Clinical manifestations

Presentation and course

The clinical manifestations of neuropathy depend on the type and distribution of affected nerve modalities, the degree of axonal or myelin damage, and the course of the disease. Demyelinating neuropathies primarily affect the myelin sheaths, whereas axonal neuropathies target the peripheral nerve axons. When motor nerves are affected, weakness and muscle atrophy occur. Damage to sensory nerves can cause numbness, paresthesia, dysesthesia, pain, and sensory ataxia. Involvement of small myelinated and unmyelinated sensory fibers typically results in impaired pin prick and temperature sensation, numbness, and painful burning, cold, or stinging paresthesias. Large diameter sensory fiber involvement manifests as loss of vibration and position sensation, sensory ataxia, and numbness or paresthesias. Autonomic dysfunction can result in postural hypotension, impotence, gastrointestinal and genitourinary dysfunction, abnormal sweating, and hair loss. Deep tendon reflexes are frequently diminished or absent, particularly in demyelinating neuropathies. Because most nerve trunks have a mixture of fiber types, damage to the peripheral nerves often affects more than one of these modalities (20).

Peripheral neuropathy can be divided into several categories:

Neuropathies are classified according to the clinical syndrome, pathological features, associated underlying condition, or other specific etiology. A classification of peripheral neuropathies is shown in the differential diagnosis section (Tables 1 and 2).

Approach to the patient with suspected peripheral neuropathy

History. A detailed history can help in identifying the modalities of nerve involvement (motor/sensory/sensorimotor/autonomic), identifying the pattern of involvement (symmetric, asymmetric, length dependent or not), and understanding the temporal course. Patients often minimize or neglect to notice “negative” symptoms (loss of function), but frequently complain of “positive” symptoms (altered function) listed in Table 3. Negative symptoms, therefore, should be specifically elicited. Weakness often impairs specific function; proximal or distal weakness can be deduced from changes in daily abilities. Difficulties in climbing stairs and getting up from a low seated position indicate proximal weakness, whereas foot slapping is a common complaint for distal weakness of the lower extremities. Similarly, combing hair, brushing teeth, or reaching high shelves can become difficult with proximal upper extremity weakness, and using utensils and other fine motor movements can be affected with distal upper extremity weakness. Heaviness, numbness, and balance difficulty--especially in the dark--are common descriptions with large fiber neuropathy. Paresthesia and shooting or stabbing pain are common small fiber symptoms and may be more prominent when walking; comfortable shoes are usually adopted by the patient. Patients may note altered temperature perception, especially differences in water temperature sense with different body areas or misperception of hot for cold. Symptoms tend to be worse at night when other sensory distractions are less. Cold and dry distal extremities are frequently noted. Autonomic symptoms (commonly present in diabetic and amyloid neuropathies) are often underreported by patients, and associated sexual dysfunctions can be perceived as embarrassing, unless directly inquired about (68; 20; 09; 27). Erectile dysfunction can be the first presentation of diabetic autonomic neuropathy and may affect up to 75% men with diabetes (45).

Not all symptoms of distal numbness, tingling, pain, and weakness are caused by peripheral nerve dysfunction; a central nervous system process or even a somatoform disorder may be responsible. A detailed history, including general medical history with current and prior illnesses, current and prior medications, and other medical and alternative therapies, can improve diagnostic accuracy when combined with the knowledge of functional neuroanatomy and nerve physiology.

Diabetes mellitus accounts for 30% to 50% of cases of distal sensory polyneuropathy (75; 32). If questioned, patients acknowledge a prior “high sugar” or prediabetes but may not admit to frank diabetes. Peripheral neuropathy has been reported as the presenting symptom of impaired glucose tolerance (59; 23). Patients with systemic rheumatological diseases are also vulnerable to peripheral neuropathy (31). Many medications, especially chemotherapeutic agents, may cause neuropathy (56; 70; 50). A long but partial list of neuropathy causes is presented in Table 1. Other pertinent social, recreational, and occupational exposures are important but are less frequently involved, except for alcohol. A more general review of systems is useful to reveal signs suggestive of underlying conditions, especially systemic signs of malignancy, collagen vascular disease, infection, or vasculitis. Gastrointestinal symptoms could provide clues to inflammatory bowel disease or celiac disease (15). Some hereditary disorders are asymptomatic into adulthood so a thorough family history and age of onset is essential. Inquiring about hereditary neuropathy or Charcot-Marie-Tooth disease often fails to prompt recognition, so more direct questions such as: “does anyone in your family have high arched feet, or hammer/curled up toes?” are more probative. Childhood difficulty with running or other sporting activities may be helpful to establish a hereditary condition. Other questions include: “Do you have difficulty walking on heels or rising from a kneeling position?”, “Is there associated wasting of the hands or feet?”, and “Are there any hand, foot, or spinal deformities?” Patients should be questioned about HIV risk factors, recent travel. Dietary habits can help in assessing nutritional dysfunction, including supplementation-related vitamin B6 toxicity (46). In addition, inquiring about factors for the metabolic syndrome is important as it predisposes patients beyond glucose dysmetabolism to painful neuropathy (44).

Physical examination. The general examination should include a detailed assessment of motor, sensory, and autonomic systems, including reflexes, gait, and cranial nerves.

Muscles should be inspected for the presence of atrophy (which typically begins in distal muscles), fasciculations, and myokymia (worm-like movement under the skin). A thorough manual muscle strength testing should be performed. Functional assessments (such as having patients walk on their toes and heels or hop on one leg at a time) may detect more subtle weakness. Orthopedic signs, such as high-arched feet, fallen arches, and hammer toes, suggest a longstanding condition. Prominent motor deficits (comparable to or greater than sensory deficits) may suggest an underlying demyelinating disorder, such as chronic inflammatory demyelinating polyneuropathy (CIDP), or a hereditary neuropathy. CIDP patients may have proximal muscle weakness (05; 20).

The sensory examination can be challenging, and patient cooperation is important. Both small and large sensory fiber modalities should be tested, most commonly pin sensation for small fiber function and vibration and joint position for large fiber function. Cold and warm sensation may also be tested. Pseudoathetosis may be present with significant large fiber impairment. The Romberg sign can be helpful in assessing sensory ataxia. The pattern of sensory loss should be ascertained; occasionally a sensory level is found that diverts the localization (05; 20; 09).

Deep tendon reflexes can be diminished in a length-dependent manner, and often the ankle jerk can be absent in the more common phenotype of distal symmetric neuropathy. Elicitation of deep tendon reflexes may require reinforcement methods if initially absent (eg, Jendrassik maneuver—pulling apart interlocked hands). A search for diffuse loss of reflex or hyporeflexia may suggest demyelinating neuropathy or hereditary neuropathy. Asymmetric reflex can be seen in superimposed mononeuropathy or a radiculopathy. Concomitant central nervous system problems (such as myelopathy, cervical stenosis, subacute combined degeneration from vitamin B12 deficiency) may complicate the findings of reflex exam (20).

Cranial nerve assessment can provide further diagnostic clues. Optic atrophy can be present in inherited neuropathies with central and peripheral demyelination. Absent pupillary light reflex and anisocoria may imply autonomic dysfunction. Ophthalmoparesis can be present in certain variants of Guillain-Barre syndrome or mitochondrial cytopathies (05).

A search for autonomic dysfunction should include orthostatic blood pressure measures, a thorough inspection of the skin and orthopedic integrity, palpation of distal pulses, palpation of nerves, and a focused systemic examination that may expose the presence of underlying systemic disease. A fall of greater than 20 mmHg of systolic blood pressure or greater than 10 mmHg of diastolic blood pressure recorded at least 3 minutes after standing following 5 minutes of supine rest is the definition of orthostatic hypotension. A sustained heart rate increase of greater than 40 beats per minute within 10 minutes of standing for individuals aged 12 to 19 years, and a sustained heart rate increase of greater than 30 beats per minute in individuals aged greater than 20, in the absence of orthostatic hypotension, is the definition of postural tachycardia syndrome, or POTS (28; 27). It is important to note that both orthostatic hypotension and POTS may occur in the absence of neuropathy or may be related to a concomitant neuropathy as a dysautonomic feature (27). Common distal skin changes suggestive of small fiber and autonomic dysfunction include skin thinning and scaling, hair loss, coldness, and dryness.

Prognosis and complications

Prognosis and complications depend on the type and severity of the neuropathy.

Clinical vignette

Vignette 1. A 56-year-old woman with hypertension, hyperlipidemia, and prediabetes presented with painful paresthesia in her lower extremities for 3 years. It started in her feet but progressed up to her ankle in the last 8 to 12 months, and the intensity was much more severe now. She denied having any other focal neurologic symptoms. Her motor strength was intact. Sensation to monofilament was reduced, and she reported a tingling sensation when testing pinprick sensation. Vibration and proprioception were intact. Her blood pressure was 144/84 despite being on an antihypertensive. Her body mass index was 33 kg/m². Her most recent HDL level was 42 mg/dL, and her triglyceride level was 190 mg/dL. Fasting blood glucose was 130 mg/dL. The rest of the basic work-up, including vitamin B12 level, SPEP, and immunofixation, was normal. Her presentation was consistent with cryptogenic sensory peripheral neuropathy likely from metabolic syndrome (she fit the diagnostic criteria of metabolic syndrome as defined by the International Diabetes Federation). Apart from symptomatic treatment, exercise-based lifestyle modification was strongly recommended (44)

Vignette 2. A 29-year-old man without any significant past medical history presented with progressive painful lower extremity paresthesia and difficulty in ambulation for the last 3 to 4 weeks. He did not have any other focal neurologic symptoms. His exam reflected intact cranial nerves, mild distal motor weakness in the lower extremities, and significant sensory loss to all modalities in the lower extremities. His nerve conduction studies showed severe sensory motor axonal neuropathy. MRI lumbar spine did not show any nerve root thickening or contrast enhancement. CSF analysis did not show any albuminocytological dissociation. On further questioning, he admitted to having been following a special diet for weight loss and had lost 30 kgs in the last 6 months. His vitamin B1 level was undetectable, and symptoms improved with vitamin B1 infusion followed by oral supplementation. Although neuropathy from vitamin B1 deficiency is rare, it can occasionally mimic Guillain-Barre syndrome, and a careful history can be helpful. This is commonly encountered in nutritionally deficient individuals and following gastric bypass surgery. Vitamin B1 deficiency–related neuropathy is usually of axonal type and if treated early, may respond to supplementation (41; 26).

Vignette 3. A 45-year-old female with no significant past medical history presents with progressive paresthesias over the left side of her face and hands more prominently than her feet. The patient denied any changes in vision, gait unsteadiness, focal weakness, urinary or bowel incontinence, or difficulty swallowing or speaking. On neurologic exam she was found to have decreased sensation to pinprick in her left face, hands, interscapular area, thighs, and feet. MRI of the brain was unremarkable. Nerve conduction studies and electromyography were normal. Skin biopsy of the left thigh showed decreased intra-epidermal nerve fiber density. Serum testing revealed elevated antibody levels of tissue transglutaminase IgA, gliadin IgG, and gliadin IgA. There was normal complete blood count, comprehensive metabolic panel, fasting glucose, oral glucose tolerance test, serum Vitamin B12, TSH, gliadin IgA, ANA, anti-dsDNA, SSA, SSB, ESR, and Lyme testing. Duodenal biopsy revealed significant villous atrophy and lymphocytosis. The patient was diagnosed with celiac disease with an associated multifocal small fiber neuropathy and was started on a gluten-free diet.

Biological basis

Etiology and pathogenesis

Peripheral neuropathy may be either inherited or acquired. More than 200 specific types of peripheral neuropathy have been identified, each with characteristic--but usually not distinctive--features (36). Acquired peripheral neuropathies are more common and can be grouped into several broad categories: those caused by systemic disease, those caused by trauma from external agents, and those caused by infections or autoimmune disorders affecting nerve tissue (Table 1).

Neurologic manifestations of COVID-19, including symptoms involving the peripheral nervous system, have been reported. It is not clear to what extent the nervous system involvement is related to a direct involvement of the virus on nervous tissue or to the effect of a robust immune response (52; 54; 61).

Medications, particularly chemotherapies, can lead to neuropathy (70; 62; 50). Immune checkpoint inhibitors can also be associated with neuropathy (21). Additional causes of neuropathy are also continuously being recognized, such as postsurgical inflammatory neuropathy and ischemic monomelic neuropathy (69; 16). Inherited forms of peripheral neuropathy are caused by inborn errors in the genetic code or by new genetic mutations. The most common inherited neuropathies result from abnormalities in genes responsible for neuron cell development, Schwann cell development, myelin sheath maintenance, or myelin sheath folding. These are collectively referred to as Charcot-Marie-Tooth disease, or hereditary motor and sensory neuropathy (11). A rare but important cause of polyneuropathy includes hereditary transthyretin amyloidosis, a progressive disease with a range of clinical manifestations. Patients typically present with polyneuropathy, and nearly 70% exhibit diffuse motor weakness, sensory loss, and autonomic insufficiency; concurrently, over 60% of patients also develop cardiomyopathy (39; 77). Hereditary transthyretin amyloidosis should be recognized as early as possible as disease-modifying therapies are available (02; 03; 04; 10).

The peripheral nervous system is made up of anatomically and functionally distinct neurons, which subserve motor, sensory, and autonomic functions. Cell bodies, or perikarya, of motor nerves that innervate skeletal muscle lie in the anterior horn of the spinal cord. Their axons travel through the anterior spinal roots and peripheral nerve trunks, terminating at the neuromuscular junction. Sensory nerves convey impulses from special receptors or bare nerve endings in the skin and internal organs. Their perikarya lie in sensory ganglia adjacent to the spine (dorsal root ganglia), and their processes extend from the receptor organs in the periphery through the dorsal roots into the spinal cord. Autonomic nerves innervate the heart, glands, and smooth muscles; they consist of preganglionic fibers that emanate from the brainstem and spinal cord and postganglionic fibers that emanate either from the sympathetic ganglia on either side of the thoracic spine or from parasympathetic ganglia embedded in or near the target organ. The various elements of the peripheral nerves are interconnected and communicate with the spinal cord and each other through their processes, spanning the body in a manner analogous to a fine electrical network.

The neuronal processes, or axons, travel as bundles within fascicles in peripheral nerves. Individual axons are enveloped by Schwann cell processes, or myelin sheaths, and are embedded in a loose matrix of connective tissue called the endoneurium. Each fascicle is surrounded by a dense band of connective tissue called the perineurium, which functions as a blood-nerve barrier and helps maintain the specialized endoneurial environment necessary for nerve function. Peripheral nerves are ensheathed by a dense collagenous layer called the epineurium through which blood vessels and lymphatic drainage provide nutrients and drainage to the nerve.

Nerve signals are propagated by the axonal membrane, with myelinated axons conducting impulses faster and at higher frequencies than unmyelinated axons. Each myelinating Schwann cell ensheathes an axon segment of 500 to 1500 µm in length called an internode. Adjacent internodes are separated by 1 µm of unmyelinated axonal segments called nodes of Ranvier. The myelinated fibers conduct impulses from node to node, whereas the internodal membranes remain relatively inert. When demyelination occurs, axonal conduction is slowed or blocked as unmyelinated fibers conduct in a continuous rather than salutatory fashion along their entire length (23).

Epidemiology

Large-scale population-based studies have suggested that 1% to 7% of the general population may have some form of neuropathy depending on location and age group (32). The overall prevalence of peripheral neuropathy (defined by monofilament insensitivity) is about 13.5% in the U.S. population over 40 years of age. The prevalence increases with age, and about 25% to 42% population over the age of 70 years may have peripheral neuropathy with or without diabetes (37). The most common attributable cause of neuropathy is diabetes, which may account for approximately one third of all neuropathies. The remaining two thirds of neuropathies are split between idiopathic and all other known causes (13; 09).

Prevention

Preventative measures vary according to the type of peripheral neuropathy, such as lifestyle modification and avoidance of offending agents. In diabetic neuropathy, intensive glycemic control does not reduce the risk of diabetic neuropathy but does delay the onset (40). Based on a large-scale prospective study from the UK, glycemic control may also have some potential benefit in preventing diabetic neuropathy (06; 67). Based on meta-analyses, exercise interventions may improve glycemic control, balance, and nerve conduction velocities. Combined endurance and sensorimotor training programs appeared to be more beneficial (71; 35). Despite some positive findings of various measures (vitamin E, cryotherapy, compression therapy) suggesting the potential role of some agents in preventing chemotherapy-induced peripheral neuropathy (CIPN), there are methodological limitations, and the most recent guideline from ASCO does not recommend any agents for the prevention of CIPN (50; 55; 48; 79).

Differential diagnosis

When approaching a patient with neuropathy, the differential diagnosis can be broad (Table 1). As discussed earlier, a careful history provides information about the symptoms, distribution, and course of the neuropathy. Medical history, social history, and a review of systems may alert the examiner to a possible systemic, toxic, or nutritional etiology. A thorough family history can uncover a hereditary neuropathy. A detailed neurologic examination is required to confirm the presence of neuropathy and to provide information regarding the distribution, severity, and functional impairment of the disease. As information is gathered and condensed, a narrower differential diagnosis comes into focus, and further testing can help with exact diagnosis (Table 2 and 4). Some etiologies may cause more than one type of presentation. Diabetes, for example, may cause of variety of different clinical presentations (64).

Table 1. A Classification of the Peripheral Neuropathies

Table 2. Differential Diagnosis of Peripheral Neuropathy Based on Clinical Time Course

Table 3. Positive and Negative Symptoms of Peripheral Neuropathy

Table 4. Partial List of Tests to Consider in Evaluation of Peripheral Neuropathy

Table 5. Etiologies Based on The Pattern of Clinical Presentation

Diagnostic workup

Blood studies can aid in the diagnosis of inflammatory, paraneoplastic, infectious, endocrine, metabolic, toxic, nutritional, or hereditary causes of neuropathies. The most common pattern of polyneuropathy is a length-dependent, distal symmetric sensory greater than motor polyneuropathy (09). Initial laboratory screening for causes of distal symmetric polyneuropathy usually includes fasting blood glucose, comprehensive metabolic panel, liver function test, complete blood count and differential, serum vitamin B12, and serum immunofixation electrophoresis (IFE) (25). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (25). CSF studies are reserved for suspected autoimmune, infectious, or neoplastic etiologies.

Electrodiagnostic studies, including electromyography and nerve conduction studies, may be used to confirm the presence of peripheral neuropathy; reveal whether the underlying process is demyelination or axon loss; determine whether motor, large fiber sensory, or a combination of fibers are involved; assess the severity and distribution pattern of neuropathy; and follow the course of the disease. Nerve conduction studies are of limited value in assessing proximal lesions, but electromyography of proximal muscles can assess involvement of motor axons or neurons. Additionally, nerve conduction studies largely assess the function of large diameter nerve fibers, whereas the majority of axons are small, and commonly employed electromyography/nerve conduction studies techniques fail to detect small fiber neuropathy (14). In case of normal nerve conduction studies when investigating sensory polyneuropathy, epidermal nerve fiber density and autonomic function testing provide complementary diagnostic data as these modalities assess small unmyelinated fibers.

Autonomic and small fiber neuropathies may be assessed using epidermal nerve fiber density, sweat gland nerve fiber density, autonomic function testing, or quantitative sensory testing. Proposed diagnostic “gold standards” for small fiber neuropathies include the presence of at least two abnormal results in the clinical, quantitative sensory testing, and skin biopsy examinations (19). Epidermal skin punch biopsy is now commonly employed to measure epidermal nerve density using the nerve specific marker PGP 9.5 and is characteristically abnormal when conventional electrodiagnostic studies are normal in small fiber neuropathies (47; 24; 34). It can also be used to quantitate sweat gland nerve fiber density and is complementary to epidermal nerve fiber density measurement. Quantitative sensory testing is a psychophysical test dependent on factors such as subject cooperation, alertness, site of stimulation, and site of study. It is used extensively in clinical trials but is not widely accepted for routine clinical application. Somatosensory evoked potentials are sometimes helpful when severe peripheral nerve disease is present and nerve conduction studies are inadequate, or when the afferent nerves to be studied present insurmountable technical difficulties. They are also extremely helpful in the evaluation of chronic inflammatory sensory polyradiculopathy (CISP) and CISP-plus (65).

Nerve biopsy is most helpful once adequate clinical, laboratory, and electrodiagnostic evaluations have been performed. Its indications are very limited, and the overwhelming majority of neuropathy patients do not require nerve biopsy to establish their diagnosis. Nerve biopsy leads to permanent sensory loss in that particular nerve distribution and is avoided unless indicated. Nerve biopsy can be particularly useful in the diagnosis of autoimmune or vasculitic neuropathies, sarcoidosis, or amyloidosis (80).

Genetic testing may play an important role in the workup and diagnosis of peripheral neuropathy, and there are multiple commercially available genetic panels. It is becoming increasingly important to identify patients with certain hereditary neuropathies as future gene therapy and molecular-based therapies become available (11).

Magnetic resonance imaging (MRI) can aid in the identification of structural spinal pathology that can cause neuropathy. MR neurography can be similarly helpful in diagnosing abnormalities of the thoracic outlet, brachial plexus, lumbosacral plexus, and peripheral nerves. MRI with contrast of the spine or the lumbosacral or brachial plexus can aid in the identification of inflammatory lesions, such as chronic inflammatory demyelinating polyneuropathy or meningitis (22; 53; 72; 51).

High-resolution ultrasound is a noninvasive diagnostic tool that can accurately identify focal nerve enlargement seen with focal nerve entrapments. It can also identify multifocal or diffuse nerve enlargement to aid in the diagnosis of hereditary and inflammatory neuropathies (78). A prospective multicenter study showed that there is little interobserver variability in nerve ultrasound, even across different hospital sites, using different sonographic devices. Therefore, nerve ultrasound is a reproducible tool for diagnostics in routine clinical practice and research (73).

Advanced techniques to be considered for further evaluation of peripheral neuropathy include corneal confocal microscopy and laser Doppler image flare. Corneal confocal microscopy images the subbasal nerve plexus of the cornea. Reductions in corneal nerve fiber density and fiber length correspond to polyneuropathy severity. It is noninvasive, repeatable, and particularly useful in the evaluation of length-independent neuropathies due to the proximal location. Limitations include a lack of hardware and personnel for the procedure to be performed (12; 43).

Laser Doppler image flare evaluates the axon reflex response to heat stimulus with Doppler. The area of vasodilation due to neurogenic flare is measured, and the flare area is reduced in neuropathy or in the setting of local anesthetic. It has also been used to demonstrate early sequelae of diabetes prior to detection of neuropathy with other methods (01).

Management

Apart from acquired inflammatory neuropathy, compressive neuropathies, and some neuropathies of infectious etiology, the majority of neuropathies are not curable. Therapy is often directed at symptomatic management, supportive care, and improving quality of life (09).

Acquired inflammatory neuropathies (such as CIDP) often respond to standard immunotherapy with glucocorticoid, intravenous and subcutaneous immunoglobulin, and plasmapheresis (49; 76). However, acute inflammatory demyelinating polyneuropathy does not respond to glucocorticoids (38). Other autoimmune inflammatory neuropathies associated with systemic autoimmune diseases, including neuropathy associated with checkpoint inhibitors, respond to judicious short-term use of glucocorticoids as well as immunoglobulin and plasma exchange (21; 31; 18). In more refractory cases, B-cell depletion therapy (such as rituximab) or cyclophosphamide can be used (57).

Neuropathic pain and muscle cramps are often prominent symptoms of peripheral neuropathy. Tricyclic antidepressants (amitriptyline and nortriptyline), anticonvulsants (gabapentin and pregabalin), and serotonin-norepinephrine reuptake inhibitors (duloxetine and venlafaxine) are commonly used to treat neuropathic pain (07; 09). Even in the absence of strong comparative data, the European Federation of Neurologic Societies has previously recommended that these drugs have similar efficacy in painful polyneuropathy (07). One large-scale study suggested essentially similar efficacy of pregabalin, amitriptyline, and duloxetine in painful diabetic polyneuropathy (OPTION-DM). Combination therapy of drugs with different mechanisms of action can be considered when response to monotherapy is suboptimal (74). However, only duloxetine and pregabalin are approved by the U.S. Food and Drug Administration (FDA) for the treatment of diabetic neuropathic pain (09). Treatment approaches are similar for any painful neuropathy. A large-scale study from the U.S. suggested possibly better performance of nortriptyline and duloxetine in treating patients with cryptogenic sensory polyneuropathy (08). Duloxetine is the only agent with moderate evidence to be used in painful chemotherapy-induced peripheral neuropathy (CIPN) (50). In the absence of any clear-cut superiority of any of these medications in most of the situations, treatment decisions are usually driven by patients’ comorbidities and potential adverse effects of an individual agent in discussion between the clinician and the patient. Rarely, there is a role for oral opiate or tramadol. The use of tramadol and tapentadol for chronic neuropathic pain is strongly discouraged due to limited data on long-term efficacy, risk of abuse potential being higher than that of morphine, and increased all-cause mortality (07; 60). Spinal cord stimulator can be helpful in refractory painful diabetic neuropathy (58).

Multiple other approaches, including topical agents, anticonvulsants, and antidepressants, are used with variable benefits and limited evidence. Often, a sequential trial of titration to effective dose, side effects, or nonefficacy is needed. Patient education is also important and may include suggestions for regular foot inspection, orthopedic shoes, podiatric evaluation, as well as fall and injury prevention, such as avoidance of loose rugs and testing water temperature with the hands or elbows. Furthermore, nutritional deficiencies should be addressed. Based on level II evidence, a systematic review suggested that vitamin B12 may have a beneficial effect on post-herpetic neuralgia; the evidence was weaker for painful peripheral neuropathy (42). Despite growing interest in ketamine for neuropathic pain and some potential benefit in terms of pain control, the quality of data is limited by heterogeneity in study and dosage and mode of administration (29). Significant adverse effects were reported, including psychedelic effects. Similarly, botulinum toxin A may also have some benefit in treating neuropathic pain, but it is not recommended as a first-line agent (30).

We are in an era of medicine wherein specific genetic and molecular therapies are available for a number of neurologic diseases. For example, in hereditary transthyretin amyloidosis neuropathy, there are three disease-modifying therapies available. Both patisiran and vutrisiran, silencing or small interfering RNAs, and inotersen, an antisense oligonucleotide, have been shown to improve multiple clinical manifestations of hereditary transthyretin amyloidosis. These drugs cause the degradation of mutant and wild-type TTR mRNA and are FDA-approved in the U.S. for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults (02; 10; 63). Lacosamide showed benefit in patients with sodium channel 9 mutation–related small fiber neuropathy (mutations in SCN9A, encoding for Nav1.7) (17). Therefore, as novel therapies continue to be discovered we expect that more options will become available to treat various neuropathies.