Polyneuropathy

Key Question No. 1: What Is the Temporal Course and Progression of the Polyneuropathy (Acute, Subacute, Chronic; Progressive, Stepwise, Relapsing/Remitting)?

The temporal course and progression can be obtained by the history alone and often confirmed by electrophysiologic studies. Most polyneuropathies are chronic, and their onset cannot be easily determined. Acute polyneuropathies are notably less common ( Box 29.1 ). Among them, Guillain-Barré syndrome (GBS) (and its most common variant, acute inflammatory demyelinating polyneuropathy [AIDP]) is the most distinctive, with an onset over a few days or a few weeks at most. Similarly, most polyneuropathies are slowly progressive ( Fig. 29.2 ). Polyneuropathies that progress in a stepwise fashion are infrequent and are often associated with a mononeuropathy multiplex pattern (discussed later). Likewise, the history of a relapsing/remitting course is distinctly unusual and suggests either an intermittent exposure/intoxication or a variant of chronic inflammatory demyelinating polyneuropathy (CIDP).

Key Question No. 2: Which Fiber Types Are Involved (Motor, Large Sensory, Small Sensory, Autonomic)?

The next step is to determine which fiber types are involved. This information is obtained primarily from the history and confirmed by physical examination and electrophysiologic tests. Nerve fibers can be categorized either by the modality carried (motor, sensory, autonomic) or by fiber size. All motor fibers are large-diameter, myelinated fibers, whereas all autonomic fibers are small-diameter, mostly unmyelinated fibers. However, sensory fibers may be either large or small in diameter. Large sensory fibers mediate vibration, proprioception, and touch, whereas small sensory fibers convey pain and temperature sensations.

When nerve is diseased, it can react in a limited number of ways. Thus, many peripheral nerve disorders present with similar symptoms despite different etiologies. Symptoms and signs of nerve dysfunction result either from lack of function ( negative symptoms and signs) or from abnormal function or overfunctioning ( positive symptoms and signs). For example, anyone who has fallen asleep on his or her arm can remember the initial numbness or lack of feeling (negative symptoms), followed by intense pins-and-needles paresthesias (positive symptoms) as circulation is restored. Characteristic positive or negative sensory symptoms and signs caused by diseased nerves help one recognize which fiber types are involved ( Table 29.1 ).

Determining which fiber types are involved has important diagnostic implications. Most polyneuropathies involve both sensory and motor fibers on electrophysiologic testing, even though, clinically, most distal axonal polyneuropathies exhibit sensory symptoms and findings long before the disease process becomes sufficiently severe to cause actual weakness. Patients with certain hereditary polyneuropathies (e.g., Charcot-Marie-Tooth [CMT] polyneuropathy) and conditions such as lead poisoning, porphyria, and GBS may exhibit predominantly motor symptoms and signs. On the sensory side, pure sensory neuropathies also are unusual and often suggest a primary process affecting the dorsal root ganglia. These sensory neuronopathies are quite rare and are characteristically seen acutely or subacutely as a paraneoplastic syndrome, postinfectious process, or associated with Sjögren syndrome or pyridoxine (B ₆ ) intoxication. Chronic sensory neuronopathies may be seen in the inherited sensory neuropathies and as a component of some inherited neurodegenerative conditions (e.g., Friedreich’s ataxia).

Large and small fibers are affected in most polyneuropathies. Only a few polyneuropathies preferentially affect small fibers ( Box 29.2 ). Manifestations include autonomic dysfunction and a distal sensory deficit, particularly for pinprick, often associated with painful, burning dysesthesias. It is essential to appreciate that routine NCSs assess only large myelinated fibers. A patient who has a pure small-fiber polyneuropathy, with complete sparing of the large fibers , may have completely normal electrophysiologic studies. Conversely, large-fiber polyneuropathies always show abnormalities on electrophysiologic testing. Predominantly large-fiber polyneuropathies result in clinical sensory deficits (particularly for vibration and touch), weakness, and loss of tendon reflexes, with little or no autonomic and pain/temperature sensation loss.

Key Question No. 3: What Is the Pattern of the Polyneuropathy (Distal Dying Back [Distal-to-Proximal Gradient], Short Nerves, Multiple Nerves; Symmetry, Asymmetry)?

The overall pattern of the polyneuropathy is determined largely based on the clinical examination and is supplemented and confirmed by electrophysiologic studies. In most polyneuropathies, there is a distal-to-proximal gradient of symptoms and signs. Distal symptoms and findings occur in most polyneuropathies, in part indicating the frequency with which axonal loss is the underlying pathologic process. Most axonal polyneuropathies exhibit a distal-to-proximal, dying back pattern, reflecting that the chance of damage to a nerve is length dependent ( Fig. 29.3 ). Thus, the longest nerves are affected first, resulting in a stocking-glove distribution of symptoms. Patients initially develop numbness or weakness of the toes and feet, which then slowly progresses up the leg. When the process reaches the upper calf, the fingertips become involved as well, because the distance from the lumbosacral spinal cord to the upper calf is the same as that from the cervical spinal cord to the fingertips. Only rarely will polyneuropathies preferentially affect the shorter, more proximal nerves before the distal ones (e.g., in porphyria, proximal diabetic neuropathy, and some cases of inflammatory demyelinating polyneuropathy).

After determining whether a distal-to-proximal gradient is present, one should next assess the polyneuropathy for symmetry. Nearly all polyneuropathies are symmetric. The presence of any significant asymmetry is a key finding; it usually excludes a large number of toxic, metabolic, and genetic conditions that cause only a symmetric pattern . Asymmetry implies the possibility of (1) a mononeuropathy multiplex pattern, (2) a superimposed radiculopathy or entrapment neuropathy, or (3) a variant of CIDP. NCSs and EMG frequently are useful in sorting out these possibilities.

The pattern of a mononeuropathy multiplex is one of the most important patterns to recognize and differentiate from the length-dependent, dying-back, axonal polyneuropathy. The clinical presentation is distinctive: there is an asymmetric, stepwise progression of individual cranial and/or peripheral neuropathies ( Fig. 29.4 ). Over time, a confluent pattern may develop, which may be difficult to distinguish from a generalized polyneuropathy. In most cases, the individual neuropathies are of named nerves (i.e., median, ulnar, peroneal, etc.) as opposed to small nerve twigs. Mononeuropathy multiplex has a limited differential diagnosis ( Box 29.3 ) and most often occurs in the setting of vasculitis and vasculitic neuropathy. As each subsequent nerve is infarcted, pain develops (often severe), followed hours or days later by weakness and numbness in the nerve’s distribution. Although other organ systems are often involved, the initial clinical presentation of systemic vasculitis may involve only the peripheral nervous system. Indeed, there are now well-recognized cases in which vasculitis remains confined to the peripheral nervous system.

Key Question No. 4: What Is the Underlying Nerve Pathology (Axonal, Demyelinating, or Mixed)?

Pathologically, injury to nerves consists of two major processes: axonal loss or demyelination. The vast majority of polyneuropathies are primarily axonal. In demyelinating polyneuropathies, the initial injury to the nerves reflects damage to or dysfunction of the Schwann cells and the myelin sheaths. As a consequence of demyelination, conduction is impaired with marked slowing of conduction velocity or frank conduction block. In establishing the differential diagnosis of a peripheral nerve disorder, the presence of demyelination is always a key finding (see later). Demyelination may be demonstrated either by nerve biopsy and pathologic examination or, more easily, by electrophysiologic testing. When NCSs demonstrate a polyneuropathy to be predominantly demyelinating, the differential diagnosis is readily narrowed to a small group of disorders ( Box 29.4 ).

Key Question No. 5: Is There a Family History of Polyneuropathy?

For any patient with a polyneuropathy, especially when the diagnosis is not clear, particular attention must be paid to family history. There are a large number of inherited polyneuropathies. Although for most of them only symptomatic therapy is available, correct diagnosis is important for genetic counseling and prognosis and to avoid unnecessary or inappropriate further testing and treatment. Of course, this may change in the future as more genetic modifying treatments become available. CMT neuropathy refers to a group of inherited disorders characterized by a chronic motor and sensory polyneuropathy. CMT accounts for the majority of inherited polyneuropathies and, in many large series, represents a significant proportion of patients with difficult-to-diagnose polyneuropathies. Four major types of CMT are defined based on their inheritance and physiology: the demyelinating autosomal dominant form is CMT1; the axonal autosomal dominant form is CMT2; the autosomal recessive form, most of which are demyelinating, is CMT4; and the X-linked demyelinating form is CMTX. Within each type, there are several subtypes based on the specific genetic defect. In contrast to CMT, there are a smaller group of inherited polyneuropathies associated with defects of metabolism that have been described. Most are extremely rare and are associated with other systemic abnormalities.

Inherited polyneuropathies may affect certain individuals so minimally or may progress so slowly over an individual’s lifetime that the person never seeks medical attention. Therefore, it is often beneficial to examine family members, both clinically and with NCSs and EMG, to help determine whether the underlying etiology of the patient’s polyneuropathy is genetic. Several clinical clues, however, suggest the possibility of an inherited polyneuropathy ( Fig. 29.5 ):

• Foot deformity (pes cavus, hammer toes, high arches)

• History of a long-standing polyneuropathy (many years and often decades)

• History of very slow progression

• Few positive sensory symptoms

• Family history of “polio,” “rheumatism,” “arthritis,” or other disorders that actually might have been inherited polyneuropathy

Key Question No. 6: Is There a History of Medical Illness or Are There Signs Suggesting a Medical Illness Associated With Polyneuropathy?

A careful history and general physical examination are essential in evaluating a patient with polyneuropathy. Several medical conditions are strongly associated with polyneuropathy. Most prominent among them are diabetes and other endocrine disorders, cancer, connective tissue disorders, porphyria, vitamin and other deficiency states, and human immunodeficiency virus (HIV) infection.

Key Question No. 7: Is There Any History of Occupational or Toxic Exposure to Agents Associated With Polyneuropathy?

Finally, it is always important to ask about occupational and exposure history. Among drugs, most notable are cancer chemotherapeutic agents, which frequently result in polyneuropathy that is detectable either clinically or electrically. In addition, a large number of prescription drugs, as well as over-the-counter medicines, can cause polyneuropathy. A careful review of all medicines is always important.

Asking about a patient’s occupational and recreational activities occasionally elicits a toxic source for the neuropathy. One should always inquire about the patient’s use of alcohol, which is one of the most frequent causes of toxic polyneuropathy.

Clinical

Clinically, the patient with an axonal polyneuropathy usually presents with a stocking-glove distribution of symptoms and signs, including distal sensory loss and weakness. Ankle reflexes usually are absent, whereas knee and upper extremity reflexes are preserved, unless the polyneuropathy is severe.

In severe cases, the pattern of abnormalities may become more complex. Sensory symptoms and signs may develop not only over the limbs but also over the anterior chest and abdomen (escutcheon sign, which is the shape of a shield), reflecting distal degeneration of the thoracic intercostal nerves, which originate from the back and run around the abdomen and chest. If this pattern is not appreciated, a mistaken impression of a spinal level may result. ( Note : A level will only be found examining the front, not the back.) In the most extreme cases, sensory loss may develop over the top of the head due to degeneration of the distal trigeminal and cervical nerves.

Electrophysiology

Axonal polyneuropathies are associated with a characteristic pattern of nerve conduction results, provided the polyneuropathy has been present long enough for wallerian degeneration to have occurred (i.e., 3–9 days). In general, motor and sensory amplitudes decrease, with normal or only slightly slowed distal latencies, late responses, and conduction velocities. The changes are always more marked in the lower extremities, where the pathology is the greatest.

Likewise, evidence of axonal loss is found on needle EMG examination, more prominent distally than proximally, with the lower extremities more affected than the upper extremities. Of course, EMG findings are dependent on the length of time a polyneuropathy has been present. Denervation typically develops within weeks and reinnervation after weeks to months. Different patterns also develop depending on the tempo of the illness. If the process is relatively active and progressive, a combination of denervation and reinnervated motor unit action potentials (MUAPs) with decreased recruitment will be seen and again will be more prominent distally. In cases in which the polyneuropathy is long-standing and only very slowly progressive, reinnervation may completely keep pace with denervation. In such cases, only reinnervated MUAPs with decreased recruitment will be seen distally, with little or no active denervation.

Most polyneuropathies have been present for several months or years before coming to evaluation. Accordingly, when a patient with an axonal polyneuropathy is first seen in the EMG laboratory, a combination of denervation and reinnervation is usually present.

Diabetes

In any discussion of axonal neuropathies, special mention should be made of diabetic neuropathy. Peripheral nervous system manifestations of diabetes are numerous and varied. Isolated mononeuropathies of cranial nerves (e.g., facial palsy), intercostal nerves (known as diabetic thoracoabdominal neuropathy), or peripheral nerves may occur. Several types of polyneuropathy may occur. The most common, a distal sensorimotor polyneuropathy, is a typical axonal polyneuropathy affecting both large and small sensory fibers. On EMG, however, findings of a polyradiculoneuropathy are usually present. Diabetic patients may also present with a pure autonomic polyneuropathy or a small-fiber sensory polyneuropathy, with distal burning and pain. If large sensory and motor fibers are spared, such patients will have completely normal EDX studies. Other patients with diabetes will present with more proximal nerve syndromes, either at the root or plexus level, especially in the lower extremity (i.e., proximal diabetic neuropathy, diabetic amyotrophy, etc.). Large-fiber diabetic neuropathies usually demonstrate axonal changes on NCSs. Although most axonal polyneuropathies, including those associated with diabetes , have some secondary demyelination, the electrophysiologic criteria for primary demyelination are not met. Only in some cases of uremic polyneuropathy, especially when combined with diabetic polyneuropathy, do nerve conduction velocities slow sufficiently to approach or exceed the criteria set for demyelinative slowing.

Guillain-Barré Syndrome (GBS)

GBS is now most properly thought of as a syndrome that comprises several variants, with AIDP being the most common in North America . GBS is an immune-mediated, rapidly progressive, predominantly motor polyneuropathy that often leads to bulbar and respiratory compromise. It is one of the most common of all neuromuscular emergencies. Although the overall prognosis is favorable in more than 80% of patients, the hospital course is frequently long, followed by a prolonged recuperation. NCSs and EMG play an important role in the diagnosis of GBS because early recognition is necessary to begin appropriate treatment and avoid potential medical complications.

People of all ages can be affected, although GBS is most common in young adults. An antecedent event, often an upper respiratory tract infection or gastroenteritis, is found in approximately 60% of patients. Precipitating factors include campylobacter, cytomegalovirus, Epstein-Barr virus, Zika virus, and HIV infection, as well as vaccination, surgery, trauma, and malignancy (especially lymphoma). More recently, GBS has been seen as a rare complication in cancer patients treated with immune checkpoint inhibitors (ICPIs). These are monoclonal antibodies that target cytoplasmic t-lymphocyte associated antigen-4, programed cell death receptor-1, or programmed cell death ligand-1. These agents inhibit normal physiologic mechanisms that protect against autoimmunity. Although they are highly effective as immunotherapy in several types of refractory cancers, they can result in a large number of immune-related adverse effects (irAEs) that include several neuromuscular conditions, including GBS, CIDP, myasthenia gravis, and myositis. GBS is the second most common neuromuscular irAE associated with ICPIs. The clinical course and electrophysiology are similar to other cases of GBS (see later). The major exception is that a CSF pleocytosis is seen in 56% of patients.

Chronic Demyelinating Polyneuropathy

When a patient with a chronic polyneuropathy is found to have evidence of a primary demyelinating process on NCSs ( Box 29.6 ), the differential diagnosis narrows considerably. However, some of the disorders that might be considered in the differential diagnosis ( Box 29.4 ) are associated with other prominent symptoms outside of the peripheral nervous system, some of which involve the central nervous system or have an onset in early childhood. From a practical point of view, the differential diagnosis of an isolated chronic demyelinating polyneuropathy in an adult without central nervous system or systemic findings likely is limited to either an inherited polyneuropathy (most often CMT type 1A) or CIDP or one of its related disorders. NCSs can often differentiate among these conditions.