Peripheral

Following trauma to a nerve, sodium channels accumulate in a higher than normal concentration around the area of injury and along the entire axon, resulting in hypersensitivity of the nerve and ectopic foci. This is often the basis for the use of sodium channel blockers and membrane stabilizers in neuropathic pain. It has also been suggested that nerve injury can result in the release of neuropeptides that might further cause peripheral sensitization through neurogenic inflammation. Nerve injury can also result in the sprouting of sympathetic fibers into the dorsal root ganglia of the affected nerve. In partially injured nerves, the uninjured fibers may increase expression of alpha-adrenoreceptors. In both of these circumstances, sympathetically mediated pain may occur. This pain can often be blocked, at least temporarily, by the application of sympathetic blocks or by the administration of systemic alpha-adrenoreceptor antagonists (phentolamine). More recently, attention has focused on not only changes in the neuronal pathway following nerve damage, but also the complex interplay of neuronal support cells, including Schwann cells, satellite cells in the dorsal root ganglia, spinal microglia, astrocytes, and components of the peripheral immune system. Processes in this interaction could contribute to the development and presence of neuropathic pain. Another proposed but poorly documented mechanism is that of ephaptic transmission—peripheral nerve injury resulting in “cross-circuiting” of peripheral fibers. In theory, sympathetic efferents would be able to activate nociceptive afferent fibers, explaining spontaneous pain and worsening of pain with activation of the sympathetic nervous system in some patients with neuropathic pain. However, there is little evidence to support this long-standing theory.

Central

The CNS undergoes changes with peripheral nerve injury. In fact, this mechanism may be a primary one in those conditions where peripheral neuropathy results in reduced input to the CNS (postherpetic neuralgia, diabetic neuropathy). In diabetic neuropathy, there is little evidence that peripheral sensitization (as might be seen with increased sodium channels or with ephaptic transmission) occurs; rather, the evidence points toward reduced neural input to the CNS.

Several potential mechanisms exist for a central contribution to the pain from peripheral neuropathy. Loss of large fiber (Aβ) sensory input could result in a reduction in nonnociceptive sensory input, thereby reducing the effectiveness of the “gate,” as proposed by Wall and Melzack. In experimental models of nerve injury, opioid and gamma-aminobutyric acid (GABA) receptors (both involved in inhibition of nociceptive transmission in the CNS) are downregulated, and the amount of GABA in the dorsal horn is reduced. Another mechanism suggests death of dorsal horn interneurons in lamina II (many of which are involved in the inhibition of nociceptive transmission in the dorsal horn) by overexposure to excitatory amino acids (EAA). Cholecystokinin, involved in opioid receptor inhibition, has also been found to be upregulated in the spinal cord following experimental nerve injury. The net effect of these changes in the spinal cord results in “disinhibition” of nociceptive transmission, thereby creating an imbalance of painful over nonpainful impulses. These changes might also explain the relative opioid resistance seen in neuropathic pain.

A central mechanism that may explain the allodynia seen in some peripheral neuropathies involves Aβ fiber sprouting and Aβ fiber “phenotypic switching.” Aβ fibers normally synapse in all lamina of the spinal cord except lamina II, where C fiber input predominates. However, following peripheral C fiber nerve injury, Aβ fiber “sprouting” into lamina II occurs, therefore allowing mechanical nonnociceptive input via the peripheral Aβ fibers to trigger second-order pain pathways. Aβ fibers in the dorsal horn also do not normally express substance P (as seen in C fibers), but following peripheral nerve injury, they can (phenotypic switching). When this happens, they thereby allow nonnociceptive input to trigger CNS nociceptive transmission.

These mechanisms are likely far from complete in terms of explaining the changes in the CNS following peripheral nerve injury. It is very likely that significant changes also occur throughout the spinal cord, even in levels not directly involved with the peripheral injury, including the contralateral side, midbrain, and cerebral cortex. The wide variability in how individuals respond to peripheral nerve injury is likely the result of genomic differences. Differences in the ability of Aβ fibers or sympathetic fibers to sprout, the amount of neuropeptide available for release peripherally, and the susceptibility of inhibitory interneurons to EAA in the dorsal horn are all likely to be highly variable between patients. This may explain why patients with the same condition (e.g., diabetic neuropathy) may or may not have pain. Animal models of neuropathic nociception demonstrate notable differences between strains in their reaction to peripheral nerve injury and in their responsiveness to analgesics.

History

Pain is often the presenting symptom for polyneuropathy, but it rarely presents in the absence of other sensory abnormalities. In fact, most patients have an incongruous presentation of pain, as well as sensory deficits. Many of the terms used to describe these abnormalities are listed in Table 32.2 ; paresthesias (“tingling” or “pins and needles” sensations) are particularly common. However, since the characteristics of neuropathic pain are almost always multiple (e.g., varying combinations of burning, stabbing, aching, etc.), they cannot be used as a useful guide to determine the etiology of the neuropathy. The location of the pain and other symptoms is frequently the most important piece of historical information.

Neurologic Examination

In the patient suspected of having polyneuropathy, the clinician should focus on sensory evaluation. Strength and deep tendon reflexes are preserved in many patients with polyneuropathy. In addition to testing vibration, proprioception, and light touch, the sensory examination should include several special stimuli including light-touch rubbing, ice, single pinprick, and multiple pinpricks. Lightly stroking the affected area with a finger will assess for allodynia (pain provoked by nonnoxious stimuli), which has been shown to be present in 20% of patients with neuropathic pain (and higher in particular neuropathic pain states, such as postherpetic neuralgia). Ice application will test for both temperature sensation and abnormal sensations such as pain and lingering after-sensations. Single pinprick testing may elicit a sensory deficit or hyperpathia (an exaggerated response to a normally painful stimulus). Repeated pinprick testing may elicit summation (pain growing more intense with subsequent stimuli) or lingering after sensations, both common findings in polyneuropathy.

Electrodiagnostic Testing

Patients suspected of having polyneuropathy can be considered for electromyography (EMG) and nerve conduction velocity (NCV) studies, which may offer insights into whether the process is a demyelinating (reductions in nerve conduction velocities) or axonal (reductions in the amplitude of evoked responses) neuropathy. However, such differentiation rarely offers any change in therapy when managing neuropathic pain. These tests are best used to demonstrate large fiber involvement, but as many painful peripheral neuropathies involve small fibers, these tests may be completely normal in patients with painful polyneuropathy. Quantitative sensory testing (QST) may be the most useful in the assessment and longitudinal monitoring of painful peripheral neuropathies. While large fibers are assessed through the use of sensory thresholds to vibration, small fibers can be assessed by threshold for detection of heat, painful heat, cold, and painful cold stimuli. Thermography has been found to have little role in the assessment, management, or tracking of painful peripheral neuropathies, despite much published literature on the method. The role of skin biopsies remains controversial ; however, it has been used to successfully diagnose loss of small peripheral nerve fibers such as nociceptive afferents.

Screening Tools

There are several screening tools, including the Neuropathic Pain Questionnaire, the painDETECT Questionnaire, ID Pain and the Leeds Assessment of Neuropathic Symptoms and Signs that evaluate patient’s description of their pain to differentiate neuropathic pain from nonneuropathic pain. Diagnostic accuracy appears to be highest when these screening tools are used in conjunction with the physical exam.

Metabolic Causes of Peripheral Polyneuropathy—Diabetes

The reported frequency of neuropathy in patients with diabetes mellitus ranges from 4% to 8% at the time of initial presentation, and rises to 15%–50% after 20–25 years of follow-up. Other studies report an incidence of neuropathy (not necessarily painful) of up to 66%, but clearly the likelihood of neuropathy increases with the duration of the disease. The incidence of painful neuropathy was reported in one study to average about 11.6% in insulin-dependent diabetes mellitus (IDDM) and 32.1% in noninsulin-dependent diabetes mellitus (NIDDM). The cause of diabetic neuropathy has not been determined with certainty. Current hypotheses focus on the possibilities of metabolic and ischemic nerve injury. Hyperglycemia may lead to oxidative stress, which in turn decreases the functioning of proteins in the peripheral nerves and can lead to cell death. Pathologic examination of nerves taken from diabetic patients has shown evidence of microvascular disease supporting the ischemic nerve theory. Metabolic abnormalities include (1) accumulation of sorbitol in diabetic nerve as excess glucose is converted to sorbitol by the enzyme aldose-reductase, (2) auto-oxidation of glucose resulting in reactive oxygen molecules, and (3) inappropriate activation of protein kinase C. Other theories suggest that impaired nerve regeneration may contribute to the polyneuropathy in diabetes, as demonstrated in animal models of nerve injury.

Therapeutic strategies aimed at reducing sorbitol accumulation (aldose-reductase inhibitors) have demonstrated only minor improvements in neuropathy. There is strong evidence, however, that good glycemic control can prevent the appearance and worsening of polyneuropathy in patients with both IDDM and NIDDM. A major trial found that the incidence of neuropathy was reduced by 60% over a 5-year period with aggressive glycemic control.

Diabetic neuropathy can be divided by the pattern of distribution of involved nerves ( Table 32.3 ). The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It is predominantly a sensory disturbance. Patients often present with gradual onset of paresthesias and pain in the legs and feet. Symptoms begin in the toes and gradually ascend over months to years to involve more proximal levels. The fingertips and hands become involved later, usually when symptoms in the lower extremities have ascended to the knee level. Allodynia and burning pain are common and are often worse at night. Examination shows graded distal sensory loss predominantly affecting vibration and position sensation. Reflexes may be diminished or absent. Electrophysiologic testing shows a decrease in the amplitude of evoked responses to a greater degree than reduction in nerve conduction velocities as the neuropathy progresses. This reflects primarily axonal damage rather than demyelination. Severe sensory loss may allow repeated trauma to go unnoticed, resulting in the development of foot ulcers and diabetic neuroarthropathy (Charcot’s joints). This last condition is critical to identify in the diabetic patient with a unilateral, painful, swollen foot.

The syndrome of acute painful diabetic neuropathy may also occur in diabetics. This uncommon disorder is characterized by the rapid onset of severe pain in the distal lower extremities characterized by constant burning in the feet, dysesthesia, allodynia, and lancinating leg pains. Examination shows little or no sensory loss with preserved reflexes. Electrophysiologic testing shows decreased amplitude or absent sensory potentials, but may also be normal. This type of neuropathy often remits within a year after blood sugars are controlled.

Autonomic neuropathy manifestation by abnormalities in tests of autonomic function occurs in 20%–40% of diabetics. Symptomatic autonomic neuropathy most often occurs as a component of distal symmetric polyneuropathy. Autonomic nervous system abnormalities include postural hypotension, impaired heart rate control (resting tachycardia and fixed heart rate), esophageal dysmotility, gastroparesis, and erectile dysfunction.

Lower extremity proximal motor neuropathy is an uncommon painful disorder associated with diabetes. It is characterized by acute or subacute onset of moderate to marked weakness and wasting of the pelvifemoral muscles, accompanied by back, hip, and thigh pain, with preserved sensation in the regions of pain. The condition may be painless or accompanied by pain described as a constant, severe, deep ache. Complete recovery occurs in 60% of patients over 12–24 months.

Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) is sometimes referred to as diabetic amyotrophy, proximal diabetic neuropathy, diabetic polyradiculopathy, Bruns–Garland syndrome, or diabetic lumbar plexopathy. It usually affects individuals with diabetes mellitus type II over the age of 50 years, and presents as an asymmetric weakness associated with pain in the legs that appears subacutely and progresses over weeks to months. Although motor function recovery is slow and often incomplete, the pain usually resolves. Both microvascular inflammation and autoimmune mechanisms have been proposed, with no one clear treatment plan being particularly effective.

Diabetic truncal neuropathy involves acute or gradual onset of unilateral pain in the chest or abdomen and may mimic myocardial infarction, intraabdominal pathology, or spinal disorders. Examination shows marked allodynia and hyperpathia in the distribution of pain. Truncal neuropathy occurs most often in long-standing diabetics and those over the age of 50 years. EMG typically demonstrates denervation in the abdominal or intercostal musculature.

Cranial mononeuropathies involving the oculomotor, abducens, trochlear, and facial nerves may occur in diabetic patients. The most common of these is oculomotor neuropathy that is manifested as ophthalmoplegia and ptosis. The eye is deviated laterally and has impaired movement vertically and medially. Pain occurs in 50% of patients and may precede ophthalmoplegia by several days.

Entrapment neuropathies are believed to occur more frequently in patients with diabetes mellitus. Carpal tunnel syndrome is believed to occur more than twice as frequently as in the nondiabetic population. This association must be kept in mind when evaluating the diabetic patient with an isolated peripheral mononeuropathy.

Other Metabolic Causes of Painful Peripheral Neuropathy

Metabolic causes other than diabetes mellitus (and excluding postherpetic neuralgia) are uncommon.

Amyloidosis is a disease caused by extracellular deposition of amyloid, a fibrous protein. Amyloidosis can be primary, familial, or associated with other conditions such as multiple myeloma, chronic infectious or inflammatory states, aging, and long-term hemodialysis. The biochemical composition of the amyloid protein varies with the associated disease state. Deep aching and occasional shooting pains, distal sensory loss, and autonomic and motor involvement characterize painful peripheral neuropathy in amyloidosis. As the neuropathy progresses, all modalities are affected, reflexes are lost, and there is motor involvement. Treatment of neuropathy associated with amyloidosis is aimed at the underlying condition when such is identifiable.

Multiple myeloma is due to malignant plasma cell growth. Painful neuropathy can appear in myeloma with or without amyloid deposition. The neuropathy is extremely variable in severity and rate of progression, ranging from a mild, predominantly sensory neuropathy to a complete tetraplegia. Pain in myeloma often declines with successful treatment using chemotherapy, radiation therapy (especially for isolated plasmocytomas), or plasmapheresis.

Patients with untreated hypothyroidism may also develop painful sensorimotor neuropathy. This uncommon disorder may present with long-standing pain in either the hands or the feet, accompanied by weakness in the distal limb musculature. The neuropathy often resolves with successful replacement of thyroid hormone.

Nutritional Causes of Peripheral Polyneuropathy

Thiamine deficiency is seen in alcoholics, chronic dialysis patients, and people on restrictive diets. Thiamine deficiency appears to lead to beriberi, which consists of heart failure, vasodilatation, and peripheral neuropathy. Hand, foot, and calf pains with allodynia, decreased sensation, and motor involvement characterize the neuropathy. Administration of thiamine may reduce the symptoms of neuropathy, including pain.

The incidence of neuropathy in chronic alcoholism is about 9%. Alcoholic neuropathy is characterized by motor and sensory deficits, often accompanied by pain. The pain consists of aching in the legs or feet with intermittent lancinating pains. The upper limbs are rarely involved. Burning of the soles and allodynia may also occur. Alcoholic neuropathy occurs only after chronic and severe alcohol abuse and is invariably accompanied by severe nutritional deficiency. Pathologically, alcoholic neuropathy cannot be distinguished from beriberi, and both likely result from thiamine deficiency. Treatment consists of abstinence and thiamine supplementation.

Pellagra is caused by niacin deficiency and is rarely seen in developed countries. Signs and symptoms include dermatitis, gastrointestinal (GI) complaints, neurasthenia, and spinal cord dysfunction. Pellagra is associated with a mixed, painful polyneuropathy, similar to that seen with beriberi. A predominant feature of the sensorimotor neuropathy is spontaneous pain in the feet and lower legs, with tenderness of the calf muscles and cutaneous hyperesthesia of the feet. Treatment of pellagra with niacin often results in resolution of all symptoms, except peripheral neuropathy.

Toxic Causes of Peripheral Polyneuropathy

Isoniazid is a frequently used antitubercular drug. Chronic administration in individuals with slow metabolism of the drug (slow acetylators) is associated with the development of painful neuropathy. Initial symptoms of distal numbness and tingling paresthesias are later accompanied by pain, which may be felt as a deep ache or burning. The calf muscles are painful and tender, and walking often aggravates symptoms. Symptoms may be particularly troublesome at night. Prophylactic coadministration of pyridoxine (vitamin B6) prevents development of neuropathy; however, it is not therapeutic once the neuropathy develops.

The most common neurologic complication of cancer treatment is CIPN. CIPN is a common adverse effect of treatment with platinum-derived, taxane and vinca alkaloid chemotherapeutic compounds. These chemotherapeutic agents exert their cytotoxic effect by binding to DNA and producing interstrand and intrastrand cross-linkage, thus impairing DNA synthesis and transcription. These agents are first-line chemotherapeutic agents in the treatment of solid tumors. Although penetration into the CNS is relatively poor, high levels of this drug are found in dorsal root ganglia and peripheral nerves. The development of CIPN is the most common reason a platinum-based chemotherapy regimen is changed to another agent, administered at a lower dose, or given in fewer or less frequent cycles of therapy. This change in therapy represents a deviation from the optimal life-extending therapy. Symptoms of CIPN, therefore, may directly increase morbidity and indirectly mortality. The earliest manifestations of neuropathy are decreased vibration sense in the toes and loss of ankle jerk reflexes. At larger doses, paresthesias may appear and progress to severe dysesthesias. The neuropathy is reversible, but recovery may take more than a year after discontinuation of the agent.

Other toxic agents that can potentially cause neuropathy include acrylamide, arsenic, dinitrophenol, and pentachlorophenol (pesticides).

Genetic Causes of Peripheral Polyneuropathy

The most common type of inherited neuropathic disorders is Charcot-Marie-Tooth disease (CMT), a group of disorders that affect peripheral nerves. CMT is subdivided into demyelinating and axonal forms, depending on EMG conduction studies. Common symptoms in CMT include lower extremity motor symptoms (foot deformity, difficulty ambulating), hyporeflexia, and sensory loss.

Other rare genetic neuropathies are included in the hereditary sensory and autonomic neuropathy (HSAN) category that, depending on the subtype, appear in the second to third decades of life and manifest with decreased sensation in the feet and distal legs, leaving patients prone to ulcer formation often leading to cellulitis and osteomyelitis, and distal hereditary motor neuropathies (dHMNS) that typically present with length-dependent weakness and no sensory loss. Except for supportive treatment including orthotics, orthopedic interventions (e.g., for scoliosis, foot deformity) and pain management, there is no specific treatment for dHMNS.

Ion channels are responsible for the detection and transmission of painful stimuli. The voltage-gated sodium channels (Na _v ) are essential in determining the excitability of the nociceptors. There are multiple HSAN conditions resulting from variations of voltage-gated sodium channels, four of which (Na _v 1.3, 1.7, 1.8, and 1.9) are known to be involved in propagating painful signals. Mutations of the genes that code these channels result in variable pain perception ranging from congenital insensitivity (null mutation of Na _v 1.7 or heterozygous activation of Na _v 1.9) to persistent burning pain (heterozygous activation of Na _v 1.8) to paroxysmal extreme pain disorder (heterozygous activation of Na _v 1.7). Erythromelalgia is an example of a channelopathy that results in severe burning and erythema of the hands and feet, exacerbated by heat, exercise, and prolonged standing. Most cases are isolated and primary, but about 5% of cases are familial, a result of mutation(s) in the gene that encodes the Na _v 1.7 channel.

Infectious and Inflammatory Causes of Peripheral Polyneuropathy

In developing countries, infectious or postinfectious neuropathies are very frequent. Mycobacterium leprae, although quite uncommon in North America and Europe, is among the leading cause. It usually affects the skin and nerves, but there also exists a pure neural leprosy in about 4%–10% of all leprosy cases. Symptoms are found primarily in the form of mononeuritis or mononeuritis multiplex.

Hepatitis C has also been linked to neuropathies, although here the clinical picture is varied, spanning from polyneuropathy to mononeuropathy (involving multiple or single nerves) to cranial neuropathy. Prevalence rates have been found as high as 10.6%. Borrelia burgdorferi has also rarely been associated with a chronic diffuse distal polyneuropathy, more frequent in North America than Europe.

With the development and widespread use of highly active antiretroviral therapy (HAART) and the resulting decrease in opportunistic infections of the CNS, polyneuropathy has become the most prevalent neurological complication associated with HIV infection. Although symptomatic neuropathy occurs in 10%–35% of those seropositive for HIV, pathologic abnormalities exist in almost all of those with end-stage AIDS. There are numerous types of the HIV-associated neuropathy classified by onset, putative etiology, pathology of nerve damage, and motor or sensory involvement. The sensory neuropathies associated with HIV (HIV-SN) include distal sensory polyneuropathy (DSP), due to the viral infection, and antiretroviral toxic neuropathy (ATN), due to the medical treatment of the viral illness. DSP represents the more common of the two disorders. Although these HIV-SNs may represent two distinct entities, the clinical syndrome and pathophysiologic manifestation of the two disorders are practically indistinguishable. The time course of the illness and temporal relation to the commencement of antiretroviral therapy represents the primary differentiating characteristic. The onset of DSP can occur in either the subacute or chronic phases, or following the development of an AIDS-defining illness. The clinical manifestation of ATN can appear within the first week to 6 months of the initiation of antiretroviral therapy and may subside after its cessation. The painful peripheral neuropathy results from both direct neuronal inflammatory injury to the nerve itself (DSP) and the treatment using HAART, particularly nucleoside analogue reverse transcriptase inhibitors (NRTIs), leading to mitochondrial dysfunction. The clinical features of HIV-SN are dominated by painful dysesthesia, allodynia, and hyperalgesia. Onset is often gradual and most commonly beginning with bilateral lower extremity involvement. The neuropathy progresses in a length-dependent fashion, with a worsening gradient of disease from distal structures to those more proximal. The dysesthesias commonly first involve the soles of the feet and progress proximally; when the symptoms encompass the dermatomes of the knee, the patient will often report finger involvement. The first symptoms noted are often numbness or burning sensation, following a diurnal cycle with the pain worse at night. Shortly thereafter, patients will report allodynia and hyperalgesia of the involved structures. As a result, wearing shoes and walking become painful, and the patient’s gait becomes antalgic. There is minimal subjective or objective motor involvement, and this is generally limited to the intrinsic muscles of the foot. Physical examination shows a diminution or loss of ankle reflexes in addition to the sensory findings.

Reactivation of a latent infection of varicella zoster virus (human herpes virus-3) in the trigeminal ganglia or the dorsal root ganglia can result in facial or peripheral pain in the dermatomal distribution of the affected nerves. The resulting condition, herpes zoster or “shingles,” can be excruciatingly painful and can result in a chronic pain condition called PHN. There are approximately 500,000 new cases per year of herpes zoster in the United States, and 9%–35% of these people develop PHN. Advanced age, greater severity of the rash, and presence and severity of a painful prodrome preceding the rash are well-established risk factors for the development of PHN. The clinical presentation is most common in the thoracolumbar region, following a single or multiple dermatomes with a prodromal period, followed by the eruption of a maculopapular vesicular rash. The pain is most often described as burning, stabbing, and/or throbbing, and is commonly associated with cutaneous allodynia of the region. Primary prevention of herpes zoster and PHN was achieved in 51% and 66% of people who received the varicella vaccine. Prevention of PHN in patients who had a herpes zoster reactivation was successful in those who received acyclovir. Patients who received amitriptyline within 90 days of rash onset had a reduced incidence of PHN from 35% to 16%.

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) caused by Guillain-Barré syndrome is characterized by areflexic and ascending motor paralysis with sensory paresthesias. It is often preceded by an infection—generally an upper respiratory tract infection or gastroenteritis. Most frequently, if an agent is identified, EBV, CMV, Mycoplasma pneumoniae, and Campylobacter jejuni are found, although vaccines and other viruses have been also associated with GBS. Other rare etiologies include tumors and certain toxins. The onset of symptoms develops over several days—more frequently weeks. Pain is a common early symptom; weakness, usually in the legs, may progress to respiratory failure requiring mechanical ventilation. Sensory symptoms include paresthesias, often in the presence of decreased sensation in a glove-stocking distribution. Autonomic dysfunction is also commonly evidenced by tachycardia and orthostatic hypotension. Pain may occur in up to 80% of patients. The pain is principally an ache, strain, or deep burning sensation in the thigh or buttocks, and can be quite severe. While pain in AIDP may be severe, it is usually transient. Pain is usually worse at night. Nerve conduction studies and lumbar puncture aid the diagnosis. General therapy for AIDP is supportive along with plasmapheresis and IVIG. Glucocorticoids and other immunosuppressants have not been clearly shown to be helpful.

Idiopathic Small-Fiber Neuropathy

This condition usually presents with painful feet in patients over the age of 60 years. Although most often classified as idiopathic, autoimmune mechanisms are largely suspected in those cases. While diabetes and the metabolic/genetic causes listed previously can cause small-fiber neuropathy, it can also be present in the absence of those conditions, and this state has been the subject of thorough review. It can be defined as the presence of paresthesias (usually painful) with the absence of significant large-fiber dysfunction (atrophy, loss of vibratory sense, or loss of reflexes). Diagnosis is often confirmed through tests of autonomic function, QST, or skin biopsy.