The Evaluation of Polyneuropathies

What?

The question “what?” refers to which nerve fiber modalities (sensory, motor, autonomic, or a combination) are involved. Identification of sensory nerve involvement allows the clinician to exclude from consideration neuromuscular diseases not associated with sensory dysfunction, such as myopathies, neuromuscular transmission disorders, or disease of the anterior horn cell (e.g., amyotrophic lateral sclerosis). When sensory features are present, the characterization of sensory symptoms as being positive or negative can be helpful because most acquired neuropathies are accompanied by positive neuropathic sensory symptoms (P-NSS) and most inherited polyneuropathies are not. P-NSS may be painful (“electric shock,” “burning,” “throbbing”) or painless (“tingling,” “swelling,” “bunched-up socks”). Most patients with polyneuropathy have some degree of motor nerve involvement—especially distally on examination or on EDX testing—that is sometimes overshadowed by sensory complaints. Symptoms suggesting autonomic nerve involvement, especially gastrointestinal (e.g., early satiety, constipation), cardiovascular (e.g., orthostatic symptoms), and pupillomotor (e.g., Adie pupil), can be important clues because the numbers of processes that cause clinically meaningful somatic plus autonomic polyneuropathy are relatively few and especially important to diagnose (table 1).^4,5 Most patients with polyneuropathy have some degree of motor nerve involvement—especially distally on examination or on EDX testing—that is sometimes overshadowed by sensory complaints”

Where?

“Where?” refers to the distribution of nerve involvement in terms of 1) the global distribution throughout the body and 2) the distribution of involvement along the nerves. It is important to determine whether a neuropathic process is length-dependent (e.g., distal) or not. Length-dependent polyneuropathies are common and often manifest symmetrically. In contrast, patients with non-length-dependent polyneuropathies might complain of proximal sensory or motor complaints (i.e., early symptoms in the hands). Distal, symmetric polyneuropathies usually have metabolic/toxic, idiopathic, or inherited etiologies, whereas asymmetric neuropathies are often immune-mediated or infectious.^1,3,5,–,7 There are, of course, exceptions, such as the clinical presentation of recurrent, painless, transient mononeuropathies in hereditary neuropathy with liability to pressure palsy. Polyneuropathy associated with immunoglobulin M (IgM) monoclonal protein or anti-MAG autoantibodies is another interesting exception that presents with slowly progressive, distal and symmetric sensory polyneuropathy. Some examples of non-length-dependent, asymmetric (acquired) polyneuropathies are polyradiculopathies (e.g., Lyme neuroborreliosis), polyradiculoneuropathies (e.g., Guillain-Barré syndrome [GBS], chronic inflammatory demyelinating polyradiculoneuropathy [CIDP]), dorsal root ganglionopathies (e.g., paraneoplastic subacute sensory neuronopathy, Sjögren-associated sensory ganglionopathy), plexopathies (often immune-mediated), and multiple mononeuropathies (often caused by vasculitis).

When?

“When?” refers to the temporal evolution, which can be thought of as including the onset and the progression. We prefer to describe symptom onset based on whether or not the neuropathic symptoms had a convincing date of onset. Most immune-mediated or infectious (e.g., Lyme neuroborreliosis) neuropathies have a definite date of onset. A less-exact date of onset suggests a toxic/metabolic, inherited, or idiopathic etiology. Symptom onset and tempo often correlate because they both represent the pace of disease progression. For example, patients with GBS present with a definite date of onset followed by rapid progression of impairment and disability. Conversely, the symptom onset of an inherited polyneuropathy is usually insidious and followed by very gradual progression.

What setting?

“What setting?” refers to the unique clinical circumstance of the patient. This characterization is done by considering the patient’s past medical history, current and past medications, social history, family history, and the review of systems. Knowledge of the risk factors of polyneuropathy and knowledge of symptoms and signs of the risk factors for neuropathy are necessary to take advantage of this information. When constructing the patient’s clinical setting, the clinician must remember to consider first the common causes of polyneuropathy (e.g., diabetes, alcohol, inherited) and search aggressively for any clinical clues that might suggest these etiologies. This is perhaps most important when evaluating a patient for an inherited polyneuropathy, particularly given how common they are. At a minimum, the clinician should ask specifically about each first-degree relative, for example, “Did either parent or any sibling have foot problems similar to yours?” Patients should also be asked at follow-up visits as patients often learn important family medical information only after their own diagnosis. Family members should be examined whenever possible. By doing this, clues are often uncovered that would have otherwise never been. Obtaining a precise history of alcohol intake is also very important and, in our experience, often performed perfunctorily by others. It is often illuminating to probe into an alcohol consumption history in a thorough, nonjudgmental, and nonthreatening way.⁸ Past medical and medication history are also important considerations for elaborating the patient’s unique clinical setting. Diabetes, renal disease, malnutrition, HIV, and paraproteinemia are some of the disorders that are risk factors. Toxic polyneuropathy caused by medication is common in the setting of certain chemotherapeutic or anti-HIV treatment exposures (table 2).^1,9 Age is another important consideration: young patients are much more likely to have a polyneuropathy on a genetic basis, elderly patients are much more likely to have idiopathic polyneuropathy, and middle-age patients are more likely to have acquired polyneuropathy.

The physician must also consider whether the rest of the characterization (i.e., “what?,” “where?,” “when?” characterization) fits with the clinical setting and also must consider other possible etiologies before implicating an etiology. For example, the comorbidity of diabetes in a patient with polyneuropathy does not necessarily prove diabetes is causative.¹⁰ The examination must also corroborate with the overall characterization. For example, we recently evaluated a 38-year-old man with diabetes complaining of sensory symptoms in the hands and feet whose examination demonstrated not only sensory loss but also pathologically brisk reflexes, prompting a workup that led to the diagnosis of large disk herniation causing a cervical myelopathy.

Electrodiagnostic testing.

The fifth step for characterizing a polyneuropathy utilizes EDX testing. EDX can confirm or refute the clinical characterization in terms of “what” and “where” and, to a lesser extent, “when.” EDX can also characterize the polyneuropathy as being primarily axonal or demyelinating. The metabolic/toxic and idiopathic neuropathies usually manifest with prominent axonal injury whereas immune-mediated and inherited neuropathies may be either predominantly axonal or predominantly demyelinating. For example, GBS and CIDP are 2 relatively common demyelinating immune-mediated poly(radiculo) neuropathies. Charcot-Marie-Tooth (CMT) disease 1, the most common group of inherited sensorimotor polyneuropathies, is predominantly demyelinating, whereas CMT2 is predominantly axonal. Nerve conduction studies are particularly helpful here, as patients with CMT1 will have uniform slowing of motor conduction velocities, almost always ≤35 m/s in the upper extremities and ≤28 m/s in the lower extremities. EDX can also help search for subclinical involvement and provide baseline parameters in case future EDX is necessary to monitor the patient's course. EDX will be normal in small-fiber polyneuropathy.¹¹

A detailed review of the important causes of polyneuropathy is beyond the scope of this review. Please consult other articles and chapters for information and for additional references about the individual causes of neuropathy. See table 1 for a list of common etiologies and proposed laboratory testing for various patterns of polyneuropathy. See table 2 for a list of some medications that can cause polyneuropathy.