Peripheral neuropathy refers to the various abnormal symptoms which result from damage to the peripheral nervous system and most commonly begin as impaired sensation of the distal aspects of the extremities.  The symptoms vary according to which nerves are affected.  When large motor nerves are affected, weakness is the main manifestation and muscle atrophy may be noted on the physical exam.  Loss of reflexes in the affected limb indicates significant demyelination has occurred and that the neuropathy is a chronic abnormality; whereas, preserved reflexes implicate the neuropathy is acute.  The finding of thickened palpable nerves on physical exam may indicate underlying leprosy, chronic inflammatory demyelinating polyradiculoneuopathy, Refsum's disease (peripheral neuropathy, cerebellar ataxia, retinitis pigmentosa, with bone and skin abnormalities inhereted in a recessive pattern), amyloidosis, or hereditary neuropathy with pressure palsy. The symptoms of sensory nerve damage may be more varied and include paresthesias (“pins and needles” sensations), dysesthesias (unpleasant sensation in excess of the stimulus causing it), hypoesthesia (decreased or absent ability of sensory perception), and hyperesthesia (an increased sensory perception in excess of the stimulus causing it).  Impaired proprioception (the ability to determine position of a limb without visual imput) and vibration sense indicate large-fiber neuropathy; whereas, an impaired ability to sense pain or temperature is seen with small-fiber neuropathy.  Demyelinating neuropathies are characterized by paresthesias and weakness without atrophy; whereas, axonal neuropathies produce atrophy. When the autonomic nervous system is involved symptoms may include orthostatic hypotension, resting tachycardia, syncope, constipation, urinary retention, and impotence.

The characteristic symptoms of a small fiber neuropathy include pain, burning, numbness, and autonomic dysfunction with a characteristic stocking-glove distribution and normal reflexes. Symptoms tend to flare at night and interfere with the patient's sleep habits. Causes of small fiber neuropathies include impaired glucose metabolism (both diabetes mellitus and impaired glucose tolerance), connective tissue diseases (rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus), hypothyroidism, hyperthyroidism, vitamin B12 deficiency, HIV infection, hepatitis C virus infection, celiac disease, restless legs syndrome, and paraneoplastic syndromes. If symptoms are consistent with small fiber neuropathy, then treatment may be started as a work-up for the underlying etiology is initiated. If the diagnosis is in doubt then skin biopsy with  immunostaining with anti-protein gene product 9.5 antibody with determination of small nerve fiber density (lower than normal densities are diagnostic) or quantitative sudomotor axon reflex testing may be undertaken.

     The differential diagnosis of neuropathy is extensive.  A family history of neuropathy is consistent with Charcot-Marie-Tooth disease or hereditary neuropathy with predisposition to pressure palsies (HNPP).  Patients should be questioned regarding the symptoms of diabetes mellitus as a glove and stocking neuropathy is a common presentation of hyperglycemia including impaired glucose tolerance.  The social history should evaluate alcohol consumption, and if an ischemic neuropathy is suspected, the history should be directed towards risk factors (family history of peripheral vascular disease, tobacco history, or a medical history of hypertension, diabetes mellitus, or hypercholesterolemia).  Symptoms occurring after trauma or in association with back pain may indicate nerve root compression with radiculopathy (sciatica) or HNPP.  Mononeuropathies (carpal tunnel syndrome, cubital tunnel syndrome, sciatica, meralgia paresthetica, etc) are often caused by entrapment of a peripheral nerve; however, diabetes mellitus is also associated with mononeuropathies (mononeuritis multiplex).

     After a careful history and physical examination with careful attention to the neurologic exam along with an appropriate biochemical work-up, nerve-conduction studies and electromyography (NC/EMG) are often helpful in confirming the presence of a neuropathy and the type of nerve injury involved.  EMG also helps distinguish neuropathy from myopathy.  In some cases, the characteristic changes noted on NC/EMG may help implicate or establish a diagnosis such as with radiation plexopathies.  With small fiber neuropathies, there is a lack of abnormalities on NC/EMG which is characteristic and should prompt an appropriate evaluation for the eitologies of small fiber neuropathies. In appropriate cases, laboratory studies to include TSH, glucose, hemoglobin A1C, B12, syphilis serologies, ANA, RF, urine protein, HIV testing, BUN/creatinine, hepatitis C virus serology, serum immunoelectrophoresis or immunofixation, and ESR may provide a helpful evaluation.  CPK muscle isoenzyme or an aldolase level may be useful to screen for myopathy. Further evaluation may require whole nerve biopsy or skin-punch biopsy and immunohistochemical staining of the peripheral nerves. If nerve root compression is suspected, MRI scanning of the spine may provide a useful evaluation.  In certain cases such as vasculitic neuropathy, amyloidosis or sarcoidosis, nerve biopsy may prove useful for establishing the diagnosis.

Specific labs for specific neuropathies include PMP22 gene on chromosome 17 duplication or presence of the P0 gene in Charcot-Marie-Tooth disease type 1a, connexin-32 gene mutation in Charcot-Marie-Tooth X, chromosome 17 deletion with hereditary neuropathy with pressure palsy, IgG anti-GQ1b with the Miller-Fisher syndrome (Guillain-Barre variant with ophthalmoparesis, ataxia, and areflexia), and GM1 with multifocal motor neuropathy with conduction block. Guillain-Barre and chronic inflammatory demyelinating polyradiculoneuropathy are characterized by an elevated protein level and a lack of pleocytosis on CSF examination.

     Therapy includes treating the underlying etiology when possible.  In patients with diabetic neuropathy, tight glycemic control should be instituted.  However, this does not always provide relief.  Medications used to treat the symptoms of neuropathy and provide relief include capsaicin cream, tricyclic antidepressants, carbamazepine, gabapentin, pregabalin, topical lidoderm, topical clonidine, and mexiletine HCl.  Refractory cases may require narcotics, acupuncture or transcutaneous/percutaneous electrical nerve stimulation for pain control.  Nerve root compression such as with chronic lumbar pain and sciatica may respond to epidural steroid injections or surgical diskectomy. Consultation with a neurologist may be helpful and if no etiology can be determined then involving a pain specialist may be required.

     Often times, the autonomic nervous system is involved in patients with long standing poorly controlled diabetes mellitus.  Cardiovascular autonomic neuropathy may manifest as a resting heart rate greater than 90 bpm or postural hypotension.  Gastric autonomic neuropathy may manifest as either gastroparesis or diarrhea.  Excessive variability in glucose levels is characteristic of gastroparesis as is early satiety, nausea, and postprandial vomiting.  Gastroparesis can be treated by having patients ingest frequent, small volume meals and by using promotility agents (metoclopramide or erythromycin).  Diarrhea may be treated with cyclic antibiotics using tetracycline, amoxicillin or metronidazole.  Erectile dysfunction is a common neuropathy in diabetic males and may be treated with phophodiesterase inhibitors, penile implants, suction devices, or injections.

Treatment of neuropathy is aimed at correcting the underlying etiology and pain control. Medications used in providing pain control include gabapentin, pregabalin, tricyclic antidepressants, carbamazepam, tramadol, the serotonin-norepinephrine reuptake inhibitor duloxetine, and narcotics. Topical agents to include capsaicin or lidoderm patches may be helpful.