Anatomy and Physiology of Peripheral Nerves

The anatomic site of involvement may range from the nerve cell body (neuronopathy, e.g., acute ataxic sensory neuronopathy), to the nerve roots (acute inflammatory demyelinating polyradiculoneuropathy [AIDP]), to the nerve proper, to the axon terminals (twig neuropathy, e.g., hyperparathyroidism). Nerve fibers react to injury through two primary mechanisms, axonal degeneration and demyelination. In axonal degeneration the cytoplasm disintegrates. Eventually, the axolemma becomes discontinuous, and the myelin sheath, but not the Schwann cell, secondarily disintegrates. Fragments of axolemma and myelin form linear arrays of myelin ovoids. Macrophages phagocytose and eventually remove the debris. Conditions affecting the axon typically begin in the most terminal axon twigs, and the pathologic changes move proximally with progression of the disease, a phenomenon known as dying back. Clinically, signs and symptoms begin in the longest axons, those innervating the feet and toes, and progressively involve more proximal areas, a feature known as length dependency. Wallerian degeneration specifically refers to axonal degeneration distal to a traumatic nerve injury.

In demyelinating neuropathies, the primary insult is to the myelin sheath or the Schwann cell, and varying degrees of interference with myelin maintenance are produced. In the earliest stages, the demyelination is paranodal, but with progression, the rest of the internodal segment becomes involved. Segmental demyelination refers to the involvement of several internodes over a segment of nerve. In some conditions the Schwann cells are involved diffusely and the demyelination is uniform along the length of the nerve (e.g., Charcot-Marie-Tooth [CMT] disease). In most acquired myelinopathies, the involvement is multifocal (e.g., Guillain-Barré syndrome [GBS]). In compression neuropathies, the demyelination is focal and involves only a discrete segment (e.g., carpal tunnel syndrome).

With severe demyelination, there may be secondary axon loss. In compression neuropathies, the myelin is more susceptible to injury and axon loss reflects chronicity and severity. In dysimmune inflammatory neuropathies, the axon may be an accidental victim of the attack, the bystander effect. The secondary axon loss in myelinopathies and the secondary demyelination in axonopathies add another measure of complexity to the evaluation of neuropathies. Clinically and electrophysiologically, these secondary changes may create a mixed picture of axonopathy and myelinopathy. For example, uremia characteristically produces an axonopathy with secondary demyelination, and severe GBS, a primarily demyelinating and inflammatory neuropathy, is often associated with significant secondary axon loss as a result of the bystander effect.

With the use of clinical, electrodiagnostic, pathologic, and laboratory data, neuropathies can be classified according to their anatomic site of involvement, time course, distribution, pattern of deficit, type of functional fiber involved, and whether the process is primarily axonal, primarily demyelinating, or mixed. It is helpful to classify a neuropathy in as many ways as possible in the hope of uncovering a characteristic signature. There are two primary patterns of clinical involvement: generalized, diffuse, or symmetrical versus focal or multifocal. The time course may vary from acute, evolving over a period of days to weeks, to chronic, evolving over a period of months to years, to very chronic or lifelong, to relapsing and remitting. Neuropathies may be predominantly motor (e.g., GBS) or predominantly sensory (e.g., amyloidosis). Most neuropathies produce symmetrical distal involvement, but some may cause primarily proximal weakness (e.g., porphyria), proximal sensory loss (e.g., Tangier disease), or acral sensory loss over the coolest parts of the body (e.g., leprosy). Sensory neuropathies may preferentially affect large fibers (e.g., vitamin B₁₂ deficiency) or small fibers (e.g., hereditary sensory neuropathy). Particular neuropathies may or may not have associated autonomic dysfunction. As defined by clinical features, by electrodiagnostic profile as determined by nerve conduction studies and needle electromyography (EMG), and occasionally by pathologic examination, a neuropathy may be primarily axonal (e.g., CMT type 2 [CMT2]), primarily demyelinating (e.g., chronic inflammatory demyelinating polyradiculoneuropathy [CIDP]), mixed but mainly axonal (e.g., chronic renal disease), or mixed but with significant demyelination (e.g., diabetes).

To establish an etiologic diagnosis, the neuropathy must be characterized and classified as precisely as possible. To separate the cause of a particular neuropathy from the protean possibilities, an attempt should be made to construct a profile of clinical and electrophysiologic characteristics to narrow the differential diagnosis. From the long list of causes of neuropathy, only a short list of conditions emerges that cause a chronic, predominantly sensory, large-fiber axonopathy or an acute, predominantly motor, multifocal demyelinating neuropathy. Knowledge of the relevant anatomic, physiologic, and pathologic concepts helps greatly in this exercise.

Clinical Signs and Symptoms of Peripheral Neuropathy

The cardinal manifestations of peripheral neuropathy are weakness, alterations in sensation, and changes in reflexes. The patterns of abnormality are important in the differential diagnosis, and detailed clinical examination in which the details and specifics are explored is often rewarded. The first step in the differential diagnosis is determining the pattern of motor and sensory dysfunction. Is the neuropathy predominantly motor or sensory? If weakness has occurred, is it proximal, distal, or diffuse? Is atrophy present? Are the changes in reflexes dependent on length or are they global? Do the sensory changes demonstrate a predilection for large or small fibers? Is there autonomic dysfunction? Are the findings symmetrical?

Generalized, length-dependent peripheral neuropathies are typically symmetrical in onset, with numbness beginning initially in the toes and feet and affecting the lower part of the legs as the neuropathy progresses. The fingers and hands begin to be affected about the time that lower extremity involvement reaches the knees. This reflects the length-dependent nature of the process because nerve length from the lumbosacral dorsal root ganglia to the knees is comparable to the length from the cervical dorsal root ganglia to the fingers. The most terminal distribution of the intercostal nerves is a strip along the chest and upper part of the abdomen, and in a length-dependent process, sensory loss can sometimes be found in this region, referred to as a cuirass distribution. With motor involvement, weakness typically begins in the toe flexors and extensors, followed by the development of footdrop. The foot plantar flexors are so powerful that it is seldom possible to find weakness unless the neuropathy is very severe. In very chronic neuropathies, it is common to see high arched feet and hammer toes because the greater strength of the extrinsic than the intrinsic foot muscles in the lower part of the leg pulls the toes into this position. Obvious atrophy of the intrinsic muscles with ridging between the long toe extensor tendons is often present. In a length-dependent process the first tendon reflexes to disappear are the ankle jerks; as the disease progresses, knee jerks are lost at about the same time as the upper extremity reflexes begin to be depressed because of the similar length of their axons.

In the differential diagnosis, age at onset, pace of evolution, presence of associated medical or neurologic conditions, and medication history are very important. The family history is crucial but often tricky because many individuals with hereditary neuropathies do not recognize their own condition. Other family members with odd-looking feet (pes cavus, characteristic of CMT disease) or feet that are difficult to fit with shoes may be the only clue to a condition that is rampant but unrecognized in a kindred.

Quantitation of the degree of deficit is useful for longitudinal follow-up. Sophisticated instrumentation is available for this purpose but is expensive and not in wide use outside academic centers. Simple bedside testing can provide a great deal of useful information. Strength is most often described according to the Medical Research Council scale. The power in small hand muscles can be nicely described with techniques that compare the patient’s strength with the examiner’s.² Two-point discrimination is quantitative and easily performed. Inexpensive handheld esthesiometers can quantitate touch sensibility. Vibratory sensation is a sensitive parameter of peripheral nerve function and can be simply quantitated by noting where the patient can perceive the sensation and for how long (e.g., “vibration absent at the great toes and metatarsal heads, can perceive a maximally vibrating 128-Hz fork for 5 seconds over the medial malleoli”). If the patient returns and is found to have lost vibration sensibility over the malleoli, the condition is progressing. If on follow-up vibration sensation is present for 12 seconds over the malleoli and can now be perceived for 3 seconds over the metatarsal heads, the patient is improving. Functional testing is invaluable. The time required to walk a set distance or get up from the floor, arm and leg outstretch time, the ability to support the entire body weight on one tiptoe, and similar functions are objective and quantifiable.

The onset of neuropathy may be relatively acute or subacute and evolve over a period of several days to several weeks or be more chronic and evolve over a period of several months to many years. There is some unavoidable overlap in the middle, between what might be called subacute and what might be called chronic. Some neuropathies have a predilection for certain types and sizes of fiber. Large-fiber neuropathies affect strength, reflexes, and proprioception, with relative sparing of pain and temperature sensation, whereas small-fiber neuropathies primarily affect pain, temperature, and autonomic function, often with strength and reflexes being spared. Differential involvement of large versus small sensory fibers can sometimes be discerned clinically. Standard nerve conduction studies evaluate the conduction characteristics of only large, myelinated fibers.

Electrophysiology of Peripheral Neuropathies

Demyelinating neuropathies and axonopathies generate quite different electrophysiologic pictures. In brief, primary myelinopathies produce marked slowing of conduction velocity (CV) with preservation of distal compound muscle action potential (CMAP) amplitudes, whereas axonopathies produce marked loss of distal amplitudes with relative preservation of CV. When the disease process affects only myelin, conduction is impaired because of loss of saltatory conduction. If the process is uniform and diffuse with all myelin being affected, as in a hereditary myelinopathy, the conduction abnormalities involve all nerves and all segments of nerves to an approximately equal degree. If the process is focal, only the involved nerve is affected. If the process is multifocal, the abnormalities may be widespread but manifested to different degrees in different nerves and in different segments of the same nerve. In either case, with a myelinopathy the axon is intact and there is no loss of trophic influences on the target motor and sensory organs. Muscle atrophy does not occur, and denervation potentials, fibrillations, and positive sharp waves do not appear in the affected muscles.

In contrast, a disease process that primarily affects axons also causes loss of the axon-mediated trophic influences on target organs. The muscle becomes atrophic, with a resultant decline in CMAP amplitude. Axon loss produces a diminution in sensory or compound nerve action potential amplitude. Involvement of all the axons in a nerve may render the nerve inexcitable, and no motor or sensory potentials can be elicited. However, any surviving axons will conduct at their normal velocity. If a disease process produces dropout of 50% of the axons in a nerve, the electrodiagnostic picture would be a 50% (Å) loss of CMAP amplitude but relatively normal CV. Clinical and electrophysiologic characteristics helpful in distinguishing axonopathy from myelinopathy are summarized in Table 233-2.

TABLE 233-2 Clinical and Electrodiagnostic Features That Help Distinguish Axonopathy from Myelinopathy

CMAP, compound muscle action potential; CSF, cerebrospinal fluid; CV, conduction velocity; DML, distal motor latency; NAP, nerve action potential; SNAP, sensory nerve action potential.

Unfortunately, as is often the case, findings do not always follow the classic or typical pattern. Some neuropathies are truly mixed, with electrophysiologic features of both demyelination and axon loss. In addition, axonopathies can produce some degree of slowing of CV. Random involvement of axons will inevitably affect some of the largest and fastest conducting fibers, whose dropout will then lower the maximum CV. If the largest and fastest conducting axons are preferentially affected, significant slowing could occur as a result of an axonopathy. The severity of an axonopathy is reflected by the degree of muscle fiber atrophy and its attendant loss of CMAP amplitude. A severe axonopathy can be expected to involve at least some of the fastest conducting fibers and will therefore produce more CV slowing than will a mild axonopathy. For this reason, if the CMAP amplitude is decreased, more severe conduction slowing must be present before one can be confident of the existence of demyelination. Because of these complicating factors, criteria for demyelination have been developed. Despite the lack of universal consensus, the use of some criteria set is coming into increasingly wide acceptance, but debate continues regarding precise details.

Although CV and CMAP amplitude are the primary parameters, other electrodiagnostic variables may be useful as well. Disproportionate prolongation of distal motor latency or late response latency, beyond that explicable on the basis of axon loss, may also indicate demyelination. Axonopathies are length dependent and exhibit a “dying-back” process that affects the most distal nerve terminals first and involves more proximal nerve segments with progression. Disproportionate conduction abnormalities in the most distal nerves can thus indicate axonopathy. A gradient of abnormality on needle examination, with greatest involvement of the most distal muscles and progressively less involvement of more proximal muscles, suggests a length-dependent process.

Another major indicator of demyelination is conduction block or temporal dispersion. This is a change in amplitude or configuration of the CMAP waveform on stimulation proximal to a given point. In temporal dispersion, focal demyelination of axons produces CV slowing that involves some fibers to a greater degree than other fibers and thereby causes loss of synchrony. The CMAP conducted through the demyelinated region is dispersed and spread out, with an increased duration and loss of amplitude. However, all fibers successfully conduct through the affected region, so the total area under the CMAP curve remains the same with both proximal and distal stimulation. In conduction block, some fibers are so severely demyelinated that they do not conduct at all. There is not only a diminution in CMAP amplitude but also a diminution in total area under the curve, thus indicating that fewer muscle fibers have been successfully depolarized with proximal stimulation than with distal stimulation.

Clinical weakness seems to correlate with conduction block, not with CV slowing or temporal dispersion. A great deal has been made of distinguishing between conduction block and temporal dispersion, but the distinction is of questionable utility because both these phenomena indicate a focal demyelinating lesion in the subjacent nerve.³ As a result, the fairly simple criterion of a significant loss of negative spike or peak-to-peak amplitude with proximal stimulation as compared with distal stimulation may suffice to indicate demyelination, and whether the loss of amplitude is due to conduction block, temporal dispersion, or a combination of the two is relatively immaterial.

Demyelination may occur in two major patterns. Disorders that affect myelin diffusely because of a genetic defect, biochemical abnormality, or the effect of certain drugs or toxins produce global, uniform demyelination. There is little variation from nerve to nerve or from segment to segment of any given nerve.⁴ In the majority of patients with familial demyelinating neuropathy, distal motor latencies are prolonged in proportion to CV, median and ulnar forearm CV does not vary by greater than 5 m/sec, and there is no evidence of conduction block or temporal dispersion. Such uniform slowing of conduction suggests a generalized dysfunction of myelin or Schwann cells.

In acquired demyelinating neuropathies, distal motor latency and CV vary more randomly, differences between median and ulnar CV of greater than 5 m/sec or even 10 m/sec are common, and conduction block or temporal dispersion may occur. Such a pattern of conduction abnormality suggests a multifocal attack on peripheral nerves that may become widespread but does not truly affect myelin diffusely.

Other laboratory tests are often useful. Macrocytosis on the hematology profile may be a clue to vitamin B₁₂ deficiency or to alcohol abuse. If alcoholism is strongly suspected, carbohydrate-deficient transferrin may be useful. It reflects the level of alcohol intake over the preceding weeks or months in the same way that glycosylated hemoglobin reflects chronic blood sugar levels. An elevated carbohydrate-deficient transferrin level may be a clue to occult alcohol abuse as the cause of a generalized polyneuropathy.⁵ Abnormal liver function test results, especially γ-glutamyltransferase, may reflect alcohol abuse or a neuropathy related to underlying hepatitis, especially hepatitis C. Hepatitis C may cause a neuropathy associated with cryoglobulinemia. Cryoglobulins are difficult to detect; they are large complex molecules that may cross-react with rheumatoid factor, so a positive rheumatoid factor test may be a clue to hepatitis C. Many other systemic diseases may be manifested as a peripheral neuropathy, including connective tissue disorders, systemic vasculitis, vitamin B₁₂ deficiency, Lyme disease, paraproteinemias, porphyria, hypothyroidism, human immunodeficiency virus (HIV) infection, amyloidosis, sarcoidosis, and occult malignancy.

In GBS and CIDP, cerebrospinal fluid (CSF) protein is often elevated, and lumbar puncture should be performed whenever these conditions are in the differential diagnosis. In CIDP, magnetic resonance imaging of the lumbosacral spine may reveal enlarged and inflamed lumbosacral roots. Formal autonomic testing may help establish whether a neuropathy has a component of dysautonomia. In recent years, skin biopsy has emerged as a safe, minimally invasive tool for assessing small epidermal nerve fibers that are inaccessible for routine neurophysiologic tests. Biopsy of hairy skin can be used to evaluate unmyelinated and thinly myelinated fibers, and biopsy of glabrous skin can be used to examine large myelinated fibers. Standard morphometric techniques have been developed and proven to be reliable and reproducible. Pathologic changes in cutaneous nerves have been found to occur very early in the course of peripheral neuropathies. Comparison of the density of the epidermal nerve fiber layer between a proximal and a distal biopsy site can sometimes document the length dependency of a neuropathy, as well as occasionally make the diagnosis in a condition such as amyloidosis.

Peripheral neuropathy is obviously common in patients with diabetes mellitus. Recently, controversy has arisen regarding the diagnosis of neuropathy in patients with an abnormal 2-hour glucose tolerance test but without frank diabetes and the proper screening test for patients with idiopathic peripheral neuropathy, especially sensory neuropathy. Undiagnosed impaired fasting glucose metabolism appears to be associated with neuropathy at a higher frequency than in the general population when the 2-hour oral glucose tolerance test is used as opposed to a fasting blood sugar and glycosylated hemoglobin level.⁶ In a study of 100 consecutive patients with apparently idiopathic peripheral neuropathy, the prevalence of undiagnosed abnormal fasting glucose metabolism was found to be nearly twofold higher (62%) in patients with neuropathy than in controls. The 2-hour oral glucose tolerance test provided a higher diagnostic rate with the 2003 revised American Diabetes Association criteria. There is increasing evidence that abnormal glucose metabolism, or prediabetes, may be a risk factor for neuropathy and that a 2-hour oral glucose tolerance test may be more sensitive than fasting blood sugar and glycosylated hemoglobin in detecting this condition.

In Tables 233-3 to 233-6, neuropathies are classified into demyelinating versus axonal and whether the onset is acute/subacute versus subacute/chronic. Other common classifications include (1) mixed axonopathy/myelinopathy: diabetes, end-stage renal disease (ESRD), and some cases of acute or chronic inflammatory demyelinating neuropathy; (2) primarily motor polyneuropathies: most cases of GBS, CIDP, porphyria, dapsone and lead intoxication, and CMT disease; (3) large-fiber sensory neuropathies: uremia, diabetes (pseudotabes), paraneoplastic neuropathy, Sjögren’s syndrome, vitamin B₁₂ deficiency, Friedreich’s ataxia, certain toxins (e.g., pyridoxine, cisplatin, and metronidazole), acute idiopathic sensory neuronopathy, and some cases of CIDP; (4) small-fiber sensory neuropathies: diabetes mellitus (pseudosyringomyelia), amyloidosis, hereditary sensory autonomic neuropathies, and leprosy; and (5) neuropathies with major autonomic dysfunction: diabetes, alcoholism, amyloidosis, hereditary sensory autonomic neuropathy type III (Riley-Day syndrome), GBS, porphyria, vincristine toxicity, and idiopathic pandysautonomia.

TABLE 233-3 Acute/Subacute Myelinopathies

* Both patterns have been reported.

† Recall that Guillain-Barré syndrome is a syndrome, not a disease, and can occur as part of several conditions.

TABLE 233-4 Subacute/Chronic Demyelinating Neuropathies

CIDP, chronic inflammatory demyelinating polyneuropathy; HIV, human immunodeficiency virus; HMSN, hereditary motor-sensory neuropathy; SLE, systemic lupus erythematosus.

* Includes CIDP–monoclonal gammopathy of undetermined significance (MGUS), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes), multifocal motor neuropathy, and anti–myelin-associated glycolipid (MAG) neuropathy.

TABLE 233-5 Acute/Subacute Axonopathy

TABLE 233-6 Subacute/Chronic Axonopathy

AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; HMSN, hereditary motor-sensory neuropathy.

Common Neuropathies

The following sections discuss some of the more common or interesting neuropathic syndromes. Space limitations do not permit discussion of every syndrome. Detailed elaboration is available elsewhere.^1,7

Several possible mechanisms are possibly operative in the various diabetic neuropathies. Reversible metabolic changes may account for some of the conduction abnormalities. Aldose reductase converts glucose into sorbitol, which accumulates in the nerve, decreases myoinositol levels, and impairs the action of the Na/K pump. CV begins to improve within hours of reversing the hyperglycemia.^8,9 Diabetic microangiopathy and intraneural hypoxia probably play a significant role as well. Enzymatic reactions between glucose and proteins produce advanced glycosylation end products, which may contribute to neuropathy by damaging the extracellular matrix and enhancing basement membrane thickening and reduplication.¹⁰

Some patients, especially those with asymmetric or proximal neuropathy, may have a treatable inflammatory vasculopathy, and some diabetics have a disorder indistinguishable from CIDP.¹¹

On electrodiagnostic studies, diabetic generalized sensorimotor polyneuropathy commonly shows evidence of both chronic axonal degeneration and significant demyelination. The combination of axonal degeneration and marked CV slowing is characteristic of diabetic neuropathy. The demyelination is beyond that expected for most axonal neuropathies, and the axon loss is in excess of that seen in most myelinopathies.⁴ It seems increasingly clear that good diabetic control can improve the long-term outlook for patients with most forms of diabetic neuropathy.¹²

The Neuropathy of Chronic Renal Failure

The typical neuropathy of ESRD is a distal, symmetrical, subacute, slowly progressive sensorimotor axonopathy. Approximately 60% to 80% of patients with ESRD have neuropathy at the onset of dialysis. Although primarily an axonopathy, the neuropathy of ESRD may be associated with significant secondary demyelination, and there may be preferential large-fiber involvement clinically and pathologically.^13,14 Although the neuropathy may stabilize with dialysis, significant improvement occurs only after transplantation. A rapidly progressive neuropathy can occur. Diabetes is a common cause of ESRD, and some patients have coexistent diabetic and uremic polyneuropathy.

Alcoholic Neuropathy

The pathogenesis of the neuropathy in chronic alcoholics is still being debated. Most alcoholics suffer from malnutrition, but no specific nutritional deficiencies seem to explain the neuropathy. Alcohol has direct toxic effects on the central nervous system and possibly on the peripheral nervous system. A study of 107 alcoholics showed that 32% had peripheral neuropathy by EMG and 24% had dysautonomia. The neuropathies correlated directly with the level of alcohol intake and bore no relationship to nutritional status.¹⁵ Subsequent literature continues to suggest a direct neurotoxic effect, perhaps mediated by acetaldehyde.¹⁶ Clinically and electrodiagnostically, the neuropathy is a nondescript, distal, symmetrical, generalized sensorimotor axonopathy with variable pain, weakness, and dysautonomia. Sensory dysfunction is more prominent than motor; mild weakness is common but severe weakness is rare.

Vitamin B₁₂ Deficiency

Inhibition of the vitamin B₁₂–dependent enzyme methionine synthase creates disturbed methylation reactions leading to impaired DNA synthesis and a host of attendant complications. Neurologic manifestations include neuropathy, myelopathy, and dementia. The neuropathy is generally said to be an axonopathy, but demyelination is prominent pathologically in the central nervous system, and there is little electropathologic correlative information regarding the peripheral neuropathy. Clinically, the neuropathy is predominantly sensory and symmetrical with a predilection for large fibers. An important clue is evidence of an associated myelopathy. The combination of absent ankle jerks and upgoing toes is highly suggestive of vitamin B₁₂ deficiency. Significant neurologic involvement can occur in the absence of hematologic abnormalities.

Dysimmune Neuropathies

Dysimmune neuropathies are those in which peripheral nerve damage results from some aberration of the immune system. Most involve abnormalities in both cellular and humoral immunity, and the majority are associated with inflammation and demyelination. The two most common disorders are AIDP (or GBS) and CIDP.¹⁷ A number of other less common disorders may fall under this rubric, including the demyelinating neuropathies associated with the various paraproteinemias, the syndrome of multifocal motor neuropathy (MMN), anti–myelin-associated glycoprotein (MAG) neuropathy, antisulfatide neuropathy, and gait ataxia, late-onset polyheuropathy (GALOP) syndrome. Acute motor axonal neuropathy (AMAN) is a variant of GBS in which the immune attack is directed at the axolemma at the nodes of Ranvier of large motor fibers. Most AMAN cases follow Campylobacter jejuni infection, in which antibodies directed against some epitope or epitopes on the organism attack GM₁-reactive epitopes on the nodal axolemma.¹⁸

The resemblance of AIDP and CIDP to experimental allergic neuritis strongly suggests that disordered cellular immunity is involved in the pathogenesis. In addition, antibody and complement have been implicated in several syndromes. Impairment of the blood-nerve barrier (BNB) is another important factor. The acute and chronic inflammatory demyelinating polyneuropathy syndromes may well involve a combined “land-air attack” in which sensitized cells breach the BNB, thereby paving the way for antibodies, which then induce demyelination.

A number of antinerve antibodies have been described in association with various syndromes, but their exact pathogenetic role remains enigmatic. The antibodies described are primarily directed against the glycolipid and glycoprotein components of peripheral nerve myelin. Sialic acid–bearing glycolipids (gangliosides), including GM₁, GD_1b, and GQ_1b, as well as the asialo form of GM₁, are frequent targets. The majority of patients with CIDP have autoantibodies against β-tubulin. Antibodies to GM₁ are particularly associated with the syndrome of MMN. Antibodies against MAG and an associated sulfoglucoronyl paragloboside appear to produce a slightly different syndrome. Whether the various syndromes are distinct disease entities or variants of CIDP remains a matter of debate between lumpers and splitters.¹⁹

Most of the dysimmune neuropathies are potentially treatable, but the best treatment may vary with the syndrome. Steroids, immunosuppressants, plasma exchange, and intravenous immunoglobulin (IVIG) have all been used.²⁰

CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; HIV, human immunodeficiency virus; VDRL, Venereal Disease Research Laboratory.

Modified from American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of CIDP. Neurology. 1991;41:617-618.

There are several variants of the CIDP syndrome in which a demyelinating polyneuropathy occurs in association with other clinical and electrodiagnostic features. CIDP sometimes occurs in association with a monoclonal gammopathy of undetermined significance (MGUS). Patients with CIDP-MGUS tend to be slightly older and have a more chronic course, more sensory involvement, and more predominantly lower extremity involvement. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) is essentially CIDP associated with osteosclerotic myeloma. The clinical picture of the neuropathy is essentially the same as for CIDP, but patients have other abnormalities on clinical and laboratory evaluation, including organomegaly, endocrinopathy (usually diabetes), a monoclonal paraprotein, and skin changes. A plain film skeletal survey is usually required to detect the osteosclerotic myeloma because radioisotope bone scans are negative. The electrodiagnostic features of CIDP-MGUS and POEMS syndrome are basically the same as for CIDP. The neuropathy associated with antibody to MAG tends to be symmetrical, with predominantly lower extremity involvement and more striking sensory alterations. Electrophysiologically, anti-MAG neuropathy is primarily a demyelinating syndrome. A purely sensory variant of CIDP in which motor involvement may develop late in the course has been reported.

MMN is a neuropathy that may be a mimicker of amyotrophic lateral sclerosis (ALS).²⁵ These patients have very chronic, asymmetric weakness involving the upper more than the lower extremities and associated with impressive conduction block on nerve conduction studies. The authors speculated that the condition was probably a variant of CIDP, and most current evidence supports this conclusion.²⁶ The condition may be manifested as weakness, atrophy, cramps, fasciculations, and preserved reflexes with minimal sensory complaints or findings, all suggestive of ALS.²⁷ Further experience has shown that with careful evaluation, some degree of clinical sensory involvement is the rule rather than the exception in MMN. Lewis and colleagues had previously reported a very similar condition and speculated that it was a variant of CIDP.²⁸ Sensory nerve action potentials tend to be normal, thus suggesting there may be sensory conduction block in some segment of nerve not usually tested. There is an association between this syndrome and antibodies against GM₁ and other gangliosides. Patients with ALS and other neurologic conditions may also have antiganglioside antibodies, albeit generally at lower titer than in those with MMN.

It now appears that many patients with MMN respond to IVIG, which is also of benefit in AIDP and probably in CIDP. It appears more and more likely that so-called MMN is probably not a separate entity but a variant of CIDP characterized by asymmetry and prominent conduction block. A condition clinically identical but without conduction block has been reported and termed multifocal acquired motor axonopathy.²⁹ Many patients, perhaps most patients, do have sensory complaints and findings. Some patients have antiganglioside antibodies.

The dysimmune neuropathies are primarily demyelinating syndromes, with the single exception of antisulfatide neuropathy. These patients exhibit a painful, predominantly sensory, predominantly axonal clinical syndrome associated with antibody reactivity to peripheral nerve sulfatide components and a generalized axonopathy electrophysiologically.

Amyloidosis

Amyloidosis develops in a variety of circumstances. It may occur as a primary process or complicate paraproteinemias or any chronic systemic disease, especially chronic renal failure and dialysis. Many cases are familial. The disease causes intercellular deposition of insoluble, beta-pleated fibrillary protein. Its signs and symptoms are highly variable, and the disease should be suspected in patients with unexplained proteinuria, cardiomyopathy, congestive heart failure, hepatosplenomegaly, or cranial neuropathy. Peripheral neuropathy develops in approximately 10% of cases, and the most severe neuropathies tend to occur in the familial forms. The mechanism whereby amyloid deposition causes neuropathy remains obscure, but mechanical compression, ischemia, and metabolic abnormality have been invoked as explanations. Deposition of amyloid in the transverse carpal ligament produces carpal tunnel syndrome. When suspected, confirmation of the diagnosis is often sought by sural nerve biopsy. However, the utility of sural nerve biopsy for diagnosis has been questioned by a study in which six of nine biopsy specimens in patients with amyloid neuropathy demonstrated no amyloid. The diagnosis was subsequently made by examination of other tissue or the contralateral sural nerve.³⁰ Even the slightest appearance of abnormality of the transverse carpal ligament, such as discoloration or thickening, should prompt sending a ligament specimen for pathologic examination. The diagnosis of amyloidosis has been made many times in this way.

Hereditary amyloidosis with neuropathy has many forms that have had colorful designations—e.g., Portuguese, van Allen, Indiana, Finnish, German—but are now generally referred to as familial amyloid polyneuropathy (FAP) types I to IV. Most are due to mutations in the gene coding for the protein transthyretin (prealbumin), the primary component of amyloid protein. FAP type I produces a sensory-dominant neuropathy characterized by dissociated sensory loss in a small-fiber pattern, autonomic dysfunction, pain, and trophic changes, with amyloid deposition in the endoneurium of peripheral nerves, dorsal root ganglia, and sympathetic ganglia. Type II is often manifested as carpal tunnel syndrome. Type III is associated with a painful, distal axonopathy. Type IV FAP is characterized by progressive cranial neuropathy, corneal dystrophy, and distal sensorimotor neuropathy. The abnormal amyloid subunit protein in type IV is derived from a variant molecule of gelsolin, an actin-modulating cytoskeletal protein.

Nonhereditary amyloidosis is divided into primary and dysproteinemic types, which are clinically and electrophysiologically indistinguishable. The progressive neuropathy is primarily sensory, small fiber, and accompanied by dysautonomia. Electrodiagnostically, the neuropathy is a distal, symmetrical sensorimotor axonopathy.

Infection-Related Neuropathies

Aside from HIV-related neuropathies, infection-related neuropathies are rare except in developing countries.³¹ In fact, the most common cause of peripheral neuropathy in the undeveloped world is leprosy; in the developed world it is diabetes. The peripheral nervous system disorders complicating HIV infection are heterogeneous and highly prevalent. Inflammatory demyelinating neuropathy occurs early in the course of the disease, frequently at the time of seroconversion, and is clinically and electrophysiologically indistinguishable from AIDP and CIDP. In the late stages of the disease, usually when the CD4⁺ T-cell count is less than 50, the most common neuropathy is a painful, distal, sensory axonopathy. Less commonly, lymphomatous or vasculitic neuropathy may develop in HIV-infected patients. Neuropathies may also occur as a result of antiretroviral therapy, other drugs, malnutrition, and vitamin B₁₂ deficiency. Herpes-zoster frequently causes radiculopathy, and cytomegalovirus may produce a severe polyradiculoneuropathy or diffuse mononeuritis multiplex.

Lyme disease can produce several different peripheral neurologic complications in up to a third of the patients with late disease. Vasculitis is probably an important pathophysiologic mechanism. Most common are a mild, chronic, axonal sensorimotor polyradiculoneuropathy and facial nerve palsy.³²

Critical Illness Polyneuropathy

Sepsis and multiorgan failure may trigger critical illness polyneuropathy, a common cause of severe generalized weakness and weaning failure in critically ill patients.³³ Critical illness polyneuropathy may occur in some form in as many as 50% of critically ill patients who have been in a septic state for more than 2 weeks. The origin is probably multifactorial and related to the systemic inflammatory response syndrome. The pattern of weaning failure gradually changes from that of the underlying disease to one of neuromuscular ventilatory failure. Proximal muscles, including the facial and paraspinal musculature, are often involved, but tendon reflexes may be paradoxically preserved. Critical illness polyneuropathy is most often a distal sensorimotor axonopathy, but a purely motor form may represent a variant. Differentiation from early AIDP with minimal electrodiagnostic abnormalities may be problematic. Recovery is usually rapid and clinically complete, provided that the patient recovers from the critical illness, although electrodiagnostic evaluation may disclose residua.

Paraneoplastic Neuropathies

Neuromuscular complications of cancer can result from direct effects of the tumor, from side effects of therapy, or from paraneoplastic syndromes. Through remote effects, tumors can produce a paraneoplastic subacute sensory axonopathy, a sensory neuronopathy, or more commonly, a nondescript distal sensorimotor axonopathy. Paraproteinemic disorders and lymphomas may cause a demyelinating neuropathy resembling AIDP or CIDP. Tumors may also produce vasculitis with an attendant neuropathy. In most instances, the paraneoplastic effect is immunologically mediated. Anti-Hu antibody (type 1 anti–neuronal nuclear autoantibody) is a polyclonal IgG directed against neurons throughout the central and peripheral systems and associated primarily with the subacute sensory neuropathy/neuronopathy syndrome and chiefly with underlying small-cell lung carcinoma, which is sometimes otherwise silent. The tumor expresses neuronal antigens or antigenically indistinguishable epitopes and induces a cross-reaction with various tissues in the nervous system. An immune response intended to limit the growth and spread of a neoplasm is then misdirected and causes autoimmunologically mediated neurologic injury. Anti-Hu antibody probably enters the dorsal root ganglion through an incomplete BNB to cross-react with dorsal root ganglion neurons and thereby induce inflammation and cell loss.

Vasculitic Neuropathies

Polyarteritis nodosa (PAN), Churg-Strauss syndrome, and hypersensitivity angiitis account for most instances of vasculitic neuropathy. Other causes include rheumatoid arthritis, systemic lupus erythematosus, undifferentiated connective tissue disease, Wegener’s granulomatosis, primary Sjögren’s syndrome, lymphoid granulomatosis, and cryoglobulinemia. Vasculitis may also complicate cancer, HIV infection, and Lyme disease. Peripheral neuropathy is often an early and dominant feature of systemic necrotizing vasculitis and may be the only manifestation of the underlying process.³⁴ PAN and Churg-Strauss syndrome are characterized by inflammation of medium and small arteries and hypersensitivity angiitis by inflammation of capillaries and venules. A painful multiple mononeuropathy syndrome is the most common clinical finding, but as more nerves are involved, the neuropathy may become confluent and appear as a generalized but asymmetric polyneuropathy. A distal symmetrical polyneuropathy also occurs. Nerve conduction abnormalities are variable. Electrodiagnostic studies may reveal abnormalities in patients with no symptoms of neuropathy. Electrical abnormalities of the sural nerve correlate well with the subsequent yield on biopsy. Some patients have vasculitis isolated to the peripheral nervous system, or the syndrome of nonsystemic vasculitic neuropathy. The clinical and electrodiagnostic features and pathology are similar to PAN, but the peripheral nervous system is affected in isolation and other systems are spared. It may be an organ-specific variant of PAN.

Hereditary Neuropathies

There are numerous forms of hereditary neuropathy (Table 233-9). The widely used Dyck classification scheme divides the hereditary neuropathies into motor-sensory (HMSN) and sensory-autonomic forms (HSAN) and numbers the subtypes. The HMSN syndromes are now more often referred to as CMT disease in recognition of the original discovers of the disease. There are currently seven subtypes of CMT/HMSN disease, numbered CMT1 to CMT7 or HMSN I to VII. The many other forms of hereditary neuropathy are not included in this scheme.

TABLE 233-9 Hereditary Neuropathies

ALD, adrenoleukodystrophy; AMN, adrenomyeloneuropathy; CMT, Charcot-Marie-Tooth; HMSN, hereditary motor-sensory neuropathy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory-autonomic neuropathy; MLD, metachromatic leukodystrophy.

CMT1, also known as HMSN I, peroneal muscular atrophy, or the hypertrophic form of CMT disease, is a uniform, diffuse demyelinating neuropathy with marked slowing of nerve CV that does not vary significantly from nerve to nerve or from segment to segment, with no evidence of conduction block or temporal dispersion.³⁵ Nerve CVs are frequently as slow as 50% of normal, and there is often secondary axon loss. Clinically, CMT1 is a slowly progressive, symmetrical distal sensorimotor neuropathy with associated muscle wasting most evident distal to the knee (stork leg or inverted–champagne bottle deformity) and palpably enlarged nerves that is frequently accompanied by skeletal deformities such as pes cavus or scoliosis. Sensory dysfunction is less prominent than motor dysfunction. Nerve pathology demonstrates demyelination, remyelination, and onion bulb formation.

CMT1 is most often transmitted in autosomal dominant fashion but may be X-linked. The dominant form is divided into CMT1A, located on chromosome 17, and CMT1B, located on chromosome 1. CMT1A is much more common and usually involves duplication of the region of 17p, which codes for peripheral myelin protein (PMP-22). The abnormal genes in the other forms also involve Schwann cell and myelin proteins—P₀ (an important myelin structural protein) in CMT1B and connexin-32 (which localizes to nodes of Ranvier and Schmidt-Lanterman incisurae) in CMT1X.³⁶

CMT2, also known as HMSN II, or the neuronal form of CMT disease, makes up about a third of cases of autosomal dominant CMT. It is associated with selective degeneration of lower motoneurons and dorsal root ganglion cells. There is considerable overlap between CMT1 and CMT2. The clinical picture is identical except for the presence of nerve hypertrophy in CMT1. CMT2 may be autosomal dominant or recessive, and there are numerous subtypes because of different genetic abnormalities, currently designated CMT2A through CMT2L. Electrophysiologically, conduction slowing is less severe and may even be absent. Distal sensory potentials are abnormal in about half the cases.

Hereditary neuropathy with liability to pressure palsies (HNPP) is the genetic mirror image of CMT1A.³⁷ In CMT1A, the PMP-22 gene on chromosome 17 is duplicated (70% of cases) or sustains a point mutation, whereas the same region shows large deletions in HNPP. Clinically, patients with HNPP are initially seen in the second or third decade with a mononeuropathy, multiple mononeuropathy, or brachial plexopathy, often precipitated by trivial trauma. Conduction studies may show a mild underlying neuropathy, but the prominent abnormality is a focal or multifocal picture of demyelinating lesions at common pressure sites. Nerve biopsy shows characteristic focal hypermyelination involving many internodes that causes segments of thickened myelin resembling links of sausage (tomaculi), hence its original name of tomaculous neuropathy.

The rare HSANs are divided into three groups according to the degree of involvement of electrophysiologic modalities and the age at onset. All are primarily sensory axonopathies by EMG. HSAN I is dominantly inherited and features small-fiber sensory loss and painless foot ulcers, with onset in the second decade. HSAN II develops in infancy and results in anesthesia and mutilation of the extremities. HSAN III (Riley-Day syndrome, familial dysautonomia) causes small-fiber sensory loss with prominent autonomic dysfunction.

Toxic Neuropathies

Although an important consideration in the differential diagnosis of generalized peripheral nerve disease, toxic neuropathies are either rare conditions or fairly obvious, as in chemotherapy patients. Potential toxins include heavy metals, environmental toxins, and pharmaceutical agents. There are numerous potential offenders, and this discussion must of necessity focus on only a few agents.

Intoxication with several heavy metals may cause neuropathy, but the agents of greatest practical importance are lead and arsenic. There is a correlation between cumulative exposure to lead and electrophysiologic abnormalities. Classically, lead produces a predominantly motor neuropathy with a predilection for the radial nerve and is manifested as wristdrop. Demyelination is impressive experimentally, but human lead neuropathy is an axonopathy.⁷ The neuropathy of arsenic intoxication is usually a sensory more than motor axonopathy, but in acute cases the electrodiagnostic picture may resemble GBS.

Hexacarbon neuropathies are due to exposure to either n-hexane or methyl butyl ketone (MBK); the neurotoxic effect from both agents is primarily mediated by their common metabolite 2,5-hexanedione. Peripheral neuropathy may develop in workers exposed to only a few parts per million of MBK.³⁸ These agents produce giant axonal swellings that contain accumulations of neurofilaments resembling those in hereditary giant axonal neuropathy. Exposure may occur occupationally or recreationally (glue sniffing, huffer’s neuropathy). The neuropathy is primarily a distal sensorimotor axonopathy with secondary demyelination, and severity correlates with duration of exposure. Worsening may continue after cessation of exposure (coasting), but the long-term prognosis is good.

Chemotherapy-Related Neuropathies

The majority of toxic neuropathies are iatrogenic and related to drugs used to treat a variety of conditions ranging from cancer and acquired immunodeficiency syndrome to gout. Unfortunately, the antimitotic effects of several important chemotherapeutic agents are accompanied by incidental damage to the peripheral nervous system. The taxoid class of agents, paclitaxel and docetaxel, bind to tubulin and promote microtubule polymerization, which leads to the accumulation of bundles of disordered microtubules that interrupt normal mitotic operations and possibly interfere with axonal transport. In one study, docetaxel produced a sensorimotor peripheral neuropathy in 11% of the patients exposed.³⁹ The vinca alkaloids, vincristine and vinblastine, in contrast, induce microtubule disassembly, which impairs neurotubule function and axonal transport. The neuropathy of vincristine is a sensorimotor axonopathy with variable dysautonomia. Cisplatin is a heavy metal complex that cross-links DNA in a manner similar to alkylating agents. The neuropathies of both cisplatin and paclitaxel/docetaxel are predominantly sensory and dose dependent.^39,40 The cisplatin neuropathy is primarily large fiber with loss of proprioception and sensory ataxia. Chemotherapy may unmask a previously unrecognized neuropathy.⁴¹ A long-standing quest to find agents that can at least partially negate the neurotoxic side effects of chemotherapeutic agents has been unproductive.

Other Drug-Related Neuropathies

Among the numerous medications that may cause neuropathy, colchicine and pyridoxine merit particular mention because of the prevalence of their use. Like some chemotherapeutic agents, colchicine interferes with microtubule growth and impairs microtubule-dependent functions; it may cause a generalized sensorimotor axonopathy, frequently associated with a myopathy. Pyridoxine, commonly used for such conditions as premenstrual syndrome and carpal tunnel syndrome, has significant neurotoxic potential, primarily involving dorsal root ganglion neurons. It is also frequently prescribed, in potentially toxic doses, for the empirical treatment of neuropathies that are seldom if ever due to pyridoxine deficiency. Initial reports described a profound, often permanent ataxic neuropathy with massive doses. Lower doses, in the 100- to 200-mg/day range, taken over a long period can also produce neuropathy. In one study, a high serum vitamin B₆ level was present in 172 women, 60% of whom had neurological symptoms, which disappeared when B₆ was withdrawn. The mean dose of vitamin B₆ in the 103 women with neurological symptoms was 117 ± 92 mg, and the average duration of ingestion was 2.9 ± 1.9 years. The symptoms included paraesthesia, hyperesthesia, bone pain, muscle weakness, numbness, and fasciculations. Intoxication from acute high-dose pyridoxine can leave a severe residual sensory ataxia, but patients taking a lower dose of vitamin B₆ had complete recovery within 6 months of stopping B₆.⁴² Vitamin B₆ tablets containing 500 to 1000 mg are available over the counter. The daily requirement is in the range of 2 mg/day. Physicians should be aware of the neurotoxic effects of pyridoxine before prescribing it for trivial conditions and in situations in which it is extremely unlikely to have a true therapeutic benefit.

Most pharmaceuticals cause a chronic, generalized sensorimotor axonopathy. Notable exceptions are the sensory neuropathy/neuronopathy secondary to pyridoxine, cisplatin, and the taxoids and the motor neuropathy of dapsone. Amiodarone, perhexiline, and cytosine arabinoside may cause a myopathy in conjunction with a neuropathy.⁷

Mononeuropathy Multiplex

A mononeuropathy affects only one peripheral or cranial nerve, and the most common cause is trauma, most often resulting from compression or entrapment. The term mononeuropathy multiplex, or multiple mononeuropathy, refers to a condition that produces two or more nontraumatic mononeuropathies. A patient with more than one mononeuropathy at common entrapment sites (e.g., bilateral carpal tunnel syndrome) probably has multiple compression syndromes rather than mononeuropathy multiplex in the true sense of the term. Occasionally, features suggesting both generalized polyneuropathy and mononeuropathy multiplex may be present simultaneously. Late in the course of mononeuropathy multiplex, when many nerves have become involved, the pattern may begin to resemble a generalized polyneuropathy. Subtle asymmetry on clinical or electrodiagnostic testing is an important clue to the possibility of such a confluent or summated mononeuropathy multiplex syndrome. Any generalized neuropathy may render nerves more susceptible to injury and produce focal accentuation of the diffuse process as a result of vulnerable nerve syndrome. For instance, a patient with a mild generalized neuropathy caused by diabetes may be initially evaluated for carpal tunnel syndrome, and the underlying polyneuropathy only becomes apparent with electrodiagnostic testing of apparently unaffected nerves.

Generally, the primary diagnostic concern in a patient with mononeuropathy multiplex is vasculitis causing multiple nerve infarctions.^43,44 In underdeveloped countries, leprosy is an important consideration. Some causes of mononeuropathy multiplex are listed in Table 233-10.

TABLE 233-10 Some Causes of Mononeuropathy Multiplex