Hepatitis C virus (HCV) coinfection may further compromise immunological and cognitive function in people with HIV (PWH). This study compared laboratory and neuropsychiatric measures across the periods of HCV seroconversion and direct-acting antiviral (DAA) therapy with sustained virologic response (SVR) among PWH who initiated antiretroviral therapy (ART) during acute HIV infection (AHI) and acquired HCV after 24 weeks of ART.

Participants from the RV254 AHI cohort underwent paired laboratory and neuropsychiatric assessments during follow-up visits. The former included measurements of CD4 + and CD8 + T-cell counts, HIV RNA, liver enzymes, and lipid profiles. The latter included the Patient Health Questionnaire-9 (PHQ-9), Distress Thermometer (DT), and a 4-test cognitive battery that evaluated psychomotor speed, executive function, fine motor speed, and dexterity. The raw scores in the battery were standardized and averaged to create an aggregate performance (NPZ-4) score. Parameters of HCV-coinfected participants were compared across the periods of HCV seroconversion and DAA treatment.

Between 2009 and 2022, 79 of 703 RV254 participants acquired HCV after ≥ 24 weeks of ART; 53 received DAA, and 50 (94%) achieved SVR. All participants were Thai males (median age: 30 years); 34 (68%) denied past intravenous drug use, and 41 (82%) had a history of other sexually transmitted infections during follow-up. Following SVR, aspartate transferase (AST) and alanine transaminase (ALT) decreased (p < 0.001), while total cholesterol, low-density lipoprotein, and triglycerides increased (p < 0.01). The median CD4 + /CD8 + ratio increased from 0.91 to 0.97 (p = 0.012). NPZ-4 improved from 0.75 to 0.91 (p = 0.004). The median DT score increased from 1.7 to 2.7 (p = 0.045), but the PHQ-9 score remained unchanged.

HCV coinfection is common in this group of high-risk PWH, highlighting the need for regular screening, early diagnosis, and treatment. The study participants exhibited a modest improvement in the CD4 + /CD8 + T-cell ratio and cognitive performance following DAA therapy and SVR. Future studies should examine potential neuropsychiatric impacts during early HCV infection as well as the longer-term neuropsychiatric outcomes after DAA treatment with SVR.

Vasculitic neuropathies are a diverse group of inflammatory polyneuropathies that result from systemic vasculitis (e.g., polyarteritis nodosa, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis), vasculitis resulting from rheumatological disorders (e.g., rheumatoid arthritis and Sjögren's syndrome), paraneoplastic conditions, viruses, and medications. Occasionally, vasculitis is restricted to the peripheral nerves and termed nonsystemic vasculitic neuropathy. Presenting with an acute or subacute onset of painful sensory and motor deficits, ischemia to individual peripheral nerves results in the classic "mononeuritis multiplex" pattern. Over time, overlapping mononeuropathies will result in a symmetrical or asymmetrical sensorimotor axonal polyneuropathy. The diagnosis of vasculitic neuropathies relies on extensive laboratory testing, electrodiagnostic testing, and nerve and/or other tissue biopsy. Treatment consists primarily of immunosuppressant medications such as corticosteroids, cyclophosphamide, rituximab, methotrexate, or azathioprine, in addition to neuropathic pain treatments. Frequently, other specialists such as rheumatologists, pulmonologists, and nephrologists will comanage these complex patients with systemic vasculitis. Prompt recognition of these conditions is imperative, as delays in treatment may result in permanent deficits and even death.

This review explores diverse infectious etiologies of peripheral nervous system (PNS) dysfunction, spanning sensory and motor neurons, nerves, and associated structures. Progress in viral and bacterial infections reveals multifaceted mechanisms underlying neuropathies, including viral neurotoxicity and immune-mediated responses. Latest diagnostic advances facilitate early PNS complication detection, with ongoing research offering promising treatment avenues. Emerging pathogens like severe acute respiratory syndrome coronavirus 2, Zika virus, and EV-D68 highlight the evolving infectious neuropathy paradigm. Recognizing characteristic patterns and integrating clinical factors are pivotal for precise diagnosis and tailored intervention. Challenges persist in assessment and management due to varied pathogenic mechanisms. Advancements in understanding pathogenesis have improved targeted therapies, yet gaps remain in effective treatments. Ongoing research is crucial for optimizing approaches and improving patient outcomes.

Hepatitis C virus (HCV) coinfection may further compromise immunological and cognitive function in people with HIV (PWH). This study compared laboratory and neuropsychiatric measures across the periods of HCV seroconversion and direct-acting antiviral (DAA) therapy with sustained virologic response (SVR) among PWH who initiated antiretroviral therapy (ART) during acute HIV infection (AHI) and acquired HCV after 24 weeks of ART.

Participants from the RV254 AHI cohort underwent paired laboratory and neuropsychiatric assessments during regular follow-up. The former included measurements of CD4 + and CD8 + T-cell counts, HIV RNA, liver enzymes, and lipid profiles. The latter included the Patient Health Questionnaire-9 (PHQ-9), Distress Thermometer (DT), and a 4-test cognitive battery that evaluated psychomotor speed, executive function, fine motor speed and dexterity. The raw scores in the battery were standardized and averaged to create an overall performance (NPZ-4) score. Parameters of HCV-coinfected participants were compared across HCV seroconversion and DAA treatment groups.

Between 2009 and 2022, 79 of 703 RV254 participants acquired HCV after ≥ 24 weeks of ART; 53 received DAA, and 50 (94%) achieved SVR. All participants were Thai males (median age: 30 years); 34 (68%) denied past intravenous drug use, and 41 (82%) had a history of other sexually transmitted infections during follow-up. Following SVR, aspartate transferase (AST) and alanine transaminase (ALT) decreased (p < 0.001), while total cholesterol, low-density lipoprotein, and triglycerides increased (p < 0.01). The median CD4+/CD8 + ratio increased from 0.91 to 0.97 (p = 0.012). NPZ-4 improved from 0.75 to 0.91 (p = 0.004). The median DT score increased from 1.7 to 2.7 (p = 0.045), but the PHQ-9 score remained unchanged.

HCV coinfection is common in this group of high-risk PWH, highlighting the need for regular screening, early diagnosis, and treatment. There was a modest improvement in the CD4+/CD8 + T-cell ratio and cognitive performance after DAA therapy in patients who achieved SVR. Future studies should examine potential neuropsychiatric impacts during early HCV infection as well as the longer-term neuropsychiatric outcomes after DAA treatment with SVR.

Chronic hepatitis C virus (HCV) infection is characterized by a variety of extra-hepatic manifestations; peripheral neuropathy (PN) is one of the most common, especially when mixed cryoglobulinemia (MCG) is present. The prevalence and risk factors of HCV-related PN in the absence of MCG are largely unknown. We conducted a prospective, single-center study, examining the prevalence and reversibility of HCV-associated neuropathy in the absence of MCG. Nerve fiber density in the epidermis was evaluated through skin biopsy and electroneurography (ENG) before HCV-treatment initiation and 1 year post sustained virological remission (SVR). Forty HCV-infected individuals (nine HIV co-infected) with no other neuron-harming factors were included; four other HCV mono- and three HIV co-infected individuals were excluded due to presence of diabetes, B12 insufficiency, or neurotoxic drugs. Twelve consecutive controls with no neuron-harming conditions were also recruited; eight more were excluded due to meeting exclusion criteria. Four patients had ENG signs of polyneuropathy (two with HCV mono- and two with HIV co-infection), while seven more (five with HCV mono- and two with HIV co-infection) had signs of mono-neuropathy, leading to PN prevalences of 22.5% and 44% for mono- and co-infection, respectively (p value 0.179). The two patients with HCV mono-infection and polyneuropathy and the one with ulnar nerve damage showed ENG improvement 1 year post SVR. Regarding intraepidermal nerve density, HCV infection, irrespective of HIV co-infection, was correlated with a lower intraepidermal neuron density that improved 1 year post SVR (p value 0.0002 for HCV and 0.0326 for HCV/HIV co-infected patients). PN is common in HCV infection; successful eradication of HCV leads to PN improvement.

This article discusses the clinical manifestations and management of infectious peripheral neuropathies.

Several infectious etiologies of peripheral neuropathy are well-recognized and their treatments are firmly established. The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with several central and peripheral nervous system manifestations, including peripheral neuropathies. Additionally, some COVID-19 vaccines have been associated with Guillain-Barré syndrome. These disorders are an active area of surveillance and research. Recent evidence-based guidelines have provided updated recommendations for the diagnosis and treatment of Lyme disease.

Infectious agents of many types (primarily bacteria and viruses) can affect the peripheral nerves, resulting in various clinical syndromes such as mononeuropathy or mononeuropathy multiplex, distal symmetric polyneuropathy, radiculopathy, inflammatory demyelinating polyradiculoneuropathy, and motor neuronopathy. Knowledge of these infections and the spectrum of peripheral nervous system disorders associated with them is essential because many have curative treatments. Furthermore, understanding the neuropathic presentations of these disorders may assist in diagnosing the underlying infection.

This exploratory analysis investigates the prevalence and risk factors of neurocognitive toxicity in postpartum women on HIV treatment in response to a concern of an Isoniazid Preventive Therapy (IPT)/Efavirenz interaction.

Pregnant women on HIV treatment from countries with high TB prevalence were randomized in IMPAACT P1078 to 28 weeks of IPT started either during pregnancy or at 12 weeks postpartum. Partway through study implementation, the Patient Health Questionnaire 9, the cognitive complaint questionnaire, and the Pittsburg Sleep Quality Index were added to evaluate depression, cognitive function, and sleep quality at postpartum weeks. Screening for peripheral neuropathy was conducted throughout the study.

We summarized percentages of women with depression symptoms, cognitive dysfunction, poor sleep quality and peripheral neuropathy and assessed the association of 11 baseline risk factors of neurotoxicity using logistic regression, adjusted for gestational age stratum.

Of 956 women enrolled, 749 (78%) had at least one neurocognitive evaluation. During the postpartum period, the percentage of women reporting at least mild depression symptoms, cognitive complaint and poor sleep quality peaked at 13%, 8% and 10%, respectively, at 12 weeks, and the percentage of women reporting peripheral neuropathy peaked at 13% at 24 weeks. There was no evidence of study arm differences in odds of all four neurotoxic symptoms.

Timing of IPT initiation and EFV use were not associated with symptoms of neurotoxicity. Further study is advised to formally assess risk factors of neurotoxicity.

Peripheral neuropathy is not an uncommon manifestation in patients with chronic hepatitis. The role of cryoglobulin (CG) in neuropathy in patients with chronic hepatitis remains controversial. There is limited information about the autonomic neuropathy in chronic hepatitis. This study aimed to evaluate autonomic function in treatment-naive patients with chronic hepatitis B or hepatitis C infection and to elucidate the association between autonomic neuropathy and CG in these patients.

A total of 29 treatment-naive patients with chronic, yet mild degrees of hepatitis B or C infection were evaluated for autonomic function, including those in the sympathetic sudomotor, cardiovagal, and adrenergic domains, to compare with the control subjects. The autonomic impairment was graded using the Composite Autonomic Scoring Scale. Then, association analyses between autonomic parameters/scores and CG were performed.

Patients with chronic hepatitis B or C infection had significantly worse autonomic function than control subjects, especially in the sudomotor and cardiovagal domains. The autonomic manifestations in cases with and without CG were similar. There was no significant difference in autonomic dysfunction between patients with hepatitis B and C infections.

The study demonstrated that autonomic neuropathy was not uncommon in patients with chronic hepatitis B or C infection. There was no association between autonomic neuropathy and CG.

Hepatitis C Virus (HCV), despite being a hepatotropic virus, is the causative agent of many systemic disorders, such as vasculitis, autoimmune diseases, lymphoproliferative disorders, and a broad spectrum of neurological and psychiatric manifestations. Although symptoms have been misdiagnosed or underdiagnosed, only recently, evidence of direct (inflammatory) or indirect (immune-mediated) HCV-dependent cerebral effects has been established. HCV infection can promote acute inflammatory response, pro-coagulative status and ischemic disorders, and neurodegeneration. These effects rely on cerebral HCV replication, possibly mediated by blood-brain barrier alterations. Further study is needed to better understand the HCV-related mechanisms of brain damage.

HCV-related extra-hepatic complications include peripheral neuropathies, with important prevalence and impact. A recent metanalysis of previous intervention trials concluded for insufficient data to support evidence-based treatments for this complication. In this longitudinal study, we assessed for the first time prevalence and outcome of neuropathy in a cohort of patients with chronic HCV, before and after direct-acting antiviral agent (DAA) treatment.

Ninety-four patients (mean age 58.5 ± 9.9, infection duration 22.2 ± 6.3 years) without systemic and metabolic diseases, underwent neurological examination and electroneurography studies before (T0) and 10.4 ± 1.7 months after the end of DAA therapy (T1), and cryoglobulins (CG) assessment. Muscle strength was evaluated by Medical Research Council (MRC) score; neuropathic pain, sensory function, disability, quality of life were assessed by validated questionnaires (DN4, NPSI, SSS, INCAT and Euro-QoL).

At T0, sensory-motor neuropathy was detected in 22 patients (23%), reflexes were depressed in 32 (34%) with no association with infection duration, viral load, age, CG. Neuropathic pain (DN4 ≥4) was present in 37 patients (39%). At T1, out of the 22 patients with altered electroneurography, 3 had died or developed HCC, 4 showed normal electroneurography, and nerve amplitude parameters tended to improve in the whole group. Only 11 patients (12%) had depressed reflexes and 10 (11%) DN4 ≥4 (P < .05 compared to T0). Scores for MRC, questionnaires and Euro-QoL improved significantly (P < .05).

Our study confirms the high prevalence of clinical and subclinical peripheral sensory-motor neuropathy in patients with HCV infection and indicates improvement after eradication by DAA. These results support the need for larger intervention studies.

Axonal loss denervates muscle, leading to an increase of fat accumulation in the muscle. Therefore, fat fraction (FF) in whole limb muscle using MRI has emerged as a monitoring biomarker for axonal loss in patients with peripheral neuropathies. In this study, we are testing whether deep learning-based model can automate quantification of the FF in individual muscles. While individual muscle is smaller with irregular shape, manually segmented muscle MRI images have been accumulated in this lab; and make the deep learning feasible.

To automate segmentation on muscle MRI images through deep learning for quantifying individual muscle FF in patients with peripheral neuropathies.

Retrospective.

24 patients and 19 healthy controls.

3T; Interleaved 3D GRE.

A 3D U-Net model was implemented in segmenting muscle MRI images. This was enabled by leveraging a large set of manually segmented muscle MRI images. B1+ and B1- maps were used to correct image inhomogeneity. Accuracy of the automation was evaluated using Pixel Accuracy (PA), Dice Coefficient (DC) in binary masks; and Bland-Altman and Pearson correlation by comparing FF values between manual and automated methods.

PA and DC were reported with their median value and standard deviation. Two methods were compared using the ± 95% confidence intervals (CI) of Bland-Altman analysis and the Pearson's coefficient (r2 ).

DC values were from 0.83 ± 0.17 to 0.98 ± 0.02 in thigh and from 0.63 ± 0.18 to 0.96 ± 0.02 in calf muscles. For FF values, the overall ± 95% CI and r2 were [0.49, -0.56] and 0.989 in thigh and [0.84, -0.71] and 0.971 in the calf.

Automated results well agreed with the manual results in quantifying FF for individual muscles. This method mitigates the formidable time consumption and intense labor in manual segmentations; and enables the use of individual muscle FF as outcome measures in upcoming longitudinal studies.

3 TECHNICAL EFFICACY STAGE: 1.

Hepatitis C virus (HCV) infection can affect the neurological system, and neuropathy is one of these manifestations. Hepatitis C virus infection is associated with diabetes mellitus (DM) type II, and diabetic patients are at higher risk of acquiring HCV infection. Sweat function has been proposed to assess early autonomic neuropathy. This study aimed to evaluate small fiber neuropathy in asymptomatic HCV-related cirrhotic patients with or without DM through sweat function assessment by Sudoscan test. Three groups were involved: 47 healthy controls, 48 HCV-related cirrhotic patients without DM (group 1), and 49 HCV-related cirrhotic patients with DM type II (group 2). All participants were subjected to liver panel tests, renal function tests, cell blood counts, HbA1c, and abdominal ultrasound. Sweat function was assessed in all patients and controls by measuring hand and feet electrochemical skin conductance (ESC, microSiemens [µS]) using Sudoscan. Peripheral neuropathy was detected in none of the controls, 39% of group 1 patients, and 62% of group 2 patients (P < 0.0001). The mean feet ESC (FESC) was 88.3 ± 6.8 µS in controls, 67.2 ± 19.2 µS in group 1, and 57.9 ± 19.4 µS in group 2 (P < 0.0001). A significant correlation was observed between FESC and bilirubin, albumin, creatinine, international normalized ratio, transaminases, and splenic size. Electrochemical skin conductance measurement is a valuable, noninvasive method for early detection of small fiber neuropathy in asymptomatic HCV-related cirrhosis, with or without DM.

To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sjögren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV.

From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma.

1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7-20.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7-14.4) and less frequently C4 hypocomplementemia and peripheral neuropathy.

pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS.

Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients. Conventional therapeutics for DNP are quite challenging due to their serious adverse effects. Hence, there is a need to investigate novel effective and safe options. The novelty of the present study was to provide available therapeutic approaches, emerging molecular mechanisms, signaling pathways and future directions of DNP as well as polyphenols' effect, which accordingly, give new insights for paving the way for novel treatments in DNP.

A comprehensive review was done in electronic databases including Medline, PubMed, Web of Science, Scopus, national database (Irandoc and SID), and related articles regarding metabolic pathways on the pathogenesis of DNP as well as the polyphenols' effect. The keywords "diabetic neuropathy" and "diabetes mellitus" in the title/abstract and "polyphenol" in the whole text were used. Data were collected from inception until May 2019.

DNP complications is mostly related to a poor glycemic control and metabolic imbalances mainly inflammation and oxidative stress. Several signaling and molecular pathways play key roles in the pathogenesis and progression of DNP. Among natural entities, polyphenols are suggested as multi-target alternatives affecting most of these pathogenesis mechanisms in DNP.

The findings revealed novel pathogenicity signaling pathways of DNP and affirmed the auspicious role of polyphenols to tackle these destructive pathways in order to prevent, manage, and treat various diseases. Graphical Abstract .

Equine recurrent laryngeal neuropathy (RLN) is a naturally occurring model of length-dependent axonopathy characterized by asymmetrical degeneration of recurrent laryngeal nerve axons (RLn). Distal RLn degeneration is marked, but it is unclear whether degeneration extends to include cell bodies (consistent with a neuronopathy).

With examiners blinded to RLN severity, brainstem location, and side, we examined correlations between RLN severity (assessed using left distal RLn myelinated axon count) and histopathological features (including chromatolysis and glial responses) in the nucleus ambiguus cell bodies, and myelinated axon count of the right distal RLn of 16 horses.

RLN severity was not associated with RLn cell body number (P > .05), or degeneration. A positive correlation between the left and right distal RLn myelinated axon counts was identified (R² = 0.57, P < .05).

We confirm that RLN, a length-dependent distal axonopathy, occurs in the absence of detectable neuronopathy.

Axonal neuropathies encompass a wide range of acquired and inherited disorders with electrophysiologic characteristics that arise from the unique neurophysiology of the axon. Accurate interpretation of nerve conduction studies and electromyography requires an in-depth understanding of the pathophysiology of the axon. Here we review the unique neurophysiologic properties of the axon and how they relate to clinical electrodiagnostic features. We review the length-dependent Wallerian or "dying-back" processes as well as the emerging body of literature from acquired axonal neuropathies that highlights the importance of axonal disease at the nodes of Ranvier. Neurophysiologic features of individual inherited and acquired axonal diseases, including primary nerve disease as well as systemic immune mediated, metabolic, and toxic diseases involving the peripheral nerve, are reviewed. This comprehensive review of electrodiagnostic findings coupled with the current understanding of pathophysiology will aid the clinician in the evaluation of axonal polyneuropathies.

Chronic hepatitis C virus (HCV) infection has been associated with myriad extrahepatic manifestations, often resulting from aberrant immune responses. Among the most common immune-mediated manifestations of HCV infection, mixed cryoglobulinemia is the best known extra-hepatic complication. Areas covered: Here we review less common extrahepatic manifestations of HCV infection, with ascertained or presumed immune pathogenesis and the role of the new all oral direct-acting antiviral agents. Rheumatologic, dermatologic, ophthalmologic, renal, pulmonary, hematologic, cardiovascular, and neuropsychiatric manifestations of HCV infection have been considered. Expert commentary: Pathogenesis of HCV-induced aberrant immune responses resulting in peculiar clinical manifestations is not restricted to a single mechanism. A sound approach would therefore consider implementation of an etiologic treatment, through use of antiviral medications, to stop upstream in the pathogenic process all the immune mechanisms leading to hepatic and extrahepatic abnormalities. With the recent introduction of interferon-free, direct antiviral agents, capable of warranting cure for nearly all HCV-infected patients subjected to therapy, both common and uncommon extrahepatic manifestations of chronic hepatitis C are expected to no longer constitute a matter of comorbidity in the course of HCV infection.

Immunomodulating drugs are widely used in autoimmune, transplant, and cancer patients. However, these drugs are associated with various autoimmune neuromuscular diseases such as demyelinating polyneuropathy, myasthenia gravis, and myositis. Early recognition of these complications and immediately terminating these drugs are very essential since some are life-threatening conditions. This review provides a general overview of drug-induced autoimmunity and autoimmune neuromuscular diseases associated with tumor necrosis factor alpha (TNF-α) antagonists, immune checkpoint inhibitors, and interferon (IFN) type 1 (IFN-β and IFN-α).

Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as cryoglobulinemia and accounts for up to 90% of all cases of mixed cryoglobulinemia (MC). The present study aimed to evaluate the effect of sofosbuvir-daclatasvir therapy on symptomatic HCV-related MC and sustained virologic response (SVR) achievement.

This prospective cohort study was carried out on 120 patients with chronic HCV infection, clinically suspected to have MC, but only 63 of whom were positive for cryoglobulins. HCV-MC patients were treated with sofosbuvir 400 mg and daclatasvir 60 mg once daily for 3 months. The serum cryoglobulins levels, complement 3 (C3), complement 4 (C4) (using ELISA assay kits) and rheumatoid factor (RF) (using immunoturbidimetric assay kit), were measured in the included HCV infected patients (to confirm HCV-MC diagnosis), in addition to quantitave HCV-RNA assays, using real time PCR. All these measurements have been done before stating therapy and 12, 24 weeks post-therapy for assessments of immunological recovery, viral load and SVR.

Significant increase in the serum cryoglobulin levels and RF with significant decrease in C3 and C4 serum levels were detected in only 63 out of 120 included HCV infected patients, upon whom the study has been completed. They showed significant decrease in their mean cryoglobulin levels from 41.47 µg/mL ±12.32 SD to 5.12 µg/mL ±3.59 SD then to 5.09 µg/mL ±3.02 SD, 12 to 24 weeks post-therapy respectively (p<0.001), with significant decline in RF concentrations and rise in C3 and C4 serum levels approaching the normal values. There were improvements in the presenting HCV-MC clinical manifestations in variable degrees, ranging from 5 (71.42%) in patients with glomerulonephritis to 62 (98.4%) in patients with purpura. Eighty-seven percent of the included patients showed complete response (clinical, virological and immunological recovery) and 13% showed partial response (virological and immunological recovery without clinical improvement of cryoglobulinemia associated manifestations).

A combined therapy of sofosbuvir 400 mg and daclatasvir 60 mg once daily for 3 months was associated with a significant decrease in serum cryoglobulin levels and appears as a reasonable treatment option for HCV-associated MC.

Hepatitis C virus (HCV) infection deregulates function of many organs and systems, affecting patient's daily functioning. The results of treatment of HCV infection recurrence after liver transplantation have improved significantly as a result of the introduction of direct-acting antiviral agents (DAA). This study was aimed at prospective assessment of the effect of HCV elimination with DAA on physical performance of liver transplant recipients.

Eight women and 21 men, median age 61.3 (range, 20.1-71.5) years, participated in the study. Assessment of serum total bilirubin, alanine and aspartate aminotransferase, muscle strength, body composition, and 6-minute walk test (6MWT) were performed before treatment and 12 weeks after the end of the treatment period.

In the 6MWT test we observed significant subjective (dyspnea: 58.3% pretreatment vs 27.6% posttreatment, P = .018; fatigue: 96.6% pretreatment vs 51.7% posttreatment, P = .0001) and objective improvement (distance: 415.4 meters pretreatment vs 505.2 meters posttreatment, P < .0000001). We did not observe an increase in muscle mass nor improvement in blood biochemical parameters.

A significant objective and subjective improvement in physical performance was seen in liver transplant recipients after successful treatment of HCV infection with DAA.

Charcot-Marie-Tooth (CMT) disease is a complex of peripheral nervous system disorders. CMT type 2U (CMT2U) is an autosomal dominant (AD) disease caused by mutations in the MARS gene encoding methionyl-tRNA synthetase; this disease has thus been newly called AD-CMTax-MARS. A few families with mutations in the MARS gene have been reported, without detailed histopathological findings. We describe a 70-year-old woman who had bilateral dysesthesia of the soles since the age of 66 years. Sural nerve biopsy showed a decrease in the density of large myelinated nerve fibers. Increased clusters of regenerating myelinated nerve fibers were noted. Electron microscopic analyses revealed degeneration of unmyelinated nerves. There was no vasculitis or inflammatory cell infiltration. Genetic analysis identified a heterozygous p.P800T mutation, a reported mutation in the MARS gene. We report the detailed histopathological findings in a patient with CMT2U/AD-CMTax-MARS. The findings are similar to those found in CMT2D caused by mutations in the GARS gene, encoding glycyl-tRNA synthetase.

Peripheral neuropathy is one most common, limiting and invalidating neurological symptom in subjects with hepatitis C virus and mixed cryoglobulinemia. Notably, the medical therapy proposed to eradicate HCV, can frequently exacerbate the painful neuropathy. Therefore, neuropathy therapies are insufficient and inadequate, and comprise immunosuppressive drugs, such as steroid or cyclosporine, intravenous immunoglobulin or plasma exchange. These have shown variable success in case reports, with a presumably temporary effect, but with major side effects.

We assessed the effects of oxcarbazepine treatment in 67 cases of cryoglobulinemia related neuropathy, who did not respond to either steroid or Gabapentin, or Pregabalin. Oxcarbazepine was chosen based on the promising preliminary results.

Patients treated with Oxcarbazepine showed a rapid, discrete and persistent relief of polyneuropathic signs, without consistent side effects, and with a limited interaction with concomitant drugs.

These data favor the use of oxcarbazepine as a useful tool in the management of neuropathic pain associated with Hepatitis-C cryoglobulin neuropathy.

The hepatitis C virus (HCV) is recognized as one of the hepatic viruses most often associated with extrahepatic manifestations (EHMs). It is currently accepted that cryoglobulinemic vasculitis (CV) is the key autoimmune extrahepatic disease associated with HCV infection. Therapeutic approaches have mainly been based on the use of old antiviral interferon (IFN)-based regimens and immunosuppressive therapies, often with an inadequate balance between therapeutic benefits and excess side effects. Areas covered: Therapeutic management of HCV patients with EHMs, including both non-autoimmune (cardiovascular, hematological, general features) and autoimmune complications (organ-specific and systemic autoimmune diseases). Therapies included antiviral (IFN, ribavirin, direct-acting antivirals - DAAs-) and non-antiviral (immunosuppressive agents, rituximab, plasma exchanges) options. The review analyses the current evidence for proposing a treat-to-target (T2T) approach for HCV-related autoimmune EHMs based on an organ-by-organ strategy. Expert commentary: Eradication of HCV must be considered the key T2T in the therapeutic approach to HCV-related EHMs, as there has been a disruptive change due to the appearance of direct-acting antivirals (DAAs) as game-changers in HCV therapy, with an efficacy reaching nearly 100%. In this scenario, the central role played until now by IFN and ribavirin is not currently supported and they will not be used in the future.

A 56-year-old man with behavioural disorders and facial-brachio-crural right hemiparesis presented with a brain lesion studied with computed tomography, magnetic resonance imaging and brain biopsy, leading to the diagnosis of cerebral vasculitis. Hepatitis C virus (HCV) infection in a phase of activity, without cryoglobulins, was also detected. Brain biopsy, laboratory analysis and response to a specific therapy supported the diagnosis of central nervous system vasculitis that was HCV related.

Peripheral neuropathy (PN), the major neurological complication of chronic HCV infection, is frequently associated with mixed cryoglobulinaemia (MC) and small-vessel systemic vasculitis. While humoral and cell-mediated immune mechanisms are suspected to act together in an aberrant immune response that results in peripheral nerve damage, the role of HCV remains largely speculative. The possible demonstration of HCV in peripheral nerve tissue would obviously assume important pathogenic implications.

We studied sural nerve biopsies from 11 HCV-positive patients with neuropathic symptoms: five with and six without MC. In situ hybridization (ISH) and immunofluorescence studies were carried out to detect genomic and antigenomic HCV RNA sequences and HCV-encoded E2-glycoprotein, respectively.

Epineurial vascular deposits of E2-glycoprotein were found in four (80%) MC and in two (33.3%) non-MC patients, respectively. These findings were enhanced by the perivascular deposition of positive-, though not negative-strand replicative RNA, as also found in the nerve extracts of all patients. Mild inflammatory cell infiltrates with no deposits of immunoglobulins and/or complement proteins were revealed around small vessels, without distinct vasculitis changes between MC and non-MC patients.

These results indicate that nerve vascular HCV RNA/E2 deposits associated to perivascular inflammatory infiltrates were similar in chronically HCV-infected patients, regardless of cryoglobulin occurrence. Given the failure to demonstrate HCV productive infection in the examined sural nerve biopsies, nerve damage is likely to result from virus-triggered immune-mediated mechanisms.

Mononeuritis multiplex due to hepatitis C infection and cryoglobulinemia has no specific treatment guidelines. Despite the favorable evolution of the liver disease after treatment with interferon and ribavirin, neurological symptoms might not respond very efficiently to antiviral therapy.

We report the case of a 50-year-old woman, with a mononeuritis multiplex related to cryoglobulinemia and hepatitis C virus infection, who was treated with rituximab. Hepatitis C virus infection was treated successfully with interferon-α and ribavirin, but the neurological symptoms were still worsening until rituximab therapy. Significant improvement of paraparesis and painful hypoesthesia were evident after the fourth infusion of rituximab. However, every 6 months, the neurological symptoms relapsed and the patient was subjected to a new cycle of rituximab therapy, with the disappearing of the paraparesis and hypoesthesias.

This case highlights the potential use of rituximab in immune-mediated neuropathies, especially the mononeuritis multiplex associated with hepatitis C infection.

Chronic hepatitis C virus (HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.

A 61-year-old man with bilateral purpura of the lower limbs and subsequent edema, was hospitalization after renal dysfunction developed. The presence of hepatitis C virus (HCV) RNA and cryoglobulin and the finding of membranoproliferative glomerulonephritis on renal biopsy led to a diagnosis of HCV-related glomerulonephritis due to cryoglobulinemia. Because of the pre-existence of nephrotic syndrome and the continuously increasing serum level of creatinine, treatment with cryofiltration, interferon, and steroids was started. After 5 cryofiltration sessions, the cryocrit level had decreased to 1% and the levels of serum creatinine and proteinuria had also decreased. However, 3 weeks after the start of treatment, nephrotic syndrome developed again and was accompanied by lower-extremity mononeuropathy and renal dysfunction. Thereafter, the patient showed disorientation, an affective disorder, and delirium, and his condition gradually deteriorated. Radiological examination of the head and examination of the cerebrospinal fluid showed no abnormalities. Despite the withdrawal of the interferon therapy and the reduction of the steroid dose, the patient's conditions remained unchanged, and the level of consciousness deteriorated. Although cryofiltration had beneficial effects and plasma exchange was continuously performed, the patient died on the 74th hospital day. Because of the significant changes due to ventilatory support and hemorrhage associated with disseminated intravascular coagulation, the autopsy findings did not allow us to definitively determine whether the symptoms had been caused by the HCV-related membranoproliferative glomerulonephritis or the interferon therapy or both. We have reported this case to provide insight into whether interferon therapy should be administered for HCV-related membranoproliferative glomerulonephritis with marked neurological symptoms due to cryoglobulinemia.

To investigate the existence of peripheral and optic neuropathies in asymptomatic individuals with hepatitis C infection.

Thirty consecutive patients who were followed in a hepatitis C outpatient clinic were recruited for electrophysiological evaluation together with 30 age- and gender-compatible healthy controls. All patients had a detailed neurological examination. The information regarding the disease duration and management with interferons were collected. Nerve conduction studies and visual evoked potentials (VEP) were recorded in all subjects. The results of the patient and control groups were statistically compared.

Of the patients with hepatitis C infection, 16 were females and 14 males. The mean age was 57.5 years, and the average disease duration was 6.43 years. The P100 latencies in the patient group were within normal limits, while the amplitudes were meaningfully small by comparison with the controls. There were some abnormalities in the nerve conduction studies of 15 patients. Sensorial neuropathy was detected in two patients, sensorimotor polyneuropathy in four, carpal tunnel syndrome in seven, and carpal tunnel syndrome and sensorimotor polyneuropathy as comorbid states in another two patients. The nerve conduction studies and VEP parameters were entirely normal in the control group.

Hepatitis C-related neurological abnormalities may occur both in the central and peripheral nervous system. Mononeuritis multiplex, sensorial axonal neuropathy, and multiple mononeuropathies are some of the presentations of the peripheral nervous system involvement. The mode of infection is considered to be via vasculitic mechanisms. In addition, optic neuropathy is a known complication of interferon treatment. Autoantibodies, cytokines, chemokines, and cryoglobulins are accused to play roles in the pathogenesis. In this study, we investigated the involvement of the peripheral nervous system and optic nerves in a group of patients with hepatitis C. The results were in favor of peripheral nerve injury of various types and optic neuropathy of the axonal type.

Hepatitis E is hyperendemic in many developing countries in Asia and Africa, and is caused by hepatitis E virus (HEV) genotypes 1 and 2, which are spread via the faecal-oral route by contaminated water. Recent data show that HEV infection is also endemic in developed countries. In such geographical settings, hepatitis E is caused by HEV genotypes 3 and 4, and is mainly a porcine zoonosis. In a minority of cases, HEV causes acute and chronic hepatitis, but infection is commonly asymptomatic or unrecognized. HEV infection is associated with a number of extrahepatic manifestations, including a range of neurological injuries. To date, 91 cases of HEV-associated neurological injury--most commonly, Guillain-Barré syndrome, neuralgic amyotrophy, and encephalitis/myelitis--have been reported. Here, we review the reported cases, discuss possible pathogenic mechanisms, and present our perspectives on future directions and research questions.

Infections are important, potentially treatable causes of peripheral nervous system disease. This article reviews the clinical presentation and management of several common peripheral nervous system diseases due to viral, bacterial, spirochetal, and parasitic infections.

The clinical presentation and evaluation of infectious peripheral nervous system diseases are well established. Advances in the treatment and, in some cases, the prevention of these diseases are still evolving.

A diverse range of peripheral nervous system diseases, including peripheral neuropathy, radiculopathy, radiculomyelopathy, cranial neuropathy, and motor neuropathy, are caused by numerous infectious agents. In some patients, peripheral neuropathy may be a side effect of anti-infectious drugs. Infectious neuropathies are important to recognize as they are potentially treatable. This article discusses the clinical presentation, evaluation, and treatment of several common peripheral nervous system diseases caused by viral, bacterial, spirochetal, and parasitic infections, as well as some peripheral nerve disorders caused by adverse effects of the treatments of these infectious diseases.

Peripheral neuropathy is a common complication of a variety of diseases and treatments, including diabetes, cancer chemotherapy, and infectious causes (HIV, hepatitis C, and Campylobacter jejuni). Despite the fundamental difference between these insults, peripheral neuropathy develops as a combination of just six primary mechanisms: altered metabolism, covalent modification, altered organelle function and reactive oxygen species formation, altered intracellular and inflammatory signaling, slowed axonal transport, and altered ion channel dynamics and expression. All of these pathways converge to lead to axon dysfunction and symptoms of neuropathy. The detailed mechanisms of axon degeneration itself have begun to be elucidated with studies of animal models with altered degeneration kinetics, including the slowed Wallerian degeneration (Wld(S)) and Sarm knockout animal models. These studies have shown axonal degeneration to occur through a programmed pathway of injury signaling and cytoskeletal degradation. Insights into the common disease insults that converge on the axonal degeneration pathway promise to facilitate the development of therapeutics that may be effective against other mechanisms of neurodegeneration.

Peripheral neuropathy is the most common neurologic complication of hepatitis C virus (HCV) infection. The pathophysiology of the neuropathy associated with HCV is not definitively known; however, proposed mechanisms include cryoglobulin deposition in the vasa nervorum and HCV-mediated vasculitis. The optimal treatment for HCV-related peripheral neuropathy has not been established.

To assess the effects of interventions (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) for cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection.

On 26 August 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We also searched two trials registers, the Networked Digital Library of Theses and Dissertations (NDLTD) (October 2014), and three other databases. We checked references in identified trials and requested information from trial authors to identify any additional published or unpublished data.

We included all randomized controlled trials (RCTs) and quasi-RCTs involving participants with cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection. We considered any intervention (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) alone or in combination versus placebo or another intervention ('head-to-head' comparison study design) evaluated after a minimum interval to follow-up of at least six months.

We used standard methodological procedures expected by The Cochrane Collaboration. The planned primary outcome was change in sensory impairment (using any validated sensory neuropathy scale or quantitative sensory testing) at the end of the follow-up period.  Other planned outcomes were: change in impairment (any validated combined sensory and motor neuropathy scale), change in disability (any validated disability scale), electrodiagnostic measures, number of participants with improved symptoms of neuropathy (global impression of change), and severe adverse events.

Four trials of HCV-related cryoglobulinemia fulfiled selection criteria and the review authors included three in quantitative synthesis. All studies were at high risk of bias. No trial addressed the primary outcome of change in sensory impairment. No trial addressed secondary outcomes of change in combined sensory and motor impairment, disability, or electrodiagnostic measures. A single trial of HCV-related mixed cryoglobulinemia treated with pegylated interferon alfa (peginterferon alfa), ribavirin, and rituximab versus peginterferon alfa and ribavirin did not show a significant difference in the number of participants with improvement in neuropathy at 36 months post treatment (risk ratio (RR) 4.00, 95% confidence interval (CI) 0.27 to 59.31, n = 9). One study of interferon alfa (n = 22) and two studies of rituximab (n = 61) provided adverse event data. Severe adverse events were no more common with interferon alfa (RR 7.00, 95% CI 0.38 to 128.02) or rituximab (RR 3.00, 95% CI 0.13 to 67.06) compared to the control group.

There is a lack of RCTs and quasi-RCTs addressing the effects of interventions for peripheral neuropathy associated with HCV infection. At present, there is insufficient evidence from RCTs and quasi-RCTs to make evidence-based decisions about treatment.

Infectious causes of peripheral nervous system (PNS) disease are underrecognized but potentially treatable. Heightened awareness educed by advanced understanding of the presentations and management of these infections can aid diagnosis and facilitate treatment. In this review, we discuss the clinical manifestations, diagnosis, and treatment of common bacterial, viral, and parasitic infections that affect the PNS. We additionally detail PNS side effects of some frequently used antimicrobial agents.

The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord. Systemic autoimmune diseases can affect both the central and peripheral nervous systems in a myriad of ways and through a heterogeneous number of mechanisms leading to many different clinical manifestations. As a result, neurological complications of these disorders can result in significant morbidity and mortality. The most common complication of peripheral nervous system (PNS) involvement is peripheral neuropathy, with symptoms of numbness, sensory paresthesias, weakness, or gait imbalance. The neuropathy may be multifocal and asymmetric or, less frequently, distal and symmetric.

Infectious neuropathies are heterogeneous neuropathies with multiple causes. They still represent an important world health burden and some of them have no current available therapy.

Leprosy incidence has decreased by 50% during the last years, but leprosy-related neuropathies still cause severe disability. The pure neuritic leprosy is a diagnostic challenge that may require nerve biopsy or nerve aspiration cytology. The treatment itself may lead to a 'reversal reaction', which further causes injuries to the nerve. HCV-related neuropathies may be related or not to the presence of cryoglobulins. The absence of vasculitis, the most frequent form is a peripheral sensory neuropathy involving small nerve fibers, and more accurately diagnosed by pain-related evoked potentials. HIV-related neuropathy has become the major neurological complication of HIV infection. Both HIV-induced neuropathy and antiretroviral toxic neuropathy are clinically indistinguishable. The existence of an isolated chronic polyneuropathy due to Borrelia burgdorferi remains highly controversial. Lastly, an active infectious ganglioneuritis caused by varicella zoster virus, producing shingles, is the most frequent infectious neuropathy in the world and may cause various neurological complications. Zoster sine herpete remains frequently undiagnosed.

Recent data have improved our knowledge and diagnostic tools of infectious neuropathies. Treatment of the injured nerves is not yet available, and prevention and rapid diagnosis remain the main priorities for the clinician.

The vasculitic neuropathies are a diverse group of disorders characterised by the acute-to-subacute onset of painful sensory and motor deficits that result from inflammatory destruction of nerve blood vessels and subsequent ischaemic injury. They are common in patients with primary systemic vasculitis and are seen in vasculitis secondary to disorders such as rheumatoid arthritis, viral infections, and diabetic inflammatory neuropathies. It is imperative that neurologists recognise these disorders to initiate treatment promptly and thereby prevent morbidity and mortality. To simplify the approach to patients with vasculitis of the peripheral nerves, a straightforward, dichotomous classification scheme can be used in which the vasculitic neuropathies are divided into two groups-nerve large arteriole vasculitis and nerve microvasculitis-on the basis of the size of the involved vessels. The size of the affected blood vessels correlates with the clinical course and prognosis in patients with vasculitic neuropathy.

We herein report the case of a patient with hepatitis C virus (HCV)-associated neuropathy with atypical pathological findings of a biopsied sural nerve. A 48-year-old man was admitted for a gait disturbance. Purpura and edema on the legs and hyperalgesia on the distal extremities were noted. The plasma HCV viral load was high, and cryoglobulin was positive. In the biopsied sural nerve, perivascular eosinophilic infiltration was associated with extravascular granuloma formation in the epineurium. The patient's symptoms disappeared following treatment with interferon-α and ribavirin. The present case suggests that HCV infection can lead to peripheral neuropathy associated with eosinophilic infiltration and granuloma formation.

Vasculitic neuropathy is a heterogeneous disorder that usually occurs in systemic diseases, but less commonly appears as nonsystemic vasculitic neuropathy (NSVN). This review is intended to highlight recent developments in the field of vasculitic neuropathies.

A Peripheral Nerve Society guideline provides data-driven consensus recommendation on classification of vasculitic neuropathies and diagnosis/treatment of NSVN. NSVN is sometimes accompanied by subclinical inflammation of adjacent skin. Amyotrophic lateral sclerosis with sensory involvement can mimic NSVN. Systemic vasculitides with neuropathy include polyarteritis nodosa, microscopic polyangiitis (MPA), rheumatoid vasculitis, Churg-Strauss syndrome (CSS), and hepatitis C-related mixed cryoglobulinemic vasculitis (MCV). At autopsy, MPA affects limb nerves diffusely, with maximal damage in proximal/middle segments. CSS can be accompanied by antineutrophil cytoplasmic antibodies (ANCAs), but most patients with neuropathy lack ANCAs. Cryoglobulinemic neuropathies are usually caused by vasculitis, irrespective of phenotype. Two randomized trials revealed rituximab to be noninferior to cyclophosphamide for inducing remission in ANCA-associated vasculitis. Many reports also document efficacy of rituximab in MCV.

Consensus guidelines on NSVN should be evaluated prospectively. MPA-associated vasculitic neuropathy results from vasculitic lesions distributed diffusely throughout peripheral extremity nerves. Rituximab is effective for ANCA-associated and cryoglobulinemic vasculitis with neuropathy.

Peripheral neuropathy is an important factor of disability in the elderly, which is significant now that up to 20% of the population is older than 60 years in industrialized countries. Potentially treatable neuropathies including primary inflammatory polyneuropathies and systemic disorders, especially vasculitic neuropathies, are as common in this age group as in younger patients. Neuropathies associated with diabetes, malignancy, and monoclonal gammopathies are even more common in these patients. It is thus essential to identify the causes of these neuropathies in this group of patients and treat them whenever feasible.

Vasculitis is a primary phenomenon in autoimmune diseases such as polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and essential mixed cryoglobulinemia. As a secondary feature vasculitis may complicate, for example, connective tissue diseases, infections, malignancies, and diabetes. Vasculitic neuropathy is a consequence of destruction of the vessel wall and occlusion of the vessel lumen of small epineurial arteries. Sometimes patients present with nonsystemic vasculitic neuropathy, i.e., vasculitis limited to peripheral nerves and muscles with no evidence of further systemic involvement. Treatment with corticosteroids, sometimes in combination with other immunosuppressants, is required to control the inflammatory process and prevent further ischemic nerve damage.