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Peripheral neuropathy

Peripheral neuropathy is a disorder characterized by damage to the peripheral nervous system, which consists of nerves outside the brain and spinal cord that transmit signals between the central nervous system and the rest of the body.^[1] This condition disrupts nerve function, resulting in symptoms such as numbness, tingling, pain, and muscle weakness, primarily affecting the hands and feet but potentially involving other areas.^[2] It encompasses over 100 types^[3] and impacts approximately 2.4% of the global population, with prevalence increasing to 5-7% among individuals aged 45 and older.^[4] The peripheral nervous system includes sensory nerves (which carry information about touch, temperature, and pain), motor nerves (which control muscle movement), and autonomic nerves (which regulate involuntary functions like heart rate and digestion).^[1] Damage can occur in these nerve types individually or in combination, leading to varied presentations; for instance, sensory neuropathy often causes prickling or burning sensations, while motor involvement results in cramps, twitching, or loss of coordination.^[4] Autonomic neuropathy may manifest as issues with blood pressure, sweating, or gastrointestinal motility.^[2] Symptoms typically develop gradually and may worsen over time if untreated, though they are rarely life-threatening.^[1] Causes of peripheral neuropathy are diverse and can be broadly classified as acquired or inherited. Acquired forms, which account for the majority of cases, are most commonly linked to diabetes mellitus, affecting over 50% of individuals with the disease due to prolonged high blood sugar damaging nerves.^[2] Other significant causes include chronic alcohol misuse, vitamin B-12 deficiency, infections (such as HIV or Lyme disease), autoimmune disorders (like Guillain-Barré syndrome), exposure to toxins or chemotherapy, and trauma.^[1] Inherited neuropathies, such as Charcot-Marie-Tooth disease, result from genetic mutations affecting nerve structure or function.^[1] In up to 30% of cases, no clear cause is identified, termed idiopathic neuropathy.^[5] Diagnosis typically begins with a thorough medical history and physical examination, followed by tests such as electromyography (EMG), nerve conduction studies, blood tests for underlying conditions, imaging (MRI or CT), or nerve biopsy to confirm nerve damage and identify the etiology.^[1] Treatment focuses on addressing the underlying cause where possible—for example, blood sugar control in diabetic neuropathy or immunosuppressive therapy for autoimmune-related cases—and managing symptoms through medications like gabapentin or pregabalin for pain, physical therapy for strength and balance, or assistive devices like braces.^[2] Lifestyle modifications, including exercise, a balanced diet, and avoidance of alcohol and toxins, play a crucial role in prevention and symptom alleviation.^[4] While there is no universal cure, early intervention can halt progression and improve quality of life.^[1]

Introduction

Definition

Peripheral neuropathy refers to damage or dysfunction of the peripheral nerves, which are the nerves located outside the brain and spinal cord, leading to impaired sensory, motor, or autonomic function.^[1] The peripheral nervous system (PNS) consists of the cranial nerves (except the optic nerve) and spinal nerves that connect the central nervous system (CNS)—comprising the brain and spinal cord—to the rest of the body, transmitting sensory information from the periphery to the CNS and motor commands from the CNS to muscles and glands.^[1] This distinguishes peripheral neuropathy from central nervous system disorders, as the PNS is responsible for voluntary and involuntary functions beyond the brain and spinal cord.^[4] Common manifestations include numbness, tingling (paresthesia), muscle weakness, or pain, often starting in the extremities such as the hands or feet and potentially progressing inward in a distal-to-proximal pattern known as a "stocking-glove" distribution.^[2] These symptoms arise from disrupted nerve signaling, which can affect sensation, movement, or organ regulation depending on the nerves involved.^[6] The condition affects approximately 2.4% of the global population, with prevalence rising to approximately 8% among older adults over age 55 due to age-related risks and comorbidities.^[7] The term "neuropathy" was first used in medical literature circa 1834, reflecting early 19th-century recognition of nerve diseases, while modern understanding advanced significantly in the 20th century through electrophysiologic techniques like nerve conduction studies that enabled precise assessment of nerve function.^[8] Polyneuropathy represents the most common form, involving multiple nerves symmetrically.^[9]

Epidemiology

Peripheral neuropathy affects approximately 2.4% of the global population, with prevalence rising to approximately 8% among individuals over 55 years of age.^[7] In the United States, incidence rates are estimated at approximately 250 cases per 100,000 person-years, reflecting a substantial burden on healthcare systems.^[10] Demographic patterns reveal higher prevalence among males compared to females, potentially due to differences in exposure to risk factors such as occupational hazards and metabolic conditions.^[11] Among individuals with type 2 diabetes, up to 50% develop peripheral neuropathy, making diabetes a leading contributor.^[12] Elevated rates are also observed in those with chronic kidney disease, where prevalence can exceed 60%, and in patients with alcohol use disorder, affecting 25-66% of chronic users.^[13]^[14] Geographic variations show higher reported rates in developed countries, driven by aging populations and increasing diabetes prevalence, whereas underdiagnosis is common in low-resource settings due to limited access to diagnostic tools.^[15]^[16] The increasing global prevalence of diabetes and obesity, which are major risk factors, contributes to higher rates of peripheral neuropathy.^[17]

Classification

Mononeuropathy

Mononeuropathy refers to damage or dysfunction affecting a single peripheral nerve, typically resulting from localized compression, trauma, or entrapment, which disrupts the nerve's ability to transmit sensory, motor, or autonomic signals.^[18]^[19] This focal involvement distinguishes it from more widespread forms of neuropathy, as the symptoms are confined to the specific distribution of the affected nerve.^[20] Common examples include carpal tunnel syndrome, which involves compression of the median nerve at the wrist, leading to symptoms in the thumb, index, middle, and part of the ring finger; peroneal neuropathy, often causing foot drop due to common peroneal nerve injury near the knee; and ulnar neuropathy at the elbow, affecting the ulnar nerve and resulting in issues with the fourth and fifth fingers.^[21]^[22]^[23] Clinical features typically manifest as localized weakness, sensory loss such as numbness or paresthesia, and pain or burning sensations within the nerve's territory, with motor deficits like muscle atrophy or clumsiness in advanced cases.^[20]^[19] Risk factors for mononeuropathy often involve repetitive motions, direct trauma, or anatomical entrapment, with conditions like obesity, diabetes, or occupational exposures increasing susceptibility.^[21]^[22] For instance, carpal tunnel syndrome affects 1% to 5% of the general population, with a higher incidence in females and those aged 40 to 60.^[21] Prognosis is generally favorable compared to diffuse neuropathies, as symptoms are often reversible with early intervention to relieve compression or address trauma, though delays can lead to permanent axonal damage.^[19]^[20]

Polyneuropathy

Polyneuropathy refers to a diffuse process involving symmetric damage to multiple peripheral nerves, typically in a length-dependent manner that begins distally in the longest nerves, such as those in the feet and hands, progressing proximally in a "stocking-glove" distribution.^[24] This pattern arises because longer axons are more vulnerable to metabolic, toxic, or degenerative insults that impair axonal transport or energy supply.00378-X/fulltext) Polyneuropathy is the most common form of peripheral neuropathy, accounting for the majority of cases, and is often chronic and progressive, with prevalence estimates ranging from 1-3% in the general population and rising to approximately 7% in individuals over 65 years.^[24]^[25] Subtypes of polyneuropathy are classified based on the primary site of nerve pathology: axonal degeneration, which is the most prevalent and involves direct damage to nerve fibers (e.g., in diabetic polyneuropathy), or demyelinating processes, which affect the myelin sheath insulating the nerves (e.g., in Guillain-Barré syndrome).^[24] Axonal polyneuropathies predominate in metabolic conditions like diabetes, where up to 50% of patients develop neuropathy within 10 years of diagnosis, while demyelinating forms are often immune-mediated.^[24] Clinical patterns vary, including sensorimotor polyneuropathy, which affects both sensory and motor functions with symptoms like numbness, tingling, and weakness; pure sensory polyneuropathy, characterized by isolated loss of sensation or pain; or motor-only polyneuropathy, featuring predominant muscle weakness without sensory involvement.^[25]^[26] Notable examples include chronic inflammatory demyelinating polyneuropathy (CIDP), a demyelinating subtype with a relapsing-remitting course over weeks to months, often leading to significant motor impairment if untreated.^[27] In some cases, polyneuropathy may involve autonomic nerves, resulting in symptoms such as orthostatic hypotension or gastrointestinal dysfunction, particularly when small fibers are affected.^[24]

Mononeuritis multiplex

Mononeuritis multiplex, also known as multiple mononeuropathy, is a peripheral nerve disorder characterized by the patchy, asynchronous involvement of two or more noncontiguous peripheral nerves, resulting in multifocal sensory and motor deficits.^[28]^[29] This syndrome manifests as damage to individual nerve trunks in an irregular distribution, distinguishing it from more uniform patterns of nerve injury.^[30] It is commonly associated with underlying conditions such as vasculitis (including polyarteritis nodosa and ANCA-associated forms), diabetes mellitus, and infections like HIV or cytomegalovirus reactivation.^[28]^[29]^[30] In patients with ANCA-associated vasculitis who develop neuropathic features, mononeuritis multiplex occurs in approximately 70-90% of cases.^[31] Other etiologies include sarcoidosis, amyloidosis, and less frequently, paraneoplastic syndromes or immune-mediated reactions.^[28]^[29] Clinically, it presents with a stepwise progression of symptoms, featuring sudden-onset deficits in distinct nerve territories that lead to asymmetric sensory disturbances (such as pain, tingling, burning, or loss of sensation) and motor impairments (including weakness, paralysis, or foot drop).^[29]^[30] For instance, a patient may experience acute weakness in one limb followed by sensory loss in an unrelated area weeks later, creating an irregular pattern of neurological involvement.^[29] Diagnosis poses challenges due to its mimicry of stroke-like focal events, requiring electromyography (EMG) and nerve conduction studies (NCS) to confirm multifocal axonal damage rather than demyelinating or symmetric processes.^[28]^[29] Blood tests for vasculitis markers, glucose levels, or infectious agents, along with possible nerve biopsy, aid in identifying the etiology.^[28]^[30] It differs from polyneuropathy through its asymmetry and non-length-dependent distribution, and from isolated mononeuropathy by the multiplicity of affected nerves.^[29]

Autonomic neuropathy

Autonomic neuropathy refers to damage to the peripheral nerves of the autonomic nervous system, which regulates involuntary bodily functions including heart rate, blood pressure regulation, gastrointestinal motility, and thermoregulation through sweating.^[32] This form of neuropathy disrupts the transmission of signals from the brain to organs such as the heart, blood vessels, digestive tract, and sweat glands, leading to impaired automatic control of these systems.^[33] It manifests in two primary forms: pure autonomic neuropathy, a rare degenerative condition primarily affecting the autonomic nerves without significant somatic involvement, and mixed autonomic neuropathy, which often coexists with somatic peripheral neuropathy, as frequently observed in chronic conditions like diabetes mellitus.^[32] Characteristic symptoms include orthostatic hypotension causing dizziness or fainting upon standing, gastroparesis resulting in delayed stomach emptying and nausea, erectile dysfunction in males, and anhidrosis or abnormal sweating patterns.^[32] These manifestations arise from selective involvement of sympathetic and parasympathetic fibers, varying by the extent of nerve damage.^[33] The prevalence of autonomic neuropathy is notable in certain populations, affecting approximately 20% of individuals with diabetes, with rates increasing to 30-40% in those with long-standing diabetic neuropathy; it is even higher in hereditary transthyretin amyloidosis, where autonomic involvement occurs in up to 80% of cases.^[34]^[35] Cardiovascular autonomic neuropathy, a common subtype, is associated with a five-fold increased risk of mortality due to heightened susceptibility to cardiac events and sudden death.^[36] This subtype often develops insidiously and can occur alongside other forms of polyneuropathy, compounding overall neurological impairment.^[33]

Pathophysiology

Nerve damage mechanisms

Peripheral neuropathy arises from damage to peripheral nerves through several primary mechanisms, including axonal degeneration, demyelination, and mixed patterns. Axonal degeneration, often manifesting as Wallerian degeneration, involves the breakdown of the axon distal to the injury site due to loss of nutrient supply from the neuronal cell body, leading to fragmentation and clearance by macrophages.^[37] This process affects approximately 80% of symmetrical polyneuropathies and is characterized by cytoskeletal disruption and impaired axonal transport.^[7] Demyelination, conversely, targets the myelin sheath produced by Schwann cells, resulting in slowed or blocked nerve conduction while sparing the axon initially; it accounts for about 20% of such neuropathies and is frequently immune-mediated.^[7] Mixed neuropathies combine these features, complicating classification and requiring targeted therapeutic approaches.^[7] Key pathological processes driving nerve damage include oxidative stress, inflammation, and ischemia. Oxidative stress promotes axonal degeneration by inducing calcium-dependent breakdown of the neuronal cytoskeleton, generating reactive oxygen species (ROS) that overwhelm cellular antioxidants.^[7] Inflammation, particularly in demyelinating forms, involves cytokine release from immune cells, which damages Schwann cells and myelin integrity.^[7] Ischemia contributes through reduced blood flow to vasa nervorum, causing nerve infarction and exacerbating Wallerian degeneration.^[7] At the molecular level, voltage-gated sodium channels play a critical role in neuronal hyperexcitability, a hallmark of neuropathic damage. Channels such as Na_v1.7 and Na_v1.8, expressed in sensory neurons, undergo gain-of-function alterations post-injury, shifting activation thresholds and increasing persistent sodium currents, which lower action potential firing thresholds and promote ectopic firing.^[38] This hyperexcitability can lead to axonal overload and degeneration via excessive sodium influx and subsequent calcium dysregulation.^[38] Mitochondrial dysfunction further compounds energy failure in nerves, impairing ATP production through defects in the electron transport chain and elevating ROS, which triggers apoptosis and axonal transport deficits.^[39] Nerve damage progresses in distinct stages: acute phases, such as those following trauma, involve rapid Wallerian degeneration and inflammatory responses within days to weeks, often resolving with regeneration if the proximal stump remains intact.^[37] Chronic stages, seen in metabolic conditions like diabetes, develop gradually over months to years through cumulative insults like hyperglycemia-induced oxidative stress, leading to persistent axonal loss and incomplete recovery.^[7] A key concept in these mechanisms is length-dependent vulnerability, where the longest axons—such as those innervating the distal extremities—face the highest metabolic demands and are most susceptible to degeneration due to their distance from the cell body, explaining the characteristic "stocking-glove" distribution in polyneuropathies.^[7]

Types of nerve fiber involvement

Peripheral nerve fibers are classified based on their diameter, myelination, and conduction velocity into groups A, B, and C, with further subdivisions influencing their functional roles in neuropathy. Group A fibers are myelinated and include A-alpha (Aα) fibers, which are large-diameter (12-20 μm) and conduct rapidly (70-120 m/s), primarily serving motor functions to skeletal muscles; A-beta (Aβ) fibers, also large (5-12 μm, 30-70 m/s), mediate touch, vibration, and proprioception; and A-delta (Aδ) fibers, small-diameter (1-5 μm, 4-36 m/s), involved in sharp pain and cold sensation. Group B fibers are lightly myelinated preganglionic autonomic efferents (3 μm, 3-15 m/s), while group C fibers are unmyelinated postganglionic autonomic and sensory fibers (0.2-1.5 μm, 0.4-2.8 m/s) that transmit dull pain, warmth, and itch.^[40]^[41]^[42] In peripheral neuropathy, involvement patterns often distinguish between small-fiber and large-fiber types, reflecting selective damage to specific fiber classes. Small-fiber neuropathies predominantly affect Aδ and C fibers, leading to isolated sensory or autonomic dysfunction without motor deficits, as seen in conditions like idiopathic small-fiber neuropathy where these fibers degenerate distally in a length-dependent manner. In contrast, large-fiber neuropathies target Aα and Aβ fibers, resulting in motor weakness and loss of proprioception or vibration sense, exemplified by alcoholic neuropathy, which causes axonal degeneration of large myelinated fibers and contributes to gait ataxia due to impaired position sense. Autonomic involvement typically implicates B and C fibers, as in diabetic autonomic neuropathy, where postganglionic C-fiber loss disrupts visceral regulation.^[42]^[41]^[43] Pathological changes vary by fiber type and neuropathy subtype, with axonal loss being common in small-fiber cases affecting unmyelinated C fibers, while demyelinating neuropathies more frequently involve loss of myelinated A fibers, reducing intraepidermal nerve fiber density in skin biopsies. In axonal neuropathies, distal degeneration of unmyelinated fibers predominates, whereas demyelinating processes disrupt the myelin sheath around large A fibers, slowing conduction. These changes are confirmed histologically, showing reduced densities of specific fiber types without widespread involvement.^[42]^[44]^[45] Selective fiber involvement underlies the diverse presentations of peripheral neuropathy, such as pure motor deficits in multifocal motor neuropathy, where conduction block occurs almost exclusively in Aα motor fibers without sensory fiber damage. This selectivity explains why some neuropathies spare certain functions, like preserved touch in small-fiber predominant cases, highlighting the need for targeted diagnostics like nerve conduction studies for large fibers and skin biopsies for small fibers.^[46]^[41]

Signs and symptoms

Sensory symptoms

Sensory symptoms in peripheral neuropathy result from dysfunction or damage to sensory nerve fibers, leading to a range of abnormal perceptions and sensory deficits. These manifestations are broadly categorized into positive symptoms, which involve spontaneous or evoked abnormal sensations, and negative symptoms, which reflect a loss of normal sensory function. Positive symptoms commonly include paresthesia, described as tingling, "pins and needles," or prickling sensations often starting in the extremities.^[4]^[1] Dysesthesia refers to unpleasant abnormal sensations, such as burning or crawling feelings, while allodynia occurs when typically non-painful stimuli, like light touch, provoke pain.^[47]^[2] These symptoms arise due to aberrant neural signaling and can be intermittent or persistent, varying in intensity. In contrast, negative symptoms involve diminished sensory processing, including hypoesthesia, a reduced perception of touch, vibration, or temperature, and anesthesia, the complete absence of sensation in the affected regions.^[1]^[48] Such deficits contribute to risks like unnoticed injuries, as patients may not feel pain or pressure adequately. Sensory symptoms typically follow a distal symmetric distribution, often termed the "stocking-glove" pattern, beginning in the toes and fingers before advancing proximally along the limbs if untreated.^[49]^[50] This progression reflects the vulnerability of longer nerve fibers. These disturbances are frequently linked to small-fiber damage, which selectively affects unmyelinated C-fibers and thinly myelinated A-delta fibers responsible for pain and temperature sensation. To quantify symptom severity, particularly for neuropathic pain, the Neuropathic Pain Symptom Inventory (NPSI) is employed as a validated self-assessment tool that evaluates distinct pain qualities, such as burning, pressing, or evoked pain, across multiple subscales.^[51]^[52] Chronic sensory symptoms, especially pain, profoundly affect daily functioning, with reports of disrupted sleep, depressed mood, and diminished quality of life; approximately one-third of patients with peripheral neuropathy experience neuropathic pain.^[9]

Motor symptoms

Motor symptoms in peripheral neuropathy result from dysfunction of motor nerve fibers, which control voluntary muscle movements, leading to progressive impairment in muscle strength and coordination. The hallmark is muscle weakness, often starting distally in the extremities due to the length-dependent nature of many neuropathies.^[7]^[4] In polyneuropathies, lower limbs are typically affected first, with weakness manifesting as difficulty rising from a chair, climbing stairs, or dorsiflexing the ankle, commonly resulting in foot drop—a condition where the front of the foot cannot be lifted, causing tripping or a high-stepping gait.^[7]^[2] Upper extremity involvement may include hand weakness or clumsiness, impairing tasks such as grasping objects, writing, or buttoning clothing.^[4] Accompanying distal muscle atrophy leads to visible shrinking and wasting of muscles in the feet, calves, and hands, sometimes resulting in deformities like high arches or hammertoes.^[1]^[4] Additional features include muscle cramps, which are sudden, painful contractions often occurring at rest or during activity, and fasciculations, involuntary twitching of muscle fibers visible under the skin.^[1]^[4] In advanced stages, reduced deep tendon reflexes or complete areflexia develop, further diminishing motor control and stability.^[7]^[1] Symptoms often progress gradually over months to years, evolving from mild fatigue and subtle weakness to profound paralysis in motor-predominant forms, such as multifocal motor neuropathy, which can mimic amyotrophic lateral sclerosis through asymmetric, progressive weakness without sensory involvement.^[7]^[53] Functionally, these symptoms cause gait instability, frequent falls, and increased dependency in activities of daily living, often necessitating assistive devices like ankle-foot orthoses or canes to maintain mobility and prevent injuries.^[2]^[4] The risk of falls is notably elevated, contributing to complications such as fractures and reduced quality of life.^[7]

Autonomic symptoms

Autonomic symptoms in peripheral neuropathy result from dysfunction of the autonomic nervous system, which regulates involuntary bodily functions such as heart rate, digestion, and sweating, often due to damage to small unmyelinated nerve fibers. These symptoms can manifest independently or alongside other features of neuropathy and may significantly impair quality of life by disrupting homeostasis.^[32]^[33] Cardiovascular involvement commonly presents as orthostatic hypotension, characterized by a sustained drop in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within three minutes of standing, leading to symptoms like dizziness, lightheadedness, fainting, and exercise intolerance from inadequate heart rate adjustment.^[33] Tachycardia may also occur as a compensatory response to maintain blood pressure during positional changes.^[54] In severe cases, this autonomic impairment heightens the risk of silent myocardial ischemia and sudden cardiac death, with studies showing a 3.5-fold increased mortality rate in symptomatic individuals compared to those without autonomic involvement.^[55] Gastrointestinal symptoms arise from impaired motility and secretion due to vagal and enteric nerve damage, including gastroparesis with delayed gastric emptying that causes early satiety, nausea, vomiting, bloating, and heartburn.^[54] Alternating constipation and diarrhea, or fecal incontinence, may also occur from disrupted colonic function.^[32] Genitourinary manifestations include bladder dysfunction, such as urinary retention from detrusor muscle atony or overflow incontinence, increasing infection risk, and difficulties sensing bladder fullness.^[54] Sexual dysfunction is prevalent, with erectile dysfunction affecting up to 75% of men with diabetes due to impaired vasodilation and nerve signaling, alongside retrograde ejaculation or reduced libido; in women, vaginal dryness and decreased arousal or orgasmic function are common.^[56] Sudomotor dysfunction leads to anhidrosis, or reduced sweating, particularly in distal extremities, resulting in heat intolerance and dry skin, though compensatory hyperhidrosis may occur proximally or during meals.^[32] This impairment of thermoregulation can exacerbate systemic risks in hot environments.^[57]

Causes

Metabolic causes

Metabolic causes of peripheral neuropathy encompass disorders that disrupt normal biochemical processes, leading to nerve damage through endogenous imbalances such as hyperglycemia, uremia, thyroid dysfunction, and vitamin deficiencies. Diabetes mellitus stands as the predominant metabolic etiology, responsible for approximately 50% of all peripheral neuropathy cases worldwide.^[58] In individuals with diabetes, the lifetime risk of developing diabetic peripheral neuropathy reaches 50% to 66%, with prevalence escalating alongside disease duration—for example, exceeding 50% in type 2 diabetes patients after 10 years of diagnosis.^[59]^[60] The pathogenesis of diabetic neuropathy involves chronic hyperglycemia activating several damaging pathways. A key mechanism is the polyol pathway, where elevated glucose is shunted to sorbitol via aldose reductase, resulting in intracellular osmotic stress, depletion of antioxidants like myo-inositol, and subsequent oxidative damage to Schwann cells and axons.^[59] Complementing this, advanced glycation end-products (AGEs) accumulate from non-enzymatic glycation of proteins and lipids, binding to receptors on endothelial cells and neurons to provoke inflammation, microvascular ischemia, and further nerve fiber degeneration.^[60] Beyond diabetes, chronic kidney disease induces uremic neuropathy through the buildup of uremic toxins, manifesting as a primarily axonal polyneuropathy that symmetrically affects sensory and motor nerves, with greater involvement in the lower limbs.^[61] This condition impacts up to 90% of patients on long-term dialysis and around 70% of those approaching end-stage renal disease, though symptoms often partially reverse following successful kidney transplantation or intensified dialysis.^[61] Hypothyroidism contributes to peripheral neuropathy via metabolic slowdown and impaired energy metabolism, typically producing a reversible sensorimotor polyneuropathy with mixed axonal loss and demyelinating features, often improving with thyroid hormone replacement therapy.^[62] Vitamin deficiencies also drive metabolic neuropathies by impairing essential enzymatic functions. Vitamin B12 deficiency leads to demyelination of large-diameter sensory and motor fibers in the peripheral nerves, frequently alongside subacute combined degeneration of the spinal cord, exacerbated by elevated homocysteine levels that promote oxidative stress and vascular injury.^[63] Similarly, thiamine (vitamin B1) deficiency, prevalent among chronic alcoholics due to poor nutrition and impaired absorption, causes dry beriberi—a symmetrical distal polyneuropathy characterized by axonal degeneration, sensory loss, and motor weakness that can be reversed with prompt thiamine supplementation.^[64]

Inherited causes

Inherited peripheral neuropathies, also known as hereditary neuropathies, result from genetic mutations that affect the structure, function, or maintenance of peripheral nerves. These conditions are typically chronic and progressive, often presenting in childhood or early adulthood. Charcot-Marie-Tooth disease (CMT), the most common inherited neuropathy, affects approximately 1 in 2,500 individuals worldwide and is caused by mutations in genes such as PMP22, MPZ, or MFN2, leading to demyelination or axonal degeneration.^[65] Symptoms include distal muscle weakness, atrophy, sensory loss, and foot deformities like high arches. Other inherited forms include hereditary neuropathy with liability to pressure palsies (HNPP) due to PMP22 deletions, causing episodic nerve palsies, and hereditary sensory and autonomic neuropathies (HSAN), which primarily affect sensory and autonomic fibers. Diagnosis involves genetic testing, and management is supportive, focusing on symptom relief and rehabilitation. Inherited causes account for about 20-30% of chronic polyneuropathies in adults.^[66]

Toxic causes

Toxic causes of peripheral neuropathy encompass exposure to exogenous agents such as alcohol, chemotherapeutic drugs, industrial chemicals, and certain medications, which can induce nerve damage through various mechanisms including axonal degeneration and mitochondrial dysfunction. These neuropathies are typically dose-dependent, symmetrical, and length-dependent, often presenting with sensory symptoms like numbness and paresthesia in a stocking-glove distribution.^[67] While some overlap exists with metabolic factors in cases like chronic alcoholism, the primary etiology here stems from direct toxic effects.^[14] Chronic alcohol consumption is a leading toxic cause, resulting in axonal sensorimotor polyneuropathy that predominantly affects small sensory fibers. This condition manifests in 25-66% of heavy drinkers, with symptoms including painful dysesthesias, burning sensations, and gait ataxia due to direct neurotoxicity from ethanol and its metabolites, compounded by oxidative stress.^[14]^[67] Chemotherapeutic agents frequently induce peripheral neuropathy as a side effect, with platinum compounds like cisplatin causing a dose-dependent sensory neuropathy that affects up to 30-40% of patients through DNA cross-linking and apoptosis in dorsal root ganglia neurons.^[68] Symptoms include persistent paresthesia and loss of vibration sense, often worsening after treatment cessation due to a "coasting" effect.^[69] Vinca alkaloids, such as vincristine, primarily produce a mixed sensory-motor neuropathy by disrupting microtubule-based axonal transport, leading to weakness and areflexia in up to 96% of pediatric cases at higher doses.^[68] Industrial toxins, particularly heavy metals, contribute to occupational neuropathies; lead exposure results in a motor-predominant axonal neuropathy characterized by wrist drop and muscle weakness from impaired energy metabolism and neurofilament accumulation.^[67] Arsenic poisoning, common in contaminated water sources, induces a painful sensory neuropathy with burning paresthesias and hyperpigmentation, mediated by oxidative damage and axonal degeneration.^[67] Certain antiretroviral drugs for HIV, such as stavudine, cause distal symmetric sensory polyneuropathy in approximately 31-50% of treated patients via mitochondrial toxicity from inhibition of DNA polymerase gamma, presenting with burning foot pain and numbness.^[67]^[68] Most toxic neuropathies demonstrate partial reversibility upon prompt cessation of exposure, with axonal regeneration possible in milder cases, though high cumulative doses often lead to permanent deficits due to neuronal loss.^[67]^[69]

Other acquired causes

Acquired causes beyond metabolic and toxic include trauma and compression, which often result in focal or multifocal neuropathies. Traumatic injuries, such as nerve lacerations or stretch during accidents, can cause immediate or delayed nerve damage, leading to mononeuropathies like radial nerve palsy from humeral fractures.^[1] Repetitive trauma or entrapment, as in carpal tunnel syndrome, compresses nerves like the median nerve, producing sensory and motor deficits in the affected distribution. These are common, with carpal tunnel syndrome affecting up to 3-6% of adults.^[70] Treatment may involve surgical decompression or conservative measures.

Infectious and inflammatory causes

Peripheral neuropathy can arise from various infectious agents that directly invade peripheral nerves or trigger secondary immune responses. Human immunodeficiency virus (HIV) infection often leads to distal sensory polyneuropathy, characterized by symmetric pain, paresthesia, and numbness in the feet and hands, primarily due to direct viral effects on sensory neurons and associated mitochondrial toxicity from antiretroviral therapies. Leprosy, caused by Mycobacterium leprae, is a major infectious cause in endemic regions, resulting in multibacillary forms that involve skin lesions and peripheral nerve damage through bacterial infiltration and granulomatous inflammation, leading to sensory loss, motor weakness, and deformities if untreated. Lyme disease, transmitted by Borrelia burgdorferi, can manifest as Bannwarth syndrome, an acute radiculoneuritis with severe radicular pain, facial palsy, and peripheral nerve involvement, typically occurring weeks after a tick bite in endemic areas. Inflammatory processes, often autoimmune-mediated, represent another key category of peripheral neuropathy etiologies. Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy frequently triggered by preceding infections such as Campylobacter jejuni or respiratory viruses, involving molecular mimicry where antibodies against microbial antigens cross-react with peripheral nerve components like gangliosides, leading to rapid-onset ascending weakness and areflexia. The incidence of GBS is approximately 1-2 cases per 100,000 people annually worldwide, with higher rates in certain populations such as those over 50 years old. Chronic inflammatory demyelinating polyneuropathy (CIDP), a related but persistent condition, features relapsing or progressive sensorimotor deficits over months, responsive to immunomodulatory treatments like intravenous immunoglobulin (IVIG), and affects about 1-9 per 100,000 individuals, often without a clear infectious prodrome. Autoimmune mechanisms further contribute to inflammatory neuropathies, sometimes linked to systemic diseases or malignancies. Paraneoplastic neuropathies, such as sensory neuronopathy associated with anti-Hu antibodies, occur in patients with underlying cancers like small-cell lung carcinoma, where immune responses against tumor antigens mistakenly target dorsal root ganglia neurons, causing subacute, asymmetric sensory loss and ataxia. Vasculitic neuropathies, exemplified by those tied to rheumatoid arthritis or polyarteritis nodosa, involve immune-mediated vessel wall inflammation that compromises nerve blood supply, resulting in mononeuritis multiplex with painful, stepwise deficits in multiple nerve distributions. In post-infectious cases like GBS, molecular mimicry exemplifies how inflammatory cascades amplify nerve damage through antibody and complement-mediated attacks on myelin or axons.

Idiopathic causes

In up to 30% of peripheral neuropathy cases, no underlying cause can be identified, classifying them as idiopathic. These are often chronic, distal symmetric sensorimotor polyneuropathies, more common in older adults, and may involve small fiber damage leading to painful symptoms without motor involvement. Diagnosis requires exclusion of known etiologies through comprehensive testing, and management focuses on symptom control.^[4]

Diagnosis

Clinical evaluation

The clinical evaluation of peripheral neuropathy commences with a comprehensive history to characterize the disorder and identify potential etiologies. Patients are queried regarding the temporal profile of symptoms, including onset (acute if less than 4 weeks, subacute if 4–12 weeks, or chronic if exceeding 12 weeks) and progression pattern, as rapid subacute worsening may indicate inflammatory processes.^[71] A detailed exposure history encompasses occupational hazards, medications (e.g., chemotherapy agents like vincristine), recreational substances such as alcohol, and environmental toxins (e.g., heavy metals), all of which can precipitate toxic neuropathies.^[72] Family history is scrutinized for hereditary conditions, such as Charcot–Marie–Tooth disease, particularly if there is evidence of chronic distal weakness or foot deformities in relatives.^[24] Screening for associated systemic conditions is routine, including diabetes mellitus (via inquiries about glycemic control and polyuria), autoimmune disorders, malignancies, or infectious risks, as these frequently underlie acquired neuropathies.^[1] Laboratory testing is an essential component of the clinical evaluation to identify treatable underlying causes. Routine initial tests include a complete blood count, comprehensive metabolic panel (assessing renal and liver function), fasting blood glucose or HbA1c (for diabetes), serum vitamin B12 with methylmalonic acid (for deficiency), thyroid function tests, and erythrocyte sedimentation rate or C-reactive protein (for inflammation). Additional tests, such as serum protein electrophoresis for paraproteins or tests for infections (e.g., HIV, Lyme), may be indicated based on history.^[9]^[73] The physical examination then systematically assesses neurological function to confirm peripheral nerve involvement and delineate its distribution and severity. Sensory evaluation targets both large and small fiber modalities: vibration sense is tested at the toes using a 128-Hz tuning fork, with diminished perception indicating large-fiber dysfunction, while pinprick sensation (using a safety pin or similar) probes small-fiber integrity and may reveal hyperalgesia or allodynia—pain elicited by light touch in symptomatic regions.^[74] Motor examination employs the Medical Research Council (MRC) scale to grade strength from 0 (no muscle contraction) to 5 (normal power against full resistance), often revealing distal weakness such as foot drop before proximal involvement.^[75] Deep tendon reflexes are elicited throughout, with distal areflexia (e.g., absent ankle jerks) being a hallmark of length-dependent axonopathies, whereas generalized hyporeflexia may suggest demyelination.^[71] Characteristic neurologic patterns guide differential diagnosis; the classic stocking-glove distribution—symmetric sensory loss starting in the distal lower extremities and progressing proximally, then involving the hands—predominates in metabolic and toxic causes.^[76] Bedside screening tools, such as the Michigan Neuropathy Screening Instrument, offer a validated, rapid assessment combining patient questionnaire and foot inspection to detect abnormalities like ulceration or deformity, especially in diabetic cohorts where it demonstrates high sensitivity for distal symmetric polyneuropathy.^[77] Red flags warranting urgent specialist referral include acute symmetric weakness (suggestive of Guillain-Barré syndrome), multifocal asymmetry (indicative of vasculitis or mononeuritis multiplex), or prominent autonomic features like orthostatic hypotension, as these signal potentially treatable or progressive etiologies.^[24]

Electrophysiological tests

Electrodiagnostic testing, encompassing nerve conduction studies (NCS) and needle electromyography (EMG), plays a central role in confirming the presence of peripheral neuropathy and characterizing its underlying pathophysiology. These tests provide objective measures of nerve function by assessing electrical conduction along peripheral nerves and muscle electrical activity, helping to distinguish between axonal and demyelinating forms of the disorder.^[78] Nerve conduction studies involve stimulating peripheral nerves with electrical impulses and recording the resulting compound muscle action potential (CMAP) or sensory nerve action potential (SNAP). Key parameters include conduction velocity, which is typically greater than 40 m/s in healthy adults, amplitude reflecting the number of functioning axons, and distal latency, the time from stimulation to response onset. Reduced conduction velocity and prolonged distal latency suggest demyelination, as seen in conditions like chronic inflammatory demyelinating polyneuropathy (CIDP), while preserved velocity with decreased amplitude indicates axonal damage. For instance, in carpal tunnel syndrome, NCS often reveals prolonged distal latency of the median nerve, confirming focal compression.^[78]^[79] Electromyography complements NCS by inserting a needle electrode into muscles to evaluate spontaneous and voluntary electrical activity. Abnormal spontaneous activity, such as fibrillations and positive sharp waves, signifies active denervation due to axonal loss, typically appearing 2-3 weeks after injury. In chronic phases, reinnervation manifests as motor unit action potentials (MUAPs) with increased amplitude and duration, reflecting collateral sprouting from surviving axons. These EMG patterns aid in localizing the lesion and assessing its chronicity.^[78]^[79] Indications for these tests include differentiating neuropathy subtypes; for example, slowed conduction velocities and conduction blocks on NCS strongly support a diagnosis of CIDP over axonal polyneuropathies like those caused by diabetes. They are particularly useful when clinical history suggests large-fiber involvement, guiding further management.^[78] Despite their utility, electrophysiological tests have limitations. NCS and EMG primarily evaluate large myelinated fibers and thus often yield normal results in small-fiber neuropathy cases, where unmyelinated or thinly myelinated fibers are affected. Additionally, results are operator-dependent, requiring expertise for accurate stimulation, recording, and interpretation to avoid false positives or negatives.^[78]

Imaging and biopsy

Imaging techniques play a crucial role in evaluating structural abnormalities in peripheral neuropathy, particularly when identifying nerve entrapment or enlargement. Magnetic resonance imaging (MRI) is particularly effective for visualizing deep-seated nerves, such as the brachial plexus, where it can detect entrapment through findings like nerve flattening, proximal enlargement, and hyperintense signals on T2-weighted sequences.^[80]^[81] Ultrasound complements MRI by providing high-resolution assessment of superficial nerves, such as the median, ulnar, and peroneal nerves, through measurement of cross-sectional area (CSA), where enlargement (e.g., median nerve CSA >10-15 mm² at the wrist) indicates pathology like entrapment or inflammatory changes.^[82]^[80] Nerve biopsy, often of the sural nerve, serves as a gold standard for diagnosing specific etiologies like amyloidosis and vasculitis by revealing amyloid deposits or vascular inflammation in tissue samples.^[83] In cases of demyelinating neuropathies, biopsy may show characteristic onion-bulb formations, consisting of concentric layers of Schwann cell processes surrounding denuded axons.^[84] Skin punch biopsy offers a less invasive alternative for assessing small-fiber involvement, quantifying intraepidermal nerve fiber density via PGP 9.5 immunostaining, where a density below 5 fibers/mm indicates significant loss.^[85]^[86] These procedures are typically indicated when nerve conduction studies are normal yet clinical suspicion for inflammatory or infiltrative causes remains high, such as in rapidly progressive or asymmetric neuropathies.^[83]^[85] Risks of sural nerve biopsy include wound infection, neuroma formation, and permanent sensory loss in the lateral foot, occurring in approximately 5-10% of cases.^[83] Skin punch biopsy has a lower risk profile, with primarily minor issues like bruising or scarring.^[86] The diagnostic yield is positive in about 40-60% of idiopathic cases, often identifying treatable etiologies like vasculitis or amyloidosis.^[87]

Management

Pharmacological treatments

Pharmacological treatments for peripheral neuropathy primarily target neuropathic pain relief and, in specific etiologies, address underlying disease processes to modify progression. First-line therapies focus on symptom management, with medications selected based on efficacy, tolerability, and patient-specific factors such as comorbidities. Guidelines from organizations like the American Academy of Neurology and the European Federation of Neurological Societies recommend starting with anticonvulsants or antidepressants for pain control, reserving opioids for refractory cases due to risks of dependence and side effects.^[9]^[73] Gabapentinoids, including gabapentin (typically dosed at 900-3600 mg/day in divided doses) and pregabalin (150-600 mg/day), are first-line options for neuropathic pain due to their modulation of calcium channel activity in the central nervous system, reducing neurotransmitter release and pain signaling. Clinical trials demonstrate that these agents provide at least 50% pain reduction in approximately 30-40% of patients, with number needed to treat (NNT) values of 4-7 for significant relief compared to placebo.^[73]^[88] They are particularly effective in diabetic peripheral neuropathy and postherpetic neuralgia, with pregabalin showing faster onset in some studies. Common side effects include dizziness, affecting up to 30% of users with gabapentin, and peripheral edema or weight gain with pregabalin.^[89]^[90] Antidepressants also serve as first-line agents by influencing serotonin and norepinephrine reuptake, which modulates pain pathways. Tricyclic antidepressants (TCAs) like amitriptyline (25-150 mg/day at bedtime) are effective for various neuropathic pains, though their anticholinergic effects limit use in older adults. Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine (60 mg/day), are FDA-approved specifically for diabetic peripheral neuropathic pain, showing moderate efficacy in reducing pain intensity by 30-50% in randomized trials.^[91]^[92] TCAs and SNRIs have comparable NNT values of around 3-5 for 50% pain relief, but SNRIs may have a better tolerability profile.^[93] For severe, refractory pain, opioids such as tramadol or tapentadol are considered second- or third-line options per CDC guidelines, which emphasize short-term use and monitoring for addiction risk. Tramadol (50-400 mg/day) provides dual action via mu-opioid agonism and serotonin-norepinephrine reuptake inhibition, while tapentadol extended-release (100-500 mg/day), FDA-approved for diabetic neuropathic pain, demonstrates efficacy in reducing pain scores by 30% or more in clinical studies, though with risks of nausea and constipation.^[94] These are reserved for cases unresponsive to non-opioid therapies due to potential for tolerance and overdose.^[95] In inflammatory subtypes like chronic inflammatory demyelinating polyneuropathy (CIDP), disease-modifying treatments include intravenous immunoglobulin (IVIG), corticosteroids, and plasma exchange. IVIG is administered as an induction dose of 2 g/kg over 2-5 days, followed by maintenance dosing of 1 g/kg every 3-6 weeks, leading to improvement in 60-80% of patients by suppressing autoimmune-mediated nerve damage.^[96] Corticosteroids, such as oral prednisone (1 mg/kg/day initially, tapered over months) or pulsed dexamethasone, induce remission in up to 61% of responders, though long-term use requires monitoring for osteoporosis and hypertension.^[97] Plasma exchange (plasmapheresis), typically 5-7 sessions over 2 weeks, removes autoantibodies and inflammatory factors, achieving improvement in about 60-70% of patients, particularly those unresponsive to other first-line therapies.^[98]^[99] For uremic neuropathy in end-stage renal disease, erythropoietin-stimulating agents (e.g., epoetin alfa at 50-100 IU/kg thrice weekly) can improve nerve conduction and symptoms by correcting anemia and reducing uremic toxins, with studies showing modest electrophysiological benefits after 6 months.^[100] These targeted therapies are etiology-specific and often combined with pain management for optimal outcomes.

Non-pharmacological interventions

Non-pharmacological interventions play a crucial role in managing peripheral neuropathy symptoms by focusing on symptom relief, functional improvement, and slowing disease progression through rehabilitative and lifestyle strategies. These approaches aim to enhance mobility, reduce pain, and prevent complications such as falls, often complementing other treatments. Evidence supports their use in various etiologies, including diabetic peripheral neuropathy, with benefits observed in balance, pain modulation, and overall quality of life. Physical therapy, including balance training and strengthening exercises, is recommended to address gait instability and reduce fall risk in individuals with peripheral neuropathy. Programs incorporating sensorimotor training, such as supervised sessions twice weekly for 12 weeks, have demonstrated significant improvements in balance, lower extremity strength, and walking speed, with effects sustained for up to six months. For example, Tai Chi, a low-impact exercise emphasizing controlled movements, has been shown to enhance postural control, single-leg stance duration, and functional mobility in people with peripheral neuropathy, potentially reducing fall incidence through better proprioception and coordination. These interventions can improve stability by 20-30% in key metrics like timed up-and-go tests, based on systematic reviews of exercise programs. Assistive devices provide targeted support for specific deficits, such as foot drop and neuropathic pain. Ankle-foot orthoses (AFOs) are commonly prescribed to maintain foot alignment during gait, preventing excessive plantarflexion and improving balance in patients with peripheral neuropathy-related weakness. These devices enhance proprioceptive feedback and reduce energy expenditure while walking, thereby minimizing fall risk. Transcutaneous electrical nerve stimulation (TENS) units offer a non-invasive option for pain management, delivering low-level electrical currents to modulate nerve activity. Clinical trials indicate mixed evidence, with some showing 26-50% pain intensity reduction on visual analog scales compared to sham treatments, though overall quality is low due to study limitations; benefits are more consistent in diabetic and postherpetic neuropathies when used daily at home. For refractory painful diabetic peripheral neuropathy, spinal cord stimulation (SCS) is an FDA-approved neuromodulation therapy as of 2023. Involves implanting a device to deliver electrical impulses to the spinal cord, SCS has shown in clinical trials to reduce pain by at least 50% in over 70% of patients, with additional benefits in improving sleep, mood, and potentially nerve function. It is recommended for cases unresponsive to conventional therapies, per updated guidelines.^[101]^[102] Lifestyle modifications are essential for mitigating progression, particularly in diabetic peripheral neuropathy. Tight glycemic control through diet, exercise, and monitoring can significantly slow neuropathy advancement; for instance, intensive insulin therapy in type 1 diabetes reduced the relative risk of clinical neuropathy by 60% over five years in landmark trials. Smoking cessation is advised to improve vascular health and nerve perfusion, as continued smoking exacerbates microvascular damage and pain sensitivity in diabetic neuropathy, while quitting correlates with reduced symptom severity over time. Weight management, targeting a 5-10% body weight reduction in overweight individuals, supports better glycemic regulation and may stabilize neuropathy progression by alleviating inflammatory and metabolic stressors. Acupuncture, involving needle insertion at specific points, provides moderate relief for neuropathic pain, particularly in diabetic cases. Meta-analyses of randomized controlled trials report significant reductions in pain scores, with acupuncture yielding a mean difference of -1.62 points on a 0-10 visual analog scale compared to controls, translating to approximately 20-30% improvement in symptom intensity when combined with standard care. These effects are attributed to neuromodulation and anti-inflammatory mechanisms, with benefits observed in both short- and medium-term follow-up. Topical capsaicin, derived from chili peppers, is applied as a cream or 8% patch for localized neuropathic pain relief. The 8% patch, administered under supervision for 30-60 minutes every three months, depletes substance P in sensory nerves, leading to desensitization and reduced pain transmission. Clinical evidence supports its use in diabetic peripheral neuropathy, with trials showing moderate pain reduction lasting up to 12 weeks, though initial application may cause transient burning.

Surgical options

Surgical interventions for peripheral neuropathy are typically reserved for cases involving structural compression, trauma, or specific autonomic complications, rather than diffuse polyneuropathy. Decompression surgery aims to relieve pressure on entrapped nerves, such as in carpal tunnel syndrome where the median nerve is compressed at the wrist. Carpal tunnel release, performed via open or endoscopic techniques, demonstrates clinical success rates of 75-90% in alleviating symptoms, particularly in mild to moderate cases, with recurrence occurring in 4-25% of patients depending on the definition used.^[103] For other entrapment neuropathies, such as cubital tunnel syndrome affecting the ulnar nerve, surgical decompression yields symptom resolution in approximately 88-90% of cases when managed arthroscopically or openly.^[104] In trauma-induced mononeuropathy, nerve repair procedures, including direct suturing or grafting for lacerations and defects, are employed to restore continuity and function. Autologous nerve grafting is commonly used for gaps up to 3 cm, with outcomes varying significantly based on timing; repairs performed within 3 months of injury, ideally less than 6 months, yield better sensory and motor recovery compared to delayed interventions exceeding 1 year.^[105] Overall, fewer than 50% of patients achieve good to excellent motor or sensory function following repair, influenced by factors like defect length and injury mechanism, such as blunt trauma where a 2-3 week delay allows zone-of-injury demarcation before grafting.^[106]^[107] Indications for these surgeries include refractory nerve compression unresponsive to conservative measures or focal lesions like tumors causing neuropathy, where excision or decompression can preserve function; however, they are not suitable for widespread polyneuropathy lacking a correctable structural cause.^[108]^[109] Common risks encompass infection in about 5-11% of cases, particularly in open procedures, and incomplete symptom relief in up to 20% of chronic entrapments due to scar tissue formation or persistent nerve damage.^[110] Post-surgical rehabilitation, including immobilization for 10-14 days followed by gradual mobilization, supports recovery but does not mitigate all risks.^[111]

Prognosis and prevention

Factors affecting outcomes

Early diagnosis is a key positive factor in improving outcomes for peripheral neuropathy, as it allows for timely intervention to prevent irreversible nerve damage.^[9] For reversible causes, such as vitamin B12 deficiency, prompt treatment can lead to significant recovery, with many patients experiencing substantial improvement in neurological symptoms within months of supplementation initiation.^[112] Younger age also favors better prognosis, particularly in traumatic or inflammatory neuropathies, where regenerative capacity is higher compared to older individuals.^[113] Conversely, prolonged disease duration exceeding one year often results in axonal loss that becomes irreversible, limiting functional recovery due to the slow rate of nerve regeneration.^[7] In diabetic peripheral neuropathy, poor glycemic control with HbA1c levels above 7% is associated with accelerated progression and worse outcomes, including increased severity of sensory and motor deficits.^[114] Comorbidities such as obesity exacerbate neuropathy risk and impair recovery, promoting inflammation and metabolic stress on peripheral nerves independent of diabetes.^[115] Outcomes vary significantly by subtype; for Guillain-Barré syndrome (GBS), approximately 80% of patients achieve independent walking within six months, though full motor recovery occurs in about 60% by one year.^[116] In contrast, idiopathic axonal polyneuropathy, while often considered benign, can lead to reduced quality of life and functional impairments due to gradual progression and limited response to therapy.^[117] The Neuropathy Impairment Score (NIS) serves as a validated metric for tracking disease progression and treatment response, assessing muscle weakness, reflex loss, and sensory deficits to quantify impairment over time.^[118] Autonomic involvement in peripheral neuropathy elevates mortality risk by 2- to 3-fold, primarily through cardiovascular complications like silent ischemia and arrhythmias.^[119] Long-term, chronic pain affects approximately one-third of patients with peripheral neuropathy, significantly impacting quality of life, and can lead to disability with reduced mobility and independence over time.^[9] Adherence to management strategies can mitigate these risks but does not alter underlying prognostic factors.^[120]

Preventive strategies

Preventive strategies for peripheral neuropathy focus on modifiable risk factors to reduce incidence or delay onset, particularly in high-risk populations such as those with diabetes or occupational exposures.^[1] For individuals with diabetes, the primary preventive measure is tight glycemic control, which has been shown to significantly lower the risk of developing diabetic peripheral neuropathy. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive insulin therapy, targeting near-normal blood glucose levels, reduced the risk of clinical neuropathy by 60% compared to conventional therapy in patients with type 1 diabetes.^[121] Similarly, in type 2 diabetes, achieving an HbA1c below 7% through lifestyle and pharmacological interventions can mitigate neuropathy progression.^[122] Annual comprehensive foot examinations, including monofilament testing for loss of protective sensation, are recommended by the American Diabetes Association to enable early detection and intervention in at-risk patients.^[59] Lifestyle modifications play a crucial role in prevention across various etiologies. Limiting alcohol intake is essential, as chronic consumption is a leading cause of alcoholic neuropathy; abstinence is advised to halt nerve damage, though moderate limits of up to 14 units per week for men and 7 for women may reduce risk in non-dependent individuals.^[123] A balanced diet rich in B vitamins (B1, B6, B12) supports nerve health and prevents deficiency-related neuropathy, with sources including whole grains, leafy greens, and fortified foods; supplementation may be considered if dietary intake is inadequate.^[124] Regular aerobic exercise, such as brisk walking for at least 150 minutes per week at moderate intensity, can delay the onset of diabetic neuropathy by improving glycemic control and nerve function.^[125] In occupational settings, ergonomic interventions prevent entrapment neuropathies like carpal tunnel syndrome by minimizing repetitive strain and awkward postures. Using wrist supports or splints during tasks involving prolonged hand use maintains neutral wrist alignment and reduces median nerve compression.^[126] Adhering to Occupational Safety and Health Administration (OSHA) guidelines on permissible exposure limits (PELs) for neurotoxic substances, such as lead and organic solvents, is vital to avoid toxic neuropathies; this includes proper ventilation, personal protective equipment, and monitoring workplace air quality.^[127]^[128] Vaccination against varicella-zoster virus prevents shingles-related neuropathies. The recombinant zoster vaccine (Shingrix), recommended by the CDC for adults aged 50 years and older, is over 90% effective in preventing herpes zoster and its complication, postherpetic neuralgia, a form of peripheral neuropathy.^[129] Screening in high-risk groups, such as those with prediabetes, facilitates early identification of subclinical neuropathy. Monofilament testing detects loss of sensation in up to 30% of prediabetic individuals, allowing timely lifestyle interventions to avert progression to overt diabetes and neuropathy.^[130]

Research directions

Emerging therapies

Gene therapy targeting sodium channels, particularly Nav1.7 encoded by the SCN9A gene, represents a promising approach for managing pain in peripheral neuropathy. Preclinical studies since 2020 have demonstrated that silencing Nav1.7 expression in dorsal root ganglion neurons via adeno-associated virus-delivered short hairpin RNA provides long-lasting analgesia in rodent models of neuropathic and inflammatory pain without affecting motor function.^[131] A 2023 review highlights how gain-of-function mutations in SCN9A contribute to chronic pain, supporting gene therapy as a strategy to restore normal channel function in peripheral neuropathies.^[132] More recent preclinical work in 2025 using vectorized microRNA for SCN9A knockdown has shown durable reduction in pain behaviors in chronic pain models, underscoring the potential for non-opioid gene-based interventions.^[133] Stem cell therapies utilizing mesenchymal stem cells (MSCs) aim to promote nerve regeneration in diabetic peripheral neuropathy. Phase II clinical trials, such as one evaluating intravenous MSC transfusion, have investigated improvements in clinical symptoms including pain and sensory loss.^[134] A 2024 meta-analysis of human studies reported significant enhancements in nerve conduction, with weighted mean differences of 2.2 m/s (95% CI: 1.6–2.8) for motor nerve conduction velocity and 1.8 m/s (95% CI: 1.2–2.4) for sensory, corresponding to 30-50% improvements in nerve function parameters in diabetic patients.^[135] These multipotent cells exert paracrine effects to support axonal regrowth and reduce inflammation, offering regenerative potential beyond symptomatic relief.^[136] Emerging anti-inflammatory therapies for chronic inflammatory demyelinating polyneuropathy (CIDP) include biologic agents targeting immune pathways, building on approvals of novel immunomodulators since 2022. Although anti-TNF agents like etanercept have shown mixed results in small pre-2022 pilot studies for refractory CIDP, with some patients experiencing symptom stabilization, larger randomized controlled trials (RCTs) post-2022 have focused on other biologics such as FcRn inhibitors (e.g., nipocalimab) demonstrating delayed relapse in ongoing phase II/III studies.^[137] These agents aim to reduce autoantibody-mediated nerve damage, with current RCTs evaluating long-term efficacy and safety in CIDP cohorts unresponsive to standard intravenous immunoglobulin.^[138] Neuroprotective strategies, such as intravenous alpha-lipoic acid (ALA), target oxidative stress in peripheral neuropathy. Administered at 600 mg daily for three weeks, ALA has been approved in Europe since the early 2010s for symptomatic diabetic polyneuropathy, leading to clinically relevant reductions in pain scores and improvements in nerve function.^[139] ALA acts as a potent antioxidant, scavenging reactive oxygen species and enhancing mitochondrial function to mitigate oxidative damage in peripheral nerves.^[140] Clinical data confirm its role in decreasing total symptom scores by up to 51% in responsive patients, positioning it as a supportive emerging option for oxidative stress-related neuropathies.^[141] Implantable devices like spinal cord stimulation (SCS) offer neuromodulation for refractory neuropathic pain. The U.S. Food and Drug Administration approved SCS systems in the 2020s specifically for painful diabetic peripheral neuropathy, including Abbott's Proclaim XR in 2023 and Medtronic's Intellis in 2022.^[142]^[143] Prospective studies report 50-70% pain relief in a majority of patients, with one trial showing over 50% reduction in numeric rating scale scores in 86% of participants at one year and sustained benefits in 55% at five years.^[144] By delivering electrical pulses to the spinal cord, SCS interrupts pain signal transmission, providing an opioid-sparing alternative for chronic cases.^[145]

Clinical trials and future prospects

Ongoing clinical trials for peripheral neuropathy encompass a range of interventions targeting pain relief, nerve regeneration, and prevention, particularly in diabetic and chemotherapy-induced cases. For instance, a phase 3 trial evaluating VM202 (Engensis), a gene therapy delivering hepatocyte growth factor via plasmid DNA, completed in 2025 and aimed to assess safety and efficacy in reducing pain from diabetic peripheral neuropathy through bilateral intramuscular injections.^[146] Similarly, the EPPIC-Net platform trial is investigating multiple novel analgesics, including suzetrigine (VX-548), a selective NaV1.8 sodium channel inhibitor, for painful diabetic peripheral neuropathy, focusing on pain reduction and quality-of-life improvements in a multi-arm adaptive design; suzetrigine received FDA approval in January 2025 for moderate-to-severe acute pain, with breakthrough therapy designation for diabetic peripheral neuropathy.^[147]^[148] In chemotherapy-induced peripheral neuropathy, the AIUR trial tests compression therapy using surgical gloves during paclitaxel administration to prevent onset, showing preliminary reductions in incidence rates in interim analyses.^[149] Non-pharmacological approaches are also advancing in trials, such as spinal cord stimulation for small fiber neuropathy, where a 2024-initiated study (NCT06287736) evaluates long-term pain relief and functional outcomes, with estimated completion in 2026.^[150] Stem cell therapies represent another frontier; a 2024 systematic review of human studies reported significant improvements in nerve conduction velocity following mesenchymal stem cell transplantation in diabetic peripheral neuropathy patients, with no major adverse events, supporting phase II expansions.^[135] Cryoneurolysis trials for diabetic foot neuropathy, like NCT06646731 starting in 2025, are exploring targeted nerve freezing to alleviate intractable pain, with early data indicating up to 50% pain score reductions at 6 months.^[151] Future prospects hinge on regenerative and precision medicine strategies to address underlying nerve damage rather than symptoms alone. Gene editing technologies, such as CRISPR-based approaches for inherited peripheral neuropathies, show promise in preclinical models by correcting mutations in genes like PMP22, with initial human trials anticipated by late 2020s.^[152] Peripheral sodium channel blockers, including next-generation selective inhibitors, could revolutionize treatment by minimizing central side effects, as evidenced by 2024 Yale studies demonstrating targeted pain blockade in rodent models of neuropathy.^[153] A 2025 narrative review emphasizes multimodal therapies integrating neuromodulation, biologics, and pathway-specific drugs (e.g., targeting S100A4/TLR4/NF-κB in astrocytes), predicting personalized regimens based on neuropathy subtype and biomarkers to improve outcomes beyond current 30-50% response rates.^[154] Overall, these developments signal a shift toward disease-modifying treatments, contingent on larger, mechanism-driven trials to validate efficacy and safety.

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Peripheral Nerve Trauma: Mechanisms of Injury and Recovery - PMC
Peripheral nerve injuries are common conditions with broad ranging groups of symptoms depending on the severity and nerves involved.
[37]
The Role of Voltage-Gated Sodium Channels in Pain Signaling | Physiological Reviews | American Physiological Society
Summary of each segment:
[38]
Role of Mitochondrial Dysfunction in Neuropathy - MDPI
... peripheral neuropathy, mitochondrial dysfunction ... symptoms of diabetic patients, this metabolic disease leads primarily to peripheral neuropathy.
[39]
Neuroanatomy, Unmyelinated Nerve Fibers - StatPearls - NCBI - NIH
C-type fibers are unmyelinated fibers that form 1 of these groups, and they are involved in the afferent transfer of temperature, burning pain, and itch.
[40]
https://www.ncbi.nlm.nih.gov/books/NBK554461/
[41]
Small Fiber Neuropathy - StatPearls - NCBI Bookshelf
Dec 12, 2022 · Peripheral neuropathy is a prevalent problem, affecting an estimated 15 to 20 million people in the United States above the age of 40.
[42]
Alcohol-related peripheral neuropathy: a systematic review and ...
Nov 22, 2018 · Alcohol abuse is known to cause a range of neurological disorders, including cerebellar ataxia, confusion, cognitive impairment, and peripheral ...
[43]
Pathological changes of human unmyelinated nerve fibers: a review
The aim of this article is to review (1) the normal appearance including postmortem changes, (2) the age-related changes, and (3) the pathological alteration in ...
[44]
Small Fiber Neuropathy: A Clinical and Practical Approach
SFN affects the thinly myelinated and unmyelinated nerve fibers, leaving the larger myelinated fibers relatively unaffected. Neuropathic pain is a key symptom ...
[45]
Multifocal Motor Neuropathy - StatPearls - NCBI Bookshelf - NIH
Treatment is supportive, and most patients recover spontaneously.[3]. Go to: Prognosis. The prognosis of multifocal motor neuropathy is usually good.Missing: intervention | Show results with:intervention
[46]
Terminology - International Association for the Study of Pain | IASP
The term allodynia was originally introduced to separate from hyperalgesia and hyperesthesia, the conditions seen in patients with lesions of the nervous system ...
[47]
Paraesthesia and peripheral neuropathy - RACGP
If a detailed history is taken, the diagnosis of peripheral neuropathy should be straightforward. The suspicion should have been established and features such ...History · Focal Neuropathies · TreatmentMissing: first | Show results with:first
[48]
Peripheral Neuropathy: Differential Diagnosis and Management
Apr 1, 2010 · The term peripheral neuropathy is usually used to describe symmetric and universal damage to adjacent nerves. The damage and clinical ...Missing: coined | Show results with:coined
[49]
Stocking glove neuropathy: Symptoms, causes, and treatment
Mar 16, 2023 · Stocking glove neuropathy refers to symptoms of peripheral neuropathy that cause numbness, weakness, or sensory changes in the hands and feet.What it is · Symptoms · Causes · Treatment
[50]
Conceptual adequacy of the neuropathic pain symptom inventory in ...
The purpose of this study was to determine whether the Neuropathic Pain Symptom Inventory (NPSI) adequately assesses neuropathic pain symptoms.
[51]
Development and validation of the Neuropathic Pain Symptom ...
This study describes the development and validation of the Neuropathic Pain Symptom Inventory (NPSI), a new self-questionnaire specifically designed to evaluate ...Missing: neuropathy | Show results with:neuropathy
[52]
Neuropathic Pain Related to Peripheral Neuropathies According to ...
In the present paper, we aimed to assess neuropathic pain frequency and clinical characteristics of peripheral neuropathies due to different aetiologies.
[53]
Does Neuropathic Pain Affect the Quality of Sleep? - PMC
In a previous study on patients with diabetic peripheral neuropathy, patients with severe pain reported more sleep problems [13]. Moreover, it has been reported ...
[54]
Amyotrophic lateral sclerosis mimic syndromes - PMC
Multifocal motor neuropathy with conduction block is another mimic of ALS. It presents by onset of focal motor weakness, usually in a distal upper extremity, ...
[55]
Autonomic Neuropathy - NIDDK
What are the symptoms of autonomic neuropathy? · Heart rate and blood pressure · Digestive system · Bladder · Sex organs · Sweat glands · Eyes · Ability to feel ...
[56]
The Association Between Cardiovascular Autonomic Neuropathy ...
Jun 1, 2003 · In contrast, individuals with symptomatic autonomic neuropathy experienced a 3.5-fold higher mortality rate than those in the CAN− group (18 of ...
[57]
Sexual Dysfunction in Diabetes - Endotext - NCBI Bookshelf - NIH
Jun 8, 2021 · Men with diabetes may have sexual disorders other than erectile dysfunction. Examples include diminished sexual desire, lack of ejaculation with ...
[58]
Anhidrosis - StatPearls - NCBI Bookshelf - NIH
Jun 21, 2023 · Anhidrosis is the inability to sweat. It is important to recognize anhidrosis as it can be potentially life-threatening due to heat-related illnesses.Introduction · Etiology · Evaluation · Differential Diagnosis
[59]
Peripheral neuropathy in prediabetes and the metabolic syndrome
Diabetes is the most common cause of neuropathy, accounting for 50% of cases. Over half of people with diabetes develop neuropathy, and diabetic peripheral ...
[60]
Diabetic Peripheral Neuropathy - StatPearls - NCBI Bookshelf - NIH
Feb 25, 2024 · The most prevalent subtype, diabetic peripheral neuropathy (DPN), can lead to significant complications ranging from paresthesia to loss of limb and life.
[61]
Diabetic peripheral neuropathy: pathogenetic mechanisms and ...
Abnormal glucose-lipid and insulin resistance and its sequelae cause alterations in mitochondrial function, inflammation, oxidative stress, specific gene ...
[62]
Neurological complications in chronic kidney disease - PMC
Peripheral neuropathy. Peripheral neuropathy in CKD, also known as uraemic neuropathy, is the most common neurological complication of CKD and affects ∼90% of ...
[63]
Severe Hypothyroidism Complicated by Myopathy and Neuropathy ...
May 19, 2021 · The frequently observed neurological manifestations of acquired hypothyroidism include mild to moderate myopathy and sensorimotor neuropathy.
[64]
The Relationship of Vitamin B12 and Sensory and Motor Peripheral ...
B12 deficiency may cause demyelination of nerves in the peripheral and central nervous system and has been associated with peripheral neuropathy, loss of ...
[65]
Vitamin B1 (Thiamine) Deficiency - StatPearls - NCBI Bookshelf
Thiamine deficiency can affect the cardiovascular, nervous, and immune systems, as commonly seen in wet beriberi, dry beriberi, or Wernicke-Korsakoff syndrome.Introduction · Epidemiology · History and Physical · Prognosis
[66]
Update on Toxic Neuropathies - PMC - PubMed Central
Typical causes of toxic neuropathies include alcohol, drug therapies, biological toxins, industrial toxins, metabolic causes, and heavy metals.Industrial Toxins · Heavy Metals · Drugs
[67]
Drug-Induced Peripheral Neuropathy: A Narrative Review - PMC
Drug-induced peripheral neuropathy is a common and painful condition caused by many different and frequently prescribed medications.5. Chemotherapeutic Agents · 6. Antibiotics · 7. Immunosuppressive Agents
[68]
Toxic Peripheral Neuropathies: Agents and Mechanisms - PMC
Two of the most prevalent causes of polyneuropathy, diabetes mellitus and alcoholism, could arguably be considered toxic neuropathies due to the involvement of ...
[69]
Diagnostic approach to peripheral neuropathy - PMC
Peripheral neuropathy is a general term that indicates any disorder of the peripheral nervous system. It is a common neurological disorder, with variable ...Missing: coined | Show results with:coined
[70]
Diagnosis of peripheral neuropathy - PMC - NIH
Jul 15, 2020 · A thorough workup including clinical history and examination, nerve conduction studies, and comprehensive laboratory tests is warranted to identify treatable ...
[71]
Basics in Diagnosing Diabetic Polyneuropathy With the Tuning Fork!
Sep 1, 2005 · The single use of the 128-Hz tuning fork produces results similar to the extended scores of the ICDF and much better than those of monofilaments ...
[72]
Muscle Strength Grading - StatPearls - NCBI Bookshelf
Apr 27, 2025 · The Medical Research Council (MRC) Scale for Muscle Strength is the most widely accepted method of grading muscle strength clinically.[1] This ...Function · Issues of Concern · Clinical Significance · Other Issues
[73]
Peripheral Neuropathy: Evaluation and Differential Diagnosis
Dec 15, 2020 · ... stocking and glove" distribution of the extremities. Later stages may involve proximal numbness, distal weakness, or atrophy. Physical ...
[74]
Use of the Michigan Neuropathy Screening Instrument as a measure ...
The Michigan Neuropathy Screening Instrument (MNSI) is used to assess distal symmetrical peripheral neuropathy in diabetes. It includes two separate assessments ...
[75]
Electrodiagnostic Evaluation of Peripheral Neuropathy - NCBI - NIH
Jan 30, 2023 · Electrodiagnostic testing, which includes nerve conduction studies (NCS) and needle electromyography (EMG), can support the diagnosis of peripheral neuropathy.
[76]
Nerve Conduction Studies and Electromyography - StatPearls - NCBI
Feb 10, 2025 · NCS and EMG can help confirm the diagnosis of peripheral neuropathy and determine whether it is demyelinating, axonal, or mixed. NCVs ...
[77]
Imaging in peripheral neuropathy: Ultrasound and MRI
Jun 30, 2021 · Both ultrasound (US) and magnetic resonance imaging (MRI) enable excellent evaluation of the peripheral nerves.Missing: biopsy sural punch risks yield
[78]
Magnetic Resonance Neurography for Evaluation of Peripheral ...
May 14, 2021 · In this review, we discuss the clinical applications of MRN in the diagnosis, as well as pre- and postsurgical assessments of patients with peripheral ...
[79]
Current and future applications of ultrasound imaging in peripheral ...
Sural nerve biopsy specimens confirm intraneural amyloid accumulation with associated axonal loss. As such, and in contrast to other typical axonal ...Missing: punch | Show results with:punch
[80]
Nerve biopsy: Current indications and decision tools - PMC
This review explores the current indications for nerve biopsies and some of the issues surrounding its use.
[81]
Onion-bulb patterns predict acquired or inherited demyelinating ...
We investigated whether OB patterns (generalized, mixed, or focal) correlate with acquired or inherited neuropathies.
[82]
Diagnosing Small Fiber Neuropathy Through the Use of Skin Biopsy
A simple test can easily determine the presence of small fiber neuropathy. Here's what you need to know.Missing: MRI ultrasound indications
[83]
Contribution of Skin Biopsy in Peripheral Neuropathies - MDPI
Skin biopsy is a minimally invasive technique with the advantage, compared to sural nerve biopsy, of being suitable to be applied to any site in our body.Missing: MRI | Show results with:MRI<|control11|><|separator|>
[84]
Nerve biopsies in patients with peripheral neuropathy: A prospective ...
Nerve biopsy did help in making the diagnosis of unexplained neuropathy in approximately 50% of the cases. Leprosy was the most common diagnosis among these ...
[85]
Peripheral neuropathy - Diagnosis and treatment - Mayo Clinic
Sep 2, 2023 · Learn what may cause the prickling, tingling or numb sensations of nerve damage and how to prevent and treat this painful disorder.
[86]
a systematic review with meta-analysis of randomised controlled trials
Feb 27, 2023 · We found that pregabalin and gabapentin were more efficacious than placebo (≥ 30% and ≥ 50% pain intensity reduction). The NNTs of pregabalin ...
[87]
Can gabapentin (Neurontin) cause dizziness? - Dr.Oracle
Apr 28, 2025 · Dizziness typically occurs in about 20-30% of patients taking gabapentin, especially during the initial treatment phase or after dose ...
[88]
Pregabalin vs. gabapentin in the treatment of neuropathic pain
Jan 7, 2025 · Pregabalin demonstrated superior and faster efficacy in alleviating neuropathic pain than gabapentin did.
[89]
[PDF] CYMBALTA (duloxetine - accessdata.fda.gov
The maximum dose studied was 120 mg per day. Administer 60 mg once daily in adults with diabetic peripheral neuropathic pain. There is no evidence that doses ...
[90]
Duloxetine in the management of diabetic peripheral neuropathic pain
Two medications are currently approved by the US Food and Drug Administration (FDA) for the management of DPNP; duloxetine and pregabalin. Duloxetine is an ...
[91]
A Comprehensive Algorithm for Management of Neuropathic Pain
Jun 1, 2019 · Medications form the basis of first- and second-line therapy for neuropathic pain (Table 1). Tricyclic antidepressants (TCAs), serotonin ...
[92]
Tapentadol for neuropathic pain: a review of clinical studies - PMC
Tapentadol has proved to be effective in relieving NP in diabetic peripheral neuropathy and in chronic low back pain.
[93]
Pharmacologic management of chronic neuropathic pain
Tramadol and other opioids are recommended as second- line agents, while cannabinoids are newly recommended as third-line agents.
[94]
Intravenous Immunoglobulin Initiation in Patients with Chronic ...
The usual dosing regimen of IVIG used for CIDP is a total induction dose of 2 g/kg, divided over 2–5 days, followed by maintenance dosing (most commonly 1 g/kg ...
[95]
Corticosteroids for chronic inflammatory demyelinating ...
Monthly dexamethasone and daily prednisolone may be of similar benefit in CIDP, but monthly dexamethasone may have fewer side effects. The evidence is up to ...
[96]
Effect of Erythropoietin-stimulating agent on uremic neuropathy in ...
May 12, 2022 · This study was designed to investigate whether ESA therapy will improve uremic neuropathy using electrophysiological studies in newly diagnosed ESKD patients.
[97]
Long-term outcomes of carpal tunnel release: a critical review ... - NIH
Clinical success is shown to occur at a rate of 75–90 %, while recurrence is reported in 4–57 % of cases. Both recurrence and success are variously defined in ...
[98]
The incidence and decompression rates of median and ulnar ...
May 31, 2024 · 88.00% (22/25) arthroscopic cases and 90.00% (9/10) open cases achieved symptom resolution through surgical management. Arthroscopic and open ...Missing: entrapment | Show results with:entrapment
[99]
Factors predicting sensory and motor recovery after the repair of ...
[15] suggested that nerve repair should be performed within 3 months of the injury, and that the time from injury to repair should not exceed 1 year. Length of ...
[100]
Peripheral Nerve Reconstruction after Injury: A Review of Clinical ...
Less than half of patients who undergo nerve repair after injury regain good to excellent motor or sensory function.
[101]
Evidence-Based Approach to Timing of Nerve Surgery: A Review
In cases of blunt trauma or gunshot wounds, a wait time of 2 to 3 weeks for zone of injury demarcation may be recommended for peripheral nerve repair. During ...
[102]
Primary hyperhidrosis: an updated review - PMC - PubMed Central
187 Sympathectomy is effective in 68–100% of cases, though satisfaction rates ... Autonomic dysfunction in palmar hyperhidrosis. J Auton Nerv Syst. 1983;8(1): ...
[103]
Effect of Surgical Release of Entrapped Peripheral Nerves in ...
Feb 17, 2023 · Targeted surgical decompression reduces external strain on the affected nerve and, therefore, may alleviate symptoms, including pain and sensory ...Missing: indications | Show results with:indications
[104]
Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors ...
In general, PN carries an increased risk of malignant transformation. This holds true for NF1 patients with a lifetime risk increase of 8–13% to develop a ...
[105]
Effectiveness of mini-open carpal tunnel release: An outcome study
Jul 15, 2019 · In our study, 11% of patients suffered from an early complication (within 3 months post-intervention) (Table 6), which is in accordance with the ...
[106]
Peripheral Nerve Injury: Principles for Repair and Regeneration - PMC
Postoperatively nerve repairs should be protected by immobilization for 10-14 days and sometimes surgeons advocate up to six-weeks depending on the nerve injury ...
[107]
Vitamin B12 Deficiency: Recognition and Management - AAFP
Sep 15, 2017 · Oral and injectable vitamin B12 are effective means of replacement, but injectable therapy leads to more rapid improvement and should be ...
[108]
Factors predicting sensory and motor recovery after the repair of ...
Predictors of outcome after the repair of peripheral nerve injuries include age, gender, repair time, repair materials, nerve injured, defect length, and ...<|separator|>
[109]
Association Between HbA1c Levels and Diabetic Peripheral ... - NIH
Jun 20, 2022 · Higher 3-year mean hemoglobin A1c levels were significantly associated with diabetic peripheral neuropathy records (indicating the receipt of ...
[110]
Central obesity is associated with neuropathy in the severely obese
Normoglycemic obese patients have a high prevalence of neuropathy indicating that obesity alone may be sufficient to cause neuropathy.
[111]
Guillain-Barre syndrome - Diagnosis and treatment - Mayo Clinic
Jun 7, 2024 · About 80% can walk independently six months after diagnosis. About 60% fully recover motor strength one year after diagnosis. About 5% to 10% ...Symptoms and causes · Doctors and departments · Care at Mayo Clinic
[112]
https://www.aafp.org/pubs/afp/issues/2017/0915/p384.html
[113]
Neuropathy Impairment Score (NIS) | hATTR Evaluation Tools
The Neuropathy Impairment Score (NIS) is the summed scores of standard items of the neuromuscular examination of weakness, reflex loss, and sensation loss.<|control11|><|separator|>
[114]
Autonomic Neuropathy - an overview | ScienceDirect Topics
Patients with cardiac autonomic neuropathy have a 40% greater mortality compared with people without this neuropathy; the increased mortality is due to silent ...
[115]
Managing Chronic Neuropathic Pain: Recent Advances and New ...
Oct 12, 2022 · Neuropathic pain affects 7–10% of the population, with most of the patients receiving inadequate and incomplete treatment. Owing to the high ...
[116]
Improvement in Neuropathy Outcomes With Normalizing HbA 1c in ...
Nov 19, 2018 · Normalizing HbA 1c in type 2 diabetes of short duration improves microvascular complications including neuropathy and nephropathy more effectively than ...Introduction · Research Design and Methods · Results · Conclusions
[117]
Evaluation and Prevention of Diabetic Neuropathy - AAFP
Jun 1, 2005 · The Diabetes Control Complications Trial (DCCT)17,20 demonstrated that tight glycemic control may result in a 60 percent reduction in the risk ...<|separator|>
[118]
Prevention of Peripheral Distal Polyneuropathy in Patients ... - MDPI
Conclusions: The main preventive strategy for DPN is intensive glycemic control with a target HbA1c < 6% in patients with TIDM and standard control of 7.0–7.9 ...
[119]
Alcoholic neuropathy: possible mechanisms and future treatment ...
Incidence of alcoholic polyneuropathy was found to be higher in women compared with men [9]. The findings were supported by the results from preclinical studies ...
[120]
Diabetic neuropathy: Can dietary supplements help? - Mayo Clinic
Jan 27, 2024 · Research into the relationship between dietary supplements and diabetic neuropathy is ongoing. In the meantime, focus on eating a balanced diet.Vitamin B-12 · Alpha-Lipoic Acid · Acetyl-L-Carnitine
[121]
Physical Activity/Exercise and Diabetes: A Position Statement of the ...
Oct 11, 2016 · Regular aerobic exercise may also prevent the onset or delay the progression of peripheral neuropathy in both type 1 and type 2 diabetes (163).
[122]
Carpal tunnel syndrome: Learn More – Wrist splints and hand ...
Dec 17, 2024 · A wrist splint can be worn for support. Splints aren't always effective enough, but they have hardly any side effects compared with other treatment options.
[123]
29 CFR Part 1910 Subpart Z -- Toxic and Hazardous Substances
OSHA Permissible Exposure Limits: Time Weighted Average, 0.1 fiber/cc ... The peripheral neuropathy resulting from lead exposure characteristically ...
[124]
https://www.mayoclinic.org/diseases-conditions/diabetic-neuropathy/in-depth/diabetic-neuropathy-and-dietary-supplements/art-20095406
[125]
Recombinant Zoster Vaccine VIS - CDC
Recombinant shingles vaccine provides strong protection against shingles. By preventing shingles, recombinant shingles vaccine also protects against PHN and ...At A Glance · Why Get Vaccinated? · Recombinant Shingles Vaccine
[126]
Prevalence of peripheral neuropathy in pre-diabetes: a systematic ...
May 18, 2021 · There was a wide range of prevalence estimates (2%–77%, IQR: 6%–34%), but the majority of studies (n=21, 72%) reported a prevalence ≥10%. The ...
[127]
Long-lasting analgesia via targeted in situ repression of NaV1.7 in ...
Consequently, despite preclinical studies demonstrating that decreased NaV1.7 activity leads to a reduction in inflammatory and neuropathic pain (8, 9, 16, 17), ...
[128]
A Review of the Therapeutic Targeting of SCN9A and Nav1.7 for ...
May 4, 2023 · It has been found that mutations associated with Nav1.7 lead to the loss of the ability to perceive pain in individuals that are otherwise ...
[129]
News & Events - Encoded Therapeutics
Oct 9, 2025 · Preclinical data show the vectorized miRNA candidate achieved durable knockdown of SCN9A (NaV1.7), a genetically validated pain target ...Missing: Nav1. 2020-2025
[130]
https://drc.bmj.com/content/9/1/e002040
[131]
Human studies of the efficacy and safety of stem cells in the ...
Nov 19, 2024 · Stem cell therapy shows significant promise in improving clinical outcomes for DPN, with evident benefits in nerve conduction and sensory parameters.Missing: percentage phase II
[132]
Evaluating the efficacy of mesenchymal stem cells for diabetic ...
May 5, 2024 · Recent preclinical studies suggest that mesenchymal stem cells (MSCs) may represent a promising solution for the treatment of diabetic neuropathy.
[133]
NCT05327114 | Efficacy and Safety Study of Nipocalimab for Adults ...
The main purpose of this study is to evaluate the safety and efficacy of nipocalimab compared to placebo in delaying relapse in adults with chronic ...
[134]
Chronic Inflammatory Demyelinating Polyradiculoneuropathy
Feb 26, 2024 · Current first-line evidence-based therapies for CIDP include intravenous and subcutaneous immunoglobulins, corticosteroids and plasma exchanges.
[135]
Alpha-Lipoic Acid as an Antioxidant Strategy for Managing ...
[97] concluded that intravenous treatment with ALA (600 mg/day) for three weeks significantly reduced the symptoms of peripheral diabetic neuropathy in patients ...
[136]
Alpha Lipoic Acid for Symptomatic Peripheral Neuropathy in ... - NIH
When given intravenously at a dosage of 600 mg/day over a period of 3 weeks, alpha lipoic acid leads to a significant and clinically relevant reduction in ...Missing: Europe | Show results with:Europe
[137]
Alpha-Lipoic Acid: Biological Mechanisms and Health Benefits - MDPI
Alpha-lipoic acid activates AMPK to protect against oxidative stress and apoptosis in rats with diabetic peripheral neuropathy. Hormones 2023, 22, 95–105 ...
[138]
FDA Approves Abbott's Spinal Cord Stimulation for People Living ...
Jan 26, 2023 · The new indication for Abbott's Proclaim™ XR SCS system provides a non-medication option for people with painful diabetic peripheral neuropathy ...Missing: 2020s percentage
[139]
Spinal Cord Stimulation for Painful Diabetic Peripheral Neuropathy
Treatment success, defined as > 50% pain reduction on the NRS scale, was observed in 86% of patients after 1 year and 55% of patients after 5 years; 80% of ...
[140]
FDA Approves Medtronic Spinal Cord Stimulators for Diabetic ...
May 12, 2025 · In a long-term follow-up study, 47% of people treated with spinal cord stimulation reported a 50% decrease in pain during the day; roughly 35% ...Missing: 2020s percentage
[141]
https://www.mdpi.com/2076-3921/13/10/1228
[142]
EPPIC-Net: Novaremed Painful Diabetic Peripheral Neuropathy ISA
Recruitment status. Not yet recruiting: The study has not started recruiting participants. Recruiting: The study is currently recruiting participants.
[143]
https://news.medtronic.com/2022-01-24-Medtronic-announces-FDA-approval-of-spinal-cord-stimulation-therapy-for-treating-chronic-pain-resulting-from-diabetic-peripheral-neuropathy
[144]
https://pmc.ncbi.nlm.nih.gov/articles/PMC8586096/
[145]
The Effect of Cryocompression on Peripheral Neuropathy in Patients ...
Aug 20, 2025 · Participant recruitment will begin on August 10, 2025, and will be completed by December 31, 2025. Official Title. The Effect of ...
[146]
Gene Therapy Options as New Treatment for Inherited Peripheral ...
Recent advances in gene manipulation technology have brought novel approaches to gene therapy and its clinical application for IPN treatment.
[147]
Peripheral Sodium Channel Blocker Could Revolutionize Treatment ...
Nov 7, 2024 · A novel generation of pain medications could be on the horizon. The drugs, known as peripheral sodium channel blockers, would mark the first ...Missing: prospects | Show results with:prospects
[148]
Evolving Treatment Strategies for Neuropathic Pain: A Narrative ...
Jun 10, 2025 · Clinical trials and longitudinal studies have demonstrated significant reductions in pain intensity and improvements in quality of life in ...