> Table of Contents > Neuropathy, Peripheral
Neuropathy, Peripheral
Amy Chen, MD, PhD
David N. Herrmann, MBBCh
image BASICS
DESCRIPTION
  • Peripheral neuropathy (PN) is a functional or structural disorder of the peripheral nervous system (PNS).
  • PN affects any combination of motor, sensory, or autonomic nerves.
  • The motor PNS comprises spinal cord motor neurons, their nerve roots that combine to form plexus, and branches that form individual nerves innervating skeletal muscles. Peripheral motor involvement causes muscle atrophy, weakness, cramps, and fasciculations.
  • The sensory PNS consists of sensory organs, which transmit touch, vibration, and position sensation in large-diameter myelinated fibers; pain and temperature in small-diameter, lightly myelinated and unmyelinated C fibers to the dorsal root ganglia. Sensory signals are relayed to the central nervous system (CNS) for integration. Disorders of sensory nerves produce negative phenomena (loss of sensibility, lack of balance) or heightened phenomena (tingling or pain). Large sensory fiber dysfunction impairs touch and vibration sensation, whereas small fiber sensory neuropathy (SFN) affects pin and thermal sensation and causes neuropathic pain.
  • The autonomic nervous system (ANS) includes the sympathetic and parasympathetic systems. ANS dysfunction causes cardiovascular, gastrointestinal, and sudomotor symptoms.
  • The PNS can be affected from the cell body (sensory ganglionopathy or motor neuronopathy), root (radiculopathy), or plexus (plexopathy) to the nerve (demyelinating or axonal neuropathy).
EPIDEMIOLOGY
Prevalence
Approximately 2.4% of general population or 8% of people >55 years old, are affected by distal symmetric PN, the most common form of PN.
ETIOLOGY AND PATHOPHYSIOLOGY
  • PN can be acquired or hereditary.
  • The most common cause of acquired PN is diabetes.
  • Other categories of acquired PN with illustrative examples are the following:
    • Vascular: ischemia, vasculitis
    • Infectious: HIV, hepatitis C, cryoglobulinemia, Lyme disease
    • Traumatic: compression, crush, or transection
    • Autoimmune: rheumatoid arthritis, Sjögren, postinfectious Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP)
    • Metabolic: diabetes, renal failure, hypothyroidism, vitamin B12 deficiency, celiac disease
    • Iatrogenic/toxic: chemotherapy, platinum, taxanes, metronidazole, colchicine, infliximab, alcoholism
    • Idiopathic: 30% of PN
    • Neoplastic/paraneoplastic: paraproteinemia, Waldenstrom macroglobulinemia, multiple myeloma, amyloidosis, neurofibromatosis
  • PN occurs due to demyelination or axonal degeneration.
  • Demyelination results from Schwann cell dysfunction, mutations in myelin protein genes, or direct damage to myelin sheaths.
  • Axonal degeneration occurs when injury/dysfunction occurs at the cell body or axon.
Genetics
  • Approximately 50% of undiagnosed PN is hereditary.
  • Currently, there are over 70 known genetic causes of hereditary PN.
  • Charcot-Marie-Tooth (CMT) neuropathies: the most common hereditary PN
    • CMT1A (duplication of the PMP22 gene) is the most common CMT.
    • A PMP22 deletion causes hereditary neuropathy with liability to pressure palsy (HNPP)
RISK FACTORS
Systemic disorders predispose to PN.
GENERAL PREVENTION
  • Healthy nutrition and avoidance of alcoholism and of pressure at nerve entrapment sites
  • Surveillance for glucose dysmetabolism and tight glycemic control may prevent diabetic PN.
image DIAGNOSIS
PHYSICAL EXAM
  • Based on exam, a functional (sensory: small-fiber vs. large-fiber vs. mixed, sensorimotor, motor, autonomic) and anatomic pattern of PN (distal symmetric, multifocal, or focal) should be established.
  • Cognition preserved in isolated PN.
  • Cranial nerves may be involved with focal or multifocal PN (e.g., bifacial weakness may occur with GBS, Lyme disease, sarcoidosis, among other causes).
  • Stocking/glove sensory loss is typical of distal symmetric sensory PN (e.g., diabetes).
  • Isolated reduced pin or thermal sensation or allodynia suggests a pure SFN.
  • Reduced vibration and joint position sense suggests large-fiber sensory neuropathy; when severe, a Romberg sign is present, and gait is wide-based or ataxic.
  • Distal muscle atrophy and weaknesses of toe extension and finger abduction are often present with distal symmetric axonal PN.
  • In acquired demyelinating PN (e.g., GBS or CIDP), weakness is commonly both proximal and distal.
  • Deep tendon reflexes may be reduced or absent, distally at the ankles in large-fiber axonal PN, or diffusely in demyelinating PN.
  • High arched or flat feet or hammer toes suggest hereditary PN.
DIFFERENTIAL DIAGNOSIS
The following categories of PN can be identified (differential diagnosis [DDx] listed when applicable):
  • Pure sensory neuropathy
    • DDx: SFN, sensory ganglionopathy, polyradiculopathy
  • Distal symmetric sensorimotor axonal PN
    • Most common type of PN
    • DDx: distal acquired demyelinating symmetric PN (DADS)
  • Motor predominant PN
    • DDx: motor neuron disease, polyradiculopathy, immune-mediated multifocal motor neuropathy (MMN)
  • Mononeuropathy
    • Most likely due to compression, entrapment, or trauma
    • DDx: monoradiculopathy
  • Mononeuropathy multiplex
    • DDx: plexopathy, polyradiculopathy
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Nerve conduction studies and electromyography (NCS/EMG)
    • Best performed by physicians with specialty training in electrodiagnostic medicine
    • Delineate axonal versus demyelinating, anatomic pattern, chronicity, and severity of PN.
  • Blood tests
    • CBC, BUN, creatinine, fasting glucose, HgA1C, vitamin B12, serum protein electrophoresis, and immunofixation
  • Specialized skin biopsy
    • In clinically suspected SFN if NCS/EMG is normal
    • Analysis of lower limb epidermal nerve fiber density (ENFD) (1)[A]
  • Autonomic tests
    • Not routinely done but useful to characterize autonomic PN
  • Neuroimaging
    • Generally not indicated in evaluation of PN but useful in evaluation of brachial plexopathies, radiculopathies, or where findings are attributable to the CNS
Follow-Up Tests & Special Considerations
  • Additional blood tests are done based on the medical history, the PN type, and NCS/EMG findings.
  • Genetic testing for diagnosis of hereditary PN should be ordered by neurologists with expertise in PN.
  • Screen patients with distal symmetric PN for unhealthy alcohol use with CAGE-AID or AUDIT-C.
P.715

Diagnostic Procedures/Other
  • Nerve biopsy (sural or superficial peroneal nerve): useful if vasculitis, amyloidosis, granulomatous disorders, or neoplastic infiltration is suspected; rarely helpful in late-onset chronic, slowly progressive distal symmetric PN
  • Lumbar puncture
    • Cytoalbuminologic dissociation in GBS or CIDP
    • Infection, inflammation, or neoplasia in polyradiculopathies
Test Interpretation
  • Demyelinating PN: disproportionate slowing of conduction velocities or prolonged distal latencies on NCS
  • Axonal PN: reduced amplitude in sensory or motor responses, with relatively preserved conduction velocities on NCS
  • Reduced ENFD on distal leg skin biopsies is supportive of SFN.
image TREATMENT
GENERAL MEASURES
Manage associated medical conditions; diseasemodifying therapy for specific forms of PN (e.g., CIDP); symptomatic relief of pain and dysautonomia; rehabilitation to optimize function.
MEDICATION
First Line
  • Treatment of neuropathic pain: evidence of efficacy derived from clinical trials in diabetic painful neuropathy (DPN) and postherpetic neuralgia (PHN):
  • Pregabalin: for DPN and PHN
  • Duloxetine: for DPN
  • Lidocaine patch: for PHN
  • Gabapentin: (off-label) for DPN
  • Tricyclic antidepressants: (off-label) for DPN
  • Venlafaxine: (off-label) for DPN
  • Tramadol: (off-label) for DPN
  • Targeted treatment for underlying systemic conditions:
    • Glycemic control, thyroid hormone supplementation, vitamin supplementation, antimicrobial therapy (e.g., Lyme disease, HIV), glucocorticoids for sarcoidosis, and cytotoxic therapy for vasculitis
  • Immunotherapy for dysimmune PN
    • Intravenous immunoglobulin (IVIG): within the first 2 weeks of GBS to hasten recovery (2)[A]; as a first-line alternative to corticosteroids for treatment of CIDP (3)[A]; and for prevention of secondary axonal loss in MMN (4)[A]
      • Loading dose 2 g/kg body weight divided into 2 to 5 days; maintenance regimen variable for CIDP and MMN
      • Adverse effects (AE): headache, fever, hypertension, and rarely, pulmonary embolism
    • Plasma exchange: first agent shown to improve functional outcome for patients with GBS (5)[A]; short-term benefit in CIDP (6)[A]
      • AE: catheter complication, hypotension, and others
    • Corticosteroids: a first-line option in treatment of CIDP (7)[C]; oral or pulsed IV regimen can induce remission
  • Treatment of autonomic symptoms
    • Compression stockings, hydration, midodrine, and fludrocortisone for orthostatic hypotension
    • Pyridostigmine for immune-mediated dysautonomia (off-label)
ISSUES FOR REFERRAL
  • Rapidly progressive symptoms, suspected demyelinating PN, or hereditary PN should be referred to a neurologist with expertise in neuromuscular disorders.
  • Patients with vasculitic PN should be referred to rheumatology.
  • Patients with paraproteinemia should have a skeletal bone survey and be referred to hematology.
  • Patients with imbalance, ataxia, or falls should be referred to physical therapy for gait and balance training.
ADDITIONAL THERAPIES
  • Combination therapy (e.g., gabapentin with TCA or venlafaxine or tramadol) can be more effective than monotherapy for neuropathic pain.
  • Long-acting opiates can be considered for refractory neuropathic pain.
  • Additional immunosuppressant agents (e.g., cyclophosphamide) may be used in refractory chronic dysimmune PN.
SURGERY/OTHER PROCEDURES
  • Decompressive surgery for entrapment neuropathy (e.g., carpal tunnel syndrome)
  • Foot and ankle surgery to improve symptoms or function in hereditary PN
  • Radiation, surgery, or bone marrow transplantation for plasmacytoma or osteosclerotic myeloma or POEMS syndrome
  • Liver transplantation for amyloidotic PN
COMPLEMENTARY & ALTERNATIVE MEDICINE
Low-intensity transcutaneous electrical nerve stimulation (TENS), acupuncture, mediation
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Patients with suspected GBS should be admitted for diagnosis, monitoring (30-60% may develop cardiovascular or respiratory failure), and for acute treatment.
  • Elective intubation may be required in GBS when forced vital capacity is <15 mL/kg body weight.
  • Other rapidly progressive undiagnosed PNs that impair independent ambulation may require admission.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Physical therapy and gait assistive devices as needed
  • Flu vaccination should be avoided in the first year following GBS.
PROGNOSIS
  • Late-onset idiopathic distal symmetric axonal PN are indolent
  • 80% of GBS have a near complete or good recovery. 80% of CIDP have moderate or good response with treatment but can be relapsing.
REFERENCES
1. Lauria G, Hsieh ST, Johansson O, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010;17(7):903-912, e44-e49.
2. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2014;(9):CD002063.
3. Nobile-Orazio E, Cocito D, Jann S, et al. Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol. 2012;11(6):493-502.
4. Cats EA, van der Pol WL, Piepers S, et al. Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy. Neurology. 2010;75(9):818-825.
5. Plasmapheresis and acute Guillain-Barré syndrome. The Guillain-Barré syndrome Study Group. Neurology. 1985;35(8):1096-1104.
6. Dyck PJ, Daube J, O'Brien P, et al. Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy. N Engl J Med. 1986;314(8):461-465.
7. Dyck PJ, O'Brien PC, Oviatt KF, et al. Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment. Ann Neurol. 1982;11(2):136-141.
Codes
&NA;
ICD10
  • G62.9 Polyneuropathy, unspecified
  • G60.9 Hereditary and idiopathic neuropathy, unspecified
  • G60.8 Other hereditary and idiopathic neuropathies
Clinical Pearls
&NA;
  • There are many causes of PN. Diagnosis is made by history and physical exam, targeted laboratory testing, NCS/EMG, skin biopsy, or ANS testing.
  • Consider hereditary neuropathy if patient has an early age of PN symptom onset, family history of PN, or foot deformity.
  • GBS is monophasic and progresses for up to 4 weeks; CIDP progresses beyond 8 weeks, and if untreated, usually has a progressive course.