Peripheral Polyneuropathy Part 1: Evaluation and Differential Diagnosis

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.

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

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.

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 trajectory is variable and hinges upon the course of the underlying etiology. 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.

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.

Since the diagnosis of peripheral neuropathy relies heavily on pattern recognition, a thorough history will provide initial clues:¹⁰

• 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 exam findings focus not soley on the neurologic exam, but also should screen for etiologic clues, and assess overall function and gait safety. A basic neuromuscular exam with a few clinic pearls is presented as follows:¹⁰

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

Musculoskeletal:

• 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

Neurologic:

• 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)

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 problems¹¹.

There is level C evidence that screening laboratory studies be considered for patients with polyneuropathy.¹² 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 yield:¹²

• 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 phenotype:¹²

• 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

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

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

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.

1. Hanewinckel R, van Oijen M, Ikram MA, et al. The epidemiology and risk factors of chronic polyneuropathy.European Journal of Epidemiology. 2016;31:5-20.
2. Barohn RJ, Amato AA. Pattern Recognition Approach to Neuropathy and Neuronopathy. Neurology Clinics 2013; 31(2): 343–361.
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.
5. Poncelet AN. An Algorithm for the Evaluation of Peripheral Neuropathy. Am Fam Physician.1998; 57(4):755-764.
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.
8. Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol. 1981; 10(3):222-6.
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.

Original Version of the Topic

Karen Barr, MD.  Peripheral polyneuropathy: evaluation and differential diagnosis. 07/17/2013.