Idiopathic Distal Sensory Polyneuropathy and Fibromyalgia Syndrome: A Comparative Phenotyping Study.

INTRODUCTION: Painful idiopathic distal sensory polyneuropathy (IDSP) and fibromyalgia syndrome (FMS) are cryptogenic chronic pain syndromes. The contribution of small fibre pathology (SFP) in FMS remains controversial. This study aims to quantify small nerve pathology in participants with IDSP and FMS and identify relationships of SFP with sensory phenotypes. METHODS: In this study, 73 individuals (FMS: 25, IDSP: 23, healthy volunteers: 25) underwent comprehensive assessment, including neurological exams, questionnaires, sensory tests, and corneal confocal microscopy. RESULTS: IDSP participants displayed lower wind-up ratio (WUR) relative to FMS (p < 0.001), loss of function to thermal and mechanical stimuli and elevated neuropathy disability scores compared to FMS and healthy volunteers (all p < 0.001). FMS participants demonstrated gain of function to heat and blunt pressure pain responses relative to IDSP, and healthy volunteers (heat: p = 0.002 and p = 0.003; pressure: both p < 0.001) and WUR (both p < 0.001). FMS participants exhibited reduced corneal nerve fibre density (p = 0.02), while IDSP participants had lower global corneal nerve measures (density, branch density, and length) relative to healthy volunteers (all p < 0.001). Utilising corneal nerve fibre length, SFP was demonstrated in 66.6% of participants (FMS: 13/25; IDSP: 22/23). CONCLUSION: Participants with SFP, in both FMS and IDSP, reported symptoms indicative of small nerve fibre disease. Although distinctions in pain distributions are evident between individuals with FMS and IDSP, over 50% of participants between the two conditions displayed both a loss and gain of thermal and mechanical function suggestive of shared mechanisms. However, sensory phenotypes were associated with the presence of SFP in IDSP but not in FMS.

In people with painful idiopathic neuropathy (pain related to nerve damage where the cause of nerve damage is unknown), fibromyalgia syndrome (a long-term condition causing widespread pain), and healthy volunteers, the small nerve fibres of the peripheral nervous system, which may be involved in generating pain were assessed. These nerve fibres can be measured at the front of the eye (cornea) which can provide details on whether they are damaged in the body. The response to temperature, light touch, pressure and pinprick stimuli can also be used to determine if there is a loss or gain of sensation, which may contribute to pain. The aim of this study was to identify the degree of damage to these nerve fibres and to determine whether this damage is associated with a loss (cannot feel or requires more intense stimulus to feel) or gain (stimulus is felt earlier or is painful earlier at lower intensity) of sensory function. The pattern of loss or gain in sensory function is known as a sensory phenotype. It was found that people with painful idiopathic neuropathy had more severe nerve damage, loss of function to temperature and touch, and fewer small nerve fibres in the cornea compared to those with fibromyalgia syndrome and healthy volunteers. People with fibromyalgia syndrome were more sensitive to heat and pressure and had fewer corneal nerve fibres relative to healthy volunteers. The presence of corneal nerve fibre damage was associated with sensory phenotypes (types of sensation felt) in painful idiopathic neuropathy but not in fibromyalgia syndrome.

The severity of distal sensory polyneuropathy increasing with HIV/AIDS stage.

Distal sensory polyneuropathy (DSP) is the most common neurological problem in HIV/AIDS Patients. It represents a complex symptom that occurs because of peripheral nerve damage related to advanced HIV disease and in association with the use of antiretroviral therapy. DSP is a frequent symptom in which the specific pathophysiology is not well understood. Recently, mitochondrial toxicity and antiretroviral toxic neuropathies have been more identified as a possible etiology of DSP. This study's objective was to determine factors associated with DSP severity in HIV/AIDS patients. This cross-sectional study was followed by 50 HIV/AIDS outpatients at some hospitals in Makassar, Indonesia who met the inclusion criteria. DSP is diagnosed using non-invasive screening tools subjective peripheral neuropathy screen (SPNS) which can determine the severity of DSP in advance. Some factors were analyzed by using Pearson's chi-square test and Spearman's correlation test. Forty-three participants (86%) had diagnosed DSP which is mostly moderate in severity (48%). Statistical analysis showed significant correlation between HIV/AIDS Stage and DSP severity (p=0.032) meanwhile CD4 count, antiretroviral, body mass index (BMI), and hemoglobin level have no significant correlation to DSP severity. In conclusion, HIV/AIDS stage and DSP severity correlate where the later the stage the more severe DSP.

Article Topic: Neuropathies Due to Infections and Antimicrobial Treatments.

Purpose of eview: The aim of this review is to discuss the presentation, diagnosis, and management of polyneuropathy (PN) in selected infections. Overall, most infection related PNs are an indirect consequence of immune activation rather than a direct result of peripheral nerve infection,  Schwann cell infection, or toxin production, though note this review will describe infections that cause PN through all these mechanisms. Rather than dividing them by each infectious agent separately, we have grouped the infectious neuropathies according to their presenting phenotype, to serve as a guide to clinicians. Finally, toxic neuropathies related to antimicrobials are briefly summarized. Recent findings: While PN from many infections is decreasing, increasing evidence links infections to variants of GBS. Incidence of neuropathies secondary to use of HIV therapy has decreased over the last few years. Summary: In this manuscript, a general overview of the more common infectious causes of PN will be discussed, dividing them across clinical phenotypes: large- and small-fiber polyneuropathy, Guillain-Barré syndrome (GBS), mononeuritis multiplex, and autonomic neuropathy. Rare but important infectious causes are also discussed.

Association Between Breastfeeding and Reduced Distal Sensory Polyneuropathy in Postmenopausal Women Aged 40-70 Years: Analysis of Data from the 1999-2004 National Health and Nutrition Examination Survey.

Background: Distal sensory polyneuropathy (DSP) is a common peripheral neuropathy subtype. We aimed to determine the association between breastfeeding and DSP among postmenopausal women aged 40-70 years, and the effect modification of obesity on this association. Methods: A cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey 1999-2004. Postmenopausal women aged 40-70 years were included. Women with diabetes, stroke, cancer, cardiovascular disease, thyroid disease, liver disease, weak/failing kidneys, or amputation were excluded. Binary logistic regression was used to analyze the association between breastfeeding and DSP. Results: Among 798 participants, 386 (44.30%) reported breastfeeding history and 51 (5.29%) were defined as having DSP using the monofilament test. A significant inverse association was observed between breastfeeding and DSP (odds ratio [OR] = 0.29; 95% confidence interval [CI]: 0.11-0.79; p = 0.017) after adjusting for other confounding variables. In subgroup analysis, this adjusted association was observed only in the obese group (OR = 0.21; 95% CI: 0.06-0.73, p = 0.013). Conclusions: Breastfeeding was found to have potential benefits in the presence of DSP in postmenopausal women aged 40-70 years, and obesity modified the association between breastfeeding and DSP. Promoting breastfeeding may reduce the burden of peripheral neuropathy in middle-aged postmenopausal women.

HIV peripheral neuropathy-related degeneration of white matter tracts to sensorimotor cortex.

Human immunodeficiency virus-associated distal sensory polyneuropathy (HIV-DSP) affects up to 50% of people with HIV and is associated with depression, unemployment, and generally worsened quality of life. Previous work on the cortical mechanism of HIV neuropathy found decreased gray matter volume in the bilateral midbrain, thalamus, and posterior cingulate cortex, but structural connectivity in this context remains under-studied. Here we examine alterations in white matter microstructure using diffusion imaging, hypothesizing that cortical white matter degeneration would be observed in continuation of the peripheral white matter atrophy previously observed in HIV-DSP. Male HIV seropositive patients (n = 57) experiencing varying degrees of HIV neuropathy underwent single-shell diffusion tensor imaging with 51 sampling directions. The scans were pooled using tractography and connectometry to create a quantitative map of white matter tract integrity, measured in generalized fractional anisotropy (GFA). The relationship between GFA and neuropathy severity was evaluated with linear regression. Correction for multiple comparisons was done using false discovery rate (FDR), a statistical method commonly used in genomics and imaging to minimize false positives when thousands of individual comparisons are made. Neuropathy severity was associated with decreased GFA along thalamocortical radiations leading along the lateral thalamus to sensorimotor cortex, with r = -0.405 (p < 0.001; FDR), as well as with the superior bilateral cingulum (r = -0.346 (p < 0.05; FDR)). Among a population of HIV neuropathy patients, greater neuropathy severity was correlated with lower white matter integrity running from midbrain to somatosensory cortex. This suggests ascending deafferentation extending from damaged peripheral nerves further downstream than seen previously, into the axons of third-order neurons. There is also evidence of cingulum degeneration, implying some more complex mechanism beyond the ascending atrophy observed here.

Early Detection of Diabetic Peripheral Neuropathy: A Focus on Small Nerve Fibres.

Diabetic peripheral neuropathy (DPN) is the most common complication of both type 1 and 2 diabetes. As a result, neuropathic pain, diabetic foot ulcers and lower-limb amputations impact drastically on quality of life, contributing to the individual, societal, financial and healthcare burden of diabetes. DPN is diagnosed at a late, often pre-ulcerative stage due to a lack of early systematic screening and the endorsement of monofilament testing which identifies advanced neuropathy only. Compared to the success of the diabetic eye and kidney screening programmes there is clearly an unmet need for an objective reliable biomarker for the detection of early DPN. This article critically appraises research and clinical methods for the diagnosis or screening of early DPN. In brief, functional measures are subjective and are difficult to implement due to technical complexity. Moreover, skin biopsy is invasive, expensive and lacks diagnostic laboratory capacity. Indeed, point-of-care nerve conduction tests are convenient and easy to implement however questions are raised regarding their suitability for use in screening due to the lack of small nerve fibre evaluation. Corneal confocal microscopy (CCM) is a rapid, non-invasive, and reproducible technique to quantify small nerve fibre damage and repair which can be conducted alongside retinopathy screening. CCM identifies early sub-clinical DPN, predicts the development and allows staging of DPN severity. Automated quantification of CCM with AI has enabled enhanced unbiased quantification of small nerve fibres and potentially early diagnosis of DPN. Improved screening tools will prevent and reduce the burden of foot ulceration and amputations with the primary aim of reducing the prevalence of this common microvascular complication.

Distal sensory polyneuropathy among HIV-infected patients at Parakou University Hospital, Benin, 2011.

Distal sensory polyneuropathy (DSP) is the most frequent neurological complication among HIV patients, and its risk increases with use of highly active antiretroviral therapy (HAART). We aimed to assess the prevalence of DSP and the factors associated with it among HIV-infected outpatients treated at Parakou University Hospital. This cross-sectional study took place from April 15 to July 15, 2011, and included 262 patients. All patients underwent a neurological examination by two neurologists with training and clinical experience in these examinations and in the Brief Peripheral Neuropathy Screening (BPNS), which was the primary tool used here. Data from nutritional status (body mass index: BMI), social and demographic information, HAART status, and CD4 count were recorded. The factors associated with DSP were studied with multivariate analysis, using a logistic regression model and a significance level of 0.05. The study included 60 men (22.9 %). Patients' ages ranged from 16 to 74 years and averaged 36.8±10 years. All patients but one patient were infected by HIV type 1 only; that one was coinfected by types 1 and 2. The mean BMI was 22.5+/-4.2 kg/m2. In all, 213 (81.3 %) received HAART, and the mean CD4 count was 355.0 cells/mm3+/-236.1. The prevalence of DSP was 42.4 %. The factors associated with it on univariate analysis were age, marital status, HAART status, duration of HIV infection, and duration of HAART. Only advanced age (OR 1.8, 95 % CI 1.1-5.3) and HAART use (OR 2.3, 95 % CI 1.5-4.9) were associated with DSP in the multivariate analysis. The main symptoms were paresthesia (numbness:75.7%; burning: 39.6%; pins and needles sensation 32.4 %) and pain (23.4 %). Vibration perception at the toes was missing or reduced for 84.4 %. According to the sensory symptoms grade, 93.7 % of patients were classified in Grades 2 or 3. This study showed that the prevalence of DSP is high and that it is associated with age and HAART.

Medial plantar-to-radial amplitude ratio: does it have electrodiagnostic utility in distal sensory polyneuropathy?

PURPOSE OF THE STUDY: We proposed a new electrophysiological parameter medial plantar (MP)-to-radial amplitude ratio (MPRAR), similar to sural-to-radial amplitude ratio (SRAR), in the diagnosis of distal sensory polyneuropathy (DSP), based on the concept that distal nerves are affected more and earlier than proximal nerves in axonal neuropathies. We aimed to investigate the diagnostic sensitivity of this parameter in diabetic DSP, together with sensitivities of SRAR and MP nerve action potential (NAP) amplitude. MATERIALS AND METHODS: In 124 healthy controls and 87 diabetic patients with clinically defined DSP and normal sural responses, we prospectively performed sensory nerve conduction studies (NCS), and evaluated the MP NAP amplitude, MPRAR and SRAR values. We determined the lower limits of normal (LLN) of these parameters in the healthy controls and calculated their sensitivities and specificities in detecting DSP in diabetic patients. RESULTS: MP nerve amplitude and MPRAR values were significantly lower in the patient group, compared to controls. However, SRAR values did not differ significantly between the two groups. The LLN of MP NAP amplitude was found to be 4.1 µV. The cutoff values for SRAR and MPRAR were determined as 0.24 and 0.16, respectively. MPRAR was abnormal in 21.8% of patients. However, the most sensitive parameter in detection of DSP was MP NAP amplitude, which showed a sensitivity of 31% and a specificity of 100%. CONCLUSIONS: Although MPRAR is more sensitive than SRAR in detecting DSP, it does not provide additional diagnostic yield to the assessment of MP NCS alone in diabetic DSP patients with normal sural responses.

HIV Glycoprotein Gp120 Impairs Fast Axonal Transport by Activating Tak1 Signaling Pathways.

Sensory neuropathies are the most common neurological complication of HIV. Of these, distal sensory polyneuropathy (DSP) is directly caused by HIV infection and characterized by length-dependent axonal degeneration of dorsal root ganglion (DRG) neurons. Mechanisms for axonal degeneration in DSP remain unclear, but recent experiments revealed that the HIV glycoprotein gp120 is internalized and localized within axons of DRG neurons. Based on these findings, we investigated whether intra-axonal gp120 might impair fast axonal transport (FAT), a cellular process critical for appropriate maintenance of the axonal compartment. Significantly, we found that gp120 severely impaired both anterograde and retrograde FAT. Providing a mechanistic basis for these effects, pharmacological experiments revealed an involvement of various phosphotransferases in this toxic effect, including members of mitogen-activated protein kinase pathways (Tak-1, p38, and c-Jun N-terminal Kinase (JNK)), inhibitor of kappa-B-kinase 2 (IKK2), and PP1. Biochemical experiments and axonal outgrowth assays in cell lines and primary cultures extended these findings. Impairments in neurite outgrowth in DRG neurons by gp120 were rescued using a Tak-1 inhibitor, implicating a Tak-1 mitogen-activated protein kinase pathway in gp120 neurotoxicity. Taken together, these observations indicate that kinase-based impairments in FAT represent a novel mechanism underlying gp120 neurotoxicity consistent with the dying-back degeneration seen in DSP. Targeting gp120-based impairments in FAT with specific kinase inhibitors might provide a novel therapeutic strategy to prevent axonal degeneration in DSP.

Sensory neuropathy and metabolic risk factors in human immune deficiency virus infected South Africans receiving protease inhibitors.

BACKGROUND: Protease inhibitors (PI)s have been associated with distal sensory polyneuropathy (DSP) and metabolic complications in high-income countries. No data exist in Africans where second-line antiretroviral therapy (ART) often include PIs. METHOD: We performed a cross-sectional study to assess the DSP frequency and metabolic risk factors in community-based South Africans taking ritonavir-boosted lopinavir as PI. Examination findings categorized subjects as having DSP (≥1 neuropathic sign) or symptomatic DSP [DSP with symptom(s)]. Fasting-state glucose and lipid profiles were assessed. We compared the ritonavir/lopinavir-group to a nested group on first-line ART [dideoxy-nucleoside reverse transcriptase inhibitors (d-drugs)] selected from a dataset collected at the same time and matched for d-drug exposure. RESULTS: The ritonavir/lopinavir-group (n = 86) consisted predominantly of women (84 %) with a median age of 36 years (IQR 32-41). The median current CD4+ count was 489 cells/µL (IQR 291-665). The median exposure time to ritonavir/lopinavir was 18 months (IQR 10-26) and to d-drugs, 24 months (IQR 16-38). DSP was present in 78 % and symptomatic DSP in 48 %; symptoms were most frequently of moderate intensity. Only age independently associated with DSP and symptomatic DSP (p = 0.08 and p = 0.04, respectively). None of the metabolic syndrome components showed associations with DSP or symptomatic DSP despite a trend towards hypertriglyceridemia overall. The ritonavir/lopinavir-group had less DSP compared to the d-drug only group (p = 0.002) but the frequency of symptomatic DSP was similar (p = 0.49). CONCLUSION: Ritonavir-boosted lopinavir did not add additional risk to developing DSP in this community-based African cohort after a median of 18 months on second-line ART.

Internalization and axonal transport of the HIV glycoprotein gp120.

The HIV glycoprotein gp120, a neurotoxic HIV glycoprotein that is overproduced and shed by HIV-infected macrophages, is associated with neurological complications of HIV such as distal sensory polyneuropathy, but interactions of gp120 in the peripheral nervous system remain to be characterized. Here, we demonstrate internalization of extracellular gp120 in a manner partially independent of binding to its coreceptor CXCR4 by F11 neuroblastoma cells and cultured dorsal root ganglion neurons. Immunocytochemical and pharmacological experiments indicate that gp120 does not undergo trafficking through the endolysosomal pathway. Instead, gp120 is mainly internalized through lipid rafts in a cholesterol-dependent manner, with a minor fraction being internalized by fluid phase pinocytosis. Experiments using compartmentalized microfluidic chambers further indicate that, after internalization, endocytosed gp120 selectively undergoes retrograde but not anterograde axonal transport from axons to neuronal cell bodies. Collectively, these studies illuminate mechanisms of gp120 internalization and axonal transport in peripheral nervous system neurons, providing a novel framework for mechanisms for gp120 neurotoxicity.

Peripheral neuropathy in HIV: an analysis of evidence-based approaches.

Peripheral neuropathy is a common and vexing symptom for people living with HIV infection (PLWH). Neuropathy occurs in several different syndromes and is identified in the literature as distal sensory polyneuropathy or distal sensory peripheral neuropathy. More recently, the HIV literature has focused on the syndrome as painful HIV-associated sensory neuropathy, addressing the symptom rather than the underlying pathophysiology. Assessment of neuropathy in PLWH is critical and must be incorporated into nursing practice for each visit. Neuropathy has been attributed to the direct effects of HIV, exposure to antiretroviral medications (particularly the nucleoside reverse transcriptase inhibitors), advanced immune suppression, and comorbid tuberculosis infection and exposure to antituberculosis medications. Evidence supports the importance of addressing neuropathy in PLWH with pharmacologic treatment regimens and complementary/alternative approaches. This paper examines the pathophysiology, evidence, and approaches to managing peripheral neuropathy. A case study has been included to illustrate a patient's experience with neuropathy symptoms.

Frequency and risk factors for distal sensory polyneuropathy in HIV infection in a developing country.

Distal sensory polyneuropathy is a source of morbidity in HIV infection. This study aims to determine the frequency and effect of demographic and clinical variables on distal sensory polyneuropathy, among HIV-positive participants in south-east Nigeria. The study involved highly active antiretroviral therapy (HAART)-naive, patients on HAART and HIV-negative matched controls conducted at the University of Nigeria Teaching Hospital, Enugu south-east Nigeria. Distal sensory polyneuropathy was diagnosed with clinical evaluation and the use of Bio Thesiometer, 10 g monofilament and ankle reflex. There were 100 participants in each of the groups, comprising 109 (36.3%) men and 191 (63.7%) women, with median age of 35 years. About 42.5% (85/200) of the HIV-positive participants (37 drug naive and 48 on HAART) had distal sensory polyneuropathy. None in the control group had distal sensory polyneuropathy. Age (p = 0.02), height (p = 0.002), low haemoglobin (p = 0.03) and mean duration on HAART (p = 0.006) were significantly associated with distal sensory polyneuropathy, while gender (p = 0.497), body mass index (p = 0.657) and CD4 count (p = 0.482) did not affect distal sensory polyneuropathy. Low haemoglobin, height, and duration on HAART were independent risk factors for distal sensory polyneuropathy. Addressing correctable causes of anaemia, and alternatives to neurotoxic HAART may minimize the risk of distal sensory polyneuropathy.

Nerve growth factor acts through the TrkA receptor to protect sensory neurons from the damaging effects of the HIV-1 viral protein, Vpr.

Distal sensory polyneuropathy (DSP) with associated neuropathic pain is the most common neurological disorder affecting patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Viral protein R (Vpr) is a neurotoxic protein encoded by HIV-1 and secreted by infected macrophages. Vpr reduces neuronal viability, increases cytosolic calcium and membrane excitability of cultured dorsal root ganglion (DRG) sensory neurons, and is associated with mechanical allodynia in vivo. A clinical trial with HIV/AIDS patients demonstrated that nerve growth factor (NGF) reduced the severity of DSP-associated neuropathic pain, a problem linked to damage to small diameter, potentially NGF-responsive fibers. Herein, the actions of NGF were investigated in our Vpr model of DSP and we demonstrated that NGF significantly protected sensory neurons from the effects of Vpr. Footpads of immunodeficient Vpr transgenic (vpr/RAG1(-/-)) mice displayed allodynia (p<0.05), diminished epidermalinnervation (p<0.01) and reduced NGF mRNA expression (p<0.001) compared to immunodeficient (wildtype/RAG1(-/-)) littermate control mice. Compartmented cultures confirmed recombinant Vpr exposure to the DRG neuronal perikarya decreased distal neurite extension (p<0.01), whereas NGF exposure at these distal axons protected the DRG neurons from the Vpr-induced effect on their cell bodies. NGF prevented Vpr-induced attenuation of the phosphorylated glycogen synthase-3 axon extension pathway and tropomyosin-related kinase A (TrkA) receptor expression in DRG neurons (p<0.05) and it directly counteracted the cytosolic calcium burst caused by Vpr exposure to DRG neurons (p<0.01). TrkA receptor agonist indicated that NGFacted through the TrkA receptor to block the Vpr-mediated decrease in axon outgrowth in neonatal and adult rat and fetal human DRG neurons (p<0.05). Similarly, inhibiting the lower affinity NGF receptor, p75, blocked Vpr's effect on DRG neurons. Overall, NGF/TrkA signaling or p75 receptor inhibition protects somatic sensory neurons exposed to Vpr, thus laying the groundwork for potential therapeutic options for HIV/AIDS patients suffering from DSP.