26 Polyneuropathy

Nerve conduction studies and electromyography (EMG) play key roles in the evaluation of patients with suspected polyneuropathy. Although polyneuropathy has hundreds of potential causes, they can be grouped into several large categories (Figure 26–1). The first step in the evaluation of a patient with polyneuropathy is to reduce the differential diagnosis to a smaller, more manageable number of possibilities. This usually can be accomplished by acquiring several critical pieces of information from the history, physical examination, and electrophysiologic studies. Electrophysiologic studies can be used (1) to confirm the presence of a polyneuropathy, (2) to assess its severity and pattern, (3) to determine whether motor, sensory, or a combination of fibers are involved, and, most importantly, (4) to assess whether the underlying pathophysiology is axonal loss or demyelination. In cases in which a demyelinating polyneuropathy is found, further differentiation between an acquired and inherited condition can often be made. The information obtained from electrophysiologic testing, in conjunction with key pieces of clinical information, usually allows the differential diagnosis to be narrowed considerably so that further laboratory testing can be more appropriately applied and a final diagnosis reached.

Although there are literally hundreds of causes of polyneuropathy, they can be grouped into several large categories. Note that even after a complete evaluation, there remain a sizable number (approximately 20%) of patients in whom the diagnosis remains uncertain. Disclaimer: the various categories are for illustrative purposes only, and their relative sizes in the chart should not be interpreted as authoritative, as there are insufficient prevalence data on the various categories of polyneuropathies. However, genetic neuropathies are very common, as are toxic, deficiency (such as vitamin deficiency), endocrine, and other medical conditions that may result in a polyneuropathy. In addition, paraproteins account for a small number (5–10%) of polyneuropathies, especially in patients with difficult to diagnose polyneuropathy.

Clinical

Polyneuropathy literally means dysfunction or disease of many or all peripheral nerves. Because peripheral nerves can react to disease in only a limited number of ways, polyneuropathies of many different causes may present with similar symptoms and signs. Indeed, most patients with polyneuropathy first present with a combination of sensory and motor symptoms and signs in the feet and lower legs, which later spread proximally in the legs and then into the hands and arms. Despite the many similarities, one can always limit the differential diagnosis of a polyneuropathy by determining the answers to seven key questions.

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 26–1). Among them, Guillain–Barré syndrome (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 (Figure 26–2). 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).

Box 26–1

Acute Polyneuropathies

Guillain–Barré syndrome

Porphyria

Diphtheria

Drugs (e.g., dapsone, nitrofurantoin, vincristine)

Toxins (e.g., arsenic, thallium, triorthocresylphosphate)

Tick paralysis

Vasculitis

FIGURE 26–2 Temporal progression of polyneuropathy.

The pattern of the temporal progression is one of the key historical points in determining the etiology of a polyneuropathy (n.b., worsening severity is denoted as going downward). A: Slowly progressive; B: Stepwise progressive; C: Relapsing / remitting.

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 26–1).

Table 26–1 Negative and Positive Symptoms and Signs of Peripheral Nerve Disease

	Negative	Positive
Motor	Weakness	Fasciculations
	Fatigue	Cramps
	Hyporeflexia or areflexia	Myokymia
	Hypotonia	Restless legs
	Orthopedic deformities	“Tightness”
	(e.g., pes cavus, hammer toes)
Sensory
Large fiber	Decreased vibration sensation	“Tingling”
	Decreased joint position sensation	“Pins and needles”
	Hyporeflexia or areflexia
	Ataxia
	Hypotonia
Small fiber	Decreased pain sensation	“Burning”
	Decreased temperature sensation	“Jabbing”
		“Shooting”
Autonomic	Hypotension	Hypertension
	Arrhythmia	Arrhythmia
	Decreased sweating	Increased sweating
	Impotence
	Urinary retention

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 polyneuropathy) and conditions such as lead poisoning, porphyria, and Guillain–Barré syndrome 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’s syndrome or pyridoxine (B₆) 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 26–2). 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 nerve conduction studies 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.

Box 26–2

Small-Fiber Peripheral Polyneuropathies

Diabetes

Amyloidosis (inherited and acquired)

Toxins (especially alcohol)

Drugs (especially ddI, ddC)

Hypertriglyceridemia

Hereditary sensory neuropathies

Tangier disease

Fabry disease

Acquired immunodeficiency syndrome

Idiopathic (especially in the elderly)

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 (Figure 26–3). 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).

FIGURE 26–3 Stocking-glove pattern of polyneuropathy.

Most polyneuropathies, especially axonal polyneuropathies, are length dependent, resulting in a stocking-glove distribution of symptoms and signs. Symptoms first present in the toes and then progress up the leg. When the polyneuropathy reaches the upper calves, the fingertips become involved as well. As the polyneuropathy worsens, symptoms may develop over the anterior chest and abdomen, representing distal degeneration of the thoracic intercostal nerves.

(Reprinted with permission from Schaumburg, H.H., Spencer, P.S., Thomas, P.K., 1983. Disorders of peripheral nerves. FA Davis, Philadelphia.)

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. Nerve conduction studies 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 (Figure 26–4). 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 26–3) 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.

FIGURE 26–4 Mononeuropathy multiplex pattern of polyneuropathy.

Mononeuropathy multiplex is a distinctive pattern, presenting as an asymmetric, stepwise progression of individual cranial or peripheral neuropathies, usually of named nerves. As time passes, a confluent pattern may develop that often is difficult to distinguish from a generalized polyneuropathy. Mononeuropathy multiplex is characteristically seen in vasculitic polyneuropathy. The pattern shown here is an asymmetric polyneuropathy with involvement of the left ulnar, right median, left distal peroneal, right saphenous, and right peroneal nerves.

(Adapted and reprinted with permission from Schaumburg, H.H., Spencer, P.S., Thomas, P.K., 1983. Disorders of peripheral nerves. FA Davis. Philadelphia.)

Box 26–3

Differential Diagnosis of Mononeuropathy Multiplex

Vasculitis (e.g., polyarteritis nodosa, Churg–Strauss syndrome, Wegener’s syndrome, hypersensitivity, cryoglobulinemia, systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, chronic active hepatitis)

Diabetes

Inflammatory demyelinating polyneuropathy (Lewis–Sumner variant)

Multiple entrapments (hereditary and acquired)

Infection (e.g., Lyme, leprosy, human immunodeficiency virus)

Infiltration (e.g., granulomatous disease [sarcoid], neoplasm [lymphoma, leukemia])

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 nerve conduction studies demonstrate a polyneuropathy to be predominantly demyelinating, the differential diagnosis is readily narrowed to a small group of disorders (Box 26–4).

Box 26–4

Demyelinating Polyneuropathies

Hereditary

Charcot–Marie–Tooth, Type I (CMT1)

Charcot–Marie–Tooth, Type IV (CMT4)

Charcot–Marie–Tooth, X-linked (CMTX)

Dejerine–Sottas disease *

Refsum disease

Hereditary neuropathy with liability to pressure palsy (HNPP)

Metachromatic leukodystrophy

Krabbe disease

Adrenoleukodystrophy/adrenomyeloneuropathy

Cockayne syndrome

Niemann–Pick disease

Cerebrotendinous xanthomatosis

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Acquired

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP, the most common variant of Guillain–Barré syndrome)

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

Idiopathic

Associated with human immunodeficiency virus (HIV) infection

Associated with MGUS (especially IgM)

Associated with anti-MAG antibodies

Associated with osteosclerotic myeloma

Associated with Waldenström macroglobulinemia

Multifocal motor neuropathy with conduction block (±GM₁ antibodies)

Diphtheria

Toxic (i.e., amiodarone, perhexiline, arsenic, glue sniffing, buckthorn shrub poisoning)

^* Dejerine–Sottas disease is a historical term used to denote a severe demyelinating neuropathy in children. The classic phenotype described a hypotonic infant with areflexia and hypertrophic nerves; on nerve conduction studies, conduction velocities were extremely slow, typically around 6 m/s. Formerly considered a distinct entity with autosomal recessive inheritance, genetic analysis has demonstrated that Dejerine–Sottas is a syndrome with either recessive inheritance or autosomal dominant inheritance with de novo mutations. The recessive forms are now incorporated into the CMT4 group. The de novo autosomal dominant forms have mutations on the same genes implicated for CMT1 (P0, PMP22, and EGR2), but with the genetic defect resulting in a much more severe demyelinating neuropathy.

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. Charcot–Marie–Tooth (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 the 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 demyelinating form 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 often is beneficial to examine family members, both clinically and with nerve conduction studies 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 (Figure 26–5):

• 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

FIGURE 26–5 Pes cavus.

Pes cavus is an orthopedic deformity of the foot, recognized as a foreshortened foot with a high arch and hammer toes. Pes cavus develops during childhood from the combination of intrinsic foot muscle weakness and relative preservation of the long flexors and extensor muscles in the calves. Because most polyneuropathies preferentially affect distal muscles, polyneuropathies that are present during development as a child commonly result in this deformity. As the vast majority of polyneuropathies that are present as a child are genetic, the presence of pes cavus in a patient with a peripheral neuropathy likely indicates that the neuropathy has been present since childhood and is most likely inherited.

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.

Axonal Polyneuropathy

The underlying pathology of the vast majority of polyneuropathies is axonal degeneration, usually affecting both motor and sensory fibers. Axonal polyneuropathies include nearly all diabetic, toxic, metabolic, drug-induced, nutritional, connective tissue, and endocrine-associated polyneuropathies. In addition, there are a small number of inherited CMT neuropathies that are axonal. The autosomal dominant axonal form of CMT is now known as CMT2. CMT2 is further divided into several subtypes based on the specific genetic defect, and accounts for approximately 10–15% of the CMT inherited neuropathies.

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 where 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.

Special Situations in Axonal Polyneuropathy: The Use of the Sural/Radial Amplitude Ratio in Mild Polyneuropathy

Nearly all axonal polyneuropathies are characterized by a distal pattern of abnormalities. Thus, the lower extremities are affected first and most prominently. Accordingly, the amplitude of the sural sensory study (normal or abnormal) takes on great significance in the EDX evaluation of most axonal polyneuropathies. However, interpretation of the sural amplitude has several limitations, especially in the following scenarios:

1. Younger individuals have much higher baseline sural amplitudes than older individuals. Thus, if a young patient had a sural amplitude of 30 µV, then developed an axonal polyneuropathy and the sural amplitude decreased to 15 µV, this value would still be considered normal in most EMG labs.

2. Older individuals may have low or difficult to obtain sural sensory responses at baseline. Thus, in an 80-year-old patient with numbness of the feet and a sural amplitude of 3 µV, it is difficult to know whether this value indicates a neuropathy or is simply consistent with age.

3. In obese individuals, the additional adipose tissue between the skin and the underlying nerve may result in an attenuation of the sensory nerve amplitude. Thus, in an obese patient with a sural amplitude of 5 µV, it may be difficulty to know if this value indicates a neuropathy or simply denotes a reduced amplitude from technical issues related to increased intervening adipose tissue in the lower leg.

In these situations, the use of the sural/radial amplitude ratio (SRAR) may be helpful. The SRAR is especially helpful in those patients with a “borderline normal” sural amplitude. The rationale for using the SRAR is straightforward: in a distal dying-back axonal neuropathy, the sural amplitude should be disproportionally affected compared to the radial amplitude. In the original description of this technique by Rutkove et al., a SRAR <0.40 had a specificity of 90% and a sensitivity of 90% in detecting an axonal polyneuropathy. In addition, the SRAR was less dependent on age than the sural amplitude alone, and also did not appear to be affected by body mass index (BMI). A latter study using a larger cohort of normal subjects suggested that a cutoff value of 0.4 may have been too high, and a more appropriate cutoff should be 0.21. Dropping the cutoff to 0.21 improved the specificity to 95% (i.e., reduced the number of false positives to under 5%).

Thus, the SRAR can be a useful adjunct in the EDX evaluation of axonal polyneuropathy. Of course, like all nerve conduction data, it relies on obtaining valid data. One needs to be sure that the amplitude of each nerve has been maximized and that the recording electrodes are optimally placed over each nerve. Moreover, in the rare situation wherein there is a superimposed sural or radial mononeuropathy, the SRAR cannot be considered valid for the electrodiagnosis of axonal polyneuropathy.

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 electrodiagnostic 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 nerve conduction studies. 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.

Borderline Cases: Differentiation Between Axonal and Demyelinative Slowing

Slowing of conduction velocity to less than 75% of the lower limit of normal is one of the fundamental electrodiagnostic criteria for establishing primary demyelination in polyneuropathy. When compound muscle action potential (CMAP) amplitudes are markedly reduced secondary to axonal loss, however, conduction velocity slowing may be seen secondary to severe axonal loss with dropout of the fastest-conducting fibers. It is in this situation, when distal CMAP amplitudes are low and conduction velocity slowing nears 75% of the lower limit of normal, that it may be difficult to differentiate between a primary demyelinating polyneuropathy and a severe axonal polyneuropathy.

In such cases, one useful technique is to compare conduction velocities recording a distal and a proximal muscle across the same segment of nerve. In the leg, the peroneal nerve is most useful for this study. Peroneal motor studies are performed stimulating below the fibular neck and at the lateral popliteal fossa and recording simultaneously from the extensor digitorum brevis (EDB), a distal muscle, and the tibialis anterior, a proximal muscle (Figure 26–6). Conduction velocities across this same segment of nerve are then compared.

FIGURE 26–6 Recording proximal and distal muscles to differentiate axonal from demyelinative slowing.

Co-recording a proximal and a distal muscle and comparing conduction velocities through the same segment of nerve may be helpful in differentiating axonal from demyelinative slowing in borderline cases. Here, recording electrodes are placed over the tibialis anterior and extensor digitorum brevis in the standard belly–tendon montage. The peroneal nerve is stimulated below the fibular neck and at the lateral popliteal fossa and conduction velocities computed across the same segment of nerve for the two recording sites.

(Reprinted with permission from Raynor, E.M., Ross, M.H., Shefner, J.M., et al., 1995. Differentiation between axonal and demyelinating neuropathies: identical segments recorded from proximal and distal muscles. Muscle Nerve 18, 402.)

In patients with demyelinating polyneuropathies, conduction velocities typically are slowed at both recording sites, with no difference between proximal and distal sites (Figure 26–7). In patients with axonal polyneuropathies, however, conduction velocities may be slowed recording the EDB but usually are normal or only mildly reduced when measured from the tibialis anterior. This distal-to-proximal gradient of conduction velocity slowing in axonal polyneuropathies may be very helpful in differentiating a primary demyelinating from axonal polyneuropathy, especially when the distal conduction velocities are near the cutoff value for demyelinative slowing.