Chronic idiopathic axonal polyneuropathy …

Alexandru C Barboi MD FACP

Peripheral Neuropathies

Updated 08.05.2024
Released 03.15.2001
Expires For CME 08.05.2027

Chronic idiopathic axonal polyneuropathy

Author: Alexandru C Barboi MD FACP

See Contributor Disclosures

Editor: Louis H Weimer MD

Chronic idiopathic axonal polyneuropathy

In This Article

Quick Link

Introduction

Overview

Idiopathic sensory and sensorimotor polyneuropathies typically present in middle to late adulthood as a distal symmetric polyneuropathy phenotype. It is important to account for normal age-related changes in both the neurologic examination and nerve conduction studies when making this diagnosis. Many disorders cause a distal symmetric polyneuropathy, and a full diagnostic evaluation must be completed before categorizing a neuropathy as idiopathic. An expanding number of conditions and risk factors are associated with polyneuropathy, including metabolic syndrome, impaired glucose tolerance, celiac antibodies, monoclonal gammopathies, and new genetic mutations. Neuropathic pain is a common presenting symptom and is often the focus of medical management. Skin biopsy for assessment of intraepidermal nerve fiber density is a valid and reliable method of confirming the diagnosis of small fiber involvement.

Key points

	• Despite being a common neurologic condition with an apparent minimal associated disability, from the patient’s point of view, idiopathic axonal sensory and motor polyneuropathy does lead to impairment of activities of daily living, reduced quality of life and is associated with other comorbidities that shorten lifespan and have significant socioeconomic impact (82).
	• There is currently no unified pathophysiologic mechanism known disease-modifying treatment.

Historical note and terminology

The term polyneuropathy is frequently used interchangeably with the term neuropathy to imply the same conditions. Chronic idiopathic axonal polyneuropathy is a useful operational term. The approach to this condition has changed over time, moving from improved recognition of various causes to isolation of an idiopathic disorder and to identification of modifiable risk factors (88).

Clinical manifestations

Presentation and course

Polyneuropathy is defined as a functional or structural disturbance of peripheral nerves causing motor, sensory, or autonomic symptoms and signs. This article pertains only to polyneuropathies that do not have an identifiable cause and are, thus, considered idiopathic. At least for idiopathic sensory polyneuropathies, standardized diagnostic criteria have been proposed (29).

Clinically, they typically present as length-dependent polyneuropathies with insidious onset of numbness or pain involving the feet. In this article, we divide idiopathic polyneuropathies into three clinical categories: sensorimotor polyneuropathy, pure sensory polyneuropathy (large fiber, small fiber, and mixed), and sensory neuronopathies, as the symptoms, exam findings, and diagnostic results differ between these groups. The routine use of a validated scoring system (Erasmus Polyneuropathy Symptoms Score) as a screening tool in clinical interviews is useful in identifying patients with a polyneuropathy in the general population (42).

In patients with sensorimotor polyneuropathies, pain is reported in 27% to 42% of patients, sensory loss in 65%, paresthesias in 33% to 68%, weakness in 26% to 82%, and difficulty with balance in 33% (63; 69; 51; 49; 61). Numbness is the most common presenting symptom. In a series of patients with sensory-only polyneuropathy or small fiber polyneuropathy, the most common symptoms are pain in 54% to 100% of patients, sensory loss in 86%, and paresthesias in 86% to 100% (69; 33; 77; 104; 49). In both groups, lower extremity symptoms usually precede upper extremity symptoms (69; 104). Patients who experience pain have higher sural amplitudes, and the pain seems to have a nonlinear relationship with the severity of the polyneuropathy (02). It is unclear why some patients develop painful and others painless polyneuropathies. A multicenter, multivariate logistic regression analysis showed that polyneuropathy severity, idiopathic etiology, presence for chronic pain in the family, patient reported fatigue, depression, pain catastrophizing are all associated with pain in polyneuropathy (30). Autonomic symptoms are typically not part of this phenotype.

On physical examination, the most common findings are reduced or absent lower extremity vibratory sense in 80% to 100% of patients, pinprick in 53% to 95%, light touch in 59% to 91%, and proprioception in 9% to 18%. Sensory abnormalities in the hands occur in 36% of patients. On motor exam, there is distal lower extremity weakness in 39% to 100% of patients and hand weakness in 10%. Reduced or absent ankle jerk deep tendon reflex is reported in 78% to 100% of patients (63; 69; 104; 51; 61). Distal atrophy may be present. Patients with loss of upper extremity reflexes typically have absent reflexes in the lower extremities. Differences in patient classification and inclusion criteria can explain much of the variability between series in reporting frequencies of symptoms and examination findings. In asymptomatic individuals, it is important to separate age-related sensory and reflex loss findings, particularly when examining an older patient population, so as not to over diagnose polyneuropathy (93).

As opposed to the chronic, slowly progressive course of idiopathic sensory and sensorimotor polyneuropathies, idiopathic sensory neuronopathies may present as an acute to subacute process. Patients present with profound, often asymmetric, vibratory, and proprioceptive loss and with early sensory ataxia (17; 37). Deep tendon reflexes are absent, but muscle strength is preserved, although some patients will use the term "weakness" when describing their ataxia. Extraocular motility and pupillary reactivity may be affected in some patients. A prior review of patients with sensory neuronopathies noted the most common clinical findings to be ataxia in the lower or upper limbs, asymmetric distribution of sensory loss, and sensory loss not restricted to the lower limbs (12).

A sensory ganglionopathy involving predominantly small fiber function in a segmental fashion has also been described. Proximal clinical symptoms include facial pain and segmental sensory loss. A non-length-dependent pattern of fiber loss on skin biopsies assessing epidermal nerve fiber density may be seen (59; 32).

Prognosis and complications

Most patients with idiopathic sensory and sensorimotor polyneuropathy follow a stable to a slowly progressive course over years (63; 34; 69; 72; 33; 104; 51; 49; 88). A plateau phase of relative stability is particularly characteristic of pure sensory polyneuropathies (69). Independent ambulation is maintained in nearly all patients (79; 88). However, walking canes and ankle bracing may be required over time in the sensorimotor population (72). The need for assistive devices in patients with pure sensory presentations appears uncommon.

In contrast, idiopathic sensory neuronopathies are progressive, with many patients becoming wheelchair-bound over time (17; 87). Recovery is partly dictated by etiology but is poor in most idiopathic cases. This is likely the result of irreversible damage to sensory ganglionic neurons early in the course, Wallerian degeneration in the dorsal root ganglia, and dorsal columns of the spinal cord during more chronic stages of the disease.

Clinical vignette

A 68-year-old man presented with a 7-year history of numbness and burning pain in both feet. He denied a family history of similar symptoms. He had no visceral autonomic symptoms. On examination, he had decreased sensation to pinprick distal to the ankles bilaterally. Vibration sense was absent at the toes and diminished at the ankles. Position sense was intact. Muscle strength was normal. Deep tendon reflexes were present except for absent responses at the ankles. Extensive laboratory testing, including CSF analysis, excluded identifiable causes. Electrophysiologic studies demonstrated an axonal sensorimotor polyneuropathy. A sural nerve biopsy revealed a severe reduction in large and small myelinated fibers. His foot burning responded favorably to pregabalin.

Biological basis

Etiology and pathogenesis

Over a hundred causes of polyneuropathy have been identified (41). No cause was found in 20% to 30% of axonal chronic polyneuropathies. Idiopathic polyneuropathy is the second most common polyneuropathy after diabetes. For idiopathic polyneuropathy, the chance of finding an etiology decreases with age (101).

Idiopathic neuropathy series

*Over 50% of patients had acute onset; # Includes all patients, including those with known causes of PN; @ Study included only patients above 60 years of age; ^ Includes 22 patients from other centers; + Patients with motor sympto...

In prior series, no more than 6% of patients demonstrated demyelinating features on nerve conduction studies (63; 69; 104). Nerve biopsy tissue generally confirms the axonal nature of these polyneuropathies. Loss of myelinated fibers, occasional regenerating cluster formations, and other axonal degeneration and regeneration features are the typical findings (63; 69; 104). Endoneurial vessels in sural nerve biopsies may show increased basal lamina area thickness, endoneurial cell area, and number of endothelial cell nuclei (97). In some cases, especially idiopathic small fiber subgroups, sural nerve biopsies are normal (33; 48; 77). In such cases, intraepidermal nerve fiber density measurements on punch skin biopsy can provide objective evidence of polyneuropathy. Although biopsy findings typically demonstrate evidence of axonal damage, a series reported eight patients with cryptogenic sensory polyneuropathy who had pathologic findings consistent with chronic myelinopathy (14). Atypical chronic inflammatory demyelinating polyneuropathy and vasculitic polyneuropathy should be considered and ruled out as an etiology of an idiopathic neuropathy in the appropriate clinical setting.

The ability to transform exogenous compounds is orchestrated by the genetic variability of detoxification enzymes, which may play a role in individual susceptibility to polyneuropathy. Glutathione S-transferases are responsible for a step in the detoxification process by catalyzing the conjugation of glutathione with a large variety of organic compounds. Glutathione S-transferases also protect tissues from reactive oxygen damage. The GSTT1 null polymorphism (impaired metabolism of toxic compounds) may lead to peripheral sensory and motor axonal damage (60).

Three biomarkers of subclinical inflammation, chemokines (CCL7, CXCL10) and an inflammation-related membrane protein (Delta/notch-like epidermal growth factor-related receptor or DNER), were discovered to partially mediate the association between anthropometric measures (overweight, obesity) and distal sensorimotor polyneuropathies (86). An increasing role of metabolic syndrome as a risk factor in peripheral neuropathy has been recognized globally (53). Findings of HLA associations also suggest that the immune system has a role in the pathogenesis of idiopathic axonal polyneuropathy (106). Loss of the blood nerve barrier related tight junction claudin-12 protein leads to a painful neuropathic phenotype, regardless of fiber loss (99).

A 2024 genome wide association study failed to identify common genetic variants associated with chronic axonal polyneuropathy in the general population (94). However, in 125 patients with sensory only (not sensory motor) idiopathic phenotype, 34% carried the biallelic AAGGG repeat expansion in the replication factor complex 1 subunit (RFC1) (16). Phenotypically RFC1 positive patients had both small and large fiber involvement. Importantly, they had other clinical clues, such as 70% had a chronic dry cough, 37% had gait ataxia, and 50% had eye movement abnormalities. RFC1 is implicated in a wider phenotype called CANVAS: cerebellar ataxia, neuropathy, vestibular areflexia syndrome. RFC1 spectrum disorder may present initially as an “idiopathic” sensory predominant polyneuropathy in 42% of genotyped patients.

Studies have demonstrated that serum from patients with idiopathic sensory neuronopathy inhibits dorsal root ganglia neurite growth and immunostains fixed cultured and cryostat rat dorsal root ganglia, providing evidence for an immune-mediated pathogenesis in this small group of patients (100). Outside of paraneoplastic and autoimmune (Sjogren syndrome, systemic lupus erythematosus, autoimmune hepatitis, and possibly celiac disease) mechanisms, infectious (human immunodeficiency virus, Epstein-Barr virus, varicella-zoster virus, human T cell lymphotropic virus-1) and toxic mechanisms (pyridoxine, cisplatin, carboplatin, oxaliplatin) need to be considered. Up to 50% of sensory neuronopathies remain idiopathic (37). Given previous paragraph discussion, the RFC1 mutation should be checked in all chronic sensory neuronopathy cases.

Epidemiology

Idiopathic axonal polyneuropathy is the second most prevalent polyneuropathy after diabetic polyneuropathy (Visser at al 2015). Most patients have a negative family history of polyneuropathy. Investigation of the true prevalence of polyneuropathy in large populations is difficult. Data based on a review of 29 population-based studies resulted in a large variability in prevalence rates: 0.1% to 12.6% across all ages, with higher prevalence rates in the elderly of 1.9% to 30.9% (41). This variability likely stems from the methods used to establish the diagnosis, specifically the sensitivity of the screening procedure, geographical location of the survey, life expectancy, and year the study was performed. Overall estimated prevalence of polyneuropathy in the general population is 1% to 3% and increases to 7% in the elderly. Both socioeconomic status and age distribution influence prevalence rates. Men are more commonly affected by idiopathic polyneuropathy than women (98). The percentage of idiopathic polyneuropathy has decreased over time (107). Polyneuropathy-caused disease burden, even adjusting for comorbidities, will worsen as populations evolve to older demographics (45). Polyneuropathy, including idiopathic polyneuropathy, is a disabling condition and may independently contribute to increased mortality (45).

Chronic, acquired, sensory, and sensorimotor polyneuropathies are common in middle and late adulthood, with an estimated prevalence of more than 3% (09). The incidence of idiopathic polyneuropathy goes from 1 in 7 at age 40 to 49 to 1 in 3 at age 80 years and older (101). The majority of acquired polyneuropathies are secondary to readily identifiable causes, such as diabetes, alcohol abuse, and a wide variety of metabolic and toxic disorders (98), including neurotoxic medications. After known etiologies are excluded, a large fraction of polyneuropathies remain idiopathic. Contemporary series of patients evaluated for sensorimotor polyneuropathy estimate 10% to 25% to be idiopathic (23; 63; 69; 104; 81).

Idiopathic neuropathy series

The percentage of idiopathic cases appears to be higher in groups of sensory-only or small fiber neuropathy, with some series reporting up to 90% without known etiology (77). However, studies that included testing for impaired glucose tolerance and celiac disease found 50% to be idiopathic (19).

The onset of idiopathic polyneuropathies occurs mainly in the sixth and seventh decades of life. The mean age of patients in published series ranges from 51 to 63 years of age (63; 72; 77; 104; 49; 61; 19). There appears to be no difference in the age of onset between sensorimotor and sensory groups.

In a study of small fiber polyneuropathy, half of whom were idiopathic, there was a greater number of women than men (19).

Factors associated with idiopathic polyneuropathies may reflect underlying etiologies. In a study, normoglycemic patients with neuropathy had more dyslipidemia than diabetic patients without neuropathy (90). Several studies support the contribution of hyperlipidemia and the metabolic syndrome to the risk of developing polyneuropathy (49; 96; 86). Population studies suggest an association of polyneuropathy with the metabolic syndrome, specifically waist circumference and elevated triglyceride levels (40). Interestingly, in the same study there was no association between impaired fasting glucose and polyneuropathy, but the former was associated with lower sural amplitudes. Schlesinger and colleagues studied the incidence of distal sensorimotor polyneuropathy in a population of 513 participants (86). After a mean follow-up of 6.5 years, 127 cases of distal sensorimotor polyneuropathy were detected. They found that general and abdominal obesity were associated with incident polyneuropathy among individuals with and without diabetes. Importantly, a diagnosis of polyneuropathy is independently associated with all-cause mortality in the general population, even in the absence of diabetes (44).

Estimates of the prevalence of idiopathic sensory neuronopathies are less well-defined. However, studies examining the etiology of sensory neuronopathies have found a significant proportion to have no known etiology. In a study of 78 patients with sensory neuronopathy, 22 patients (28%) were determined to be idiopathic (12), although other estimates get closer to 50% (87).

Differential diagnosis

Reevaluations of idiopathic polyneuropathy may eventually uncover a cause in a sizable number of patients. Dyck and colleagues found that intensive evaluation of referred unclassified polyneuropathies yielded an identifiable cause in 76% (23). Of 205 patients referred for evaluation, 42% had hereditary polyneuropathies, 21% had inflammatory-demyelinating polyradiculoneuropathies, and 13% had other acquired neuropathies. In another study, the diagnosis of idiopathic axonal polyneuropathy was revised in nearly one half of 53 patients followed for at least 3 years (81). Other studies, however, have shown reevaluation of idiopathic polyneuropathies to be low-yield. In a study of 75 patients with chronic axonal polyneuropathy followed for 5 years, only four patients (5%) had an identified cause of neuropathy (72). Another series of 40 patients followed for at least 4 years found no etiology for any patient (51). Differences in referral populations and the breadth of the initial workup are likely responsible for the contrasting yields of reevaluations between studies.

Impaired glucose tolerance is one of the more common and increasingly recognized etiologies of previously categorized idiopathic polyneuropathies. A number of studies have reported increased prevalence of impaired glucose tolerance in patients with sensory polyneuropathy, even in the absence of frank diabetes (24; 73; 89; 92; 66). A study comparing diabetic polyneuropathy with idiopathic polyneuropathy found that the former had greater involvement of pure small fibers, whereas the latter had greater involvement of pure large fibers and a higher frequency of pain phenomena (50).

Hereditary motor and sensory polyneuropathy or Charcot-Marie-Tooth disease type 2 should be considered when motor symptoms predominate, and skeletal deformities are present. Muscle cramping in the legs and feet and the absence of paresthesias favor a hereditary polyneuropathy over other etiologies (23). Onset late in life does not exclude hereditary motor and sensory polyneuropathy, as it is estimated that 15% of patients with autosomal dominant hereditary motor and sensory polyneuropathy type 2 present after 50 years of age (69).

The differential diagnosis for idiopathic sensory neuronopathies also includes paraneoplastic neuronopathies associated with anti-Hu antibodies; immune-mediated, including chronic ataxic neuropathy with disialosyl antibodies or CANDA; pyridoxine- or chemotherapy-induced toxicity; vitamin E deficiency; acute nutritional axonal neuropathy; and Sjogren syndrome (85; 35; 18; 37; 39).

Confusing conditions

On clinical grounds, idiopathic sensory and sensorimotor polyneuropathies may be indistinguishable from polyneuropathies with an identifiable cause. Therefore, the clinician must exclude potential causes, including diabetes, chronic alcoholism, metabolic disturbances, endocrine abnormalities, connective tissue diseases, malignancy or amyloidosis, HIV or other infections, pertinent toxic or pharmacologic exposure, and hereditary factors. Celiac disease must also be considered, as it has been associated with a painful axonal sensory polyneuropathy even in the absence of gastrointestinal symptoms (15).

An inflammatory response to immunomodulation, a form of idiopathic axonal polyneuropathy was proposed under the acronym of CIAP (chronic axonal inflammatory polyneuropathy). The diagnosis requires the presence of three criteria (74):

	1. Acquired, chronic progressive or relapsing symmetrical or asymmetrical polyneuropathy with duration of progression greater than 2 months
	2. Electrophysiological evidence of axonal polyneuropathy in at least two nerves without any evidence of “strict criteria of demyelination”
	3. One of two supportive criteria: high CSF protein or presence of inflammatory cells in the nerve biopsy (excluding diabetic or vasculitic polyneuropathy)

Diagnostic workup

Idiopathic polyneuropathies, by nature, are a diagnosis of exclusion, which is established after a careful medical, family, and social history, neurologic examination, and directed laboratory testing to rule out the many potential causes of a length-dependent neuropathic process (76).

Laboratory testing. Declaring a polyneuropathy idiopathic rests many times on performing a set of blood tests. The approach goes back to the recognition that peripheral nerve tissue is sensitive to various pathogenic factors arising from systemic disorders. Historically, the list of disorders causing a polyneuropathy has grown over time, explaining perhaps why this topic requires periodic reviews.

The basic and highest yield laboratory studies in distal sensory or sensorimotor polyneuropathy include fasting blood glucose, vitamin B12 level, copper level, and serum protein immunofixation electrophoresis. If those studies are normal, oral glucose tolerance testing should be completed, especially if the clinical presentation includes pain (25). Other laboratory studies also recommended in routine lab testing include a basic metabolic panel, complete blood count, erythrocyte sedimentation rate, antinuclear antigen, rheumatoid factor, and thyroid function testing. The following studies should also be considered in the appropriate clinical situation: serum levels for vitamin B1, B2, vitamin E; nicotinic acid serum protein immunofixation; urine protein immunofixation; antineutrophil cytoplasmic antigen (ANCA) antibodies; serologies for IgG and IgA antigliadin antibodies; IgA anti-transglutaminase antibodies; human immunodeficiency virus (HIV) antibody; Lyme antibodies and confirmatory western blot, if applicable; heavy metal levels; and paraneoplastic and other antibody assays (76).

Testing for vitamin B12 deficiency is relatively high-yield and should include testing levels of the cobalamin metabolites, methylmalonic acid, and homocysteine. In two series of patients with polyneuropathy, between 2.2% and 8% of patients had B12 deficiency (07; 83), and in 5% to 10% of patients with serum B12 levels in the low to normal range, methylmalonic acid and homocysteine levels were elevated (03; 84). Testing for B6 levels may be left to the clinician’s discretion, with the caveat that moderately elevated plasma levels (100-200 mcg/L) are not associated with worse polyneuropathy signs or symptoms (91).

Incidental paraproteins are found in up to 3% of the general elderly population (55). The incidence of monoclonal proteins in chronic idiopathic polyneuropathy is as high as 10%, representing a monoclonal gammopathy of uncertain significance in most patients (55; 11; 54; 80). Patients with an IgM monoclonal gammopathy commonly have specific antibody binding against peripheral nerve antigens, implicating an autoantibody pathogenesis of associated neuropathies (56). Polyneuropathy associated with IgM paraprotein may have a distinct distal demyelinating phenotype (DADS-M). However, patients with axonal polyneuropathy and monoclonal gammopathy of uncertain significance are difficult to distinguish on clinical and electrophysiological grounds from patients with idiopathic polyneuropathy without a paraprotein (71), raising questions about the pathogenic role of the immunoglobulin and whether the monoclonal gammopathy of uncertain significance, particularly IgG and IgA, is a coincidental discovery.

In earlier studies of idiopathic sensory-predominant polyneuropathy, approximately one quarter of patients selected from case records or a clinic population had anti-sulfatide antibodies (78; 67). However, other series have found anti-sulfatide antibodies in none (69; 104) or only a small percentage of the patients with idiopathic polyneuropathy (70; 77). Anti-sulfatide antibody testing does not have a clear associated phenotype or treatment and should not be pursued routinely in clinical practice at this time.

CSF analysis is largely unremarkable in idiopathic polyneuropathies when inflammatory causes are excluded. The mean CSF protein from 73 unclassified patients in a series was 43 mg/dl (69). CSF was normal in four of five patients from another series (104). In a 2001 series of eight patients who had lumbar puncture for idiopathic neuropathy, none had elevated protein (51). Although typically normal in idiopathic polyneuropathies, CSF analysis should only be considered in patients with progressive symptoms or if there is clinical suspicion of atypical chronic inflammatory demyelinating polyneuropathy or chronic axonal inflammatory polyneuropathy (CIAP).

Nerve conduction studies and electromyography. Nerve conduction studies are indicated to confidently make the diagnosis define the phenotype, establish severity, and determine whether a polyneuropathy is axonal or demyelinating and focal or generalized.

Idiopathic neuropathy series

Nerve conduction abnormalities are expected in most patients with idiopathic polyneuropathy but may be normal in cases of small-fiber neuropathy. In prior series, at least 75% of patients with idiopathic polyneuropathy had abnormal nerve conduction studies (63; 69; 104). As expected, sural sensory responses are most frequently affected. Nerve conduction abnormalities typically consist of reduced amplitudes with normal or minimal distal latency and conduction velocity changes. The radial sensory and tibial motor action potential values seem to be the strongest electrophysiological determinants of polyneuropathy severity (105). An age-adjusted, severity grading scale in patients with distal symmetric axonal polyneuropathy was proposed by Abraham and Bril in 2024 (01). This scale used the number of abnormalities (0 to 4) in the sural and peroneal nerve responses to quantify polyneuropathy severity: 0 to 1 for mild, 2 for moderate, and 3 to 4 for severe. When used in a clinical setting, this scale performed better at the extreme ends of involvement.

It is not uncommon for patients with idiopathic polyneuropathy who only have sensory symptoms and signs to demonstrate subclinical motor nerve involvement by history or on electrophysiologic studies. In a large study, 70% of patients had an abnormal electromyography (104). Fibrillations were present in 42% and neurogenic motor unit potentials in 63%. Electromyography abnormalities have also been found in smaller series of patients with pure sensory presentations (33).

Nerve conduction abnormalities are less common in patients with pure small fiber forms, with a yield of only 50% in patients presenting with painful, burning feet and minimal physical signs of neuropathy (33; 77).

Quantitative sensory testing. Quantitative sensory testing has been applied in several studies of idiopathic polyneuropathy for assessing the function of afferent sensory fibers. By measuring thermal thresholds, quantitative sensory testing has a potential advantage over routine nerve conduction studies in assessing small sensory fibers. Quantitative sensory testing commonly demonstrates abnormalities in patients with neuropathy symptoms (47; 77), and it was slightly more sensitive than nerve conduction studies in one large study (104). However, another study observed no concordance between quantitative sensory testing and intraepidermal nerve fiber density measurements (77). Quantitative sensory testing also requires subjective patient input and may reflect abnormalities outside of the peripheral nervous system (36; 27; 28). There is substantial variation among quantitative sensory testing techniques and this, in turn, introduces another element of heterogeneity (06; 52).

Autonomic testing. Autonomic testing should be considered for patients with polyneuropathy, particularly if there is clinical evidence for autonomic visceral involvement or predominant small-fiber sensory polyneuropathy. Measurements of heart rate variability and quantitative sudomotor axon reflex testing (QSART) have been shown to be sensitive and specific for polyneuropathy, especially when used in combination (26).

Imaging. Spinal cord diffusion tensor imaging enables in vivo detection of posterior column damage in patients with sensory neuronopathy compared to normal subjects and distal diabetic polyneuropathy (13).

Nerve biopsy. Nerve biopsy generally confirms the axonal nature of idiopathic polyneuropathies. All 31 nerve specimens from a large series showed axonal degeneration (69). There was no evidence of demyelination, inflammation, vasculitis, or amyloidosis. Of 14 sural nerve biopsies from another large series, 13 demonstrated typical features of axonal degeneration (104). These studies suggest that sural nerve biopsy is rarely helpful in patients with idiopathic sensory neuropathies.

Nerve biopsy should be considered, however, when there is clinical suspicion for certain types of neuropathies, including amyloid neuropathy, mononeuritis multiplex due to vasculitis, axonal inflammatory polyneuropathy (74), or atypical chronic inflammatory demyelinating polyneuropathy (CIDP) (26). A series of eight patients was reported with a presentation of sensory neuropathy, predominantly large fiber distal sensory loss on examination, normal muscle strength, and minimally abnormal or axonal pathology findings on electrodiagnostic testing. These patients had sural nerve biopsy demonstrating chronic myelinopathy, consistent with a diagnosis of CIDP (14). Patients with progressive, predominantly large fiber idiopathic polyneuropathy should be considered for a sural nerve biopsy to rule out an inflammatory, potentially treatable polyneuropathy.

Skin biopsy. Guidelines from both the American Academy of Neurology (AAN) and European Federation of Neurological Societies (EFNS) have recommended that skin biopsy for determination of IENF density (IENFD) is a valid and reliable method for diagnosis of distal sensory neuropathy, particularly small fiber sensory neuropathy (57; 25). The most commonly used technique involves a 3 mm punch biopsy of skin from the leg, which is sectioned and examined using immunostaining techniques for anti-protein-gene-product 9.5 (PGP 9.5) antibodies to count the IENFD (25). Skin biopsy for IENFD has been shown to be reliable and valid in patients with distal sensory neuropathy, particularly in patients with small fiber neuropathy, with a reported diagnostic efficiency of 88% (62; 20). It is more sensitive than quantitative sensory testing or sudomotor autonomic testing, and one series demonstrated reduced IENFD in three quarters of patients with painful sensory symptoms and normal nerve conduction studies (77). In another study, reduced IENFD was present in 39% of 158 patients with clinically suspected small fiber neuropathy, of which 50% were of idiopathic etiology (19). The incidence of abnormal IENFD in chronic idiopathic axonal polyneuropathy is 43% to 53% of patients, depending on case definitions (68). High concordance has been reported between reduced IENFD and loss of pinprick on clinical examination (102). Skin biopsy has also been shown to be more sensitive for small fiber sensory neuropathy than sural nerve biopsy, but it is typically normal in demyelinating neuropathies (43). A significant heterogeneity is found in associations between fiber density, functional characteristics, and symptomatology. The severity of epidermal denervation is consistently associated with objective signs rather than pain or symptom scores (52).

Corneal confocal microscopy. Recognition that corneal innervation correlates with epidermal nerve small fiber loss in the legs has prompted the use of corneal confocal microscopy as a noninvasive method of diagnosis (52). Either manual or automated software quantifies the following parameters: the number of nerve trunks/mm2 of corneal tissue (corneal fiber density: CNFD), the number of branches originating from nerve trunks/mm2 of corneal tissue (corneal nerve fiber density: CNBD), and the total length of all nerve fibers and branches in mm/mm2 (corneal nerve fiber length: CNFL). A study by Nieuwenhoff and colleagues showed that in chronic idiopathic axonal polyneuropathy CNFD, CNBD, CNFL, did not differ from healthy controls (68). This was in contrast with painful diabetic polyneuropathy patients where confocal microscopy was abnormal.

Genetic testing. Genetic testing for hereditary peripheral polyneuropathies, such as Charcot-Marie-Tooth disease, should also be considered in patients who have the classic phenotype of such syndromes. There may be a genetic etiology to an axonal peripheral neuropathy even in the absence of family history due to the presence of de novo mutations. The role of genetic testing in patients with idiopathic polyneuropathy without the classic phenotype is unknown (25) but estimated to be low. Depending on coexistent clinical manifestations, mutation analysis for transthyretin familial amyloidosis (38) and RFC1 can be pursued (16).

The diagnostic workup of idiopathic sensory neuronopathies focuses on excluding identifiable causes. Laboratory testing should specifically include evaluation for vitamin B6 toxicity; HIV, HTLV, EBV, and VZV infection; Sjogren syndrome; systemic lupus erythematosus; paraneoplastic etiology; and GD1b antibodies. In patients with large-fiber sensory neuronopathy, cervical spine MRI often shows signal abnormalities in the dorsal columns and can be considered to support the clinical diagnosis (58; 59). Two studies examining IENF density in sensory ganglionopathies have shown reductions in the proximal thigh greater than or equal to that of the distal leg, highlighting the non-length-dependent pattern of the process (59; 32).

Management

Given incomplete understanding of the pathogenesis of chronic idiopathic axonal polyneuropathy, there is no current disease-modifying treatment (103).

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

There is no current association between diet quality and chronic axonal polyneuropathy (95).

Treatment of neuropathic pain is the primary focus of management for most patients with idiopathic sensory and sensorimotor polyneuropathies. Treatment studies for neuropathic pain have been conducted primarily in diabetic and HIV-associated neuropathies and postherpetic and trigeminal neuralgias.

A number of review articles have stratified medications for painful polyneuropathy into first-, second-, and third-line therapies based on the evidence supporting their benefit and potential risks and side effects (05; 22; 65; 75; 76). All agree that first-line therapies for peripheral neuropathic pain include tricyclic antidepressants and calcium channel alpha2-delta ligands (gabapentin and pregabalin). Topical lidocaine, available in patch and gel forms, is considered first- or second-line therapy for localized peripheral neuropathic pain, with the greatest evidence for postherpetic neuralgia. Antidepressants with dual serotonin and norepinephrine reuptake activity (duloxetine and venlafaxine) are first-line therapy in some reviews and second-line in others. Opioid medications and tramadol have been early on demonstrated to have good efficacy for neuropathic pain, particularly in combination with gabapentin (31), but most authors consider these agents to be second- or third-line therapies based on concern for side effects and dependence. However, retrospective data analysis suggests that the long-held practice of using chronic opioids for neuropathic pain to improve outcomes is not supported by facts. Long-term opioid use for neuropathic pain caused tolerance requiring escalating doses, hyperalgesia, addiction, and physical dependence resulting in behavior aimed at continuing opioids to prevent withdrawal. Chronic opioid use for neuropathic pain did not foster any functional impairment and caused increased adverse outcomes (46).

Other medications that are typically classified as third- or fourth-line therapies with inconsistent results for efficacy include other antidepressants (selective serotonin reuptake inhibitors), other antiepileptics (carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate), topical capsaicin, cannabinoids, mexiletine, clonidine, and N-methyl-D-aspartate receptor antagonists (memantine, dextromethorphan). Agents demonstrating efficacy in trigeminal neuralgia have a separate body of evidence and recommendations regarding therapy.

A comparative effectiveness study of neuropathic pain treatment in patients with cryptogenic sensory polyneuropathy evaluated nortriptyline, duloxetine, pregabalin, or mexiletine. Even though there was no clearly superior medication, the highest utility was for nortriptyline followed in order by duloxetine and pregabalin. Of note is that the most efficacy was 25%, outweighed by quitting treatment rates of 37.3% to 58% (08). Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, but it had the highest probability (> 90%) of improvements in pain and fatigue if used to 12 weeks (10).

There are limited data to support the empiric use of immunosuppressive agents in patients with predominantly sensory idiopathic polyneuropathies. There have been individual reports of improvement of pain or motor function with intravenous immune globulin (33; 21) or other immunosuppressants, but evidence is limited and empiric treatment without known etiology is generally not recommended, particularly if the course is benign. On the other hand, if there is a relapsing-remitting course and evidence for an immune mediated mechanism, immunomodulation may be considered (74).

There have been reports since the late 1980s of individual nerve decompression surgery as a means of improving overall neuropathic sensory and motor function. A study by Meyer-Marcotty and colleagues included 13 patients with idiopathic polyneuropathy (clinical diagnosis supported by abnormal nerve conduction velocities) who underwent the Dellon triple surgical decompression (common peroneal at the fibular head, tibial in the tarsal tunnel, and deep peroneal nerve at the dorsum of the foot) (64). The authors reported postoperative improvement in pain, numbness, tingling, and improvement in monofilament testing results. The study, however, was small, retrospective, not randomized, or placebo controlled. At this time, surgical decompression surgery as a therapeutic alternative for idiopathic axonal polyneuropathy cannot be recommended.

Patient education plays an important role in the management of idiopathic polyneuropathy. Patients are often anxious about future loss of function. The clinician can be a source of reassurance by referring to available literature stating that most patients remain stable or progress slowly over time, suffer limited motor disability, and have a relatively favorable long-term prognosis. For those patients with pure sensory polyneuropathies, the prognosis may be even more favorable with long plateau periods. Simply relaying this natural history to patients can provide considerable emotional and even physical comfort. Emphasis on weight loss, treatment of hyperlipemia, and daily exercise to promote weight loss and improve strength and balance should also help.

For patients with classified or idiopathic sensory neuronopathies, therapy depends on presumed etiology (38). For idiopathic cases corticosteroids, oral immunosuppression, IVIG, and plasma exchange have all been reported from small series, and no benefit was recorded; however, most patients were treated late in their course (37). Treatment of neuropathic pain remains a “trial-and-error” approach as phenotypic classification does not fully predict response to pharmacological interventions (04).

Outcomes

Given the incomplete understanding of the pathogenesis of chronic idiopathic axonal polyneuropathy, there is no current disease-modifying treatment (103).

References

01: Abraham A, Bril V. Electrophysiological grading scale for polyneuropathy severity. PLos One 2024;19(5):e0302491. PMID 38776287
02: Abraham A, Lovblom LE, Bril V. The complex association between pain and neuropathy. Muscle Nerve 2021;63:538-45. PMID 33433915
03: Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency I: usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 1990;34(2):90-8. PMID 2339683
04: Attal N. Pharmacological treatments of neuropathic pain: the latest recommendations. Rev Neurol (Paris) 2019;175(1-2):46-50. PMID 30318260
05: Attal N, Cruccu G, Haanpaa M, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain. Eur J Neurol 2006;13(11):1153-69. PMID 17038030
06: Backonja MM, Attal N, Baron R, et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain 2013;154(9):1807-19.** PMID 23742795
07: Barohn RJ. Approach to peripheral neuropathy and neuronopathy. Semin Neurol 1998;18(1):7-18. PMID 9562663
08: Barohn RJ, Gajewski B, Pasnoor M, et al. Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS): Bayesian Adaptive Comparative Effectiveness Randomized Trial. JAMA Neurol 2020;e202590 PMID 32809014
09: Beghi E, Monticelli ML. Chronic symmetric symptomatic polyneuropathy in the elderly: a field screening investigation in two Italian regions. I. Prevalence and general characteristics of the sample. Italian General Practitioner Study Group (IGPSG). Neurology 1995;45(10):1832-6. PMID 7477977
10: Bhai SF, Gjewski B, Kimminau KS, et al. A secondary analysis of PAIN-CONTRoLS: Pain's impact on sleep, fatigue, and activities of daily living. Muscle Nerve 2022;66(4):404-10. PMID 35585718
11: Bosch EP, Smith BE. Peripheral neuropathies associated with monoclonal proteins. Med Clin North Am 1993;77(1):125-39. PMID 8380479
12: Camdessanche JP, Jousserand G, Ferraud K, et al. The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain 2009;132(Pt 7):1723-33. PMID 19506068
13: Casseb RF, de Paiva JL, Branco LM, et al. Spinal cord diffusion tensor imaging in patients with sensory neuronopathy. Neuroradiology 2016;58(11):1103-08. PMID 27561739
14: Chin RL, Latov N, Sander HW, et al. Sensory CIDP presenting as cryptogenic sensory polyneuropathy. J Peripher Nerv Syst 2004;9(3):132-7. PMID 15363060
15: Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy. Neurology 2003;60(10):1581-5. PMID 12771245
16: Curro R, Salvalaggio A, Tozza S. RFC1 expansions are a common cause of idiopathic sensory neuropathy. Brain 2021;144:1542-50.** PMID 33969391
17: Dalakas MC. Chronic idiopathic ataxic neuropathy. Ann Neurol 1986;19(6):545-54. PMID 3014995
18: Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 1992;71(2):59-72. PMID 1312211
19: De Sousa EA, Hays AP, Chin RL, Sander HW, Brannagan TH 3rd. Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy. J Neurol Neurosurg Psychiatry 2006;77(8):983-5. PMID 16844956
20: Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008;131(Pt 7):1912-25. PMID 18524793
21: Donofrio PD, Berger A, Brannagan TH 3rd, et al. Consensus statement: the use of intravenous immunoglobulin in the treatment of neuromuscular conditions report of the AANEM ad hoc committee. Muscle Nerve 2009;40(5):890-900. PMID 19768755
22: Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132(3):237-51. PMID 17920770
23: Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 1981;10(3):222-6. PMID 7294727
24: Ellenberg M. Diabetic neuropathy presenting as the initial clinical manifestation of diabetes. Ann Intern Med 1958;49(3):620-31. PMID 13571846
25: England JD, Gronseth GS, Franklin G, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009a;72(2):185-92. PMID 19056667
26: England JD, Gronseth GS, Franklin G, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology 2009b;72(2):177-84. PMID 19056667
27: Finnerup NB, Johannesen IL, Fuglsang-Frederiksen A, Bach FW, Jensen TS. Sensory function in spinal cord injury patients with and without central pain. Brain 2003;126(Pt 1):57-70. PMID 12477697
28: Freeman R, Chase KP, Risk MR. Quantitative sensory testing cannot differentiate simulated sensory loss from sensory neuropathy. Neurology 2003;60(3):465-70. PMID 12578928
29: Freeman R, Gewandter JS, Faber CG, et al. Idiopathic distal sensory polyneuropathy. ACTTION diagnostic criteria. Neurology 2020;95:1005-14.** PMID 33055271
30: Gierthmulen J, Attal N, Baskozos G, et al. What is associated with painful polyneuropathy? A cross-sectional analysis of symptoms and signs in patients with painful and painless polyneuropathy. Pain 2024. [Epub ahead of print] PMID 38968400
31: Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005;352(13):1324-34. PMID 25646621
32: Gorson KC, Herrmann DN, Thiagarajan R, et al. Non-length dependent small fibre neuropathy/ganglionopathy. J Neurol Neurosurg Psychiatry 2008;79(2):163-9. PMID 17911181
33: Gorson KC, Ropper AH. Idiopathic distal small fiber neuropathy. Acta Neurol Scand 1995;92(5):376-82. PMID 8610490
34: Grahmann F, Winterholler M, Neundörfer B. Cryptogenetic polyneuropathies: an out-patient follow-up study. Acta Neurol Scand 1991;84(3):221-5. PMID 1659105
35: Griffin JW, Cornblath DR, Alexander E, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren's syndrome. Ann Neurol 1990;27(3):304-15. PMID 2327738
36: Gruener G, Dyck PJ. Quantitative sensory testing: methodology, applications, and future directions. J Clin Neurophysiol 1994;11(6):568-83. PMID 7860720
37: Gwathmey KG. Sensory neuronopathies. Muscle Nerve 2016;53(1):8-19. PMID 26467754
38: Gwathmey KG, Pearson KT. Diagnosis and management of sensory polyneuropathy. BMJ 2019;365:l1108. PMID 31068323
39: Hamel J, Logigian EL. Acute nutritional axonal neuropathy. Muscle Nerve 2018;57(1):33-9. PMID 28556429
40: Hanewinckel R, Drenthen J, Ligthart S, et al. Metabolic syndrome is related to polyneuropathy and impaired peripheral nerve function: a prospective population-based cohort study. J Neurol Neurosurg Psychiatry 2016a;87(12):1336-42. PMID 27656045
41: Hanewinckel R, van Oijen M, Ikram MA, van Doorn PA. The epidemiology and risk factors of chronic polyneuropathy. Eur J Epidemiol 2016b;31(1):5-20. PMID 26700499
42: Hanewinckel R, van Oijen M, Taams NE, et al. Diagnostic value of symptoms in chronic polyneuropathy: the Erasmus Polyneuropathy Symptom Score. J Peripher Nerv Syst 2019;24(3):235-41.** PMID 31172622
43: Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 1999;53(8):1634-40. PMID 10563605
44: Hicks CW, Wand D, Matsushita K, et al. Peripheral neuropathy and all-cause mortality in US adults. Ann Intern Med 2021;174(2):167-74.** PMID 33284680
45: Hoffman EM, Staff NP, Robb JM, St Sauver JL, Dyck PJ, Klein CJ. Impairments and comorbidities of polyneuropathy revealed by population based analyses. Neurology 2015;84(16):1644-51. PMID 25832668
46: Hoffman EM, Watson JC, St Stauver J, Staff NP, Klein CJ. Association of long-term opioid therapy with functional status, adverse outcomes, and mortality among patients with polyneuropathy. Jama Neurol 2017;74(7):773-9. PMID 28531306
47: Holland NR, Crawford TO, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Small-fiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann Neurol 1998;44(1):47-59. PMID 9667592
48: Holland NR, Stocks A, Hauer P, Cornblath DR, Griffin JW, McArthur JC. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 1997;48(3):708-11. PMID 9065552
49: Hughes RA, Umapathi T, Gray IA, et al. A controlled investigation of the cause of chronic idiopathic axonal polyneuropathy. Brain 2004;127(Pt 8):1723-30. PMID 15201191
50: Itani M, Gylfadottir S, Kroigard T, et al. Comparison of diabetic and idiopathic sensory polyneuropathies with respect to nerve fibre affection and risk factors. BMJ Neurol Open 2022;4(1):e000247. PMID 35360409
51: Jann S, Beretta S, Bramerio M, Defanti CA. Prospective follow-up study of chronic polyneuropathy of undetermined cause. Muscle Nerve 2001;24(9):1197-201. PMID 11494273
52: Karlsson P, Hincker AM, Jensen TS, Freeman R, Haroutounian S. Structural, functional, and symptom relations in painful distal symmetric poly neuropathies: a systematic review. Pain 2019;160(2):286-97.** PMID 30157133
53: Kazamel M, Stino AM, Smith AG. Metabolic syndrome and peripheral neuropathy. Muscle Nerve 2021;63:285-93. PMID 33098165
54: Kissel JT, Mendell JR. Neuropathies associated with monoclonal gammopathies. Neuromuscul Disord 1996;6(1):3-18. PMID 8845716
55: Kyle RA. 'Benign' monoclonal gammopathy. A misnomer. JAMA 1984;251(14):1849-54. PMID 6422066
56: Latov N. Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies. Ann Neurol 1995;37 Suppl 1:S32-42. PMID 8968215
57: Lauria G, Cornblath DR, Johansson O, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol 2005;12(10):747-58. PMID 16190912
58: Lauria G, Pareyson D, Grisoli M, Sghirlanzoni A. Clinical and magnetic resonance imaging findings in chronic sensory ganglionopathies. Ann Neurol 2000;47(1):104-9. PMID 10632108
59: Lauria G, Sghirlanzoni A, Lombardi R, Pareyson D. Epidermal nerve fiber density in sensory ganglionopathies: clinical and neurophysiologic correlations. Muscle Nerve 2001;24(8):1034-9. PMID 11439378
60: Lindh J, Soderkvist P, Fredrikson M, et al. Polymorphisms of GSTT1, GSTM1, and EPHX genotypes in patients with cryptogenic polyneuropathy: a case control study. Brain Behav 2011;1(2):135-41. PMID 22399093
61: Lindh J, Tondel M, Osterberg A, Vrethem M. Cryptogenic polyneuropathy: clinical and neurophysiological findings. J Peripher Nerv Syst 2005;10(1):31-7. PMID 15703016
62: McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 1998;55(12):1513-20. PMID 9865794
63: McLeod JG, Tuck RR, Pollard JD, Cameron J, Walsh JC. Chronic polyneuropathy of undetermined cause. J Neurol Neurosurg Psychiatry 1984;47(5):530-5. PMID 6330306
64: Meyer-Marcotty MV, Attabit A, Marz V, Vogt PM. Nerve decompression in the lower leg results in an improvement in symptoms in patients with both diabetic and idiopathic polyneuropathy. Ann Plast Surg 2024;92:212-21. PMID 38170967
65: Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12(1):13-21. PMID 17372630
66: Nebuchennykh M, Loseth S, Jorde R, Mellgren SI. Idiopathic polyneuropathy and impaired glucose metabolism in a Norwegian patient series. Eur J Neurol 2008;15(8):810-6. PMID 18549398
67: Nemni R, Fazio R, Quattrini A, Lorenzetti I, Mamoli D, Canal N. Antibodies to sulfatide and to chondroitin sulfate C in patients with chronic sensory neuropathy. J Neuroimmunol 1993;43(1-2):79-85. PMID 8384638
68: Nieuwenhoff MD, Nguyen HT, Niehof SP, et al. Differences in corneal nerve fiber density and fiber length in patients with painful chronic idiopathic axonal polyneuropathy and diabetic polyneuropathy. Muscle Nerve 2024;70(4):782-90. PMID 39056231
69: Notermans NC, Wokke JH, Franssen H, et al. Chronic idiopathic polyneuropathy presenting in middle or old age: a clinical and electrophysiological study of 75 patients. J Neurol Neurosurg Psychiatry 1993;56(10):1066-71. PMID 7691991
70: Notermans NC, Wokke JH, Lokhorst HM, Franssen H, van der Graaf Y, Jennekens FG. Polyneuropathy associated with monoclonal gammopathy of undetermined significance. A prospective study of the prognostic value of clinical and laboratory abnormalities. Brain 1994a;117(Pt 6):1385-93. PMID 7820574
71: Notermans NC, Wokke JH, van den Berg LH, et al. Chronic idiopathic axonal polyneuropathy. Comparison of patients with and without monoclonal gammopathy. Brain 1996;119(Pt 2):421-7. PMID 8800937
72: Notermans NC, Wokke JH, van der Graaf Y, Franssen H, van Dijk GW, Jennekens FG. Chronic idiopathic axonal polyneuropathy: a five year follow up. J Neurol Neurosurg Psychiatry 1994b;57(12):1525-7. PMID 7798984
73: Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001;24(9):1229-31. PMID 11494278
74: Oh SJ, Lu L, Alsharabati M, Morgan MB, King P. Chronic inflammatory axonal polyneuropathy. J Neurol Neurosurg Psychiatry 2020;91(11):1175-80. PMID 32917820
75: O'Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 2009;122(10 Suppl):S22-32. PMID 19801049
76: Pasnoor M, Dimachkie MM, Barohn RJ. Cryptogenic sensory polyneuropathy. Neurol Clin 2013;31(2):463-76. PMID 23642719
77: Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999;53(8):1641-7. PMID 10563606
78: Pestronk A, Li F, Griffin J, et al. Polyneuropathy syndromes associated with serum antibodies to sulfatide and myelin-associated glycoprotein. Neurology 1991;41(3):357-62. PMID 1706491
79: Prineas J. Polyneuropathies of undetermined cause. Acta Neurol Scand Suppl 1970;44:3-72. PMID 4325955
80: Ropper AH, Gorson KC. Neuropathies associated with paraproteinemia. N Engl J Med 1998;338(22):1601-7. PMID 9603799
81: Rosenberg NR, Vermeulen M. Chronic idiopathic axonal polyneuropathy revisited. J Neurol 2004;251(9):1128-32. PMID 15372258
82: Samuelsson K, Press R. Chronic axonal idiopathic polyneuropathy: is it really benign. Curr Opin Neurol 2020;33(5):562-7. PMID 32773448
83: Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in the identification of cobalamin-deficiency polyneuropathy. Arch Neurol 2003;60(9):1296-301. PMID 12975298
84: Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med 1994;96(3):239-46. PMID 8154512
85: Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med 1983;309(8):445-8. PMID 6308447
86: Schlesinger S, Herder C, Kannenberg JM, et al. General and abdominal obesity and incident distal sensorimotor polyneuropathy: insights into inflammatory biomarkers as potential mediators in the KORA F4/FF4 cohort. Diabetes Care 2019;42(2):240-7.** PMID 30523031
87: Sghirlanzoni A, Pareyson D, Lauria G. Sensory neuron diseases. Lancet Neurol 2005;4(6):349-61. PMID 15907739
88: Singer MA, Vernino SA, Wolfe GI. Idiopathic neuropathy: new paradigms, new promise. Journal Peripher Nerv Syst 2012;(17 Suppl)2:43-9.** PMID 22548623
89: Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001;24(8):1448-53. PMID 11473085
90: Smith AG, Rose K, Singleton JR. Idiopathic neuropathy patients are at high risk for metabolic syndrome. J Neurol Sci 2008;273(1-2):25-8. PMID 18606421
91: Stewart SL, Thomas S, Hoke E, Simpson D, Singleton JR, Hoke A. Vitamin B6 levels do not correlate with severity of neuropathy in chronic idiopathic axonal polyneuropathy. J Peripher Nerv Syst 2022;27(1):31-7. PMID 34931740
92: Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003;60(1):108-11. PMID 12525727
93: Taams NE, Drenthen J, Hanewinckel R, Ikram A, van Doorn PA. Age related changes in neurologic examination and sensory nerve amplitude in the general population. Neurology 2023;101(13):e1351-8.** PMID 37541844
94: Taams NE, Knol MJ, Hanewinckel R, et al. Association of common genetic variants with chronic axonal polyneuropathy in the general population: a genome-wide association study. Front Neurol 2024;15:1422824. PMID 39022727
95: Taams NE, Voortman T, Hanewinckel R, Drenthen J, van Doorn PA, Ikram MA. Diet quality and chronic axonal polyneuropathy: a population-based study. Ann Clin Transl Neurol 2019;6(12):2460-7. PMID 31738024
96: Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352(4):341-50. PMID 15673800
97: Teunissen LL, Notermans NC, Jansen GH, Banga JD, Veldman H, Wokke JH. Thickness of endoneurial vessel basal lamina area in chronic idiopathic axonal polyneuropathy. Acta Neuropathol 2000;100(4):445-50. PMID 10985705
98: Tondel M, Lindh J, Jonsson P, Vrethem M, Persson B. Occupational determinants of cryptogenic polyneuropathy. Neuroepidemiology 2006;26(4):187-94. PMID 16569935
99: Tsung-Chieh Chen J, Hu X, Otto IUC, et al. Myelin barrier breakdown, mechanical hypersensitivity, and painfulness in polyneuropathy with claudin-12 deficiency. Neurobiol Dis 2023;185:106246. PMID 37527762
100: van Dijk GW, Wokke JH, Notermans NC, van den Berg LH, Bar PR. Indications for an immune-mediated etiology of idiopathic sensory neuronopathy. J Neuroimmunol 1997;74(1-2):165-72. PMID 9119970
101: Visser NA, Notermans NC, Linssen RS, van den Berg LH, Vrancken AF. Incidence of polyneuropathy in Utrecht, the Netherlands. Neurology 2015;84(3):259-64. PMID 25503982
102: Walk D, Wendelschafer-Crabb G, Davey C, Kennedy WR. Concordance between epidermal nerve fiber density and sensory examination in patients with symptoms of idiopathic small fiber neuropathy. J Neurol Sci 2007;255(1-2):23-6. PMID 17337273
103: Warendorf J, Vrancken AF, van Schaik IN, Hughes RA, Notermans NC. Drug therapy for chronic idiopathic axonal polyneuropathy. Cochrane Database Syst Rev 2017;6(6):CD003456.** PMID 28631805
104: Wolfe GI, Baker NS, Amato AA, et al. Chronic cryptogenic sensory polyneuropathy: clinical and laboratory characteristics. Arch Neurol 1999;56(5):540-7. PMID 10328248
105: Zis P, Hadjivassiliou M, Rao DG, Sarrigiannis PG. Electrophysiological determinants of the clinical severity of axonal peripheral neuropathy. Muscle Nerve 2019;59(4):491-3. PMID 30680742
106: Zis P, Sarrigiannis PG, Artemiadis A, Skarlatou V, Hadjivassiliou M. Chronic idiopathic axonal polyneuropathy: electrophysiological progression and human leukocyte antigen associations. Muscle Nerve 2021;63: 567-71. PMID 33440030
107: Zis P, Sarrigiannis PG, Rao DG, Hewamadduma C, Hadjivassiliou M. Chronic idiopathic axonal polyneuropathy: a systematic review. J Neurol 2016;263(10):1903-10. PMID 26961897

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Alexandru C Barboi MD FACP

Dr. Barboi of Indiana University has no relevant financial relationships to disclose.
See Profile

Editor

Louis H Weimer MD

Dr. Weimer of Columbia University has no relevant financial relationships to disclose.
See Profile

Former Authors

Gil I Wolfe MD
Jaya R Trivedi MD
Rebecca E Traub MD
Thomas H Brannagan III MD

Patient Profile

Age range of presentation: Typically > age 50
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Hereditary and idiopathic neuropathy, unspecified: G60.9

Idiopathic progressive neuropathy: G60.3
ICD-11: Idiopathic progressive neuropathy: 8C00

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Chronic idiopathic axonal polyneuropathy

Associated Disorders

RFC1 spectrum disorder (CANVAS)

Differential Diagnosis

neuropathies with an identifiable cause
diabetes
impaired glucose tolerance
chronic alcoholism
metabolic disturbances
- endocrine abnormalities
- connective tissue diseases
- malignancy
- amyloidosis
- HIV
- other infections
- pertinent toxic exposure
- pharmacologic exposure
- hereditary factors
- Celiac disease
- hereditary neuropathies
- inflammatory-demyelinating polyradiculoneuropathies
- other acquired neuropathies
- Charcot-Marie-Tooth disease type 2
- paraneoplastic neuronopathies associated with anti-Hu antibodies
- chronic ataxic neuropathy with disialosyl antibodies
- pyridoxine toxicity
- vitamin E deficiency
- Sjogren syndrome

Also Relevant

Clinical evaluation of peripheral neuropathies
Motor and multifocal motor neuropathies
Neuropathies associated with monoclonal gammopathies
Polyneuropathy associated with anti-MAG IgM antibodies
Polyneuropathy associated with antisulfatide antibodies
- Sjogren syndrome: neurologic complications

Clinical Categories

Peripheral Neuropathies

Chronic idiopathic axonal polyneuropathy …

Chronic idiopathic axonal polyneuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Familial dysautonomia

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Disulfiram neuropathy

Mercury neuropathy

Clinical evaluation of peripheral neuropathies

Carpal tunnel syndrome

Chronic idiopathic axonal polyneuropathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

NF2-related schwannomatosis

Familial dysautonomia

Peripheral nerve complications of HIV-1 infection

Neuropathies associated with cytomegalovirus infection

Disulfiram neuropathy

Mercury neuropathy

Clinical evaluation of peripheral neuropathies

Carpal tunnel syndrome

This is an article preview.
Start a Free Account
to access the full version.