P2Y13 receptor involved in HIV-1 gp120 induced neuropathy in superior cervical ganglia through NLRP3 inflammasome activation.

Cardiac autonomic neuropathy resulting from human immunodeficiency virus (HIV) infection is common; however, its mechanism remains unknown. The current work attempted to explore the function and mechanism of the P2Y13 receptor in HIV-glycoprotein 120 (gp120)-induced neuropathy in cervical sympathetic ganglion. The superior cervical ganglion (SCG) of the male SD rat was coated with HIV-gp120 to establish a model of autonomic neuropathy. In each group, we measured heart rate, blood pressure, heart rate variability, sympathetic nerve discharge and cardiac function. The expression of P2Y13 mRNA and protein in the SCG was tested by real-time polymerase chain reaction and western blotting. Additionally, this study focused on identifying the protein levels of NOD-like receptor family pyrin domain-containing 3 (NLRP3), Caspase-1, Gasdermin D (GSDMD), interleukin (IL)-1ß and IL-18 in the SCG using western blotting and immunofluorescence. In gp120 rats, increased blood pressure, heart rate, cardiac sympathetic nerve activity, P2Y13 receptor levels and decreased cardiac function could be found. P2Y13 shRNA or MRS2211 inhibited the above mentioned changes induced by gp120, suggesting that the P2Y13 receptor may be engaged in gp120-induced sympathetic nerve injury. Moreover, the levels of NLRP3, Caspase-1, GSDMD, IL-1ß and IL-18 in the gp120 group were increased, while significantly decreased by P2Y13 shRNA or MRS2211. Therefore, the P2Y13 receptor is involved in gp120-induced sympathetic neuropathy, and its molecular mechanism shows an association with the activation of the NLRP3 inflammasome, followed by GSDMD formation along with the release of inflammatory factors including IL-1ß and IL-18. This article is part of the Special Issue on "Purinergic Signaling: 50 years".

Focal Peripheral Neuropathies Observed in Patients Diagnosed With COVID-19: A Case Series.

ABSTRACT: A growing number of studies have documented a wide variety of neurological manifestations associated with the novel SARS-CoV-2 (COVID-19). Of the available literature, cranial neuropathies and central nervous system disorders, such as encephalopathy and ischemic strokes, remain the predominant discussion. Limited investigations exist examining peripheral neuropathies of those with COVID-19. This case series discusses eight patients who tested positive for COVID-19 and presented with localized weakness after a prolonged course of mechanical ventilation (>21 days). We retrospectively reviewed all patients' charts who received electrodiagnostic evaluation between March and November 2020 in the outpatient clinic or in the acute care hospital at the JFK Medical Center/JFK Johnson Rehabilitation Institute and Saint Peter's University Hospital of New Jersey. A total of eight COVID-19-positive patients were identified to have a clinical presentation of localized weakness after a prolonged course of mechanical ventilation. All patients were subsequently found to have a focal peripheral neuropathy of varying severity that was confirmed by electrodiagnostic testing. Patient demographics, clinical, and electrodiagnostic findings were documented. The findings of local weakness and focal peripheral neuropathies after diagnosis of COVID-19 raise significant questions regarding underlying pathophysiology and overall prognosis associated with COVID-19.

Sudomotor Changes in Hepatitis C Virus Infection with or without Diabetes Mellitus: A Pilot Study in Egyptian Patients.

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.

Hepatitis B Virus-related Vasculitic Neuropathy in an Inactive Virus Carrier Treated with Intravenous Immunoglobulin.

We herein report a 33-year-old woman who was an asymptomatic hepatitis B virus (HBV) carrier and presented with distal muscle weakness in the legs and asymmetrical paresthesia in the distal extremities. A nerve biopsy specimen revealed fibrinoid necrosis associated with inflammatory infiltration in the perineural space, and deposition of hepatitis B core antigen and C4d complement was detected in the vascular endothelial cells as well as around the vessels. She was diagnosed with HBV-related vasculitic neuropathy and treated with intravenous immunoglobulin (IVIG). Her symptoms completely subsided after eight weeks. Vasculitic neuropathy rarely develops in the chronic inactive stages of HBV infection. This is the first report of an HBV-inactive carrier with vasculitic neuropathy successfully treated with IVIG.

Case Report: Disseminated Strongyloidiasis in a Patient with COVID-19.

The SARS-CoV-2 virus has emerged and rapidly evolved into a current global pandemic. Although bacterial and fungal coinfections have been associated with COVID-19, little is known about parasitic infection. We report a case of a COVID-19 patient who developed disseminated strongyloidiasis following treatment with high-dose corticosteroids and tocilizumab. Screening for Strongyloides infection should be pursued in individuals with COVID-19 who originate from endemic regions before initiating immunosuppressive therapy.

Evidence for a novel subcortical mechanism for posterior cingulate cortex atrophy in HIV peripheral neuropathy.

We previously reported that neuropathic pain was associated with smaller posterior cingulate cortical (PCC) volumes, suggesting that a smaller/dysfunctional PCC may contribute to development of pain via impaired mind wandering. A gap in our previous report was lack of evidence for a mechanism for the genesis of PCC atrophy in HIV peripheral neuropathy. Here we investigate if volumetric differences in the subcortex for those with neuropathic paresthesia may contribute to smaller PCC volumes, potentially through deafferentation of ascending white matter tracts resulting from peripheral nerve damage in HIV neuropathy. Since neuropathic pain and paresthesia are highly correlated, statistical decomposition was used to separate pain and paresthesia symptoms to determine which regions of brain atrophy are associated with both pain and paresthesia and which are associated separately with pain or paresthesia. HIV+ individuals (N = 233) with and without paresthesia in a multisite study underwent structural brain magnetic resonance imaging. Voxel-based morphometry and a segmentation/registration tool were used to investigate regional brain volume changes associated with paresthesia. Analysis of decomposed variables found that smaller midbrain and thalamus volumes were associated with paresthesia rather than pain. However, atrophy in the PCC was related to both pain and paresthesia. Peak thalamic atrophy (p = 0.004; MNI x = - 14, y = - 24, z = - 2) for more severe paresthesia was in a region with reciprocal connections with the PCC. This provides initial evidence that smaller PCC volumes in HIV peripheral neuropathy are related to ascending white matter deafferentation caused by small fiber damage observed in HIV peripheral neuropathy.

Peripheral Neuronopathy Associated With Ebola Virus Infection in Rhesus Macaques: A Possible Cause of Neurological Signs and Symptoms in Human Ebola Patients.

Neurological signs and symptoms are the most common complications of Ebola virus disease. However, the mechanisms underlying the neurologic manifestations in Ebola patients are not known. In this study, peripheral ganglia were collected from 12 rhesus macaques that succumbed to Ebola virus (EBOV) disease from 5 to 8 days post exposure. Ganglionitis, characterized by neuronal degeneration, necrosis, and mononuclear leukocyte infiltrates, was observed in the dorsal root, autonomic, and enteric ganglia. By immunohistochemistry, RNAscope in situ hybridization, transmission electron microscopy, and confocal microscopy, we confirmed that CD68+ macrophages are the target cells for EBOV in affected ganglia. Further, we demonstrated that EBOV can induce satellite cell and neuronal apoptosis and microglial activation in infected ganglia. Our results demonstrate that EBOV can infect peripheral ganglia and results in ganglionopathy in rhesus macaques, which may contribute to the neurological signs and symptoms observed in acute and convalescent Ebola virus disease in human patients.

Zika virus infection causes temporary paralysis in adult mice with motor neuron synaptic retraction and evidence for proximal peripheral neuropathy.

Clinical evidence is mounting that Zika virus can contribute to Guillain-Barré syndrome which causes temporary paralysis, yet the mechanism is unknown. We investigated the mechanism of temporary acute flaccid paralysis caused by Zika virus infection in aged interferon αß-receptor knockout mice used for their susceptibility to infection. Twenty-five to thirty-five percent of mice infected subcutaneously with Zika virus developed motor deficits including acute flaccid paralysis that peaked 8-10 days after viral challenge. These mice recovered within a week. Despite Zika virus infection in the spinal cord, motor neurons were not destroyed. We examined ultrastructures of motor neurons and synapses by transmission electron microscopy. The percent coverage of motor neurons by boutons was reduced by 20%; more specifically, flattened-vesicle boutons were reduced by 46%, and were normalized in recovering mice. Using electromyographic procedures employed in people to help diagnose Guillain-Barré syndrome, we determined that nerve conduction velocities between the sciatic notch and the gastrocnemius muscle were unchanged in paralyzed mice. However, F-wave latencies were increased in paralyzed mice, which suggests that neuropathy may exist between the sciatic notch to the nerve rootlets. Reversible synaptic retraction may be a previously unrecognized cofactor along with peripheral neuropathy for the development of Guillain-Barré syndrome during Zika virus outbreaks.

Peripheral Neuropathies in Infectious Diseases.

Peripheral nerve disorders may be the presenting manifestation of a systemic infection, and early recognition of these syndromes is essential for prompt diagnosis and treatment. Mechanisms associated with infectious disorders of the peripheral nerve are often complex and multiple, with secondary inflammation, direct infectious invasion of nerves, and toxicities of antimicrobial medications playing a role. Here, we provide a complete review of the most common infectious pathogens that can affect the peripheral nerves.

Polymorphisms in CAMKK2 associate with susceptibility to sensory neuropathy in HIV patients treated without stavudine.

HIV-associated sensory neuropathy (HIV-SN) is a debilitating neurological complication of HIV infection potentiated by the antiretroviral drug stavudine. While stavudine is no longer used, HIV-SN now affects around 15% of HIV+ Indonesians. Here, we investigate whether polymorphisms within the P2X-block (P2X4R, P2X7R, CAMKK2) and/or ANAPC5 mark susceptibility to HIV-SN in this setting. As polymorphisms in these genes associated with HIV-SN in African HIV patients receiving stavudine, the comparison can identify mechanisms independent of stavudine. HIV patients who had never used stavudine (n = 202) attending clinics in Jakarta were screened for neuropathy using the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Open-array technology was used to type 48 polymorphisms spanning the four genes. Haplotypes were derived for each gene using fastPHASE. Haplogroups were constructed with median-joining methods. Multivariable models optimally predicting HIV-SN were based on factors achieving p < 0.2 in bivariate analyses. Minor alleles of three co-inherited polymorphisms in CAMKK2 (rs7975295*C, rs1560568*A, rs1132780*T) associated with a reduced prevalence of HIV-SN individually and after adjusting for lower CD4 T cell count and viremia (p = 0.0002, pseudo R2 = 0.11). The optimal model for haplotypes linked HIV-SN with viremia and lower current CD4 T cell count, plus CAMKK2 haplotypes 6 and 11 and P2X7R haplotypes 2 and 12 (p = 0.0002; pseudo R2 = 0.11). CAMKK2 haplogroup A (includes 16 haplotypes and all instances of rs7975295*C, rs1560568*A, rs1132780*T) associated with reduced rates of HIV-SN (p = 0.02, OR = 0.43 CI = 0.21-0.88). These findings support a protective role for these three alleles, suggesting a role in the pathogenesis of HIV-SN that is independent of stavudine.

Peripheral neuropathy in patients with human immunodeficiency viral infection at a tertiary hospital in Ghana.

Peripheral neuropathy (PN) is the most frequent neurological complication in people living with HIV/AIDS. Neurological damage was identified to not only be caused by the viral infection itself but also through neurotoxic antiretroviral therapy (ART). PN is associated with a variety of risk factors; however, detailed knowledge is scarce for sub-Saharan African populations, bearing among the highest HIV/AIDS infection burden.In a cross-sectional study, we assessed the prevalence of PN in 525 adult outpatients suffering from HIV/AIDS and admitted to the largest tertiary hospital in Ghana. Through a detailed questionnaire and clinical examination including neurologic assessment and laboratory blood sample testing, this study investigated associations of PN with demographic and health determinants and identified risk factors associated with sensory neuropathy.The prevalence of PN in the Ghanaian cohort was 17.7% and increased odd ratios (OR) when patients were taller (> 1.57 m; OR = 3.84; 95% CI 1.38-10.66) or reached the age > 34 years (p = 0.124). Respondents with longer education duration had significantly less PN (≥ 9 years of education; OR = 0.49; 95% CI 0.26-0.92). The study also identified significant association of PN to both waist and hip girth and neutrophil counts. Curiously, higher adjusted odd ratios (aOR) of PN of patients under ART treatment were observed when CD4 lymphocytes were elevated (aOR = 0.81; 95% CI 0.36-1.83 and aOR = 2.17; 95% CI 0.93-5.05, for 300 and 600 counts, respectively). For patients on ART, an increase of 10 CD4 cell count units increased their chance of developing PN by 1% (aOR = 1.01; 95% CI 1.00 to 1.03).Despite current drug application regulations, prevalence of PN is still unacceptably high in sub-Saharan African populations. Reduction in chronic morbidity through a health system with routine monitoring, early diagnosis and prompt intervention, and effective case management can improve people living with HIV/AIDS' quality of life.

Zika Virus and Neurologic Disease.

Zika virus (ZIKV) is an arthropod-borne virus that belongs to the Flaviviridae family. Although most cases are mild or go undetected, rare severe neurologic effects, including congenital ZIKV syndrome (CZS) and Guillain-Barré syndrome, have been identified. The serious neurologic complications associated with ZIKV prompted the declaration of the public health emergency of international concern by the World Health Organization. Overall, transmission occurred throughout South and Central America as well as the Caribbean, affecting 48 countries and territories from March 2015 to March 2017. Long-term management of CZS requires a comprehensive combination of supportive services throughout early development.

Varicella zoster lumbosacral plexopathy: a rare cause of lower limb weakness.

This is a rare case of Varicella zoster virus (VZV) lumbosacral plexopathy in an 84-year-old women presenting with lower limb weakness and rash. Contrast-enhanced MRI showed enhancement of the left L3-L5 descending nerves and left lumbosacral plexus consistent with inflammatory/infectious aetiology. Cerebrospinal fluid PCR confirmed VZV DNA and cerebrospinal fluid serological testing was positive for VZV immunoglobulin (Ig)M and IgG antibodies. The patient was treated with intravenous acyclovir but this was complicated by the development of acute renal failure attributed to acyclovir-induced nephropathy, requiring dose adjustment. After a prolonged course of oral acyclovir and inpatient rehabilitation, the patient made a partial neurological and functional recovery.

Parálisis de la musculatura abdominal tras herpes zóster. Serie de casos / Paralysis of the abdominal muscles after herpes zoster. Case series

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Sensory neuronopathy heralding human T cell lymphotropic virus type I myelopathy.

Neurological phenotypes of human T cell lymphotropic virus type I (HTLV-1) are numerous and rarely may not manifest the classic HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We report a case of HTLV-1-related sensory neuronopathy heralding the classic HAM/TSP.

MRI findings of postherpetic abdominal wall pseudohernia: A case report.

Herpes zoster is caused by the reactivation of latent varicella-zoster virus from dorsal root ganglia. Although infrequent, simultaneous damage to the anterior horn cells or anterior nerve roots at the same level may result in motor neuropathy. When motor involvement is localized in the abdominal wall, a pseudohernia may be the clinical presentation. We report a case of abdominal wall post-herpetic pseudohernia, with clinical, ultrasound and MRI correlation. MRI demonstrated increased T2/STIR signal intensity in the abdominal wall muscles, suggesting acute denervation. To our knowledge, this is the first case report of postherpetic pseudohernia with acute denervation demonstrated on MRI.