Painful polyneuropathy (PN) is a debilitating neurologic problem and frequently a challenging therapeutic management issue. Difficulties in managing patients are too often the result of poor understanding of their problem on the part of the treating physician. Many physicians assume that there is no need to work up neuropathy because the final outcome is likely to be an idiopathic, axonal disorder for which there is no effective therapy. In fact, many neuropathies are responsive to immunosuppressive and other conservative therapies. Although responses to such therapy constitute the minority, they should be vigorously sought before telling patients there is no treatment for their progressive disorder. In many cases, treatment of the PN also leads to improved pain control; however, pain is often a primary issue in and of itself and must be treated irrespective of the potential for improvement of the underlying PN. In these cases, pain management specialists may work in concert with neurologists to provide a comprehensive treatment approach.

INTRODUCTION

The first step in developing a rational approach to patient management is obtaining a working knowledge of the underlying disorders that fall under the category of neuropathy. Although it is often used loosely to refer to PN, the term neuropathy is actually not specific and implies any peripheral nerve lesion, focal or diffuse. Classification schemes used widely among peripheral neurologists are based on anatomic and physiologic characteristics of the various disorders affecting peripheral nerves. The use of these classifications is not just an academic exercise but creates a basis for rational decision making in the evaluation and management of patients. The workup and treatment of individual patients with neuropathy must be approached with a basic understanding of the clinical behavior, including the anatomic and pathophysiologic characteristics, of the various neuropathic disorders.

CLASSIFICATION AND CLINICAL COURSE

The term polyneuropathy is used to describe a condition that is fairly symmetric and generalized, as opposed to focal neuropathy (mononeuropathy) or multifocal neuropathy (mononeuropathy multiplex [MM]). This chapter focuses on the diffuse disorders, including PN and multifocal mononeuropathies. These two groups of disorders may be indistinguishable clinically and are frequently accompanied by severe and disabling pain.

When a disorder of peripheral nerves is suspected, an attempt should be made to characterize the clinical features based on the time course, anatomic distribution, and physiology. Using this information, a reasonable differential diagnosis can be developed, which will determine appropriate further workup and management. This section further discusses the clinical and physiologic features of the diffuse neuropathies; their diagnostic evaluation is covered in the next section.

Polyneuropathy

Time Course

An important clue as to the etiology of a particular PN is its time course. Generally accepted guidelines classify a neuropathy as acute (<3 weeks), subacute (weeks to months), or chronic (>4–6 months). Notably, neuropathies in each of these categories may be associated with debilitating pain. The typical clinic patient presenting with chronic, insidious PN is probably the most easily diagnosed; the more acute neuropathies may be difficult to differentiate from central nervous system (CNS) disease, particularly spinal cord compression.

Fiber Type and Distribution

Polyneuropathy may involve motor, sensory, or autonomic fibers. There is a tendency in some neuropathies for selective involvement of fibers of the same general size distribution. Thus, a neuropathy may involve predominantly large-diameter sensory fibers (mediating vibration and proprioception) in addition to intermediate-sized motor fibers. Conversely, PN may primarily involve small-diameter sensory fibers (mediating pain and temperature) with or without involvement of autonomic fibers. Typically, pain is a prominent feature of these so-called small-fiber neuropathies. Certainly, a neuropathy may be generalized in terms of the fiber type involvement (as commonly seen in diabetes); however, careful examination often reveals a predominance of one group of fibers over another.

Pathophysiology

A detailed description of the pathophysiologic mechanisms underlying PN in various disorders is beyond the scope of this chapter; instead, we focus on the relevant clinical-pathologic correlates as well as the electrodiagnostic characteristics of the different neuropathies, depending on the primary site of pathologic change.

The two primary sites of pathologic involvement in neuropathy are the axon and the myelin sheath, or Schwann cell, the former being more common in PN. In general, in axonopathies, the longest and larger diameter fibers tend to be involved first, with degeneration originating in distal portions of individual axons and proceeding proximally. This creates a length-dependent pattern, which can be demonstrated both clinically and electrophysiologically. This generalized “dying back” is theorized to result from metabolic derangement in the cell bodies or diffusely within axons. Axonopathies tend to be quite symmetric in terms of side-to-side involvement, a feature that distinguishes them from the multiple mononeuropathies. These are the most common type of PN; almost all toxic and metabolic insults to the peripheral nervous system (PNS) result in axonal degeneration.

Less frequently, the axon is largely spared, and demyelination is the primary pathologic change. Although myelinopathies may be the result of abnormal Schwann cell development or metabolism, these situations are rare, and the most frequent clinical situation is one in which segmental demyelination, or loss of myelin between the nodes of Ranvier, occurs. Segmental demyelination usually is the result of an autoimmune attack on peripheral nerves and nerve roots (as in Guillain-Barré syndrome), with the clinical pattern being somewhat variable; the limbs are involved proximally as well as distally but are usually fairly symmetric side to side.

Etiology and Prognosis

Tables 46-1 and 46-2 list the most common causes of PN based on their physiology (axonal vs. demyelinating) and time course.

Although the clinical course of various neuropathies is highly variable, depending on etiology, there are a few generalizable rules regarding prognosis. Patients with any disorder involving significant axonal injury will be less likely to recover than patients with disorders in which the primary physiology is segmental demyelination. Thus, the differentiation between these two is of practical importance for the clinician. In a disorder characterized purely by the latter, recovery occurs by remyelination and usually occurs over 6 to 8 weeks. In generalized neuropathies, even of primary demyelinating type (e.g., Guillain-Barré syndrome), there is nearly always some accompanying axonal injury and, ultimately, the prognosis depends on its severity. Thus, recovery may be complete but take months or even years.

In primary axonal neuropathies, the prognosis depends on the nature and severity of the axonal injury. For example, in typical MM, in which nerve injury results from ischemic insult, recovery occurs largely through axonal regrowth. Individual regrowth of axons occurs from the proximal nerve stump at a rate of about 1 inch per month. This form of recovery is very slow and nearly always incomplete. In neuropathies characterized by a dying-back type of physiologic change, there usually is very little regrowth of individual axons. Instead, functional recovery occurs through reinnervation of muscle fibers by nearby healthy axons, a mechanism that probably only limits the severity of the deficit related to axonal loss rather than allowing any improvement in function.

Mononeuropathy Multiplex

Clinical Course

Mononeuropathy multiplex is a diffuse neuropathic disorder, similar to PN, but it is distinguished by involvement of multiple individual nerves. MM may be impossible to distinguish from PN based on history and examination alone because the cumulative involvement of multiple nerves can produce a generalized and fairly symmetric picture. A high index of suspicion for MM is important in the appropriate clinical setting. MM is almost invariably the result of ischemic insult to nerves, the most common etiology being small- and medium-vessel vasculitis. MM occurs in the majority of cases of systemic vasculitis and may be its presenting symptom; in rare cases, vasculitis is restricted to the PNS (nonsystemic vasculitic neuropathy).¹

Regardless of etiology, MM typically presents with an acute onset of severe pain and numbness in the involved limb; motor and sensory deficits develop over days. Nerves that are often involved early are those at so-called watershed zones of the vascular tree (e.g., the sciatic nerve in the thigh, the ulnar nerve in the forearm). Progression to other nerves eventually produces a picture suggestive of severe, axonal PN; the progression may be subacute or, rarely, chronic. In all cases, pain remains a prominent feature of the disorder.

The prognosis depends on the underlying etiology of the MM. In vasculitic neuropathy, aggressive treatment of the underlying disease is aimed at preventing further ischemia. Recovery of existing lesions occurs by means of axonal regrowth at a pace of about 1 inch per month from the site of the injury. An aggressive therapeutic approach to pain is appropriate, particularly early in the course of the disorder, when immunosuppressive therapy has not reached maximum effectiveness. Over time, if the vasculitis can be adequately treated, it may be possible to reduce or withdraw pain therapies.

Etiology

Table 46-3 lists the most common etiologies of MM based on time course.

DIAGNOSTIC EVALUATION

History and Physical Examination

History

The first step in the diagnostic evaluation of any neuropathy is the history and physical examination of the patient. Several important historical points should be reviewed. One should determine the time course of the illness—acute, subacute, or chronic. Next, involvement of nerve fiber types should be ascertained—sensory, motor, and autonomic, with regard to both positive and negative symptoms. Specific inquiry should be made regarding the presence or absence of pain. Whereas positive symptoms refer to abnormal spontaneous sensory or motor phenomena (e.g., pins and needles, fasciculations), negative symptoms describe a loss of function (e.g., weakness, numbness). Inquiry should be made regarding the symptom distribution and symmetry (i.e., stocking glove vs. individual nerve territories), as well as the progression (i.e., slow and insidious vs. acute-onset deficits with plateaus).

Past medical history obviously factors into the diagnostics, especially because hyperglycemic disorders are in a spectrum and increased incidence of diabetic PN in prediabetes correlates with impaired glucose tolerance rather than fasting hyperglycemia.² A remote cancer history can also include chemotherapy. Nutritional deficiencies of the B vitamins may accompany gastric and other gastrointestinal disorders with malabsorption through one or another mechanism (treatment of gastroesophageal reflux disease, peptic ulcer disease, and other conditions can involve chronic acid suppression and resultant decreased absorption of nutrients;^3,4 gastric bypass, banding, and other gastric function alteration surgeries;^5,6 short gut syndrome from surgical resection of small or large bowel;⁷ and gluten enteropathy).⁸ Social and work history can also impact diagnostics (exposure as a child or adult to old residences with lead paint; work exposure to toxic chemicals or heavy metals; substance abuse history may be direct through heavy alcohol use or indirect through concomitant poor nutrition and infection such as hepatitis C and HIV; hunting, fishing, and other recreational activities as well as residence location may give exposure to Lyme disease; pet dogs with Lyme disease may be the best predictor of their owners contracting Lyme disease).⁹ Finally, one should obtain a family history, with an eye to excluding a congenital form of neuropathy.

Characteristic features of neuropathic pain are useful in differentiating it from pain from any other source. It is vital that these symptoms and signs are sought during the history and physical examination because they are often primary evidence for a diagnosis of PN. In some neuropathies, such as those limited to involvement of small fibers, normal laboratory studies are the rule, and the diagnosis is based on clinical grounds alone. The presence of positive symptoms is typical of the neuropathic disorders.

Positive symptoms that are typical of PN include (1) paresthesias—nonpainful, spontaneous sensory phenomena such as pins and needles or tingling; (2) dysesthesias—unpleasant spontaneous or evoked sensory phenomena such as burning; (3) hyperesthesia—increased sensitivity to stimuli, often with an unpleasant quality; (4) allodynia—pain created by a normally nonpainful stimulus, such as the bedcovers; and (5) hyperpathia or hyperalgesia—exaggerated pain response created by a normally painful stimulus.

The presence of these symptoms should be sought specifically in addition to allowing the patient to describe the precise nature of his or her pain. Also, the effect of pain on quality of life and functional status is extremely important. Specific pain measures, such as the Neuropathic Pain Scale,¹⁰ may be used to quantify the patient’s pain and its effect on the quality of life. Such scales are particularly helpful for patients involved in clinical therapeutic trials and may be used to assess efficacy of treatment regimens outside of experimental trials. However, neuropathic pain symptoms may also be found in musculoskeletal and other non-neuropathic conditions, so they are not pathognomonic by themselves.

Physical Examination

The physical examination should be guided by the patient history. For example, the suggestion of asymmetric onset of symptoms should prompt a careful search for evidence of individual nerve involvement as opposed to a stocking-glove distribution of sensory loss.

A complete neurologic examination is required. One cannot adequately localize the problem to the peripheral nerve without a careful physical examination to rule out myelopathy, polyradiculopathy, or myopathy, which may mimic or complicate PN. The details of the neurologic examination are not reviewed here, but a few points are worth emphasizing. The goal of the physical examination is to characterize the pattern, symmetry, and distribution of abnormalities and to determine which modalities are involved (motor, sensory, autonomic); the distribution with regard to fiber type should also be demonstrable. The typical pattern to look for is bilaterally symmetric, usually distally predominant. The proximal lower extremities tend to be involved before the distal upper extremities, although this is variable; the anterior thoracic region is often involved in more severe cases. However, there may be proximal predominance, and the upper extremities may be involved disproportionately. In MM, the pattern is usually multiple nerve involvement, although it may likely be impossible to differentiate from PN, other than subtle asymmetry in an otherwise stocking-glove distribution. The deep tendon reflexes are part of the overall pattern as well and are typically reduced or absent in a distribution consistent with the underlying pathophysiology. For example, whereas patients with distal axonopathies typically have absent ankle jerks, those with chronic demyelinating neuropathies are areflexic.

In patients with painful positive symptoms, correlative signs may often be found in the physical examination. Allodynia may be elicited by lightly stroking the involved area (mechanical stimulus) or by testing with a cold instrument (thermal stimulus). Hyperalgesia or hyperpathia may be elicited during pinprick testing. A single, painful stimulus may be reported as a sensory deficit, but repeated stimuli in the same area produce an exaggerated pain; this phenomenon is called summation.¹¹ Abnormal sensations may last for several seconds or minutes after discontinuation of the stimulus, a phenomenon called after sensations.¹¹ These examination findings are important because they are unique to patients with neuropathic pain.

Clinical Neurophysiology

Electrophysiologic Studies

The second logical step in the diagnostic evaluation is the electrodiagnostic examination, specifically, nerve conduction studies (NCS) and electromyography (EMG). The utility of these studies is several. First, they usually clarify the diagnosis of PN. Although important, there is a limit to the localizing value of physical examination, even when carefully performed. For example, a detailed physical examination cannot differentiate multiple root involvement from PN or MM in most cases; coexisting neurologic problems may also significantly alter the physical examination. It is important to note that NCS cannot assess the integrity of small-diameter sensory fibers (i.e., those mediating pain and temperature), so results will be normal in patients with pure small-fiber neuropathies. However, these neuropathies are rare, and in patients with involvement of larger fibers, NCS are more sensitive than physical examination for diagnosing PN.

In addition to establishing a diagnosis with accuracy, electrodiagnostic studies provide several other types of information, including the predominant pathophysiology (i.e., axonal or demyelinating), the time course and severity of the disorder, and whether motor or sensory fibers (or both) are involved. NCS can differentiate hereditary from acquired forms of PN and is much more sensitive than physical examination for identifying MM. Chapter 11 discusses the use of electrodiagnostic testing in detail. After the underlying pathophysiology and the time course are understood, the differential diagnostic possibilities are narrowed considerably.

Quantitative Sensory Testing

Quantitative sensory testing (QST) is a specialized technique for measuring the intensity of a given stimulus required to elicit specific sensory perceptions.¹² Specifically, QST assesses a sensory detection threshold to various stimuli, including touch pressure, vibration, heat, and coolness. QST, when properly performed, provides a quantitative, noninvasive means of assessing sensory function. One major advantage is that QST for thermal thresholds allows some quantifiable measure of small-fiber function, which is not possible with routine NCS. Several commercial systems exist for QST. However, a major problem with QST is that it is not widely available for clinical use, and its reliability is highly operator dependent. Notably, its sensitivity in patients with pure small-fiber neuropathies, the group in whom it is potentially of the greatest diagnostic importance, has been reported in several studies to be around 60%.^13,14 Nonetheless, it can be quite helpful in confirming the physical examination findings and substantiating the clinical suspicion of neuropathy. In small-fiber neuropathies, in particular, QST is recommended because it may provide the only objective means for establishing a diagnosis and can be used to measure efficacy of various therapeutic modalities.¹² QST is typically pursued in the evaluation of PN if the routine NCS are nondiagnostic.

Laboratory Studies

The differential diagnostic considerations in any given neuropathy depend on the physiologic characteristics and time course of the underlying disorder (Tables 46-1 to 46-3). Thus, the diagnostic evaluation should proceed initially with electrophysiologic studies, as discussed earlier, and laboratory workup should be guided by the differential diagnostic considerations raised by these findings. The laboratory workup will nearly always include blood studies and occasionally urine studies. Cerebrospinal fluid (CSF) evaluation is no longer routinely necessary; it is most commonly obtained in fairly acute neuropathies in which Guillain-Barré syndrome is suspected.

Table 46-4 outlines the appropriate laboratory workup for PN and MM based on time course and electrophysiology.

Biopsy

Nerve and Muscle

Nerve biopsy is required in a small proportion of patients with neuropathy and should be performed only in situations in which the indication is clearly defined. Only rarely is biopsy necessary to establish a diagnosis of PN. Nerve biopsy is most useful in patients with MM as a means of determining the causative disorder, which is usually inflammatory in nature and has a high morbidity and mortality if untreated. Other disorders appropriately diagnosed by nerve biopsy include sarcoidosis, amyloidosis, and (rarely) leprosy. In the cases of vasculitis and sarcoidosis, a muscle biopsy is usually obtained simultaneously. Nerve biopsy is infrequently performed in cases of progressive PN in which exhaustive workup has failed to reveal an underlying diagnosis. In these cases, the aim of the biopsy is to determine the presence or absence of a potentially treatable disorder.

Skin

In recent years, a technique has been developed for quantitative assessment of cutaneous innervation in punch biopsies of the skin. The epidermis contains free nerve endings, which are the terminals of small-caliber, unmyelinated fibers. Using control values obtained from a healthy cohort, investigators have been able to identify abnormal patterns of intraepidermal nerve fiber (IENF) density in patients with small-fiber sensory neuropathies (SFSNs).^13,15 Examination of patients with idiopathic, human immunodeficiency virus (HIV)–associated, and diabetic painful sensory neuropathies indicates a correlation between IENF density and clinical estimates of small-fiber sensory dysfunction.¹⁵ Studies of patients with idiopathic SFSNs suggest that IENF is a more sensitive diagnostic indicator of pure, small-fiber neuropathies than either QST or sural nerve biopsy.¹³ Although IENF density is still available only in specialized centers, it holds promise as an important tool for routine use in patients with painful sensory neuropathies whose routine workup results may be entirely normal, especially when small-fiber involvement predominates.