Peripheral Neuropathy Research Articles

EFFECTIVE MANAGEMENT STRATEGIES FOR TREATEMENT OF DIABETIC FOOT ULCER

Background: Diabetes mellitus is a rapidly rising disease worldwide. It has many complications affecting the overall health status of diabetic individuals as well as their life quality. Peripheral vascular and neuropathy are among the devastating complications of diabetes. They result in diabetic foot ulcer development. This should be prevented initially by preventative strategies which include annual screening of diabetic-foot and patient’s education of self-care. When ulcers happen, different approaches could be takento manage patients. Aim: the aim of this review article is to spots light on different management methods to treat diabetic foot ulcers.Material & Methods: PRISMA method is used to collect the articles from different data bases such as web of science, Scopus.Total 608 articles found relevant after applying inclusion exclusion criteria and duplication criteria total 27 articles were included in theanalysis. Findings: From the literature review eight factors are found which are discussed in detail in the paper. Conclusions: Diabetes mellitus is a long-term condition that can lead to serious complications. In their lifetime, around one-third of diabetic people may develop foot ulcers

Structural changes in the nociceptive system induced by long-term conventional spinal cord stimulation in experimental painful diabetic polyneuropathy

BackgroundClinical studies suggest that long-term conventional spinal cord stimulation (LT-SCS) for painful diabetic peripheral neuropathy (PDPN) is initially effective but may decline in efficacy over time. Preclinical studies indicate that LT-SCS alleviates mechanical hypersensitivity and enhances hind paw blood flow in PDPN rats, suggesting nociceptive system plasticity. This study hypothesized that LT-SCS induces peripheral hind paw small-fiber sprouting and reduces central protein expression of glial and P2X4 brain-derived neurotrophic factor (BDNF) pathway markers.MethodsDiabetes was induced via Streptozotocin injection in 32 rats, with 16 developing PDPN and receiving a quadrupolar lead implant. LT-SCS was applied for 4 weeks, 12 hours per day. Pain behavior was assessed using the Von Frey test for mechanical hypersensitivity and the mechanical conflict avoidance system for motivational aspects of pain. Fiber sprouting was assessed via immunohistochemical analysis of nerve fibers in the hind paw skin. Protein expression in the spinal cord was assessed using western blotting.ResultsLT-SCS increased the baseline threshold of mechanical hypersensitivity in PDPN animals, consistent with previous findings, but showed no effects on motivational aspects of pain. Hind paw tissue analysis revealed significantly increased intraepidermal nerve fiber density of PGP9.5 fibers in LT-SCS animals compared with Sham-SCS animals. Protein analysis showed significantly decreased pro-BDNF expression in LT-SCS animals compared with Sham-SCS animals.ConclusionLT-SCS induces structural changes in both peripheral and central components of the nociceptive system in PDPN animals. These changes may contribute to observed behavioral modifications, elucidating mechanisms underlying LT-SCS efficacy in PDPN management.

ANALYSIS OF NURSING CARE IN DIABETES MELLITUS PATIENTS THROUGH DIABETIC FOOT EXERCISE INTERVENTION FOR BLOOD CIRCULATION IMPROVEMENT IN TERATAI ROOM, IHC RSU WONOLANGAN PROBOLINGGO

Background: Diabetes mellitus, a chronic metabolic disease, can lead to serious complications, including impaired blood circulation in the extremities, termed diabetic foot, leading to peripheral neuropathy and poor perfusion. Objectives: This study aimed to assess the impact of diabetic foot exercise on improving blood circulation among diabetic patients. Design: This case study utilized a descriptive method on two diabetic patients in Teratai Room, RSU Wonolangan Probolinggo. Foot exercise intervention was implemented three times weekly for 15–20 minutes. Results: Both patients showed improvement in peripheral blood circulation, indicated by Ankle Brachial Index (ABI) scores within the mild obstruction range after consistent foot exercise. Conclusion: Regular diabetic foot exercises may enhance blood circulation and prevent complications among diabetes mellitus patients.

Genetic landscape of primary mitochondrial diseases in children and adults using molecular genetics and genomic investigations of mitochondrial and nuclear genome

Abstract Background Primary mitochondrial diseases (PMD) are one of the most common metabolic genetic disorders. They are due to pathogenic variants in the mitochondrial genome (mtDNA) or nuclear genome (nDNA) that impair mitochondrial function and/or structure. We hypothesize that there is overlap between PMD and other genetic diseases that are mimicking PMD. For this reason, we performed a retrospective cohort study. Methods All individuals with suspected PMD that underwent molecular genetic and genomic investigations were included. Individuals were grouped for comparison: (1) individuals with mtDNA-PMD; (2) individuals with nDNA-PMD; (3) individuals with other genetic diseases mimicking PMD (non-PMD); (4) individuals without a confirmed genetic diagnosis. Results 297 individuals fulfilled inclusion criteria. The diagnostic yield of molecular genetics and genomic investigations was 31.3%, including 37% for clinical exome sequencing and 15.8% for mitochondrial genome sequencing. We identified 71 individuals with PMD (mtDNA n = 41, nDNA n = 30) and 22 individuals with non-PMD. Adults had higher percentage of mtDNA-PMD compared to children (p-value = 0.00123). There is a statistically significant phenotypic difference between children and adults with PMD. Conclusion We report a large cohort of individuals with PMD and the diagnostic yield of urine mitochondrial genome sequencing (16.1%). We think liver phenotype might be progressive and should be studied further in PMD. We showed a relationship between non-PMD genes and their indirect effects on mitochondrial machinery. Differentiation of PMD from non-PMD can be achieved using specific phenotypes as there was a statistically significant difference for muscular, cardiac, and ophthalmologic phenotypes, seizures, hearing loss, peripheral neuropathy in PMD group compared to non-PMD group.

Potential effects of peripheral neuropathy on brain function in patients with type 2 diabetes mellitus

BackgroundThe mechanisms associated between diabetic peripheral neuropathy (DPN) and various brain function abnormalities in patients remains unclear. This study attempted to indirectly evaluate the effect of DPN on brain function in patients with type 2 diabetes mellitus (T2DM) by characterizing the resting-state functional connectivity (FC) of the lower limb sensorimotor cortex (LSM).MethodsForty-four T2DM patients with diabetic peripheral neuropathy (DPN), 39 T2DM patients without diabetic peripheral neuropathy (ND), and 43 healthy controls (HCs) underwent a neuropsychological assessment and resting-state functional magnetic resonance imaging examinations to examine the differences in FC between the LSM and the whole brain. The relationships of FC with clinical/cognitive variables were examined.ResultsIn comparison with the HCs group, the ND group showed reduced FC of the LSM with the right lateral occipitotemporal cortex (LOTC) and increased FC with the medial superior frontal gyrus (SFGmed), while the DPN group showed reduced FC of the LSM with the right cerebellar lobule VI, the right LOTC, the rostral prefrontal cortex (rPFC), and the anterior cingulate gyrus (ACC). Moreover, in comparison with the ND group, the DPN group showed reduced FC of the LSM with the ACC, SFGmed, and rPFC. In the DPN group, the FC between the LSM and right cerebellar lobule VI was significantly correlated with fasting blood glucose levels (r = -0.490, p = 0.001), and that between the LSM and ACC was significantly correlated with the Montreal Cognitive Assessment score (r = 0.479, p = 0.001).ConclusionsPatients with T2DM may show abnormal motion-related visual perceptual function before the appearance of DPN. Importantly, DPN can influence the brain regions that maintain motion and motor control, and this effect is not limited to motor function, which may be the central neuropathological basis for diabetic peripheral neuropathy.

Increased cardiovascular risk in people with LADA in comparison to type 1 diabetes and type 2 diabetes: Findings from the DPV registry in Germany and Austria

AbstractIntroductionWe aimed to characterise and compare individuals diagnosed with type 1 diabetes (T1D), latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D), in a real‐world setting.MethodsAnthropometric and clinical data from 36 959 people with diabetes diagnosed at age 30–70 years enrolled in the prospective diabetes patients follow‐up (DPV) registry from 1995 to 2022 were analysed cross‐sectionally at diagnosis and follow‐up (≥6 months after diagnosis). LADA was defined as clinical diagnosis of T2D, positivity of ≥1 islet autoantibody and an insulin‐free interval of ≥6 months upon diabetes diagnosis.ResultsAt diagnosis, age, body mass index, waist circumference, C‐peptide and HbA1c in people with LADA (n = 747) fell in between individuals with T1D (n = 940) and T2D (n = 35 272) (all p‐values < 0.01). At follow‐up, after adjusting for age, sex and diabetes duration, the prevalence of dyslipidemia and hypertension was the highest in people with LADA (90.6%, 77.7%) compared to people with T2D (81.8%, 60.4%) and T1D (75.7%, 39.7%) (p < 0.01). The prevalence of diabetic kidney disease (DKD) was higher in LADA (44.2%), than in T1D (19.9%) (p < 0.01). The prevalence of peripheral neuropathy was higher in individuals with LADA (55.1%) than in T2D (43.9%) and T1D (42.1%) (p < 0.05). Coverage of treatment for hypertension and dyslipidemia were 22.4% and 15.0% in T1D, 63.0% and 36.6% in LADA and 29.4% and 18.2% in T2D.ConclusionPeople with LADA had a higher prevalence of cardiovascular risk factors (dyslipidemia, hypertension) and cardiovascular complications (DKD and peripheral neuropathy), suggesting that people with LADA are at need for improved recognition and care.

NCMP-27. NEUROLOGICAL COMPLICATIONS IN LUNG CANCER THERAPIES: UNVEILING THE ELEVATED RISKS IN CHEMOTHERAPY AND TARGETED TREATMENT APPROACHES

Abstract BACKGROUND Neurological complications due to lung cancer treatments are a common side effect, with prevalence ranging from 19% to over 80% depending on the drug administered. Peripheral neuropathy is the most common manifestation of chemotherapy associated neurotoxicity, but there are potential central nervous system impacts as well, such as seizures, dementia, and generalized cognitive impairment. Occurrence of similar effects is less commonly reported with targeted gene therapy for cancer, however the exact prevalence has not been determined. DESIGN/METHODS We searched the US Collaboration network through TriNetX for all cases of lung cancer, identified by ICD-10 code C34. Cohort A was defined as adults 18-70 years old that had lung cancer treated with cisplatin or etoposide. Cohort B was defined as adults 18-70 that had lung cancer treated with crizotinib, alectinib, or epidermal growth factor receptor tyrosine kinase inhibitors. Outcomes were evaluated from 1 day to 5 years after the indexed event. RESULTS We reported 15,268 patients with lung cancer that were prescribed chemotherapy agents matched with 6,490 patients with lung cancer that were prescribed tyrosine kinase inhibitors. Patients prescribed chemotherapy agents were at significantly higher risk for neurological complications post treatment when compared to those treated with tyrosine kinase inhibitors (p < 0.0001). CONCLUSIONS Patients diagnosed with lung cancer on chemotherapy 18-70 years old displayed higher associated risk of various neurological disorder diagnoses. Patients undergoing chemotherapy should be educated about this increased risk and talk with their providers about alternative treatments. Further research should be conducted on the range of potential neurological complications associated with chemotherapy regimens.

CTNI-36. THE FEASIBILITY OF USING BORTEZOMIB WITH CHEMOTHERAPY IN ATYPICAL TERATOID/RHABDOID TUMORS

Abstract Atypical teratoid/rhabdoid tumors (ATRTs) are highly aggressive pediatric brain tumors with sensitivity to proteasome inhibitors in preclinical models. We evaluated the feasibility of combining the proteasome inhibitor bortezomib with chemotherapy. Patients aged 0-20 years with newly diagnosed ATRT were enrolled from January 2022 through December 2023. A modified Medical University of Vienna (MUV)-ATRT regimen was used. They were treated with bortezomib of 1.3 mg/m2/dose given intravenously or subcutaneously twice a week for 2 weeks concurrently with 6 cycles of chemotherapy and 2 additional cycles after high-dose chemotherapy. Radiation therapy was given prior to or at the end of chemotherapy. A total of 36 chemotherapy cycles with bortezomib in 6 patients were evaluated. The primary endpoint was grade 3 or higher non-hematologic toxicities. Numbers of cycles with grade 3+ toxicities included: AST/ALT elevation (1), hypokalemia (2), peripheral neuropathy (1), subdural hemorrhage (2), vomiting (2), oral mucositis (3), lung infection (2), urinary tract infection (8), sepsis (3), febrile neutropenia (20). No grade 3+ toxicities were considered bortezomib-related. Three patients completed 8 cycles of bortezomib treatment; 2 patients discontinued the study due to progressive disease after 2 and 4 cycles respectively; 1 patient completed 6 cycles of bortezomib and died of septic shock in complete remission after high-dose chemotherapy. Two patients had a surgical complete resection. Three patients were evaluable for response after bortezomib: 1 partial response and 2 stable disease. Two patients had progression-free survival for 16+ and 22+ months after diagnosis, respectively. Among the 3 patients with progressive disease, 2 had metastatic relapse and 1 had primary and metastatic relapse. There were 4 deaths due to metastatic PD (n=2), septic shock after high-dose chemotherapy (n=1), and septic shock after 2nd line treatment for PD (n=1). We conclude that adding bortezomib to standard and high-dose chemotherapy of ATRT was feasible with the occurrence of grade 3/4 toxicities no more than what was expected with chemotherapy alone. Metastatic relapse remains the major challenge of ATRT treatment.

The cumulative impact of type 2 diabetes and obstructive sleep apnoea on cardiovascular, liver, diabetes‐related and cancer outcomes

AbstractAimA bidirectional relationship exists between obstructive sleep apnoea (OSA) and type 2 diabetes (T2D). We aimed to examine the cumulative impact of having both OSA and T2D on patient outcomes, relative to having either condition alone.Materials and methodsUsing TriNetX, a global federated research network (n = 128 million), we undertook two retrospective cohort studies, using time‐to‐event analysis. Analysis 1 compared OSA with T2D versus OSA alone; analysis 2 compared T2D with OSA versus T2D alone. Propensity score matching using greedy nearest neighbour (calliper 0.1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes‐related (microvascular) and cancer events over 1–5 years.ResultsAnalysis 1 (n = 179 688): A codiagnosis of T2D/OSA significantly increased risk of all‐cause mortality (hazard ratio [HR] 1.52; confidence interval [CI]: 1.48, 1.57), dementia (HR 1.19; CI: 1.12, 1.26), liver (HR 2.20; CI: 1.77, 2.73), pancreatic (HR 1.62; CI: 1.35, 1.93), colon, renal and endometrial cancers; all cardiovascular, microvascular and liver related outcomes versus OSA alone over 1–5 5 years following OSA diagnosis. Analysis 2 (n = 240 094): A codiagnosis of OSA/T2D significantly increased the risk of peripheral (HR 1.39; CI: 1.36, 1.43) and autonomic (HR 1.63; CI: 1.51, 1.75) neuropathy; retinopathy (HR 1.13; CI: 1.09, 1.18), CKD (HR 1.21; CI: 1.18, 1.23); all cardiovascular and liver outcomes; all‐cause mortality and several obesity related cancers versus T2D alone.ConclusionsT2D significantly potentiates risk of cardiovascular, malignancy and liver‐related outcomes in individuals with OSA. OSA, in individuals with T2D, significantly potentiates risk of cardiovascular disease, malignancy, death and several microvascular complications (retinopathy, CKD, peripheral/autonomic neuropathy).

BIOS-03. CLINICAL PRESENTATION, MANAGEMENT, AND OUTCOME IN NEUROLYMPHOMATOSIS: A SYSTEMATIC REVIEW AND ANALYSIS OF INDIVIDUAL PATIENT DATA FROM 459 CASES

Abstract BACKGROUND Neurolymphomatosis (NL) refers to lymphomatous infiltration of the peripheral nervous system (PNS). NL diagnosis and treatment are challenging given the broad differential diagnosis of peripheral neuropathy, the lack of larger cohorts and the subsequent unavailability of prognostic factors or consensus therapy. This study aimed to define characteristics and prognostic factors of NL. METHODS A systematic review of the literature (2004-2023) was performed using PubMed and Scopus databases and reported following PRISMA guidelines. Clinical, radiological, pathological and outcome information were extracted. Multivariable survival analyses were performed using Cox proportional hazard models. RESULTS A total of 459 NL cases from 264 studies were accumulated. NL was the first manifestation of malignancy (primary NL) in 197 patients. PNS relapse of known non-Hodgkin lymphoma (secondary NL) occurred in 262 cases after a median 12 months. NL predominantly presented with rapidly deteriorating, asymmetric painful polyneuropathy. Infiltrated structures included peripheral nerves (56%), nerve roots (52%), plexus (33%) and cranial nerves (32%). Diagnosis was established at a median of 3 months after symptom onset with substantial delays in primary NL. It mainly relied on PNS biopsy or FDG-PET, which carried high diagnostic yields (> 90%). Post mortem diagnoses were rare (3%). Most cases were classified as B-cell (90%) lymphomas. Tumor-directed therapy was administered in 96% of patients and typically consisted of methotrexate or rituximab-based polychemotherapy. Median overall survival was 18 months. Primary NL without concurrent systemic disease outside the nervous system (hazard ratio [HR]: 0.44; 95% confidence interval (CI): 0.25-0.78; p = 0.005), performance status (ECOG < 2, HR: 0.30; 95% CI: 0.18-0.52; p < 0.0001), and rituximab-based treatment (HR: 0.46; 95% CI: 0.28-0.73; p = 0.001) were identified as favorable prognostic markers on multivariable analysis when adjusting for clinical and sociodemographic parameters. CONCLUSIONS Advances in neuroimaging modalities, particularly FDG-PET, facilitate NL diagnosis and offer a high diagnostic yield. Rituximab-based therapy improves NL outcome. Findings may assist clinicians in early recognition, prognostic stratification, and treatment of NL.

Development of a Novel Microphysiological System for Peripheral Neurotoxicity Prediction Using Human iPSC-Derived Neurons with Morphological Deep Learning

A microphysiological system (MPS) is an in vitro culture technology that reproduces the physiological microenvironment and functionality of humans and is expected to be applied for drug screening. In this study, we developed an MPS for the structured culture of human iPSC-derived sensory neurons and then predicted drug-induced neurotoxicity by morphological deep learning. Using human iPSC-derived sensory neurons, after the administration of representative anti-cancer drugs, the toxic effects on soma and axons were evaluated by an AI model with neurite images. Significant toxicity was detected in positive drugs and could be classified by different effects on soma or axons, suggesting that the current method provides an effective evaluation of chemotherapy-induced peripheral neuropathy. The results of neurofilament light chain expression changes in the MPS device also agreed with clinical reports. Therefore, the present MPS combined with morphological deep learning is a useful platform for in vitro peripheral neurotoxicity assessment.

Current Animal Models of Chemotherapy-Induced Peripheral Polyneuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic chemotherapy. In a large number of patients, this complication is highly persistent to treatment. The present review is focused on current rodent CIPN models using antineoplastic agents of different groups.

NCMP-12. AN ATYPICAL CASE OF POEMS WITH MACROFOCAL MYELOMA

Abstract Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome is a rare paraneoplastic syndrome secondary to an underlying plasma cell dyscrasia. Symptoms of peripheral neuropathy dominate the clinical picture and is postulated to be related to serum vascular endothelial growth factor (VEGF) mediated altered permeability of the blood nerve barrier. The classic presentation includes a solitary osteosclerotic plasmacytoma and an elevation of VEGF. In this case, we present a patient with neither of these features who met diagnostic criteria for POEMS though had predominantly osteolytic lesions and was diagnosed with macrofocal myeloma, a unique subset of multiple myeloma. Our patient is a young male who presented with progressive leg numbness/weakness and was found to have marked ankle weakness, diffuse areflexia and unilateral gynecomastia on examination. EMG showed a motor predominant demyelinating polyneuropathy. Labs showed a serum IgG lambda M protein, low estradiol and low testosterone. He had a normal serum VEGF level though the lab was drawn after treatment initiation. Bone biopsy of a dominant osteolytic lesion was consistent with a plasma cell neoplasm (light chain restricted). Of note, he had mild cauda equina nerve root and ventral conus enhancement initially concerning for leptomeningeal involvement however, two lumbar punctures were negative for malignant cells. Spinal enhancement has been reported in POEMS. The patient underwent chemotherapy, radiation therapy and autologous stem cell transplantation. We present a patient diagnosed with MFMM, a rare subset of multiple myeloma, comprising only 3% of all cases, along with POEMS, a rare paraneoplastic syndrome. Interestingly, as osteolytic lesions can be seen in POEMS alone though not predominantly so, it is possible the patient could have atypical POEMS without underlying multiple myeloma. POEMS may remain under-recognized when presentations or setting are atypical.

Post-marketing surveillance of anticancer drugs using natural language processing of electronic medical records

This study demonstrates that adverse events (AEs) extracted using natural language processing (NLP) from clinical texts reflect the known frequencies of AEs associated with anticancer drugs. Using data from 44,502 cancer patients at a single hospital, we identified cases prescribed anticancer drugs (platinum, PLT; taxane, TAX; pyrimidine, PYA) and compared them to non-treatment (NTx) group using propensity score matching. Over 365 days, AEs (peripheral neuropathy, PN; oral mucositis, OM; taste abnormality, TA; appetite loss, AL) were extracted from clinical text using an NLP tool. The hazard ratios (HRs) for the anticancer drugs were: PN, 1.15–1.95; OM, 3.11–3.85; TA, 3.48-4.71; and AL, 1.98–3.84; the HRs were significantly higher than that of the NTx group. Sensitivity analysis revealed that the HR for TA may have been underestimated; however, the remaining three types of AEs extracted from clinical text by NLP were consistently associated with the three anticancer drugs.

Split hand and minipolymyoclonus in spinocerebellar ataxia type 3: a case report

BackgroundSpinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in exon 10 of ATXN3. Extra-cerebellar manifestations, including external ophthalmoplegia, dystonia, Parkinsonism, and peripheral neuropathy, are predominantly present in SCA3 cases. Here, we report a case of SCA3 presenting with a split hand and minipolymyoclonus.Case presentationA 73-year-old female patient presented with a 5-year history of ataxic gait. Neurological examination revealed cerebellar ataxia and minipolymyoclonus in the digits on both sides and muscle atrophy in the right hand, consistent with the split hand pattern. Electrodiagnostic studies demonstrated decreased amplitude of compound muscle action potentials and neurogenic motor unit potentials, indicating lower motor neuron involvement.ConclusionsOur patient’s case indicated a split hand and minipolymyoclonus in SCA3. Clinicians should consider these extra-cerebellar manifestations in patients with SCA3. Although neither split hand nor minipolymyoclonus are likely to directly result in a specific etiological diagnosis, a common pathophysiological mechanism for both may be lower motor neuron involvement. This extracerebellar manifestation contributes to narrowing down the diagnostic possibilities for cases presenting with progressive cerebellar ataxia.

Assessing the diagnostic utility of urinary albumin-to-creatinine ratio as a potential biomarker for diabetic peripheral neuropathy in type 2 diabetes mellitus patients

Background and aimsDiabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN) both have microcirculation dysfunction. Urinary albumin-to-creatinine ratio (UACR) is a biomarker for DN. We aimed to explore the links between DPN and UACR in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 195 T2DM patients were defined as Control or DPN group. Clinical parameters were compared, and the association between HbA1c (or UACR) and DPN was analyzed. Risk factors for DPN were observed, and the diagnostic values of HbA1c and UACR were assessed.ResultsCompared with 104 participants without DPN, 91 individuals with DPN exhibited higher HbA1c and UACR levels. In all patients, increased HbA1c and UACR were identified as risk factors for DPN in individuals with T2DM. Moreover, increased HbA1c was a risk factor for DPN in volunteers without DN, whereas elevated UACR was determined as a risk factor for DPN in participants with DN. The cut-off point for HbA1c (7.65%) in patients without DN had a sensitivity of 86.0% and specificity of 44.6%, while the cut-off point for UACR (196.081 mg/g) in patients with DN had a sensitivity of 52.9% and specificity of 76.2%.ConclusionElevated HbA1c and UACR levels are risk factors for DPN and may serve as potential biomarkers for DPN in T2DM patients.

Structure-Activity Relationships and Discovery of (S)-5-(tert-Butyl)-11-(difluoromethoxy)-9-methoxy-2-oxo-1,2,5,6-tetrahydropyrido[2',1':2,3]imidazo[4,5-h]quinoline-3-carboxylic Acid (AB-161), a Novel Orally Available and Liver-Centric HBV RNA Destabilizer.

Lowering hepatitis B surface antigen (HBsAg) levels from covalently closed circular DNA (cccDNA) and the integrated genome could reduce the persistence of hepatitis B virus (HBV) infection. Since HBV replication occurs in the liver and to ameliorate the peripheral neuropathy observed with a first-generation tricyclic 4-pyridone PAPD5/7 inhibitor (AB-452) having high systemic exposure, we focused on increasing the hepatocyte concentration and reducing plasma levels. Optimization of a novel series of PAPD5/7 inhibitors that decrease HBsAg levels led to the tetracyclic 2-pyridone AB-161, which was similarly potent to AB-452 in vitro and in vivo but showed dramatically higher rodent liver-to-plasma ratios. There were no neurobehavioral effects with AB-161 in dogs up to 45 mg/kg after 60 days, unlike with AB-452, where these were observed at lower doses by day 14. AB-161 was then advanced into 90-day GLP toxicology studies, where the improved neurotoxicity profile persisted, but reproductive issues emerged, leading to discontinuation.

Profiles of Peripheral Neuropathy and Risk Factors in People With Treatment-Naive Type 2 Diabetes Mellitus and Prediabetes

Profiles of Peripheral Neuropathy and Risk Factors in People With Treatment-Naive Type 2 Diabetes Mellitus and Prediabetes

Isolated peripheral neuroleukemiosis mimicking Guillain‐Barré syndrome in an adolescent with relapsed B‐lymphoblastic leukemia

AbstractBackgroundNeuroleukemiosis, leukemic infiltration of the peripheral nervous system (PNS), is rare. Very few cases of isolated neuroleukemiosis, PNS leukemic infiltration without leukemia blasts in the blood or bone marrow, have been reported in pediatrics. Most cases have occurred in adults with acute myelogenous leukemia (AML) in remission who presented with peripheral neuropathy. We describe a pediatric patient presenting with isolated neuroleukemiosis mimicking Guillain‐Barré syndrome.Patient descriptionA 15‐year‐old boy presented 1 month after IVIG treatment for Guillain‐Barre syndrome with worsening ataxia and weakness. He had a past medical history of B‐cell acute lymphoblastic leukemia (B‐ALL) in remission for 8 years. Examination revealed distal greater than proximal weakness of the bilateral lower extremities, areflexia at the Achilles tendon, and 1+ patellar and upper extremity reflexes. Initial magnetic resonance imaging (MRI) of the brain and spine were normal, and lumbar puncture revealed increased protein with uninterpretable white count due to excessive red blood cells. Repeat MRI brain and spinal cord showed extensive enlargement of all nerve roots and enhancement of the cauda equina and portions of cranial nerve VII bilaterally. Repeat lumbar puncture with cytology revealed leukemic blast cells. Blasts were not detected in peripheral blood smear or by flow cytometry. Bone marrow biopsy was also free of blast cells, confirming the diagnosis of relapsed B‐ALL restricted to the nervous system.ConclusionsNeuroleukemiosis is a rare entity with typical clinical features of mono‐ or polyneuropathy. It most often occurs in adults in remission from AML. However, neuroleukemiosis should also be on the differential for pediatric patients in remission from ALL presenting with neuropathy.

LX9211, a rising star for relieving of diabetic peripheral neuropathic pain.

In a multicenter trial, LX9211 significantly reduced pain in diabetic peripheral neuropathy (DPN) patients, with the 10 mg dose showing notable relief by the first week. Although the higher dose was less effective, side effects like dizziness and nausea were generally mild. These findings highlight the importance of exploring both pharmaceutical and natural treatments, such as flavonoids, for managing DPN.