It is not always easy to decide if a peripheral neuropathy is present and clinically significant, especially with predominantly sensory symptomatology or when additional nervous system pathology is present. Common motor and sensory symptoms can be due to many other peripheral or central nervous system causes. Of 267 consecutive biopsies from the St. Michael’s laboratory (1987–1993), 33 were found to be normal or insignificantly abnormal; a diagnosis other than peripheral neuropathy was ultimately made in most, including plexopathy, radiculopathy, myelopathy, neuromuscular junction disorder, or myopathy. Others report similar findings (Prineas 1970). Electrophysiological tests are extremely important in resolving this problem but are not 100 % sensitive (vide infra). Neurological examination is also helpful in excluding a central nervous system etiology. Since many neuropathies are distal and symmetric, muscle bulk in the hands and feet should be assessed. Foot deformities, such as hammer toes and pes cavus may be seen in chronic neuropathies. Hyporeflexia or areflexia in the anatomical distribution of symptoms should be present in most peripheral neuropathies. Sensory examination should be guided by the differential diagnosis derived from history, looking specifically for sensory loss in a pattern suggesting a lesion of an individual nerve, multiple nerves, a nerve root, or in a distal symmetrical (glove and stocking) distribution. Small fiber (pain, temperature) and large fiber (vibration, proprioception) modalities should be assessed.

History, physical examination, and electrophysiological testing clarify the spatial pattern of the patient’s peripheral nerve problem. A mononeuropathy affects one nerve only. A mononeuropathy multiplex involves several individual nerve trunks, including nerve roots or cranial nerves. A polyneuropathy is a generalized disorder of peripheral nerves, with clinical findings usually symmetrical and length dependent (more pronounced distally). Making this syndromic diagnosis is important, for it narrows the diagnostic possibilities considerably and directs further testing. One would not, for example, biopsy a sural nerve if there was no evidence of disease anywhere except for isolated radial or common peroneal nerve palsy. Electrophysiological tests are critical for detection of subclinical polyneuropathy or multifocal nerve disease.

The boundary between mononeuropathy multiplex and polyneuropathy is often unclear. As the number of individual nerves involved increases, deficits become confluent and the clinical picture may be similar to that of a distally predominant polyneuropathy (Waxman et al. 1976). Again, electrophysiological testing may reveal evidence that the abnormalities are asymmetric or that there is prominent proximal involvement, both favoring a confluent mononeuropathy multiplex (Vavra and Rubin 2011; Olney 1992).

Most neuropathies impair both motor and sensory functions. Early, patients usually complain of distal sensory disturbances (paresthesias, numbness), as they are unlikely to notice distal intrinsic foot muscle weakness. In such cases, careful examination and electrophysiological testing are critical to clarify the fiber types involved. Clinically, it is important to determine if predominantly small or large sensory fibers are affected. Loss of pain and temperature sensation (small fiber) with relative sparing of joint position and vibration modalities (large fiber) is evidence of a small fiber neuropathy. This pattern is uncommon but extremely useful if found, for the differential diagnosis is limited (Table 7.​7). More common and nonspecific are nonselective fiber loss or more prominent involvement of large fibers. Notably, deep tendon reflexes and routine electrophysiological testing do not assess small fiber function and thus may be entirely normal in this setting. Small fiber neuropathies often involve the autonomic nervous system, and testing of autonomic reflexes provides some information about unmyelinated fiber pathology.

Pure sensory or pure motor neuropathies have specific differential diagnostic implications (Tables 8.1 and 8.2). Neuropathies with predominant small fiber and/or autonomic involvement are listed in Table 8.3.

In neurological parlance, an acute process evolves over less than 2–4 weeks, a chronic process evolves over years, and a subacute process lies in between (usually months to a year or two). The distinction is important, since the differential diagnosis of acute neuropathy is considerably more limited (Table 8.4). In general, an acute presentation should make one think of Guillain–Barre syndrome (GBS) or vasculitis and more rarely infections, porphyria, or some toxins (e.g., arsenic). A relapsing course is often associated with inflammatory conditions such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or vasculitis but can also occur with porphyria.