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Neuropathy, Peripheral

- Specialized skin biopsy - In clinically suspected SFN if NCS/EMG is normal - Analysis of lower limb epidermal nerve fiber density (ENFD) (1)[A]

- Neuroimaging - Generally not indicated in evaluation of PN but useful in evaluation of brachial plexopathies, radiculopathies, or where findings are attributable to the CNS

- Lumbar puncture - Cytoalbuminologic dissociation in GBS or CIDP - Infection, inflammation, or neoplasia in polyradiculopathies

- 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

para>Hemibody deficits or sensory loss below a spinal cord level suggest a CNS process.

ALERT

Hyperreflexia and spasticity are upper motor neuron signs not seen with isolated PN.

DIFFERENTIAL DIAGNOSIS

The following categories of PN can be identified (differential diagnosis [DDx] listed when applicable):

  • Pure sensory neuropathyDDx: SFN, sensory ganglionopathy, polyradiculopathy
  • Distal symmetric sensorimotor axonal PNMost common type of PNDDx: distal acquired demyelinating symmetric PN (DADS)
  • Motor predominant PNDDx: motor neuron disease, polyradiculopathy, immune-mediated multifocal motor neuropathy (MMN)
  • MononeuropathyMost likely due to compression, entrapment, or traumaDDx: monoradiculopathy
  • Mononeuropathy multiplexDDx: 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 medicineDelineate axonal versus demyelinating, anatomic pattern, chronicity, and severity of PN.
  • Blood testsCBC, BUN, creatinine, fasting glucose, HgA1C, vitamin B12, serum protein electrophoresis, and immunofixation
  • Specialized skin biopsyIn clinically suspected SFN if NCS/EMG is normalAnalysis of lower limb epidermal nerve fiber density (ENFD) (1)[A]
  • Autonomic testsNot routinely done but useful to characterize autonomic PN
  • NeuroimagingGenerally 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.

ALERT

Ordering of laboratory batteries (e.g., peripheral nerve antibody panels) without careful consideration of the clinical and NCS/EMG features should be avoided.

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 punctureCytoalbuminologic dissociation in GBS or CIDPInfection, 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.

TREATMENT

GENERAL MEASURES

Manage associated medical conditions; disease-modifying 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 PNIntravenous 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 MMNAdverse effects (AE): headache, fever, hypertension, and rarely pulmonary embolismPlasma 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 othersCorticosteroids: a first-line option in treatment of CIDP (7)[C]; oral or pulsed IV regimen can induce remission
  • Treatment of autonomic symptomsCompression stockings, hydration, midodrine, and fludrocortisone for orthostatic hypotensionPyridostigmine 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.

ALERT

Opiates have significant side effects and may cause rebound headaches, tolerance, and dependence.

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

ALERT

Vitamin B6 supplementation may cause peripheral neurotoxicity and should be avoided except for a deficiency state.

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.

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

11 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 " e49.22 Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barre syndrome. Cochrane Database Syst Rev. 2014;(9):CD002063.33 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 " 502.44 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 " 825.55 Plasmapheresis and acute Guillain-Barre syndrome. The Guillain-Barre syndrome Study Group. Neurology. 1985;35(8):1096 " 1104.66 Dyck PJ, Daube J, O 'Brien P, et al. Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy. N Engl J Med. 1986;314(8):461 " 465.77 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

ICD10

  • G62.9 Polyneuropathy, unspecified
  • G60.9 Hereditary and idiopathic neuropathy, unspecified
  • G60.8 Other hereditary and idiopathic neuropathies
  • G60.0 Hereditary motor and sensory neuropathy
  • G62.89 Other specified polyneuropathies
  • G90.09 Other idiopathic peripheral autonomic neuropathy
  • G90.9 Disorder of the autonomic nervous system, unspecified

ICD9

  • 337.00 Idiopathic peripheral autonomic neuropathy, unspecified
  • 337.09 Other idiopathic peripheral autonomic neuropathy
  • 337.1 Peripheral autonomic neuropathy in disorders classified elsewhere
  • 337.9 Unspecified disorder of autonomic nervous system
  • 356.0 Hereditary peripheral neuropathy
  • 356.2 Hereditary sensory neuropathy
  • 356.8 Other specified idiopathic peripheral neuropathy
  • 356.9 Unspecified hereditary and idiopathic peripheral neuropathy

SNOMED

  • 128208007 peripheral axonal neuropathy (disorder)
  • 193157005 Hereditary and idiopathic peripheral neuropathy
  • 230551000 Peripheral neuropathy - hereditary or idiopathic (disorder)
  • 23414001 Peripheral demyelinating neuropathy
  • 277879009 Autonomic neuropathy (disorder)
  • 302226006 peripheral nerve disease (disorder)
  • 95662005 Sensory neuropathy (disorder)
  • 95663000 Peripheral motor neuropathy (disorder)

CLINICAL PEARLS

  • 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.