Causes of peripheral neuropathy: Diabetes and beyond
Leg paresthesias can be challenging to evaluate because of the varied causes and clinical presentations. This diagnostic guide with at-a-glance tables can help.
After taking a detailed history and performing a physical exam on a patient with lower extremity numbness and tingling, electrodiagnostic testing (EDX) and laboratory testing can help further elucidate the diagnosis.
EDX can be considered an extension of the physical exam. It can assess and characterize the proportion of motor vs sensory involvement, the severity of symptoms, and distribution of deficits and dysfunction.3 EDX studies consist of both electromyography (EMG) and nerve conduction studies (NCS). These tests are complementary and should be performed together. They have essentially no contraindications, although they are usually not performed on patients who have open sores or cellulitis. EMG is avoided in certain muscles in anticoagulated patients, primarily the paraspinal muscles and tibialis anterior, to avoid either an epidural hematoma or compartment syndrome.
A systematic evaluation of sequential muscles and nerves can identify polyneuropathy, entrapment neuropathy, plexopathy, or radiculopathy. Even a normal study can be informative. For example, EDX can provide information only on large fiber nerves; small nerve fibers cannot be tested. Therefore, a normal EDX in certain clinical scenarios suggests a small fiber neuropathy, which can be confirmed by skin biopsy.
Laboratory testing is a useful adjunct because the possible causes of peripheral neuropathy are vast. According to expert opinion, lab work that should be ordered routinely when evaluating lower extremity peripheral neuropathy includes a complete blood cell count, erythrocyte sedimentation rate, fasting blood glucose (and possibly hemoglobin A1c), thyroid studies, renal function studies, and vitamin B12 level.1-3 If a patient’s B12 level is <400 pg/mL, also test methylmalonic acid and homocysteine levels due to their greater diagnostic yield.3
Serum protein electrophoresis or serum immunofixation electrophoresis are also recommended in patients over age 60, because monoclonal gammopathy is a common cause of peripheral neuropathy in this age group.1,3 If the history and physical warrant, laboratory tests for paraneoplastic, autoimmune, infectious, or toxic etiologies can be performed.
Small fiber neuropathy
Small fiber neuropathy can present similarly to DSP, with distal painful paresthesias, but can spread to the upper extremities within a few weeks or months from onset, while DSP spreads to the hands years after onset. Small fiber neuropathy is also associated with early autonomic dysfunction. Examination usually reveals decreased sensation distally, but reflexes and strength are normal.
Common causes of small fiber neuropathy are diabetes, glucose intolerance, metabolic syndrome, hypo/hyperthyroidism, monoclonal gammopathy, alcohol abuse, vitamin B12 deficiency, and hypertriglyceridemia.7 Less common causes include Sjögren’s syndrome, HIV, Lyme disease, sarcoidosis, heavy metal toxicity, amyloidosis, and celiac disease.7
Testing and treatment. Skin biopsy is used to confirm the diagnosis of small fiber neuropathy.7 (EDX results are normal.7) Persistent pain can be treated with the same agents discussed above for treating DSP.
Acquired demyelinating neuropathy
Acquired demyelinating neuropathy is a rare condition, but one in which prompt recognition and treatment can prevent significant neurologic decline. There are both acute and chronic types of acquired demyelinating neuropathies.
Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy. Nearly two-thirds of patients with GBS report a previous respiratory or gastrointestinal illness; cytomegalovirus and Campylobacter jejuni are the most frequently associated infections.8
The onset of GBS often involves pain in the back or limbs, followed by a rapid progression of sensory loss and weakness (over days to a few weeks) that typically starts in the feet and moves upward.8 Though the typical presentation of GBS is “ascending,” there are frequent exceptions to this pattern.8 Physical exam shows weakness, sensory loss, and absent reflexes. Severe cases can result in complete paralysis, even of extraocular movements. Autonomic dysfunction is common.
Testing. EDX and lumbar puncture are needed to accurately diagnose GBS.8 EDX initially may be unremarkable, but over time, areas of demyelination become apparent. Lumbar puncture shows albuminocytologic dissociation (no white cells, elevated protein).
Treatment. Patients with GBS are initially managed as inpatients because 33% of cases lead to respiratory failure.9 Treatments include intravenous immunoglobulin (IVIg) or plasmapheresis; both have similar outcomes, speeding neurologic recovery time but not affecting overall long-term prognosis.10 Response to treatment is often not immediate, and some patients continue to worsen after treatment.8 Still, long-term prognosis is good, even for severely affected patients, as long as they receive good supportive care. The relapse rate is between 2% and 6%.8
In chronic inflammatory demyelinating polyneuropathy (CIDP), patients develop stepwise nerve dysfunction over many weeks to months. One nerve is affected, then another, usually in a different limb. There is generally no antecedent illness, and pain is infrequent.8 Progressive limb weakness is by far the most common presentation, and manifests as a foot drop or wrist drop. Patients may report difficulty getting up from a chair, walking up stairs, or opening jars.8 Facial or extraocular nerve involvement is uncommon, as is respiratory involvement.8 Neurologic exam shows absent reflexes, weakness, and loss of sensation in the distribution of a particular nerve or nerves.
