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Am Fam Physician. 2020;102(12):732-739

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial affiliations.

Peripheral neuropathy, a common neurologic problem encountered by family physicians, can be classified clinically by the anatomic pattern of presenting symptoms and, if indicated, by results of electrodiagnostic studies for axonal and demyelinating disease. The prevalence of peripheral neuropathy in the general population ranges from 1% to 7%, with higher rates among those older than 50 years. Common identifiable causes include diabetes mellitus, nerve compression or injury, alcohol use, toxin exposure, hereditary diseases, and nutritional deficiencies. Peripheral neuropathy is idiopathic in 25% to 46% of cases. Diagnosis requires a comprehensive history, physical examination, and judicious laboratory testing. Early peripheral neuropathy may present as sensory alterations that are often progressive, including sensory loss, numbness, pain, or burning sensations in a “stocking and glove” distribution of the extremities. Later stages may involve proximal numbness, distal weakness, or atrophy. Physical examination should include a comprehensive neurologic and musculoskeletal evaluation. If the peripheral nervous system is identified as the likely source of the patient's symptoms, evaluation for potential underlying etiologies should initially focus on treatable causes. Initial laboratory evaluation includes a complete blood count; a comprehensive metabolic profile; fasting blood glucose, vitamin B12, and thyroid-stimulating hormone levels; and serum protein electrophoresis with immunofixation. If the initial evaluation is inconclusive, referral to a neurologist for additional testing (e.g., electrodiagnostic studies, specific antibody assays, nerve biopsy) should be considered. Treatment of peripheral neuropathy focuses on managing the underlying etiology. Several classes of medications, including gabapentinoids and antidepressants, can help alleviate neuropathic pain.

Peripheral neuropathy is one of the most common neurologic problems encountered by family physicians.1,2 Peripheral neuropathy can be classified clinically by the anatomic pattern of presenting symptoms and, if indicated, by results of electrodiagnostic studies for axonal and demyelinating disease.2,3 Peripheral nerves consist of motor, sensory, and autonomic nerve fibers. It is important to differentiate peripheral neuropathy from other disorders with similar presentations and to identify and address potential causes.

RecommendationSponsoring organization
Do not order a magnetic resonance imaging scan of the spine or brain for patients with only peripheral neuropathy (without signs or symptoms suggesting a brain or spine disorder).American Association of Neuromuscular and Electrodiagnostic Medicine

Epidemiology

The prevalence of peripheral neuropathy in the general population ranges from 1% to 7%, with higher rates among those older than 50 years.4,5 The most common identifiable causes of peripheral neuropathy include diabetes mellitus, nerve compression or injury, alcohol use, toxin exposure, hereditary diseases, and nutritional deficiencies.

Peripheral neuropathy affects 25% to 50% of patients with diabetes, depending on factors such as the patient's age, number of years with diabetes, and level of diabetes control.6,7 Peripheral neuropathy is idiopathic in 25% to 46% of cases, and this is more common with increasing patient age.8,9

Evaluation

The pathophysiology of peripheral neuropathy results from injury to small- or large-diameter nerve fibers. Damage can occur to the cell body, axon, myelin sheath, or a combination of these, leading to symptoms such as numbness, tingling, pain, and weakness.3,10 Large nerve fibers mediate motor, sensory, vibration, and proprioception functions. Small nerve fibers mediate pain, temperature, and autonomic functions.1

A systematic approach should be used to evaluate and manage patients with symptoms of peripheral neuropathy (Figure 1).11 Distinguishing peripheral neuropathy from central nervous system (CNS) and other pathology is an important first step. CNS lesions should be suspected in patients with speech disturbance, ataxia, visual disturbance, cranial nerve involvement, or bowel and bladder incontinence. Evaluation for nerve compression, radiculopathy, or peripheral nerve root lesions should be considered in patients with symptoms that are asymmetrical; follow a dermatomal pattern; or are associated with numbness, imbalance, falls, ataxia, and paresthesias.

If peripheral neuropathy is suspected, a differential diagnosis should be formulated through a history and physical examination.12 The anatomic distribution of peripheral neuropathy symptoms can be categorized as focal, multifocal, or symmetrical (Table 113 ). Symmetrical peripheral neuropathy can be further classified as distal or proximal. Less common patterns of peripheral neuropathy involve the cranial nerves, autonomic nerves, and nerves of the upper extremities.

Focal
Acromegaly
Amyloidosis
Direct trauma to nerves, such as repeated minor trauma, traction, injection, cold exposure, burns, radiation
Entrapment/compressive neuropathies
Ischemic lesions
Leprosy
Myxedema
Neoplastic infiltration
Rheumatoid arthritis
Sarcoidosis
Symptoms
Sensory and motor symptoms
Predominantly sensory symptoms, including pain and paresthesias
In severe or chronic cases, motor symptoms may include weakness and atrophy
Multifocal
Connective tissue diseasesInfections (HIV/AIDS)
Diabetes mellitusLeprosy
Hereditary predisposition to pressure palsiesVasculitis
Symptoms
Sensory and motor symptoms are asymmetrical and affect multiple areas of the body
Sensory symptoms include pain, paresthesias, vibration, and proprioception
Motor symptoms may include weakness and atrophy
Autonomic symptoms may be present
Symmetrical distal sensorimotor
Acromegaly
Alcohol use
Amyloidosis
Celiac disease
Chronic kidney disease
Connective tissue diseases
Cryoglobulinemia
Diabetes
Gouty neuropathy
Hypothyroidism/hyperthyroidism
Infections (HIV/AIDS, Lyme disease)
Inherited diseases (Charcot-Marie-Tooth disease, familial amyloidosis)
Liver disease
Malignancy
Medication induced (see Table 2)
Nutritional deficiencies (vitamins B6, B12, and E; thiamine; folate; copper; phosphate)
Postgastrectomy syndrome
Toxin exposure (heavy metals, carbon monoxide, acrylamide, hexacarbons, ethylene oxide, glue)
Vasculitis
Whipple disease
Symptoms
Distal sensory and motor symptoms involve both sides symmetrically
Sensory symptoms include pain, paresthesias, vibration, and proprioception
Motor symptoms may include weakness and atrophy
Autonomic symptoms may be present
Symmetrical proximal motor
Acute arsenic poisoning
Chronic inflammatory demyelinating polyradiculoneuropathy
Diabetes
Guillain-Barré syndrome
Hypothyroidism
Infections (HIV/AIDS, Lyme disease, diphtheria)
Malignancies
Porphyria
Vincristine exposure
Symptoms
Motor symptoms include weakness and atrophy of proximal muscles in a symmetrical anatomic distribution
Less common patterns
Neuropathies with cranial nerve involvement
Diabetes
Guillain-Barré syndrome
Infections (HIV/AIDS, Lyme disease, diphtheria)
Neoplastic invasion of the skull base or meninges
Sarcoidosis
Symptoms
Sensory and motor symptoms involve the cranial nerves, such as problems with speech, swallowing, taste, and sensory or autonomic functions; coughing; head, pharyngeal, or neck pain; and weakness of the trapezius, sternocleidomastoid, or tongue muscles
Neuropathies predominant in upper extremities
Diabetes
Guillain-Barré syndrome
Hereditary amyloid neuropathy type II
Hereditary motor sensory neuropathy
Lead toxicity
Porphyria
Vitamin B12 deficiency
Symptoms
Sensory and motor symptoms predominantly involve the upper limbs
Sensory symptoms include pain, paresthesias, vibration, and proprioception
Motor symptoms may include weakness and atrophy
Neuropathies with autonomic involvement
AmyloidosisParaneoplastic neuropathy
DiabetesPorphyria
LymphomaThallium, arsenic, or mercury toxicity
Symptoms
Autonomic symptoms may include orthostatic intolerance, gastroparesis, bowel and bladder changes, erectile dysfunction, and blurry vision

History

A detailed history of symptoms is essential. Symptom onset and timing may be most helpful in narrowing the differential diagnosis. Location and distribution help distinguish focal, multifocal, and symmetrical patterns. Aggravating and remitting factors can be clues to exogenous causes, and a complete review of systems should be performed to evaluate for autonomic and vasomotor symptoms.

Early peripheral neuropathy may present as sensory alterations that are often progressive, including sensory loss, numbness, pain, or burning sensations in a “stocking and glove” distribution of the extremities.3 Later stages may involve proximal numbness, distal weakness, or atrophy.3 One-third of patients with peripheral neuropathy have neuropathic pain.1 Other common presenting symptoms include a stabbing or electric shock sensation, allodynia, hyperalgesia, and hyperesthesia.1,4,13,14 Patients may also report autonomic symptoms such as orthostatic intolerance, gastroparesis, changes in bowel and bladder function, erectile dysfunction, and blurry vision, or vasomotor symptoms such as dryness of the eyes, mouth, or skin, and burning or flushing.1

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