Painful Neuropathies
Georgios Manousakis
Miroslav Backonja
David Walk
Pain as a Symptom of Neuropathy
Neuropathy is a common clinical problem. Pain merits attention in any discussion of neuropathy for several reasons. First, insofar as pain varies among neuropathy etiologies, the presence, absence, and type of pain when present can contribute to the diagnostic process. Second, for many people with neuropathy, pain is the chief complaint and the only cause of disability. The traditional neurologic focus on deficits rather than positive sensory phenomena does not serve these patients well. Finally, and perhaps most importantly, pain is a neurologic symptom. The study of pain due to nerve disorder or injury is providing essential insights into the function of the nervous system, as has the study of other neurologic symptoms in the past.
The Evaluation and Diagnosis of Neuropathy
NEUROPATHY CLASSIFICATION
The approach to the diagnosis of neuropathy is fully covered in textbooks devoted to this topic.1,2 The present section is a conceptual overview to allow readers unfamiliar with neuromuscular practice to better understand the balance of this chapter. Throughout this section, specific neuropathies are named for the purpose of illustration only. More comprehensive and detailed information about specific types of neuropathy can be can be found later in this chapter under “Painful Neuropathies.”
The four principal questions to address in the etiologic classification of neuropathy are the time course of symptoms, the distribution of neuropathy symptoms and signs, the modalities affected (motor, small fiber sensory, large fiber sensory, and autonomic), and the primary locus of pathology (axon or myelin). Answers to these four questions will narrow the differential diagnosis substantially.
Time course: Many common neuropathies, particularly those due to metabolic or genetic conditions, progress insidiously over years. Some, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), can progress over a period of weeks to months, often with unpredictable relapses or remissions. Relatively few neuropathies present acutely over days to weeks; among these are Guillain-Barré syndrome (GBS), toxic neuropathies, and peripheral nerve vasculitis.
Distribution: The distribution of neuropathy symptoms and signs can be identified by the history and confirmed by the examination and electrophysiologic studies. Most neuropathies conform to one of two patterns: symmetric, length-dependent versus asymmetric, multifocal, nonlength-dependent. The symmetric, length-dependent pattern begins with symptoms in both feet and progresses rostrally in a symmetric fashion. Symptoms usually do not appear in the hands until lower limb symptoms have progressed to the proximal calves or thighs. Symptoms appear last in the trunk and face. The term length dependent refers to the fact that nerve dysfunction in these patients begins in the longest axons and progresses rostrally. The implicated pathophysiology is that all nerves are exposed in equal measure to a systemic stressor and that the effect of this stressor on nerve function is closely correlated to the distance of the nerve terminal from the cell body. Many metabolic, toxic, and genetic disorders of nerve present in this fashion.
Asymmetric, nonlength-dependent neuropathies can affect proximal and distal nerve segments concomitantly in an unpredictable manner. Examples of those include CIDP, necrotizing vasculitis, granulomatous disorders such as sarcoidosis and leprosy, hereditary neuropathy with liability to pressure palsies (HNPP), and lymphomatous or carcinomatous infiltration of peripheral nerves.
Modality: The modalities affected refer to motor axons, large fiber (Aβ myelinated) sensory axons, small fiber (A∂ and C) sensory axons, and autonomic (cardiorespiratory, vasomotor, and visceromotor) axons. As with distribution, the involvement of these fiber classes can be identified by the history and confirmed by the neurologic examination and electrophysiologic studies; in addition, numerous clinical tools have been developed in recent decades to assist in the confirmation of small fiber sensory and autonomic involvement. Most symmetric, length-dependent metabolic or toxic neuropathies are clinically sensory-predominant until they are relatively advanced. The relative involvement of large and small sensory axons varies among, and in some cases within, etiologies. Patients with clinical findings isolated to small fiber modalities are often referred to as having small fiber neuropathy (SFN), although there is evidence that this progresses over time to involve large fibers as well. Etiologies of SFN are discussed in subsequent paragraphs. Large fiber sensory symptoms predominate in those neuropathies in which the primary pathology is a disorder of myelin, such as Charcot-Marie-Tooth (CMT) type I or CIDP. Necrotizing vasculitis, CMT, and CIDP demonstrate prominent motor and sensory involvement. Motor neuropathies without discernible sensory or autonomic involvement are uncommon in general clinical practice. They include multifocal motor neuropathy (MMN) and toxic neuropathy due to lead or dapsone exposure. Because pain is not a prominent feature of those, they
are not discussed further. Diabetic, uremic, amyloid, paraneoplastic, and certain hereditary neuropathies can have clinically significant autonomic involvement.
are not discussed further. Diabetic, uremic, amyloid, paraneoplastic, and certain hereditary neuropathies can have clinically significant autonomic involvement.
Locus of pathology: The primary locus of pathology (axon or myelin) may be inferred by clinical examination. For example, demyelinating neuropathies are often characterized by early loss of stretch reflexes even before the development of substantial muscle weakness, and by relatively preserved muscle bulk, because demyelination alone does not result in denervation, and therefore, denervation atrophy does not develop unless or until there is secondary axonal injury. By contrast, axonal neuropathies result in relative preservation of reflexes and early atrophy of clinically affected muscles. Nevertheless, these clinical clues require confirmation by nerve conduction studies which, if interpreted correctly, provide reliable information about the primary pathologic substrate. For this reason, nerve biopsy is rarely needed to determine whether the primary pathology is axonal or demyelinating. The only common disorders of peripheral myelin are GBS, CIDP, and CMT type I.
Pain is common in some neuropathies and uncommon in others. Pain commonly manifests in neuropathies which have a predominance of small fiber involvement. There are pain descriptors that are common in painful neuropathies and less common in other painful conditions. This clinical observation has led to the development of several neuropathic pain questionnaires.3,4,5,6 The process of validating such questionnaires has resulted in the identification of several symptoms that correlate well with the presence of neurologic pathophysiologic processes that lead to pain. These symptoms include paresthesias; spontaneous ongoing pain most frequently described as burning, numbness, and shooting; and tactile allodynia.7
The presence or absence of pain and characteristics of neuropathic pain can help the clinician identify the most likely type and etiology of a patient’s neuropathy. For example, neuropathic pain is one of the defining characteristics of SFN. Allodynia is almost universally present in postherpetic neuralgia (PHN). Severe, aching, boring pain is an essential feature of neuralgic amyotrophy (NA) and a common complaint in necrotizing vasculitis. By contrast, CMT may be associated with musculoskeletal pain, but the presence of prominent neuropathic pain would put this diagnosis in doubt. One of the neuropathic pain symptom questionnaires, whether structured or unstructured, should be included in every diagnostic evaluation for neuropathy.
HISTORY, EXAMINATION, AND DIAGNOSTIC STUDIES
The medical history of a patient with neuropathy should include a systematic assessment of positive and negative sensory, motor, and autonomic symptoms. The neuropathy symptom profile instrument includes all of these.8 As noted previously, neuropathic pain questionnaires allow systematic and comprehensive assessment of spontaneous and stimulus-evoked positive sensory symptoms, as well as pain descriptors, in patients with neuropathic pain.
The examination of the patient with neuropathy must include bedside assessments of both large and small fiber sensory modalities.
In addition to the standard neurologic examination, several laboratory investigations have proven valuable in the assessment of neuropathy in general and painful neuropathy in particular. These include psychophysical, neurophysiologic, and histopathologic investigations.
Psychophysical tests investigate the relationship between physical stimulus properties and corresponding perceptions of the stimulus.9 The sensory component of the standard neurologic examination is a series of psychophysical tests. The term quantitative sensory testing (QST) is often used to describe one of several psychophysical testing paradigms for quantitative determination of perception of thermal or mechanical stimuli. In addition to threshold testing, QST can be used to obtain an intensity rating in response to application of a stimulus with fixed suprathreshold predetermined properties. For example, QST can be used to establish either a thermal pain threshold or the perceived intensity of pain evoked by a thermal stimulus of fixed intensity. Like the neurologic examination, QST can be used to determine whether a subject’s sensory function is normal and, if not, the characteristics of those abnormalities. In addition, as a quantitative tool, QST can be used to monitor neuropathy and associated pain and as a tool in research.10,11
There is growing interest in developing a standardized assessment protocol for neuropathic pain to include tests of thermal, mechanical, and even chemical sensory function, including presence and intensity of allodynia and hyperalgesia. It is the expectation that comprehensive assessments of neuropathic pain features such as these would allow clinicians to identify patterns of pain phenotypes that would reveal underlying mechanisms irrespective of the etiology of neuropathy and point to the unique treatment options of neuropathic pain for individual patient groups. This type of development would complement now-standard neurologic examination which has proved critical for lesion localization and disease pattern recognition. Thermal hyperalgesia applying suprathreshold stimuli would be tested along with thermal sensory threshold testing, using commercially available devices. A comprehensive test of sensory thresholds, allodynia, and hyperalgesia has been designed and implemented by the German Neuropathic Pain study group.12,13 A simpler test which combines mapping of areas of allodynia or hyperalgesia with fixed stimulus intensity rating and multimodality neuropathic pain assessment has been proposed by the Neuropathic Pain Research Consortium (NPRC) in the United States.14 These efforts are still in their infancy and await further validation and large-scale implementation.
Neurophysiologic studies investigate the activity of electrically excitable tissues (nerve or muscle cells) either at rest, during normal activity, or in response to externally applied stimuli. The most commonly used neurophysiologic studies are nerve conduction studies and electromyography (NCS/EMG). NCS/EMG can provide objective evidence of dysfunction of large myelinated (Aβ) nerves, valuable evidence of whether the primary pathology is in the myelin or axon, and information about the distribution of disease.
One of the major limitations of NCS/EMG is that it provides no information about the functional status of small myelinated (Aδ) or unmyelinated (C) fibers. In the last two decades, the advent of immunohistochemical staining of skin biopsy tissue for evaluation of epidermal nerve fibers (ENFs) has allowed the identification of patients with normal nerve conduction studies but loss of cutaneous nerves.15,16 In most cases, there are corresponding signs of abnormal nociception and thermal perception, consisting of both sensory loss and spontaneous or stimulus-evoked neuropathic pain,17,18 although such patients likely lose large (Aβ) fibers over time as well.19 This syndrome is known as SFN, and the ability to diagnose it through skin biopsy has spurred tremendous interest. Because small myelinated (Aδ) fibers also innervate sweat glands, neurophysiologic quantitative assessment of the stimulated sweat gland output, by quantitative sudomotor axon reflex testing (QSART) or other methods, is also valuable to diagnose SFN.20,21 Currently, investigational approaches for the evaluation of small fiber function include microneurography,22 laser-evoked potentials, and corneal confocal microscopy.23
Pathologic examination of peripheral nerve trunks also plays an important role to establish the specific cause of the neuropathy, especially when vasculitis, amyloidosis, granulomatous, or neoplastic disorders are suspected. Nerve biopsy can also be used to support a diagnosis of CIDP or other chronic demyelinating neuropathies.24
Painful Neuropathies
There is a higher incidence of pain among some etiologic categories of neuropathy than others. In this section, we describe those common neuropathies that are often painful.
DISTAL SYMMETRIC POLYNEUROPATHIES
Metabolic Causes
Diabetic Neuropathy
The most readily recognized cause of distal symmetric polyneuropathy (DSP) in the developed world is diabetes. Diabetic neuropathy is often but not always painful. The prevalence of painful neuropathy symptoms in one community study of diabetics was 25% to 50%.25 All features of neuropathic pain, including mechanical allodynia, mechanical and thermal hyperalgesia, spontaneous shooting pains, and spontaneous burning, may occur. Like the sensory deficits of diabetic neuropathy, diabetic neuropathy pain presents in a length-dependent, symmetric pattern. Therefore, focal neuropathic pain in a diabetic should prompt consideration of an alternative etiology for the pain. Mononeuropathies in diabetes are discussed later under the heading “Painful Mononeuropathy Multiplex and Focal Neuropathic Syndromes.”
There is no established metabolic or genetic distinction between diabetics whose neuropathy is or is not associated with neuropathic pain, although it has been suggested that neuropathic pain often develops early in the course of nerve injury and recedes when neuropathy becomes more severe. Experimental models of diabetic neuropathy have provided evidence that pain in diabetic neuropathy is probably mediated by pathophysiologic processes at peripheral or central nervous system (CNS) levels. Work in the streptozotocin model has demonstrated altered expression and kinetics of voltage-gated sodium; transient receptor potential cation channel, subfamily A, member I (TRPA-I); and T-type calcium channels at the axon terminals, or shaker-potassium channels in nodes of Ranvier, mediated by methylglyoxal or other metabolites. CNS mechanisms include altered descending inhibition of pain and aberrant neuroplasticity.26 It remains to be determined whether these mechanisms apply in people with diabetic neuropathy.
Investigation of the syndrome of SFN has revealed a disproportionate number of patients with impaired glucose tolerance (IGT), suggesting that the etiology of neuropathy in such cases is incipient diabetes and the mechanism is the same as that of diabetic neuropathy. Although appealing, this remains a hypothesis only. Many such patients also have the metabolic syndrome.27 Among disorders of lipids, hypertriglyceridemia in particular has been found to be prevalent in this syndrome.28,29 Conversely, there is some evidence that, among diabetics, the prevalence or severity of neuropathy is greater if other components of the metabolic syndrome are present.30,31 These observations suggest that microvascular disease exacerbates the nerve injury associated with hyperglycemia.
Infectious Causes
Both HIV infection and several of the commonly used highly active antiretroviral therapies (HAART) for HIV infection are associated with DSP.32,33,34 The two etiologies may coexist, and the neuropathies associated with them are clinically indistinguishable; therefore, initial management for DSP in a patient on HAART usually consists of a therapeutic trial of medication change or discontinuation. DSP is most closely associated with the use of dideoxynucleoside analogues stavudine (D4T), zalcitabine (ddC), and didanosine (ddI). The mechanism of this effect is believed to be the inhibition of mitochondrial DNA polymerization, leading to mitochondrial dysfunction and, in turn, reduced energy availability. DSP in HIV infection commonly presents with symptoms of small fiber involvement, with prominent pain and paresthesias. The mechanism of HIV directly on development of pain and neuropathy is unknown, although there is some experimental evidence implicating inflammatory mechanisms triggered by infection of periaxonal Schwann cells.32
Chronic hepatitis C virus (HCV) infection is a well-recognized cause of polyneuropathy. DSP, SFN, mononeuropathy multiplex, and cranial neuropathy can all be seen in this context. Polyneuropathy due to HCV infection is usually, but not always, associated with secondary cryoglobulinemia, and nerve biopsy often demonstrates features suggestive or diagnostic of vasculitis. Depending on the severity and time course of the condition, as well as the pathologic findings, treatment can be supportive or may include antiviral therapy, immunomodulating therapy, or both.35,36
Lyme disease is a well-recognized cause of cranial neuropathy and polyradiculopathy. Less commonly, polyneuropathy and mononeuropathy multiplex have been described in the context of Lyme disease. Although direct infection is difficult to demonstrate, a diagnosis of peripheral nervous system Lyme disease can be inferred in the context of a subacute progressive neuropathy with clinical and serologic evidence of Lyme and clinical improvement with antibiotic therapy. Lyme radiculopathy, polyneuropathy, and mononeuropathy multiplex could all be associated with pain.37,38
Toxic Neuropathies
Neurotoxic substances impair a number of neural processes such as protein synthesis, axonal transport, and myelin maintenance. Exposure to several industrial toxins is well known to lead to polyneuropathy. These usually cause motor symptoms and signs, although painful and dysesthetic symptoms may ensue in a minority of patients. Very few pathologic studies have been conducted in humans. N-hexane, a common ingredient in household glue, and methyl-n-butyl ketone, an industrial solvent, are known to cause focal swelling of axons to 2 to 3 times their normal diameter and can result in painful neuropathy.39,40
Several pharmaceutical agents may cause painful polyneuropathy. Vincristine, taxanes, bortezomib, and the newer agents, ixabepilone and eribulin, all can cause painful polyneuropathy by interference with the function of microtubules.41 Recent evidence also implicates mitochondrial dysfunction in chemotherapy-induced neuropathy, which will probably dictate treatment strategies for this type of painful polyneuropathy.42 Of particular interest are the recent descriptions of immune-mediated neuropathies related to the use of immune checkpoint inhibitors for metastatic cancers, including the cytotoxic T-lymphocyte antigen 4 inhibitor, ipilimumab, and the PD-1 inhibitors nivolumab and pembrolizumab. Treatment of those neuropathies requires not only discontinuation of the offending agent but also immunosuppression.41
Many other drugs are known to cause polyneuropathies which are not always painful. Among these are isoniazid, gold, disulfiram, nitrofurantoin, amiodarone, and bezafibrate.
Nutritional Neuropathies
Pyridoxine Deficiency from Isoniazid Use
Isoniazid is an effective and inexpensive antituberculosis drug, but it is associated with distal neuropathy when administered in high doses. Patients with a genetic predisposition for slow metabolism of isoniazid are more susceptible to this adverse effect. Isoniazid interferes with essential metabolic functions of pyridoxine, leading to axonal damage. This axonopathy affects small and large fibers, causing motor deficits, sensory deficits, and pain. Pain is described as deep aching pain in calf muscles and burning paresthesias in upper and lower extremities.
Oral pyridoxine in doses of 30 to 100 mg per day can prevent or reverse isoniazid neuropathy. Excessive doses should be avoided because pyridoxine itself can cause neuropathy if given in excess.
Oral pyridoxine in doses of 30 to 100 mg per day can prevent or reverse isoniazid neuropathy. Excessive doses should be avoided because pyridoxine itself can cause neuropathy if given in excess.
Beriberi
Beriberi is the most widely recognized nutritional neuropathy and is a disease of the peripheral nerves and heart43 caused by thiamine deficiency. If the heart is affected, it presents with heart failure (wet beriberi), but the majority of patients present with neuropathy alone (dry beriberi). Presenting symptoms are slowly progressive distal weakness, paresthesias, and pain. Rarely, beriberi develops acutely. There are multiple presentations of pain symptoms, including dull, constant ache, lancinating brief pain similar to tabes dorsalis, tightness, and burning. Unlike idiopathic distal symmetric SFN, in beriberi, burning usually involves the hands as well as the feet shortly after onset. Physical examination reveals symmetric sensory loss across all modalities as well as positive phenomena such as allodynia, hyperalgesia, and hyperpathia as well as distal weakness and areflexia. Large fiber involvement is demonstrated by nerve conduction studies.44 Nutritional supplementation with thiamine is essential. With treatment, beriberi neuropathy improves slowly.
Pellagra Neuropathy
Pellagra is a nutritional disorder that when fully developed affects the skin, gastrointestinal, hematopoietic, and nervous systems. Nervous system manifestations include encephalopathy, myelopathy, and neuropathy. Neuropathy is infrequent but can be quite disabling.
Alcohol Neuropathy
It is well established that excessive and prolonged intake of alcohol is associated with a DSP which is often characterized by distal paresthesias, burning, and other features of neuropathic pain. The precise cause of alcohol polyneuropathy is unknown. For decades, the principal question has been whether alcohol polyneuropathy is due solely to deficiency of thiamine and, perhaps, other B vitamins or is due to a direct toxic effect of alcohol, its metabolites, or even other neurotoxins in alcoholic beverages. Support for a neurotoxic role of alcohol comes from an animal model of alcoholic neuropathy in which rats that are provided adequate nutritional supplementation along with alcohol develop polyneuropathy.45 Some interesting clinical observations support this as well. For example, alcohol polyneuropathy is prevalent among Danish alcoholics despite the fact that beer, which is the alcoholic beverage of choice in that country, is supplemented with B vitamins.46 In addition, an elegant series of studies of Japanese alcoholics has demonstrated that neuropathy is prevalent among alcoholics with normal serum thiamine levels and that sural nerve pathology differs between alcoholics with and without thiamine deficiency.47
Neuromuscular Manifestations of Intestinal Malabsorption after Bariatric Surgery and Other Gastrointestinal Surgical Procedures
The growing use of bariatric surgery has led to resurgence in awareness of neurologic disorders associated with malabsorption, some of which can be associated with neuropathic pain. Wernicke’s encephalopathy, beriberi, and subacute combined degeneration due to vitamin B12 or copper deficiency are among the neurologic disorders attributable to known deficiency states that have been described after bariatric surgery. In some cases, a presumed nutritional myeloneuropathy has been ascribed to multiple nutritional deficiencies or deficiency of an unknown nutrient in such patients. Neuropathic pain can occur in beriberi, and in subacute combined degeneration, the latter most likely as a result of an associated sensory neuropathy.
Hereditary Neuropathies
CMT is the most common hereditary neuropathy, with an estimated prevalence of 40 per 100,000.48 The clinical syndrome is a progressive symmetric length-dependent motor and sensory neuropathy. CMT differs from the length-dependent polyneuropathy seen in diabetes and most other metabolic, nutritional, and toxic disorders because, in CMT, weakness and atrophy are prominent early signs, and both upper and lower extremities are typically affected. Most forms of CMT are inherited in an autosomal dominant fashion, the exception being the X-linked form (CMTX). Neuropathic pain is uncommon in CMT, and when it occurs, it is usually not the most prominent symptom. Fatigue, neuromuscular discomfort, and aching pain from foot deformities and overuse syndromes do occur. Acute intermittent porphyria is an autosomal dominant disorder with neuropathy which may have pain as one of the presenting symptoms, but pain is always overshadowed by weakness.
Fabry’s Disease
Fabry’s disease is one of the few hereditary neuropathies in which neuropathic pain is the cardinal symptom. It is a multisystem disorder affecting peripheral nerves, kidneys, heart, and skin. It is inherited in X-linked recessive fashion, and its symptoms start in childhood or adolescence. The biochemical abnormality is a deficiency of α-galactosidase, a lysosomal enzyme. The estimated prevalence is about 2 per 100,000 males. The clinical features include red punctate skin lesions in the lower body and thighs, corneal opacifications, cardiac and renal failure, and polyneuropathy. Cardiac and renal failures are terminal events for these patients. The neuropathy of Fabry’s disease is characterized by continuous burning pain in the hands and feet, with spontaneous paroxysms of more severe pain. On examination, there are surprisingly modest sensory deficits, and muscle stretch reflexes are preserved. Nerve conduction studies are usually normal. In addition to pain, patients with Fabry’s disease have marked autonomic dysfunction manifesting with episodic diarrhea, vomiting, urinary retention, and diminished sweating. Gastrointestinal symptoms can be relieved with metoclopramide.49
Fabry’s disease may be unique in that it appears to exclusively affect small myelinated and unmyelinated axons, at least until such time as renal insufficiency occurs and causes a superimposed mixed polyneuropathy. This has been demonstrated pathologically by comparison of ENF density with sural nerve morphometry in the same patients. Enzyme replacement therapy has been shown to have multiple benefits, including an improvement in the Brief Pain Inventory.50,51 In a recent study of 120 patients, enzyme replacement improved proximal skin innervation only, and this effect was limited to men with preserved renal function. ENF densities and thermal thresholds remained otherwise unchanged.52 Clearly, more needs to be learned about the effect of enzyme replacement therapy on the neuropathy of Fabry’s disease.51,52
Hereditary Sodium Channelopathies
The SCN9A and SCN10A genes encode for the sodium channels Nav 1.7 and Nav 1.8, which are selectively expressed in sensory and autonomic neurons at the dorsal root ganglia. Dominant gain of function mutations in Nav 1.7 and 1.8 can lead to a number of effects including lower threshold for activation and slowed deactivation. As a result, the channel is kept open longer once activated, and normally, subthreshold stimuli can result in depolarization.53 The ultimate result is hyperexcitability and degeneration of small nerve fibers, mediated by increased sodium load and reversal of sodium-calcium exchange. The prototypical disorders described in association with SCN9A mutations are inherited erythromelalgia and paroxysmal extreme pain disorder (PEPD).54,55 Inherited erythromelalgia is characterized by episodic burning pain and red
discoloration of hands and feet, with onset usually in the first two decades of life. The attacks can be triggered by mild warming stimuli, including exercise, and can often be ameliorated by cooling the affected limbs. PEPD is characterized by attacks of pain involving the rectum, eyes, and jaw, often associated with flushing and other autonomic disturbances. Recently, SCN9A, and more rarely SCN10A, variants were found in approximately one-third of patients labeled as having idiopathic SFN.56,57 The penetrance of those variants is not fully understood, and for that reason, they may be considered major risk factors, as opposed to penetrant causative mutations for SFN. This important discovery has led to the targeted development of small molecules that inhibit Nav1.7 or Nav1.8 channels, many of which are currently in clinical trials for various conditions associated with neuropathic pain.58
discoloration of hands and feet, with onset usually in the first two decades of life. The attacks can be triggered by mild warming stimuli, including exercise, and can often be ameliorated by cooling the affected limbs. PEPD is characterized by attacks of pain involving the rectum, eyes, and jaw, often associated with flushing and other autonomic disturbances. Recently, SCN9A, and more rarely SCN10A, variants were found in approximately one-third of patients labeled as having idiopathic SFN.56,57 The penetrance of those variants is not fully understood, and for that reason, they may be considered major risk factors, as opposed to penetrant causative mutations for SFN. This important discovery has led to the targeted development of small molecules that inhibit Nav1.7 or Nav1.8 channels, many of which are currently in clinical trials for various conditions associated with neuropathic pain.58
Amyloid Neuropathy
Neuropathy is a common, early, and often prominent manifestation of amyloidosis. Neuropathy can occur in both familial and acquired amyloidosis. There are several distinct clinical groups of familial (transthyretin [TTR]) amyloidosis, but all of them have an autosomal dominant inheritance pattern. The prevalence varies greatly among ethnic groups. The initial symptoms are numbness, paresthesias, and pain in the feet and lower legs. Autonomic involvement is also common, manifesting with abnormal pupillary reflexes, miosis, anhidrosis, orthostatic hypotension, diarrhea alternating with constipation, and impotence. Cranial nerve involvement manifests late in the disease. About half of the patients have neuropathic symptoms at onset, whereas half present with cardiac, hematologic, or renal dysfunction.
Patients with familial amyloid polyneuropathy can benefit from liver transplantation59 or newly developed small molecules that function as TTR tetramer kinetic stabilizers, including tafamidis,60 which is approved in Europe. Experimental stabilization of TTR tetramer with diflunisal, and the antisense oligonucleotide patisiran, appear promising.61
OTHER WIDESPREAD BUT NONLENGTH-DEPENDENT NEUROPATHIES
Neuropathy with Paraproteinemia
Monoclonal gammopathy, defined as the presence of a single clone of immunoglobulin (Ig) identified via serum protein electrophoresis or immunofixation, is common in the elderly. Although sometimes due to myeloma or lymphoma, monoclonal gammopathy can present in the absence of a malignant lymphoproliferative disorder and, in such cases, is referred to as monoclonal gammopathy of undetermined significance (MGUS). There is an increased prevalence of neuropathy among individuals with MGUS and an increased prevalence of MGUS among individuals with otherwise unexplained neuropathy.62 Despite this, with the exception of a few well-characterized specific antibody-mediated syndromes, such as the syndromes associated with IgM antibodies to the sulfated glucuronyl paragloboside epitope of myelin-associated glycoprotein (MAG-SGPG)63 and disialosyl antibodies, there is no compelling evidence of a causal relationship between MGUS and neuropathy. Nonetheless, the association is sufficiently common that it is prudent to obtain a serum protein immunofixation as part of the evaluation of idiopathic neuropathy and to consider that MGUS in a patient with neuropathy may represent more than a chance association.
Several clinical phenotypes, both axonal and demyelinating, have been described in neuropathy with MGUS. CIDP, a chronic acquired demyelinating neuropathy that usually responds to immune manipulation, is occasionally associated with MGUS. Distal acquired demyelinating syndrome (DADS) is an indolent syndrome of sensory ataxia, often with distal weakness, with electrophysiologic evidence of distal predominant demyelination. DADS is usually associated with an IgM monoclonal gammopathy which, in about two-thirds of cases, is directed against MAG-SGPG.64 Allodynia was recently reported as presenting manifestation of DADS, with good response to intravenous Ig (IVIg).65
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