fasteners (buttons, zippers), reaching overhead, lifting, running, or performing vocational or avocational tasks
  • Medication history: query neurotoxic drugs (listed above)
  • Past medical and surgical history, attention to above listed risk factors
  • Family history: neurologic diseases, gait abnormalities (use of gait aides, orthotics), skeletal deformities (pes cavus, hammer toes, amputations, scoliosis), pedigree if needed
  • Developmental history, when applicable
  • Social history
    • Occupational and avocational history, query potential exposures to neurotoxins (above).
    • Overseas travel/residence, U.S. Military or prisoner of war experience (Agent Orange, immunizations, ALS, infectious, nutritional, and other risks)
    • Other potential environmental exposures: alcohol, illicit drug use, city vs. well water, diet, zinc-based denture adhesive use, others
  • Review of symptoms: weight loss, swallowing dysfunction, dysautonomia, endocrinopathy, anemia, skin and joint changes, others

Physical examination

In addition to neurologic examination, physical exam findings should screen for etiologic clues, assess overall function, and evaluate gait. A basic neuromuscular exam with a few clinic pearls is presented as follows10

HEENT: facial symmetry, pupillary responses, eyelid strength, vocal quality, inspection of tongue for atrophy or fasciculations
Respiratory: monitor for dyspnea during key exam components
Cardiovascular: heart rate variability, peripheral pulses, capillary refill
Skin: temperature, color, hair or lack thereof, nail bed changes (e.g., Mees’ lines)
Lymphatic: assess for lymphadenopathy


  • Gait assessment including heel walk, toe walk, monitor for pathology: steppage, vaulting, foot drop, ataxia, Trendelenburg
  • Balance: single leg stance, Romberg, tandem gait
  • Inspection for atrophy: foot intrinsics, calf (‘inverted champagne bottle’ shape), hand intrinsics, scapular atrophy or winging, paraspinals
  • Spine exam: range of motion, Spurling’s, straight leg raise, quadrant loading, etc.
  • Extremities: inspection for contractures; Tinel’s, Phalen’s, or other provocative maneuvers; palpation for enlarged peripheral nerves (superficial fibular, superficial radial, posterior auricular, others)
  • Foot exam: atrophy, pes cavus, hammertoe deformities, Charcot arthropathy, hypertrophic callouses, ulcerations, distal pulses
  • Hip and shoulder exam, when indicated


  • Manual muscle testing, including shoulder and hip girdle, axial strength (e.g., neck flexors and extensors); heel raises in single leg stance can better detect plantarflexion weakness.
  • Sensory exam
    • Vibration (early loss in large fiber neuropathies)
    • Proprioception (early loss in large fiber neuropathies)
    • Pinprick (often stocking or stocking-glove distribution loss)
    • Temperature
    • Light touch
    • Monofilament testing (loss of protective sensation)
    • Two-point discrimination may be useful in assessment of mononeuropathy
  • Muscle stretch/deep tendon reflexes
  • Pathological reflexes (Babinski, Hoffman, jaw jerk, others)

Functional assessment

Common functional impairments associated with peripheral neuropathy include balance and gait disturbances, falls, and fatigability. Assessment for orthotics, gait aids, and wheelchairs may be warranted. Evaluation of the home environment and need for equipment such as shower chairs, grab bars, handrails, and other accommodations is important. Activities of daily living may be impacted by impaired hand function resulting in difficulty with fasteners and other fine motor tasks, handwriting, eating, caregiving and homemaking. Painful neuropathies are also associated with patient-reported reduction in physical and emotional functioning, affective symptoms, and sleep problems.11

Laboratory studies

There is level C evidence that screening laboratory studies be considered for patients with polyneuropathy.12 This initial evaluation should include a complete blood count, comprehensive metabolic profile, fasting blood glucose, thyroid stimulating hormone, vitamin B12, and serum protein electrophoresis with immunofixation.25 Laboratory and additional diagnostic workup should be targeted based on clinical and electrodiagnostic findings.12

Routine laboratory screenings:

Suspected Axonopathy
(Pattern 2: Symmetric distal sensory loss with or without distal weakness):
Highest yield12

  • Fasting blood sugar; if negative then glucose tolerance test
  • Serum B12 with metabolites (methymalonic acid with/without homocysteine)
  • SPEP with immunofixation, UPEP, +/- quantitative immunoglobulins

Others to consider

  • Erythrocyte sedimentation rate and C-reactive protein
  • Rheumatoid factor (RF)
  • Antinuclear antibody (ANA)
  • TSH with reflexive T4
  • Complete blood count with differential
  • Complete metabolic panel
  • Serum folate

Suspected Demyelinating Polyneuropathy
(Pattern 3: Asymmetric distal weakness with sensory loss):

  • RF, anti-cyclic citrullinated peptide (anti-CCP) antibody
  • ANA panel (anti-dsDNA, anti-Sm, SS-A (Ro), SS-B (La), anti-RNP, anti-Jo, anti-centromere, Scl-70, others as indicated)
  • Anticytoplasmic antibodies: p-ANCA, c-ANCA
  • Cryoglobulins
  • Serum complement
  • Lyme titre

Laboratory workup for suspected neuronopathy (Pattern 9: Asymmetric proprioceptive sensory loss without weakness) is similar to that for demyelinating polyneuropathy.

Other specialty screenings

  • Serologies for various infections:
    • Campylobacter jejuni
    • Hepatitis
    • HIV
    • RPR
    • CMV
    • Others
  • Heavy metals from serum and/or 24-hour urine
  • Paraneoplastic panel (anti-Hu, others)
  • Autoantibodies:
    • Anti-MAG, anti-sulfatide: neuropathies associated with paraproteinemia
    • Anti-GM1: Multifocal motor neuropathy, AMAN
    • Anti-GQ1b: Miller-Fisher syndrome
    • Others

There is level A evidence for genetic testing in patients with suspected hereditary neuropathy and level C evidence in patents with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype12

  • CMT 1A: assay for PMP22 duplication
  • HNPP: assay for PMP22 deletion
  • X-linked CMT: Next Generation sequencing for connexin-32
  • CMT 2A: Next Generation sequencing for mitofusin 2

Supplemental assessment tools

History and physical exam are more likely to reveal peripheral neuropathy and do not require confirmation with electrodiagnostic studies. In fact, the role of this testing is being debated as studies have shown it has does not play much of a role in workup.25

There is level C evidence to support that patients with peripheral polyneuropathy should undergo electrodiagnostic testing if symptoms are concerning (i.e., acute onset, asymmetrical, autonomic symptoms, rapidly progressive) or if all initial workup is normal despite persistence of symptoms.25

There is currently no indication to order a magnetic resonance imaging (MRI) of the brain or spine for patients with peripheral neuropathy without signs or symptoms that suggest a brain or spine disorder. There is level C evidence to support this, however, in cases of polyradiculopathy, plexopathy, or radiculoplexus neuropathy an MRI may help localize an atypical neuropathy.25

Large fiber polyneuropathies can be confirmed via electrodiagnostic testing. Sufficient number and location of nerves should be examined to determine the pattern (axonal vs. demyelinating, motor vs. sensory) and distribution (symmetry, proximal vs. distal) of involvement. Axonopathy manifests as low CMAP amplitudes without significant prolongation of distal latencies or slowing of conduction velocity unless axonal loss is severe (e.g., less than 20-30% of the lower limit of normal). Criteria for demyelination are well-outlined in published guidelines6 but generally manifest as prolonged distal sensory and motor latencies and slow conduction velocities, with conduction block and temporal dispersion. Proximal conduction studies such as F waves, H-reflexes, and blink reflexes can be helpful adjuncts.

When exam findings are mild or moderate, nerve conduction studies should focus on the more involved limb, whereas they should focus on the least involved limb when exam findings suggest more severe disease.

Donofrio and Albers13 recommend a peripheral neuropathy protocol consisting of a fibular (EDB), tibial (AH), ulnar (hypothenar), and median (thenar) CMAPs with corresponding F-waves, sural (averaged if needed) and median SNAPs, followed by corresponding nerves on the contralateral limb if abnormal. Facial or blink reflex studies may be considered if cranial nerve involvement is suspected.  Needle electromyography (EMG) should include tibialis anterior, medial gastrocnemius, lumbar paraspinal muscles, possibly foot intrinsic muscles, and first dorsal interosseous (hand), followed by at least one contralateral muscle if any of the aforementioned are abnormal. Needle EMG is a pivotal component to evaluate for motor axonal loss, degree of denervation, and pattern of involvement and helps rule out competing diagnoses, such as radiculopathy(ies), myopathy, and other mimics of polyneuropathy (e.g., motor neuron disease, others).

Neuromuscular applications for diagnostic ultrasound are expanding beyond the assessment of entrapment neuropathy, now including assessment of optimal muscle for biopsy, fasciculations, atrophy, and conditions associated with peripheral nerve enlargement (CIDP, CMT, HNPP, amyloid).14

Peripheral nerve biopsy can be useful in the setting of asymmetric neuropathy with sensory loss and weakness, and particularly in the evaluation of suspected amyloid neuropathy, mononeuropathy multiplex due to vasculitis, demyelinating polyneuropathy (including atypical forms of CIDP), hereditary neuropathy, and leprosy.15,16 Literature is insufficient to recommend nerve biopsy for acquired, distal, symmetric, length-dependent peripheral neuropathies.16

Epidermal nerve fiber density testing via skin punch biopsy is a validated technique with level C evidence in the workup of small fiber neuropathy and potentially amyloidosis.16

There is level B evidence in support of the use of validated autonomic testing (R-R interval variation, sympathetic skin response, thermoregulatory sweat test, quantitative sudomotor axon reflex test or QSART, others) for suspected autonomic neuropathies.16

Laser doppler flare imaging is a method used to diagnose small fiber neuropathy and detect early manifestations of diabetes.21

Neuromuscular Medicine consultants fall into two polar groups: (A) “pragmatists” who aim to solve the clinical problem with minimal investigation, and (B) “completists” who seek to eliminate every possibility, however remote it may be, even when lacking therapeutic relevance. Pragmatists may miss rarities, whereas completists risk overuse of resources and even misdiagnosis if misled by false-positive results. It is important to maintain a balanced view and capitalize on the diagnostic clues to achieve not just a diagnosis, but clinical value. In other words, “do the right thing and not everything”.17

Consider urgent referral to neurology for acute, subacute, severe, or progressive symptoms with unremarkable workup.25

Early predictions of outcomes

Peripheral neuropathy outcomes are as varied as their etiologies. Critical illness neuropathy, for example, portends chronic disability and increased hospital mortality, whereas acquired demyelinating neuropathies respond favorably to immunotherapy. In general, neuropathies with extensive axonal loss, denervation and atrophy have a poor prognosis for full recovery. Loss of monofilament sensation can predict neuropathic ulceration in diabetic neuropathy.18 Since many forms of neuropathy are slowly progressive or stable, palliative therapies become the mainstay of treatment.

Rehabilitation Management and Treatments

See Part 2.

Cutting Edge/ Emerging and Unique Concepts and Practice

See Part 2.

Gaps in the Evidence-Based Knowledge

The Inflammatory Neuropathy Cause and Treatment (INCAT) overall disability sum score (ODSS) is a validated tool to quantify disability and track the course of AIDP/CIDP.19 Other validated tools include the Inflammatory Rasch-built Overall Disability Scale (I-RODS), which is a patient centered scale assessing activity limitations in patients with CIDP, GBS, and other polyneuropathies.22 This tool is noted to be more sensitive than the INCAT and suggested to be the primary disability measure for patients with CIDP given its effectiveness in measuring changes in the patient’s course. Treatment-induced Neuropathy Assessment Scale (TNAS v3.0) is a patient reported outcome measure used in patients who develop neuropathy secondary to cancer treatment.23 It was demonstrated to be a reliable and valid patient reported outcome tool, though more longitudinal testing is needed.

One study has shown that long COVID can cause small fiber neuropathy as soon as one month after onset of infection. It was found that in these patients, some improved with IVIG and corticosteroids while others recovered spontaneously.24 This study indicates further need to investigate the mechanism of COVID-19 in causing neuropathy.

Several studies have called out the lack of other well-developed clinimetric scales or measures with content validity, which stymies comparative effectiveness research and population-based/patient-reported outcomes research pertinent to peripheral neuropathy.


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  3. Dyck PJ, Dyck JB, Grant IA, et al. Ten steps in characterizing and diagnosing patients with peripheral neuropathy. Neurology 1996; 47:10-17.
  4. Pestronk A. Polyneuropathy Differential Diagnosis. Washington University St. Louis Neuromuscular Disease Center, website http://neuromuscular.wustl.edu/naltbrain.html; April 21, 2015; accessed 11/11/2017.
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  6. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol 2010; 17:356–363.
  7. Dumitru D, Amato AA, Zwarts, MJ. Electrodiagnostic medicine. Philadelphia: Hanley & Belfus; 2002.
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  9. Singer MA, Vernino SA, Wolfe GI. Idiopathic neuropathy: new paradigms, new promise. J of the Periph Nerv System, 2012:43-49.
  10. McDonald CM. Clinical Approach to the Diagnostic Evaluation of Hereditary and Acquired Neuromuscular Diseases. Physical Medicine and Rehabilitation Clinics of North America. 2012; 23(3):495-563.
  11. Mugdha G, Brandenburg NA, Dukes E, et al. Severity in Diabetic Peripheral Neuropathy is Associated with Patient Functioning, Symptom Levels of Anxiety and Depression, and Sleep. J Pain Symptom Manage. 2005; 30(4):374-85.
  12. England JD, Gronseth G, Franklin GT, et al. Practice parameter evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Muscle Nerve. 2009; 72:116-125.
  13. Donofrio PD, Albers JW. AAEM minimonograph 34: polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve 1990; 13:889–903.
  14. Hobson-Webb, LD. Neuromuscular ultrasound in polyneuropathies and motor neuron disease. Muscle Nerve 2013; 47:790–804.
  15. Said, G. Indications and usefulness of nerve biopsy. Archives of Neurology. 2002; 59(10): 1532-1539.
  16. England JD, Gronseth G, Franklin GT, et al. Practice parameter: the evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM&R. 2009; 1(1): 14-22.
  17. Misra UK, Kalita J, Nair PP. Diagnostic approach to peripheral neuropathy. Annals of Indian Academy of Neurology. 2008; 11(2):89-97.
  18. Paisey RB, Darby T, George AM, et al. Prediction of protective sensory loss, neuropathy and foot ulceration in type 2 diabetes. BMJ Open Diabetes Research and Care 2016; 4:
  19. Merkies ISJ, Schmitz PIM, van der Meché FGA, et al. Clinimetric evaluation of a new overall disability scale in immune mediated polyneuropathies. Journal of Neurology, Neurosurgery & Psychiatry 2002; 72:596-601.
  20. Elafros MA, Kvalsund MP, Callaghan BC. The Global Burden of Polyneuropathy—In Need of an Accurate Assessment. JAMA Neurol. 2022;79(6):537–538. doi:10.1001/jamaneurol.2022.0565
  21. Sander HW, Smith MZ, Weimer LH. Clinical evaluation of peripheral neuropathies [Internet]. MedLink Neurology. 2021 [cited 2023Apr4]. Available from: https://www.medlink.com/articles/clinical-evaluation-of-peripheral-neuropathies
  22. Allen, J. A., Gelinas, D. F., Lewis, R. A., Nowak, R. J., & Wolfe, G. I. (2017). Optimizing the use of outcome measures in chronic inflammatory demyelinating polyneuropathy. European Neurological Review13(1), 26-33. https://doi.org/10.17925/USN.2017.13.01.26
  23. Mendoza TR, Williams LA, Shi Q, et al. The Treatment-induced Neuropathy Assessment Scale (TNAS): a psychometric update following qualitative enrichment. J Patient Rep Outcomes. 2020;4(1):15. Published 2020 Feb 19. doi:10.1186/s41687-020-0180-8
  24. Oaklander AL, Mills AJ, Kelley M, et al. Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID. Neurol Neuroimmunol Neuroinflamm. 2022;9(3):e1146. Published 2022 Mar 1. doi:10.1212/NXI.0000000000001146
  25. Castelli G, Desai KM, Cantone RE. Peripheral Neuropathy: Evaluation and Differential Diagnosis. Am Fam Physician. 2020;102(12):732-739.

Original Version of the Topic

Karen Barr, MD.  Peripheral polyneuropathy: evaluation and differential diagnosis. 7/17/2013.

Previous Revision(s) of the Topic

Michele L. Arnold, MD.  Peripheral polyneuropathy part 1: evaluation and differential diagnosis. 2/14/2018.

Author Disclosure

McCasey Smith, MD, MS
Nothing to Disclose

Josephine Nwankwo
Nothing to Disclose