Polyneuropathy that involves the distal aspects of the limbs (at least initially) in a symmetric pattern is a common neurologic presentation. Sometimes referred to as a “stocking-glove” distribution, the most typical symptoms are numbness and tingling, which can take on a dysesthetic and painful quality in some patients. Symptoms tend to slowly progress in a length-dependent manner. When motor involvement occurs, it is typically milder than sensory symptoms.
Some causes of distal symmetric polyneuropathy may be apparent from the history. Most prominent of these is diabetes, which is the most common identifiable cause of polyneuropathy. Heavy, chronic alcohol use and numerous drugs have also been implicated. Chemotherapeutic agents, particularly platinum-containing agents, amiodarone, and oversupplementation of vitamin B6 (pyridoxine), are common offending agents. In chemotherapy-associated polyneuropathy, patients commonly note sensory disturbances near the latter portion of treatment, which continues to worsen for a period of time after the treatment cessation (“drift” or “coasting”). A family history of polyneuropathy, particularly at a young age, suggests a genetic cause. Most known hereditary neuropathies are dominantly inherited (e.g., Charcot-Marie-Tooth disease). It is important when inquiring about family history to focus not just on diagnosed polyneuropathy but also on functional symptoms (difficulty walking/falls) or other details (high arches and hammertoes) that may not have been diagnosed as neuropathy in previous generations. It is usually desirable to test a panel of genetic mutations associated with polyneuropathy rather than testing single genes when screening for familial neuropathies.
The duration of diabetes should be considered in comparison to the severity of disease. For example, if a patient has a severe neuropathy with recent onset of diabetes, other causes should be considered. It is reasonable to check a B12 level in all diabetic or alcoholic patients with neuropathy to exclude coexistent B12 deficiency.
Young age, rapid progression over a short period of time, very severe symptoms, and predominant motor involvement are unusual in common mild or idiopathic polyneuropathies and are “red flags” indicating the need for more detailed investigation. This will typically include electromyography (EMG) and nerve conduction studies to characterize the type of neuropathy, and extensive blood testing to identify an etiology. When these red flags are absent, a more basic, limited investigation consisting of testing for undiagnosed diabetes (Hgb1AC and/or 2-hour glucose tolerance test), B12 deficiency, and paraprotenemia (serum protein electrophoresis [SPEP] with immunofixation) is typically sufficient.
If the B12 level is in the low-normal range, a methylmalonic acid (MMA) level should be sent. An elevated MMA in this setting may indicate relative B12 deficiency.
Vasculitic neuropathies are caused by an immune-mediated attack on blood vessels supplying nerves. Vasculitic neuropathies can be seen in isolation or with systemic vasculitis. While often associated with an asymmetric pattern, a significant minority present with a distal symmetric polyneuropathy. Most patients experience pain and paresthesias in the affected nerves. Sedimentation rate and C-reactive protein are elevated in most patients with vasculitic neuropathy but are not specific. An antineutrophil cytoplasmic antibody (ANCA) is a more specific serum test seen in patients with some systemic vasculitides. The presence of other rheumatologic markers may suggest vasculitis in the setting of another rheumatologic condition.
Amyloidosis is caused by the deposition of protein fibrils that aggregate in tissues. Amyloid neuropathy can be familial or acquired. In primary amyloid, an immunoglobulin light chain is deposited in the tissues. Secondary amyloid related to other chronic rheumatologic disease is not associated with neuropathy. Familial amyloidosis is most commonly caused by transthyretin (TTR) gene mutations, though there are other known genetic causes. TTR amyloid is a target of new specific therapies, such as inotersen and patisiran, and it is therefore important to identify patients with TTR mutations.
Polyneuropathies related to heavy metal exposures are a frequent concern of patients but an atypical cause of neuropathy. Specific occupations and systemic symptoms such as gastrointestinal symptoms may raise suspicion for a toxic exposure. Lead neuropathy can be seen in children who ingest lead-based paints and can cause progressive weakness affecting the wrist and finger extensors with relative preservation of sensation.
Paraneoplastic neuropathies occur in patients with a variety of cancers. Anti-Hu (Antineuron nuclear antigen [ANNA1]) is most commonly seen with small cell lung cancer (SCLC) and is associated with distal sensory polyneuropathies or pure non–length-dependent sensory ganglionopathies. Collapsing response mediator protein 5 (CRMP-5) antibodies are associated with SCLC and thymoma. Amphiphysin is associated with SCLC and breast cancer. In addition to polyneuropathy these antibodies are associated with various central nervous system syndromes including encephalomyelitis, limbic encephalitis, and cerebellar degeneration.