Acquired Polyneuropathies

What?

“What?” refers to what nerve fiber modalities (motor, sensory, autonomic, or a combination) are involved. The identification of sensory nerve involvement, at a minimum, allows the clinician to exclude other neuromuscular diseases not associated with sensory dysfunction, such as disorders of anterior horn cells (e.g., amyotrophic lateral sclerosis), neuromuscular transmission (e.g., myasthenia gravis), or of muscle (myopathy). When sensory symptoms and signs are present, it is useful to characterize neuropathic sensory symptoms into “positive” or “negative” because acquired neuropathies are usually accompanied by positive neuropathic sensory symptoms and inherited neuropathies are usually not. Positive sensory symptoms may be painful (e.g., “burning,” “freezing,” or “shooting”), usually indicating involvement of small fibers, or symptoms may be painless (e.g., “tingling” or “swelling”). The presence of pain can be a very helpful in differentiating features because it limits the list of possible etiologies ( Box 67.2 ). Positive sensory symptoms and pain are common complaints for patients with diabetic, vasculitic, or alcoholic neuropathy or those with Guillain-Barré syndrome (GBS). Exaggerated discomfort to painful stimuli (hyperalgesia) and to nonpainful stimuli (allodynia) can occur. Painless symptoms, both negative (“numbness,” “woodiness”) and positive (“socks bunched up under one's feet,” “swelling”), are more common in patients with large-fiber involvement. Sensory ataxia from loss of proprioceptive large sensory fibers is another of the negative neuropathic sensory symptoms; patients report imbalance in the dark or after they close their eyes in the shower.

Identification of autonomic nerve involvement can be an important clue because only a small number of neuropathic processes affect both autonomic and somatic nerves (e.g., GBS, paraneoplastic neuropathy, diabetic neuropathy, amyloid neuropathy) ( Box 67.3 ). Autonomic symptoms include light-headedness, syncope, diarrhea, constipation, postprandial bloating, early satiety, urinary complaints, erectile dysfunction, abnormal or absent sweating, and dry mouth and eyes ( Fig. 67.1 ). In the foregoing vignette, our patient's symptoms of burning numbness as well as dysautonomia suggested early involvement of small unmyelinated sensory and autonomic fibers, a pattern commonly seen in neuropathy associated with amyloidosis.

Where?

“Where?” refers to the distribution of nerve damage. An important diagnostic watershed is the determination of whether the process is “length-dependent” (e.g., distal) or not. Length-dependent neuropathies manifest first in the feet and are symmetric. Non–length-dependent neuropathies are not necessarily evident initially in the feet and may be asymmetric, focal, or multifocal. The etiology of length-dependent neuropathies is usually inherited, metabolic/toxic, or idiopathic, whereas a neuropathy that is not length-dependent is often caused by an immune-mediated or infectious process. Some examples of non–length-dependent neuropathies are polyradiculoneuropathies (e.g., GBS), plexopathies (often inflammatory), sensory ganglionopathy (e.g., paraneoplastic subacute sensory neuronopathy in the setting of small-cell lung cancer), and multifocal mononeuropathies (e.g., mononeuritis multiplex caused by vasculitis). Our vignette's patient had a combination of two patterns; length-dependent polyneuropathy and focal median neuropathies at the wrist (carpal tunnel syndrome), both produced by infiltration of amyloid fibrils.

When?

“When?” refers to the temporal evolution of the neuropathy. Because of confusion over what is meant by “acute,” “subacute,” and “chronic,” it is often best to describe symptom onset based on whether or not the neuropathic symptoms had a compelling, definite date of onset. A definite date of symptom onset almost always indicates an acute or subacute onset typical of an immune-mediated or infectious etiology. A less exact date of onset suggests gradual or insidious onset, indicative of inherited, idiopathic, or toxic/metabolic etiologies. The pace of progression following symptom onset is also an important consideration. Symptom onset and pace of progression often correlate in a predictable manner, owing largely to the underlying mechanism. As an example, mononeuritis multiplex caused by systemic vasculitis typically presents with a series of painful mononeuropathies of acute onset, occurring one after the other with the rapid development of significant morbidity. In our patient, on the other hand, the onset was less well defined but the pace of progression was relatively rapid, rendering the patient significantly disabled within several short months. This tempo is too fast for diabetic or inherited neuropathies and too slow for an infectious etiology. It is, however, quite consistent with an immune-mediated or infiltrative process.

What Setting?

“What setting?” refers to an elaboration of the unique clinical circumstance of the individual patient. This is done by determining what in the patient's past medical history, medication list, social history, family history, and the review of systems may be relevant ( Fig. 67.2 ). An understanding of the significance of these clinical factors requires knowledge of the risk factors of neuropathy and of the clinical features of the diseases that may be risk factors for neuropathy. For example, unexplained weight loss raises concern for vasculitis or malignancy (e.g., small-cell lung cancer), both of which cause an immune-mediated neuropathy. The neuropathy secondary to malignancy (e.g., paraneoplastic neuropathy) usually presents differently than vasculitic neuropathy, so it is usually not too difficult to differentiate these two etiologies ( Fig. 67.3 ). A clinical setting of known diabetes mellitus or known kidney disease would elevate those comorbidities on the differential diagnosis. Heavy metal poisoning or other intoxication, although rare, must be considered in the patient with systemic symptoms (e.g., nausea, vomiting) and other manifestations suspicious for poisoning ( Fig. 67.4 ). As in the case of our vignette, known IgG kappa monoclonal gammopathy of unknown significance (MGUS) was an important clue alerting the examiner to the possibility of a neuropathy related to paraproteinemia.

Electrodiagnosis

The fifth step in characterization requires nerve conduction studies (NCSs) and electromyography (EMG). NCS and EMG can contribute to (or rarely refute) the clinical characterization in terms of “what” and “where,” as well as provide another view of the temporal evolution (“when”). NCS and EMG can also characterize the neuropathy as being primarily axonal or demyelinating. Neuropathies with axonal injury are far more common than those with demyelination, but identification of demyelinating features is very important because acquired demyelinating polyneuropathies (e.g., GBS, CIDP, MMN) are often immune-mediated and treatable ( Box 67.4 ). However, our historical concept of dividing neuropathies into disorders of myelin or axon may be too simplistic. It is now recognized that in some immune-mediated neuropathies, the primary targets are proteins and ion channels in the region of the node of Ranvier ( Fig. 67.5 ). Acute motor axonal neuropathy (AMAN), the axonal motor variant of GBS, is the prototypic nodopathy; antibodies against GM1 ganglioside—an axolemmal nodal antigen—lead to disruption of sodium channels. The ultimate outcome can be a spectrum ranging from fully reversible conduction failure to irreversible axonal degeneration.

Clinical Presentation

Polyneuropathies are among the most common neurologic disorders; the length-dependent pattern is the most prevalent. Also referred to as distal symmetric polyneuropathies (DSPs), the majority of these are axonal, symmetric, and sensory-predominant. Nutrition and other functions of nerve axons rely on metabolic activity of their cell bodies (dorsal root ganglia or anterior horn cells) and on effective axonal transport. When these mechanisms are disrupted, it is the most distal parts of the longest axons (i.e., in the toes) that become most vulnerable and degenerate, leading to the distal-to-proximal gradient of sensory and motor abnormalities (“dying back”). Demonstration of the length-dependent pattern in a patient with polyneuropathy is among the essential exercises in clinical neurology; in a typical patient, the neuropathy does not reach the fingers until lower extremity symptoms have ascended to the knee level. In advanced cases, the scalp vertex and midline trunk are involved. A similar distal-to-proximal gradient applies to the motor exam and muscle stretch reflexes.

Typical patients with length-dependent polyneuropathies (LDPNs) note tingling, numbness, or pain in their toes and feet. They describe a sense of swelling, feeling as though their socks are bunched up under their feet, or a sensation of having cotton between their toes. Motor involvement is often present on EMG but not clinically. If it is seen clinically, big-toe extensors are the first affected muscles. Ankle muscle stretch reflexes can be absent or diminished.

As in the case of our vignette, dissociation of separate sensory modalities may lend valuable clues. A small-fiber sensory neuropathy (SFN) is suggested by burning in the feet of patients with impaired pain and thermal sensation and sparing of vibration and proprioceptive sense. The EMG is characteristically normal. Most SFNs do not have identifiable etiologic mechanisms, but careful evaluation for diabetes, prediabetes, and other components of metabolic syndrome is required (see Box 67.2 ).

Most but not all sensory LDPNs have subclinical motor involvement on EMG. Those that are pure sensory neuropathies can be seen in the context of diabetes mellitus, renal disease, vitamin deficiencies, various toxins, Sjögren syndrome, and amyloidosis. Some probably represent a primary sensory ganglionopathy with distal-predominant presentation. Neuropathic pain and dysautonomia are variably present, depending on the underlying etiology (see Box 67.3 ).

Motor-predominant LDPNs are primarily genetically determined (i.e., CMT and distal hereditary motor neuropathies [dHMNs]) or, less commonly, immunologically acquired multifocal motor neuropathies presenting in a confluent LDPN-like fashion.