Resident Editor: Michael Incze, M.D., MSEd

Faculty Editor: Ryan Laponis, M.D.

Background

• Prevalence
  • 8% of persons 55 and older
  • >26% of patients with type 2 diabetes mellitus
• The most common treatable causes are diabetes, hypothyroidism, and nutritional deficiencies

Signs and Symptoms

• The first step in the evaluation of the patient complaining of numbness, weakness, or paresthesias is to localize the lesion. See “Differential Diagnosis” below. 
• In addition to the historical features, one should ask about new medications, heavy metal or solvent exposure, HIV risk factors, alcohol consumption, recent viral illness, other systemic symptoms, and a family history of neurologic disease or foot deformities (for hereditary sensory-motor neuropathy, also known as Charcot-Marie-Tooth disease)
• Autonomic involvement may present as orthostasis, constipation or diarrhea, hyperhidrosis or anhidrosis, dry eyes, or erectile dysfunction.
• Painful neuropathy can be due to alcoholism, amyloidosis, chemotherapy, diabetes, or porphyria, or it can be idiopathic. 

Differential Diagnosis

• One must distinguish symmetric, distal polyneuropathy (AKA peripheral neuropathy) from a CNS lesion, radiculopathy, peripheral nerve plexus injury (plexopathy), or myopathy/neuromuscular junction disease.
  • CNS lesions present with upper motor neuron signs (spasticity, brisk deep tendon reflexes)
  • In radiculopathy, sensory symptoms follow a dermatomal distribution
  • Plexopathy (brachial plexopathy or lumbosacral plexopathy) symptoms are asymmetric with sensory and motor involvement of multiple nerves in one extremity.
• The diagnosis of peripheral neuropathy is likely if diminished ankle reflexes, paresthesias, and/or neuropathic pain are present
• A practical approach to diagnosis:
  • 1. Determine the pattern
    • distal symmetric polyneuropathy (stocking-glove distribution) – most common, many causes (most often diabetes)
    • asymmetric polyradiculopathy – Guillain-Barre, chronic inflammatory demyelinating polyradiculopathy (CIDP), HIV, Lyme, CMV, diphtheria, HCV, diabetes, sarcoidosis, multiple myeloma, porphyria, SLE, Sjogren syndrome, polyarteritis nodosa
    • focal mononeuropathies – due to trauma (peroneal neuropathy) or nerve entrapment (carpal tunnel syndrome)
    • multiple mononeuropathies (mono neuritis multiplex) – vasculitis (especially if acute), diabetes, lymphoma, sarcoidosis (causes similar to polyradiculopathy)
  • 2. Determine the nerve type(s) involved
    • sensory, motor, autonomic
    • large fiber: proprioception, vibration, motor (diminished reflexes)
    • small fiber (diabetes, amyloidosis, HIV, hereditary neuropathies): pinprick, temperature, autonomic
  • 3. Determine the time course
    • acute neuropathies (hours to days) include Guillain-Barre syndrome, vasculitis, toxin-induced (arsenic), porphyria, and medications (vincristine, dapsone, cisplatinum)
    • subacute neuropathies (days to weeks) include vitamin B12 deficiency, toxins (such as arsenic, thallium, alcohol, n-hexane), infections (Lyme disease, HIV), and paraneoplastic neuropathies
    • most neuropathies are chronic and slowly progressive
  • 4. Determine the etiology
    • once the above characteristics have been defined, many resources contain lists and tables of the various causes of neuropathy that fit these characteristics. The articles listed in the references are a great starting point.
    • perform a thorough med rec and substance use history with the patient, as several common medications and recreational drugs have been associated with peripheral neuropathy

Evaluation

Physical Exam

• A detailed motor and sensory exam should be performed, including testing vibratory, pinprick, temperature, and proprioceptive sensation. Deep tendon reflexes and a careful strength exam are necessary.
• Inspect for signs of muscle atrophy in affected areas
• Consider testing the autonomic nerves with orthostatic blood pressures

Labs/Tests

• All patients should get a CBC, metabolic panel, fasting glucose and/or HbA1c, TSH HIV, and vitamin B12 level
• Depending on exposure history and clinical suspicion, consider ESR/CRP, RPR, LFTs, B6 level, hepatitis serologies, Lyme Ab, SPEP/UPEP and/or serum-free light chains, ANA, ANCA, UA, and/or 24-hour urine for heavy metals/porphyria. 
• If history, physical, and laboratory evaluation do not yield a diagnosis, the next step is an Electrodiagnostic study (EMG/nerve conduction studies). It can distinguish among myopathy, axonal damage, and demyelinating conditions. Notably, small fiber neuropathies may give normal nerve conduction studies.
• Testing for uncommon conditions could include anti-sulfatide antibodies for autoimmune polyneuropathy, cryoglobulins for cryoglobulinemia, SS-A/SS-B antibodies for Sjogren syndrome, CSF analysis (albuminocytologic dissociation) for acute or chronic inflammatory demyelinating neuropathy, or genetic testing for hereditary neuropathies
• If after these studies the cause remains unknown, other potential investigations include skin biopsy for small fiber neuropathies, nerve biopsy, or autonomic testing.

Treatment

• Treatment has two goals: 1) controlling the underlying disease process (glycemic control, repletion of a nutritional deficiency, thyroid hormone replacement, or treatment of a lymphoproliferative disorder) and 2) controlling pain and other bothersome symptoms
• · Urgent and aggressive management is required when encountering acute inflammatory neuropathies or vasculitis. Consider mechanical ventilation if forced vital capacity is less than 20mL/kg or maximal inspiratory pressure is less than 30cm of water.
• CIDP from an underlying lymphoproliferative disorder or paraproteinemia responds to intravenous immunoglobulin, glucocorticoids, or plasma exchange
• Multiple pharmacologic agents have been studied for the treatment of peripheral neuropathy. Tricyclic antidepressants, SNRIs, gabapentin, pregabalin, topiramate, carbamazepine, topical lidocaine, or capsaicin have all shown efficacy in treating various types of peripheral neuropathy. Opioids have a limited if any, role in treating chronic neuropathic pain.

When to refer

• Urgent evaluation necessary: acute onset or rapidly progressive symptoms, evidence of respiratory compromise, predominant motor involvement, autonomic symptoms, asymmetry, concern for vasculitis or autoimmune etiology
• Specialty evaluation is recommended when the diagnosis is uncertain after initial history, physical, and lab workup. If you are considering referring the patient for an EMG, also consider a neurology consult.
• Consider referral to Pain Management Clinic for optimization of multimodal chronic pain management for refractory symptoms

References

Azhary H, Farooq MU, Bhanushali M, et al. Peripheral neuropathy: differential diagnosis and management. Am Fam Physician. 2010; 81(7):887–892.

Vavra MW, Rubin DI. The Peripheral Neuropathy Evaluation in an Office-Based Neurology Setting. Seminars in neurology. Vol 31; 2011:102–114.