Search Results (52)

Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent complication of diabetes, affecting nearly half of all persons with diabetes. It is characterized by nerve degeneration, progressive sensory loss and pain, with increased risk of ulceration and amputation. Despite its high prevalence, disease-modifying treatments for DSPN do not exist. Mitochondrial dysfunction and Ca²⁺ dyshomeostasis are key contributors to the pathophysiology of DSPN, disrupting neuronal energy homeostasis and initiating axonal degeneration. Recent findings have demonstrated that antagonism of the muscarinic acetylcholine type 1 receptor (M₁R) promotes restoration of mitochondrial function and axon repair in various neuropathies, including DSPN, chemotherapy-induced peripheral neuropathy (CIPN) and HIV-associated neuropathy. Pirenzepine, a selective M₁R antagonist with a well-established safety profile, is currently under clinical investigation for its potential to reverse neuropathy. The transient receptor potential melastatin-3 (TRPM3) channel, a Ca²⁺-permeable ion channel, has recently emerged as a downstream effector of G protein-coupled receptor (GPCR) pathways, including M₁R. TRPM3 activation enhanced mitochondrial Ca²⁺ uptake and bioenergetics, promoting axonal sprouting. This review highlights mitochondrial and Ca²⁺ signaling imbalances in DSPN and presents M₁R antagonism and TRPM3 activation as promising neuro-regenerative strategies that shift treatment from symptom control to nerve restoration in diabetic and other peripheral neuropathies. Full article

Background and Objectives: Neuropathy is a debilitating disorder characterized by peripheral nerve dysfunction and damage to sensory, motor, and autonomic neurons and their axons. While homozygous mutations in DNAJB2/HSJ1 have been linked to early-onset neuropathy, a heterozygous DNAJB2 c.823+6C>T was discovered in an adult patient with severe sensory–motor polyneuropathy. This mutation is predicted to affect both isoforms of the protein. DNAJB2 (HSP40), a key member of the heat shock protein family, plays a critical role in cellular protection and stress, including response to heat shock. DNAJB2 traffics unfolded proteins to another heat shock protein, HSP70, and activates its ATPase activity to result in a correctly folded protein(s). In this study, we aimed to investigate the effects of the heterozygous DNAJB2 c.823+6C>T mutation on the stress response of DNAJB2 in fibroblasts obtained from the neuropathy patient. Methods: The fibroblasts were subjected to one hour of heat shock at 42 °C, and the time course of expression levels of DNAJB2 was established. Additionally, we evaluated the therapeutic efficacy of Cystamine, which has been shown to modulate DNAJB2 levels in cellular and animal models of Huntington’s disease. Results: Our results revealed reduced baseline levels of DNAJB2 between the mutant and control fibroblasts. Importantly the mutant cells exhibited a diminished response to heat shock. Thus, the mutation affects the upregulation of DNAJB2 under stress, possibly contributing to the pathogenesis of sensory–motor polyneuropathy. A 48-h pretreatment with 150 μM of Cystamine increased the levels of DNAJB2 in both the control and patient’s fibroblasts. Conclusions: To the best of our knowledge, this is the first study to explore this mutant form of DNAJB2 in neuropathy. The study demonstrated that the heterozygous DNAJB2 c.823+6C>T mutation leads to impaired DNAJB2 response to heat shock in the fibroblasts. Cystamine showed promise in restoring DNAJB2 expression, highlighting the need for further research into targeted therapeutic strategies for DNAJB2-related disorders. Full article

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe, multisystemic, autosomal dominant disease with variable penetrance caused by mutations in the TTR gene generating protein misfolding and accumulation of amyloid fibrils. The diagnosis is usually challenging because ATTRv may initially manifest with nonspecific multisystemic symptoms. Conversely, an early diagnosis is needed to start timely appropriate therapy. Hence, screening models have been proposed to improve ATTRv diagnosis. In this study, we propose a genetic screening model based on predefined “red flags” followed by “cascading screening” on first-degree relatives of patients who tested positive. Materials and methods: After obtaining written informed consent, genetic testing on salivary swabs was performed in individuals who met at least two major red flags for ATTRv (age > 65 years old, progressive sensory or sensorimotor neuropathy not responsive to steroids or immunomodulant therapies, recent and unexplained weight loss associated with gastrointestinal signs and symptoms, diagnosis of cardiac amyloidosis, bilateral or relapsing carpal tunnel syndrome, unexplained autonomic dysfunction) or one major flag and two minor flags (family history of neuropathy, ambulation disorders or cardiopathy, sudden cardiac death, a bedridden, wheelchaired patient without specific diagnosis excluding upper motor neuron diseases, infections, juvenile cardiac disease, ocular disorders, lumbar spine stenosis, biceps tendon rupture). Results: In the first screening phase, 29 suspected cases (individuals meeting at least two major red flags or one major red flag and two minor red flags) underwent genetic testing. One patient (3.5%) was diagnosed with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), carrying the Phe64Leu mutation. Then, cascade screening allowed for early recognition of two additional individuals (two pre-symptomatic carriers) among two first-degree relatives (100%). The identified patient was a 72-year-old man who had a family history of both cardiopathy, neuropathy, and a diagnosis of juvenile cardiac disease and progressive sensorimotor neuropathy unresponsive to steroids or immunomodulant therapies. Conclusions: ATTRv is a progressive and often fatal disease that should be promptly diagnosed and treated to stop progression and reduce mortality. Systematic screening for ATTRv yielded increased recognition of the disease in our neurological clinic. A focused approach for the screening of ATTRv-PN could lead to an earlier diagnosis and identification of asymptomatic carriers, enabling timely intervention through close clinical monitoring and early treatment initiation at symptom onset. Full article

Background: ATTRv and ATTRwt cardiac amyloidosis (CA) are underrecognized causes of heart failure with preserved left ventricular ejection fraction. The diagnosis of CA remains challenging due to low diagnostic suspicion and clinical overlap with more common diseases. The aim of this study was to use [^99mTc]-PYP SPECT-CT to perform a volumetric evaluation of bone scintigraphy to overcome the limitations of current practices. Methods: A monocentric prospective study was conducted to evaluate a lot of 22 patients with a mean age of 52.86 ± 13.80 years, diagnosed with hereditary cardiac transthyretin amyloidosis (ATTR). Results: Correlations between the quantitative SPECT-CT, clinical data, and morphological parameters were performed, demonstrating moderate to strong correlation of SUVmaxMyocardium/SUVmaxBone to both ECG low voltage and EchoGLS, SUVmaxMyocardium/SUVmaxLiver to myocardial gadolinium kinetics with T1 mapping MRI, diastolic disfunction, sensory–motor polyneuropathy, and EchoGLS, SUVmaxMyocardium/SUVmeanBone with diastolic disfunction and sensory–motor polyneuropathy, as well as SUVmaxMyocardium/SUVmaxSoft tissue to S II, respectively. Conclusions: The moderate to strong correlations among advanced quantitative SPECT-CT metrics and clinical and paraclinical data create the premises to use these parameters for early diagnosis of cardiac ATTR. Further multicentric studies in a larger patient population are needed to validate the newly identified quantitative SPECT-CT parameters. Full article

Objectives: The aim of this study was to evaluate the effects of spinal cord stimulation (SCS) on pain, neuropathic symptoms, and other health-related metrics in patients with chronic painful peripheral neuropathy (PN) from multiple etiologies. Methods: A prospective single center observational longitudinal cohort study assessed SCS efficacy from April 2023 to May 2024, with follow-ups at 2, 4, 6, and 12 months in 19 patients suffering from the painful polyneuropathy of diverse etiologies: diabetic (DPN), idiopathic (CIAP), chemotherapy-induced (CIPN), and others. Patients were implanted with a neurostimulator (WaveWriter Alpha^TM, Boston Scientific Corporation, Valencia, CA, USA) and percutaneous leads targeting the lower limbs (T10–T11) and, if necessary, the upper limbs (C4–C7). Stimulation programming was individualized based on patient preference and best response. Assessments were performed before and after implantation and included pain intensity (VAS and DN4), neuropathic pain symptoms (NPSI and SF-MPQ-2), autonomic symptoms (SFN-SIQ and SAS), sensory and small fiber nerve injury (UENS), functionality (GAF), sleep (CPSI), global impression of change (CGI and PGI), and quality of life (EQ-VAS and EQ-5D). Intra-epidermal nerve fiber density (IENFD) via skin biopsy was also performed at baseline (diagnostic) and after 12 months to assess potential small fiber re-growth. Statistical analyses were conducted to determine the evolution of treatment success. Results: To date, 19 patients have undergone implantation and completed follow-up. SCS produced a significant consistent and sustained improvement in pain intensity by 49% in DN4 and 76% in VAS, in neuropathic pain symptoms by 73%, in autonomic symptoms by 26–30%, in the sensorimotor physical exam by 8%, in functionality by 44%, in sleep by 74%, and in quality of life (69% for EQ-VAS and 134% EQ-5D). Both clinicians and patients had a meaningful global impression of change, at 1.1 and 1.3, respectively. Distal intra-epidermal nerve fiber density improved by 22% at 12 months while proximal intra-epidermal nerve fiber density decreased by 18%. Conclusions: SCS is an effective therapy for managing various types of PN. Full article

Backgraund/Objetive: Diabetic peripheral neuropathy is a condition that affects the motor, sensory, and autonomic fibers of the peripheral nervous system, with distal polyneuropathy being its most common form. Traditional methods for diagnosing sensory loss, such as tactile assessment, temperature evaluation, and vibratory perception threshold testing, are labor intensive and time consuming. Results: To effectively assess thermal and vibratory sensitivity, NerveCheck Master is an affordable and portable device that uses standardized stimuli to measure sensory response. Conclusions: Compared to traditional methods like the infrared laser thermometer, the Rydel–Seiffer tuning fork, and the Semmes–Weinstein monofilament, this device provides definitive results regarding the severity of DPN. Full article

Background/Objectives: Anti-MAG polyneuropathy is a demyelinating peripheral neuropathy associated with IgM monoclonal gammopathies, particularly MGUS (monoclonal gammopathy of undetermined significance) and Waldenström macroglobulinemia. It is characterized by a subacute onset of distal sensory symptoms, with distal motor dysfunction typically appearing only in the later stages of the disease. The condition is caused by the presence of autoantibodies directed against myelin-associated glycoprotein, a structural protein of myelin. This leads to abnormalities in electrophysiological studies, such as markedly delayed distal latencies without conduction blocks or temporal dispersion of potentials. While rituximab (RTX) is the primary treatment, its efficacy is limited, with improvement seen in only 30–50% of patients. Recently, acute worsening of symptoms after RTX treatment has been increasingly reported. Methods: This systematic review compiles case reports and series from inception to June 2024 published on Scopus, PubMed or Cochrane, documenting acute exacerbations after RTX treatment in patients with anti-MAG polyneuropathy. Additionally, we present a case report from our institution that highlights this phenomenon. Results: We identified 13 clinical cases of acute deterioration in patients with anti-MAG polyneuropathy. Among these, eight patients (62%) achieved full recovery following additional treatment, while five patients (38%) did not return to their previous level of function. Plasmapheresis led to complete recovery in all four patients who received this intervention. Interestingly, many patients also experienced recovery after discontinuation of rituximab (RTX) treatment without the need for further therapeutic intervention. Conclusions: Acute clinical deterioration following RTX treatment in anti-MAG polyneuropathy is a possible occurrence. However, to date, no studies have assessed the true prevalence of this phenomenon. Further research is warranted to identify potential predictors of worsening following RTX treatment in this patient population. Full article

Background and Objectives: Amyloidosis is a disorder characterized by the abnormal folding of proteins, forming insoluble fibrils that accumulate in tissues and organs. This accumulation disrupts normal tissue architecture and organ function, often with serious consequences, including death if left untreated. Light-chain amyloidosis (AL) and hereditary transthyretin-type amyloidosis (hATTR) are two of the most common types. In amyloidosis, peripheral nervous system involvement is a significant diagnostic feature, particularly when it manifests as polyneuropathy, carpal tunnel syndrome (CTS), and dysautonomia. These neurological symptoms often point to the involvement of amyloid deposits in the peripheral and autonomic nervous systems, which can help identify and differentiate between the various types of amyloidosis. Materials and Methods: This retrospective study focused on the evolution of electrophysiological parameters in two groups: AL (n = 22) and hATTR-Glu54Gln patients (n = 14), with mixed axonal polyneuropathy. Patients were followed for two consecutive years to assess disease progression. The PND scale (polyneuropathy disability) was also used to assess motor impairment for each patient. Results: In our study AL amyloidosis patients presented with mixed, axonal polyneuropathy associated with CTS in 63.6% of cases and cardiomyopathy (45.5%). Serial EMGs (electromyography) showed decreased motor amplitudes of the common peroneal and tibial nerves and sensory amplitude of the superficial peroneal nerve, with mostly preserved conduction velocities. The patients maintained stage I PND throughout the monitoring period. The entire hATTR group displayed mixed, axonal polyneuropathy and cardiomyopathy; 85.7% of them had CTS, and 42.9% had orthostatic hypotension. EMG data showed decreased motor amplitudes of the tibial and common peroneal nerves, decreased sensory amplitudes of the superficial peroneal nerve, and mildly reduced conduction velocities, with significant progression at 12 and 24 months. The patients displayed additional reduced muscle strength, some reaching stage 3A and 3B-PND at the end of the study. Conclusions: The amyloidotic polyneuropathy found in the groups was similar in its axonal, sensory-motor, and length-dependent characteristics, but the study showed significant differences in its progression, with more abrupt changes in the hATTR-Glu54Gln group. The amyloidosis AL patients remained in stage 1 PND, while the hATTR-Glu54Gln patients progressed to stage 3 PND at 24 months. Full article

Background: Hereditary Sensory Motor Neuropathy (HSMN) 1A and Multiple Sclerosis (MS) are distinct demyelinating disorders affecting the peripheral and central nervous systems, respectively. We present a case of simultaneous occurrence of both conditions, exploring the clinical presentation, diagnostic workup, and potential interplay between these diseases. Case presentation and clinical approach: A 49-year-old male with a history of optic neuritis presented with progressive numbness, weakness, and sensory loss in all extremities over four years. Neurological examination revealed distal weakness, sensory deficits in a stocking-glove distribution, pes cavus, and hammer toes. Nerve conduction studies and electromyography confirmed sensory motor demyelinating polyneuropathy. The patient’s lack of response to intravenous immunoglobulin therapy suggested hereditary neuropathy as an etiology. Genetic testing identified a PMP22 gene duplication, confirming HSMN 1A. Elevated cerebrospinal fluid protein level and oligoclonal bands, combined with magnetic resonance of the brain showing multiple T2 hyperintense lesions in the brain and spinal cord, fulfilled the diagnostic criteria for MS. Discussion: This case of co-existing HSMN 1A and MS highlights a rare overlap of peripheral and central demyelination. While HSMN 1A results from PMP22 gene duplication, primarily affecting peripheral myelin, MS is driven by immune-mediated central myelin attacks. The co-existence of these disorders suggests potential shared mechanisms, such as immune dysregulation. Some evidence suggests that overexpression of PMP22 in HSMN 1A may disturb immune tolerance, possibly triggering autoimmune responses linked to MS. Further research is needed to explore the genetic and autoimmune interplay between these two diseases, expanding our understanding of demyelinating disorders. Full article

Cerebrotendinous xanthomatosis (CTX) is a rare metabolic disorder caused by mutations in the CYP27A1 gene, leading to cholestanol accumulation in various tissues, including peripheral nerves. Polyneuropathy is an underrecognized feature with considerable variability in clinical presentation and neurophysiological findings in CTX. This review assesses the prevalence, clinical manifestations, and diagnostic methodologies of polyneuropathy in CTX, exploring its underlying mechanisms and potential treatment outcomes. A literature review was conducted using PubMed, Embase, and the Virtual Health Library databases with search terms related to CTX and polyneuropathy. A total of 892 articles were initially identified, with 59 selected for in-depth analysis. The review focused on studies examining peripheral nerve involvement in CTX, including nerve conduction studies, electromyography, and nerve ultrasound. Polyneuropathy in CTX was observed in 50% to 77.7% of patients across multiple case series. Neurophysiological findings varied, with reports of axonal, demyelinating, and mixed polyneuropathies. Clinical presentation included lower limb atrophy, pes cavus, and distal weakness, with sensory symptoms less frequently reported. Treatment with chenodeoxycholic acid (CDCA) showed potential in improving nerve conduction parameters, although the response was variable and dependent on the timing of intervention. Polyneuropathy in CTX presents significant diagnostic challenges due to its heterogeneous presentation and varying neurophysiological findings. Early recognition and intervention are crucial for improving patient outcomes. Peripheral nerve ultrasound is a promising diagnostic tool, complementing traditional neurophysiological assessments. Further research is needed to standardize protocols and explore the full therapeutic potential of CDCA in managing CTX-related polyneuropathy. Full article

Background: The link between diabetes mellitus (DM) and pathological conditions of the hand has been previously investigated. Retinopathy is one of the most common microvascular complications of DM. In this study, we aimed to evaluate the relationship between hand abnormalities and retinopathy in patients with type 2 DM. Methods: Patients with type 2 DM were assessed for hand abnormalities using tactile, functional, and sensory tests. The patients were evaluated electrodiagnostically for carpal tunnel syndrome and polyneuropathy (PNP). A comprehensive ophthalmologic examination was performed to diagnose diabetic retinopathy (DR). Subjective disability and quality of life were evaluated using the Quick DASH questionnaire. The duration of the disease and HbA1c levels were noted. Results: A total of 60 patients with type 2 DM (32 female, 28 male) were recruited for this study. The mean age was 55.1 ± 5.6 years. Among the 60 diabetic patients examined, 15 (25%) were diagnosed with DR. The mean duration of DM was 86.86 ± 51.69 months in patients without DR and 144.75 ± 82.96 months in patients with DR. The mean HbA1c level was 8.86% in the DR group and 8.64% in the non-DR group. PNP was the only hand abnormality that showed a significant association with retinopathy (p = 0.011). Conclusions: PNP might be used as a clue to the presence of retinopathy, especially in long-lasting diabetes. Particular attention should be given to hand abnormalities, especially in patients with PNP, due to their association with DR. Full article

Introduction: Diabetic neuropathy (DN) is a generic term for various neuropathies coexisting in a single patient. Clinical diagnosis alone can be misleading, yet routine electrodiagnostic studies in diabetes care are rare. Skin autofluorescence (SAF) is a recognized DN risk factor with potential screening value. This article highlights the diagnostic challenges and raises awareness of the often underdiagnosed neuropathic conditions in diabetes patients. Material and Methods: We present common entrapment neuropathy cases from our diabetes clinic’s electrodiagnosis laboratory in Iași, Romania. We selected seven type 2 diabetes patients with sensory or sensory-motor distal polyneuropathy and atypical DN presentations investigated through electroneurography (ENG) and electromyography (EMG) with the Neurosoft^® EMG instrument and SAF measured by standard procedures. Subsequently, a narrative literature review was conducted. Results: Entrapment neuropathies were diagnosed in all the patients: three carpal tunnel syndromes, two ulnar neuropathies (one proximal, one distal), one peroneal neuropathy, and one case of meralgia paresthetica. The lower-limb cases showed radiculoplexopathy, and there was one case of superficial radial nerve neuropathy. The SAF values ranged from 2.5 AU to 3.4 AU. Conclusions: Electrodiagnosis is essential for detecting focal neuropathies in patients with sensory-motor distal polyneuropathy. Elevated SAF levels may correlate with symptom severity, although further research, including large cohorts, is needed. Full article

Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a—known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 μM: 2221 ± 466 μm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities. Full article

The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN. Full article

Acrodermatitis chronica atrophicans (ACA) is not an infrequent condition in Europe. However, the characteristic skin lesions are often confused by non-dermatologists with other conditions. We report three unusual cases in which we made a definitive diagnosis of ACA complicated by cutaneous marginal zone lymphoma, juxta-articular fibrotic nodules, or bilateral sensory polyneuropathy. In all cases, correct diagnosis and adequate treatment was delayed over a period of at least 12 months. We initiated systemic antibiotics resulting in full recovery in these patients. The present case reports underscore that ACA may be associated with unusual clinical presentation which potentially result in delay of correct diagnosis and treatment. Hence, ACA diagnosis may be considerably delayed leading to inappropriate therapy exposure, prolonged patients’ suffering, and causing unnecessary cost. Thus, physicians who are not familiar with skin conditions should seek a timely dermatologist consultation. Full article