Idiopathic Neuropathy Research Articles

Scleritis and Episcleritis in Patients with Idiopathic Small Fiber Neuropathy

PurposeTo report the prevalence of scleritis and episcleritis in patients with idiopathic small fiber neuropathy (SFN). MethodsThe Mass General Brigham (MGB) hospital database was queried for patients with SFN, scleritis and episcleritis using diagnostic codes and natural language processing. Electronic medical chart review of patients diagnosed with SFN and episcleritis/scleritis who had at least one ophthalmology visit was conducted. The prevalence of scleritis and episcleritis in patients diagnosed with SFN was compared to those without SFN using logistic regression to adjust for covariates. All statistical analyses were performed in RStudio 4.2.1. ResultsFrom the 2100 SFN patients with an eye exam in the MGB database, 23 patients had episcleritis or scleritis (1.1%) confirmed by chart review. Ten patients had episcleritis (0.48%) and thirteen patients had scleritis (0.62%). Of the episcleritis and scleritis patients, 16 (69.6%) were women and 7 (30.4%) were men. Ten (43.5%) had bilateral ocular disease. The mean age of ocular diagnosis was 51.0 years (range, 22-77 years). Out of the 507,128 controls without SFN in the MGB database, 1,481 (0.29%) had scleritis and 1,430 (0.28%) had episcleritis. Episcleritis and scleritis were more prevalent in patients with SFN than in those without SFN: 0.48% vs. 0.28% for episcleritis and 0.62% vs 0.29% for scleritis (P values = 0.32 and 0.02, respectively). Conclusionsand Importance: There were higher rates of scleritis in SFN patients compared to non-SFN patients. This potential systemic disease association had not been previously reported.

Vitamin D levels do not correlate with severity of idiopathic peripheral neuropathy.

Peripheral neuropathy (PN) is a common neurological condition in elderly adults. Vitamin D deficiency has been associated with diabetic and chemotherapy-induced neuropathy, but its role in idiopathic PN, in which no underlying cause of neuropathy can be identified, has not been investigated. Two hundred thirty patients with idiopathic PN enrolled in the Peripheral Neuropathy Research Registry (PNRR) at Johns Hopkins University School of Medicine had vitamin D testing information on record. Linear and logistic regressions were used to investigate the relationship between absolute vitamin D level or vitamin D insufficiency (<20 ng/mL) and both the severity of neuropathy as measured by the reduced total neuropathy score (TNSr) and severity of neuropathic pain. Sixteen (7%) patients were vitamin D insufficient (<20 ng/mL). Controlling for factors known to correlate with severity of neuropathy, there was no correlation between absolute vitamin D levels and TNSr (correlation coefficient 0.01, 95% CI -0.03 to 0.07, p = .59) and no association between vitamin D insufficiency and TNSr (correlation coefficient 0.3, 95% CI -2.8 to 3.4, p = .86). Vitamin D insufficiency was not associated with the presence of neuropathic pain (OR 4.1, 95% CI 0.6-26.0, p = .13), and there was no correlation between vitamin D levels and pain score (correlation coefficient 0.01, 95% CI -0.02 to 0.03, p = .59). In a single-center cohort of patients with idiopathic PN, there was no correlation between vitamin D levels and the severity of neuropathy or neuropathic pain.

Nonamyloidogenic TTR gene variants c.76G>A and c.337-18G>C are not associated with idiopathic small-fiber neuropathy.

Small-fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337-18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group. In this retrospective single-center study, we analyzed the frequency of the c.76G>A and c.337-18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database. We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337-18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database. The c.76G>A and c.337-18G>C TTR gene variants are not associated with SFN.

Management Targeted Genetic Evaluation of an Idiopathic Neuropathy Cohort Through ATTRv Amyloidosis Screening.

While the reported prevalence of polyneuropathies is 1%-3%, the incidence of hereditary transthyretin amyloidosis in the United States is estimated to be 1 in 100 000 individuals. Polyneuropathies are known to be difficult to treat and lead to significant morbidity. The aim of pain management is symptomatic treatment, with varying approaches to progression prevention being based on the causative pathophysiology.We assessed the prevalence of hereditary amyloid transthyretin variant (ATTRv) amyloidosis, a progressive autosomal dominant multisystem disease caused by the abnormal formation and extracellular deposition of transthyretin protein fibrils in various tissues, in an idiopathic polyneuropathy population by using genetic analysis. Individuals aged 18 and over with an established diagnosis of polyneuropathy, via electromyography testing that was deemed to be idiopathic, at a large, urban neurology clinic consented to an institutional review board-approved protocol for genetic testing. No further exclusions were made regarding age of onset, family history, axonal neuropathy subtype, comorbidities suggestive of ATTRv amyloidosis, etc. Clinical genetic testing was performed on 134 participants via an 81-gene panel associated with inherited neuromuscular disorders or targeted TTR gene sequencing with deletion and duplication analysis. Within our cohort, 38.06% had at least one reportable finding in one of 38 distinct genes, for a total of 76 reported alterations. Four individuals were identified as having a single pathogenic alteration in an autosomal recessive gene, consistent with carrier status for the 4 following disorders: congenital insensitivity to pain with anhidrosis (NTRK1), Charcot-Marie-Tooth disease type IIP (LRSAM1), Brown-Vialetto-Van Laere syndrome type II (SLC52A2), hereditary sensory and autonomic neuropathy type III (IKBKAP). One individual was found to have a variant of uncertain significance (VUS) (p.G103D) in the TTR gene. Precision medicine on the molecular level with genetic testing in the identification of specific neuropathies may provide clinicians with more detailed information for developing a more direct therapeutic and treatment modality for better-targeted management. Further investigation is needed to expand on the knowledge and understanding of the clinical relevance surrounding the alterations found in the genetic evaluation of idiopathic neuropathy.

Automated immunohistochemistry of intra-epidermal nerve fibres in skin biopsies: A proof-of-concept study.

To develop a standardised, automated protocol for detecting protein gene product 9.5 (PGP9.5) positive intra-epidermal nerve fibres (IENFs) in skin biopsies, transitioning from the established manual technique to an automated platform. This automated method, although currently intended for research applications, may improve the accessibility of this diagnostic test for small fibre neuropathy in clinical settings. Skin biopsies (n = 274) from 100 participants (fibromyalgia syndrome n = 62; idiopathic small fibre neuropathy: n = 16; healthy volunteers: n = 22) were processed using an automated immunohistochemistry platform. IENF quantification was performed by blinded examiners, with reliability assessed via a two-way mixed-effects model to evaluate inter- and intra-observer variability. The automated staining system reproduced intra-epidermal nerve fibre density (IENFD) counts consistent with free-floating sections (mean ± standard deviation: free-floating: 5.6 ± 3.4 fibres/mm; automated: 5.9 ± 3.2 fibres/mm). A median difference of 0.3 with a lower bound 95% Confidence Interval (CI) at -0.00005 established non-inferiority against a margin of -0.4 (p = .08). Specifically, the inter-class correlation coefficient (class denotes consistency in measured observations) was 99% (95% CI: 0.9-1), indicating excellent agreement between free-floating and automated methods. The inter- and intra-class coefficient between examiners were both 99% (95% CI: 0.9-0.1) for IENFD, demonstrating high reliability using sections stained using the automated method. Automated immunohistochemistry provides high-throughput reliable and reproducible intra-epidermal nerve fibre quantification. This method, although currently proof-of-concept, for research use only, may be more widely deployed in histopathology laboratories to increase the adoption of IENFD assessment for the diagnosis of peripheral neuropathies.

Bilateral idiopathic oculomotor neuropathy in a cat

AbstractIdiopathic oculomotor neuropathy is a well‐recognised syndrome in people, and it has also been described in dogs. In dogs, the disease appears to have a good prognosis; however, only reports of a unilateral presentation exist. Evidence of oculomotor dysfunction in cats has been previously associated with intracranial neoplasia, with a poor prognosis. This case report describes the clinical and imaging findings and outcome of a 12‐year‐old, male, neutered, domestic shorthair cat with bilateral mydriasis, unresponsive to light, as the sole clinical sign. Thorough diagnostic investigations led to a diagnosis of bilateral idiopathic oculomotor neuropathy. No treatment was prescribed, and there was no change in the clinical signs with 9‐month follow‐up. To the authors’ knowledge, this is the first report of bilateral idiopathic oculomotor neuropathy in a cat, which, based on this case, suggests a good prognosis with minimal adverse impact on the patient.

Pathologic RFC1 repeat expansions do not contribute to the development of inflammatory neuropathies.

Biallelic expansions of the AAGGG repeat in the replication factor C subunit 1 (RFC1) have recently been described to be responsible for cerebellar ataxia, peripheral neuropathy and vestibular areflexia syndrome. This genetic alteration has also allowed genetic classification in up to one-third of cases with idiopathic sensory neuropathy. Here, we screened a well-characterized cohort of inflammatory neuropathy patients for RFC1 repeat expansions to explore whether RFC1 was increased from background rates and possibly involved in the pathogenesis of inflammatory neuropathy. A total of 259 individuals with inflammatory neuropathy and 243 healthy controls were screened for the AAGGG repeat expansion using short-range flanking PCR and repeat-primed PCR. Cases without amplifiable PCR product on flanking PCR and positive repeat-primed PCR were also tested for the mostly non-pathogenic expansions of the AAAGG and AAAAG repeat units. None of the patients showed biallelic AAGGG expansion of RFC1, and their carrier frequency for AAGGG was comparable with controls [n = 27 (5.2%) and n = 23 (4.7%), respectively; P > 0.5]. Data suggest that the pathologic expansions of AAGGG repeats do not contribute to the development of inflammatory neuropathies nor lead to misdiagnosed cases. Accordingly, routine genetic screening for RFC1 repeat expansion is not indicated in this patient population.

Reply to the Letter to the Editor: Diagnosis of Mild-to-moderate Idiopathic Median Neuropathy at the Carpal Tunnel Based on Signs and Symptoms is Discordant From Diagnosis Based on Electrodiagnostic Studies and Ultrasound.

Reply to the Letter to the Editor: Diagnosis of Mild-to-moderate Idiopathic Median Neuropathy at the Carpal Tunnel Based on Signs and Symptoms is Discordant From Diagnosis Based on Electrodiagnostic Studies and Ultrasound.

Phenotype spectrum of idiopathic small fiber neuropathies – Experience from a prospective registry study (n > 200)

Phenotype spectrum of idiopathic small fiber neuropathies – Experience from a prospective registry study (n > 200)

Letter to the Editor: Diagnosis of Mild-to-moderate Idiopathic Median Neuropathy at the Carpal Tunnel Based on Signs and Symptoms is Discordant From Diagnosis Based on Electrodiagnostic Studies and Ultrasound.

Letter to the Editor: Diagnosis of Mild-to-moderate Idiopathic Median Neuropathy at the Carpal Tunnel Based on Signs and Symptoms is Discordant From Diagnosis Based on Electrodiagnostic Studies and Ultrasound.

Sensory Chronic Inflammatory Demyelinating Polyradiculoneuropathy: Neglected Immunotherapy-Responsive Sensory Neuropathy.

To report an improvement with immunotherapy in 34 (85%)/40 patients who required an immunotherapy among 56 patients with sensory chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Sensory CIDP was diagnosed when two inclusion criteria are met: 1) acquired, chronic progressive or relapsing symmetrical or asymmetrical sensory polyneuropathy that had progressed for >2 months; and 2) definite electrophysiological and/or biopsy evidence of demyelinating neuropathy. Fifty-six patients with sensory CIDP were identified. Evidence of demyelination was obtained from by the routine motor nerve conduction study (NCS) in 39 (70%) patients, from a nerve biopsy in 10, and from a near-nerve needle sensory NCS in 7 patients. The most prominent laboratory abnormality was a high protein level in the cerebrospinal fluid in 21 (49%) of 43 tested patients. Immunotherapy was required in 41 (79%) of the 52 followed-up patients. An improvement with immunotherapy was observed in 36 (88%)/41 patients. In three patients, motor weakness developed in 5-8 years' follow-up period and so, their diagnosis was changed to CIDP. Sensory CIDP is responded to an immunotherapy in 88% of the treated patients. Sensory CIDP was diagnosed by the routine motor NCS in 70% of patients and by a sural nerve biopsy in 18% of patients. Thus, sensory CIDP should be recognized as a treatable CIDP variant among the different types of "idiopathic sensory neuropathy."

Idiopathic Trigeminal Neuropathy with Partial Enhancement in the Lateral Portion of Cisternal Segment

Idiopathic Trigeminal Neuropathy with Partial Enhancement in the Lateral Portion of Cisternal Segment

Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients.

Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein-protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini-Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini-Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.

CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

CORR Insights®: Diagnosis of Mild-to-moderate Idiopathic Median Neuropathy at the Carpal Tunnel Based on Signs and Symptoms is Discordant From Diagnosis Based on Electrodiagnostic Studies and Ultrasound.

CORR Insights®: Diagnosis of Mild-to-moderate Idiopathic Median Neuropathy at the Carpal Tunnel Based on Signs and Symptoms is Discordant From Diagnosis Based on Electrodiagnostic Studies and Ultrasound.

Variations of the obturator nerve and implications in obturator nerve entrapment treatment: an anatomical study.

Obturator nerve entrapment or idiopathic obturator neuralgia is an unfamiliar pathology for many physicians which can lead to diagnostic errancy. This study aims to identify the potential compression areas of the obturator nerve to improve therapeutic management. 18 anatomical dissections of lower limbs from 9 anatomical cadavers were performed. Endopelvic and exopelvic surgical approaches were utilized to study the anatomical variations of the nerve and to identify areas of entrapment. On 7 limbs, the posterior branch of the obturator nerve passed through the external obturator muscle. A fascia between the adductor brevis and longus muscles was present in 9 of the 18 limbs. The anterior branch of the obturator nerve was highly adherent to the fascia in 6 cases. In 3 limbs, the medial femoral circumflex artery was in close connection with the posterior branch of the nerve. Idiopathic obturator neuropathy remains a difficult diagnosis. Our cadaveric study did not allow us to formally identify one or more potential anatomical entrapment zones. However, it allowed the identification of zones at risk. A clinical study with staged analgesic blocks would be necessary to identify an anatomical area of compression and would allow targeted surgical neurolysis.

Diagnosis of Mild-to-moderate Idiopathic Median Neuropathy at the Carpal Tunnel Based on Signs and Symptoms is Discordant From Diagnosis Based on Electrodiagnostic Studies and Ultrasound.

Although idiopathic median neuropathy at the carpal tunnel (IMNCT) is objective and verifiable, distinction of normal and abnormal nerves is imprecise and probabilistic. The associated symptoms and signs (carpal tunnel syndrome [CTS]) vary, particularly for nonsevere (mild and moderate) median neuropathy. Discordance between diagnosis of mild or moderate median neuropathy at the carpal tunnel using symptoms and signs and diagnosis based on objective tests is a measure of the potential for overdiagnosis and overtreatment. What is the difference in the estimated prevalence of mild-to-moderate IMNCT using nonsevere signs and symptoms compared with the estimated prevalence using electrodiagnostic studies (EDS) and ultrasound (US)? We used data from an existing cross-sectional data registry. To create this registry, between January 2014 and January 2019, we considered all new adult English-speaking people who had an EDS that included the median nerve or people with a diagnosis of CTS who did not have surgery yet. A small and unrecorded number of people declined participation. The cross-sectional area of the median nerve at the distal wrist crease using US in people who already had EDS was measured. People with a diagnosis of CTS underwent both EDS and US. The six signs and symptoms of Carpal Tunnel Syndrome 6 (CTS-6, a validated tool to estimate the probability of IMNCT using ratings of symptoms and signs of CTS) were recorded. This resulted in a registry of 185 participants; we excluded 75 people for obvious, severe IMNCT (defined as nonrecordable nerve conduction velocity, thenar atrophy, or greater than 5 mm 2-point discrimination). Three of the 110 qualifying patients had missing information on ethnicity or race, but we accounted for this in our final analysis. Without a reference standard, as is the case with IMNCT, latent class analysis (LCA) can be used to establish the probability that an individual has specific pathophysiologic findings. LCA is a statistical method that identifies sets of characteristics that tend to group together. This technique has been used, for example, in diagnosing true scaphoid fractures among suspected fractures based on a combination of demographic, injury, examination, and radiologic variables. The prevalence of mild-to-moderate IMNCT was estimated in two LCAs using four signs and symptoms characteristic of mild-to-moderate IMNCT, as well as EDS and US measures of median neuropathy. The estimated prevalence of mild-to-moderate IMNCT based on signs and symptoms was 73% (95% CI 62% to 81%), while the estimated prevalence using EDS and US measurements was 51% (95% CI 37% to 65%). The notable discordance of 22% between the estimated prevalence of mild-to-moderate IMNCT using signs and symptoms and prevalence based on EDS and US criteria, and the overlapping CIs of the probability estimations, indicate considerable uncertainty and a corresponding notable potential for underdiagnosis or overdiagnosis. When signs and symptoms suggest mild-to-moderate median neuropathy and surgery is being considered, patients and clinicians might consider additional testing, such as EDS or US, to increase the probability of actual median neuropathy that can benefit from surgery. We might benefit from a more accurate and reliable diagnostic strategy or tool for mild-to-moderate IMNCT; this might be the focus of a future study. Level III, diagnostic study.

Correspondence of the Boston Carpal Tunnel Questionnaire with severity of median neuropathy.

The Boston Carpal Tunnel Questionnaire is one of the most popular patient-reported outcome measures designed specifically for people with idiopathic median neuropathy at the carpal tunnel. We used electrophysiological and ultrasound measures of median neuropathy from one hand in 185 people to create a single measure of median neuropathy severity as a continuum (through exploratory factor analysis). We assessed if our single measure of median neuropathy severity is independently associated with Boston Carpal Tunnel Questionnaire item groupings. Median neuropathy severity measured as a continuum had modest independent associations with Boston Carpal Tunnel Questionnaire magnitude of capability (adjusted R2 0.063) and paraesthesia intensity (adjusted R2 0.12) items but not with items related to pain intensity. Considering the lack of association of Boston Carpal Tunnel Questionnaire pain items with objective pathophysiology, combined with their notable association with mental health measures in previous studies, it is probably best to omit items related to pain.Level of evidence: III.

Surgical treatment of sural nerve entrapment aided by imaging- and electrography-based diagnosis: illustrative case.

The sural nerve (SN) is a cutaneous sensory nerve that innervates the posterolateral side of the distal third of the leg and lateral side of the foot. The SN has wide variation in its course and is fixed to the subcutaneous tissue and superficial fascia. Idiopathic spontaneous SN neuropathy is rarely surgically treated because of the difficulty in detecting SN entrapment. Herein, the authors present a rare case of surgically treated spontaneous SN neuropathy. A 67-year-old male patient presented with right foot pain for several years. Magnetic resonance imaging and ultrasonography showed SN entrapment slightly proximal and posterior to the lateral malleolus. A nerve conduction study showed SN disturbance. After undergoing neurolysis, the patient's foot pain was alleviated. Idiopathic SN neuropathy can be treated surgically when SN entrapment is detected with comprehensive evaluation methods.

ID: 216592 A Long Road to Treatment: Case Report of Spinal Cord Stimulator for Idiopathic Small Fiber Neuropathy

The prevalence of small fiber neuropathy (SFN) estimated to be 52.95 per 100,000 population(1). SFN is a disorder of thinly myelinated Aδ and unmyelinated C fibers. Conservative treatment with medications has been associated with significant side effects. Neuromodulation has been shown to be effective in treating diabetic peripheral neuropathies(2). However, there is little published data about the efficacy of these interventions in the relatively rare idiopathic SFN. We present a case report of spinal cord stimulator for failed conservative treatment of idiopathic small fiber neuropathy.