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Diana Hedevang Christensen,1,2 Søren Tang Knudsen,3 Sia Kromann Nicolaisen,1 Henning Andersen,2,4 Brian Christopher Callaghan,2,5 Nanna Brix Finnerup,2,4,6 Troels Staehelin Jensen,2,4,6 Reimar Wernich Thomsen11Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; 2International Diabetic Neuropathy Consortium, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark; 3Steno Diabetes Center Aarhus (SDCA), Aarhus University Hospital, Aarhus, Denmark; 4Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; 5Department of Neurology, University of Michigan, Ann Arbor, MI, USA; 6Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, DenmarkPurpose: We examined whether diabetic polyneuropathy (DPN) and diabetic foot ulcers in type 2 diabetes can be accurately identified using International Classification of Diseases, 10th revision discharge diagnosis codes, surgery codes, and drug prescription codes.Methods: We identified all type 2 diabetes patients in the Central Denmark region, 2009–2016, who had ≥1 primary/secondary diagnosis code of “diabetes with neurological complication” (E10.4-E14.4), “diabetic polyneuropathy” (G63.2), or “polyneuropathy, unspecified” (G62.9). Patients with potential painful DPN and non-painful DPN were identified based on prescription history for serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, or gabapentinoids. Likewise, type 2 diabetes patients with potential foot ulcers were identified based on diagnosis or surgery codes. We used medical record review as the reference standard and calculated positive predictive values (PPVs).Results: Of 53 randomly selected patients with potential painful DPN, 38 were classified as having DPN when validated against medical records; of these, 18 also had neuropathic pain, yielding a PPV of 72% (95% CI: 58–83%) for DPN and 34% (95% CI: 22–48%) for painful DPN. Likewise, among 54 randomly selected patients with potential non-painful DPN, 30 had DPN based on medical record data; of these, 27 had non-painful DPN, yielding PPVs of 56% (95% CI: 41–69%) and 50% (95% CI: 36–64%), respectively. Secondary E-chapter codes often denoted stroke or mononeuropathies, rather than DPN. Excluding secondary E-chapter codes from the algorithm increased the PPV for DPN to 78% (95% CI: 63–89%) for the painful DPN cohort and to 74% (95% CI: 56–87%) for the non-painful DPN cohort. Of 53 randomly selected patients with potential diabetic foot ulcer, only 18 diagnoses were confirmed; PPV=34% (95% CI: 22–48%).Conclusion: G-chapter and primary E-chapter diagnosis codes can detect type 2 diabetes patients with hospital-diagnosed DPN, and may be useful in epidemiological research. In contrast, our diabetic foot ulcer algorithm did not perform well.Keywords: positive predictive value, epidemiology, registries, diabetic polyneuropathy, diabetic foot ulcer, type 2 diabetes

Objective: To determine the association between triglyceride levels and lower-extremity amputation (LEA) risk in a large diabetic cohort.Research Design and Methods: This is a 10-year survey follow-up study (from 1995-2006) of 28,701 diabetic patients with a baseline triglyceride measure. All patients were fully insured members of the Kaiser Permanente Medical Care Program and responded to a survey at baseline that included information on ethnicity, socioeconomic status, education, behavioral factors, and information required to determine type of diabetes. The relationship between triglycerides and time to incident nontraumatic LEA, defined by primary hospitalization discharge or procedures, was evaluated using Cox proportional hazards models.Results: Triglyceride level was an independent, stepwise risk factor for nontraumatic LEAs within this large diabetic cohort: triglycerides 150-199 mg/dL, hazard ratio (HR) 1.10 (95% CI 0.92-1.32); 200-499 mg/dL, 1.27 (1.10-1.47); >500 mg/dL, 1.65 (1.30-2.10) (reference <150 mg/dL).Conclusions: Hypertriglyceridemia is a significant risk factor for LEA in diabetic patients even after controlling for known socioeconomic, health behavioral, and clinical factors. This previously unrecognized clinical risk needs to be further investigated to determine if treatment of triglycerides can reduce amputation risk. [ABSTRACT FROM AUTHOR]

Objectives: To observe medication cost trends for 5 common neurologic conditions., Methods: We quantified annual out-of-pocket (OOP) and total medication costs for patients seen by a neurologist with epilepsy, multiple sclerosis (MS), Parkinson disease (PD), peripheral neuropathy (PN), and dementia/Alzheimer's disease in a commercial claims database cross-sectionally from 2012 to 2021., Results: We identified 186,144 patients with epilepsy, 54,676 with MS, 45,909 with PD, 169,127 with PN, and 60,861 with dementia/Alzheimer. OOP costs for MS medications increased each year, by 217% on average. Branded epilepsy medications had higher OOP costs than generics. Decreases ranging from 48% to 80% in annual OOP costs of duloxetine, pregabalin, rasagiline, rivastigmine, and memantine were observed in the years after generic introduction., Discussion: Preferentially selecting generic medications reduces OOP costs, other than for MS where costs continue to increase. Policy solutions, such as cost caps, are needed.

Objective: Compare the diagnostic characteristics of intraepidermal nerve fiber density (IENFD) and confocal corneal microscopy (CCM) for distal symmetric polyneuropathy (DSP) and small fiber neuropathy (SFN)., Methods: Participants with obesity were recruited from bariatric surgery clinics and testing was performed prior to surgery. DSP and SFN were determined using the Toronto consensus definitions of probable neuropathy. IENFD was assessed from 3 mm punch biopsies of the distal leg and proximal thigh. CCM was performed on both eyes with manual and automated counting. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was also completed. Diagnostic capability was determined using areas under the receiver operating characteristics curve (AUC) from logistic regression., Results: We enrolled 140 participants (mean [standard deviation [SD]] age: 50.3 years [7.1], 77.1% female, BMI: 44.4 kg/m 2 [6.7]). In this population, 22.9% had DSP and 14.3% had SFN. Distal leg IENFD had the largest AUC (95% confidence interval) for DSP (0.78, 0.68-0.89) and SFN (0.85, 0.75-0.96). Proximal thigh IENFD (DSP: AUC: 0.59, 0.48-0.69, SFN: AUC: 0.59, 0.46-0.73) and CCM metrics (DSP: AUC range: 0.55-0.60, SFN: AUC range: 0.45-0.62) had poorer diagnostic capability than distal leg IENFD for DSP/SFN (P < 0.05). MNSIq had similar diagnostic capability to distal leg IENFD for both DSP/SFN (DSP: AUC: 0.76, 0.68-0.85, SFN: AUC: 0.81, 0.73-0.88). More participants (52%) preferred skin biopsies to CCM., Interpretation: Distal leg IENFD was the best quantitative measure of DSP/SFN. CCM had poor diagnostic characteristics and fewer patients preferred this test to IENFD. The MNSIq had similar diagnostic characteristics to distal leg IENFD, indicating its value as a diagnostic tool in the clinical setting., Clinical Trial Registration: clinicaltrials.gov: NCT03617185., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction/aims: Given the importance of early diagnosis and treatment of myasthenia gravis (MG), it is critical to understand disparities in MG care. We aimed to determine if there are any differences in testing, treatment, and/or access to neurologists for patients of varying sex and race/ethnicity with MG., Methods: We used a nationally representative healthcare claims database of privately insured individuals (2001-2018) to identify incident cases of MG using a validated definition. Diagnostic testing, steroid-sparing agents, intravenous immunoglobulin (IVIG), plasma exchange (PLEX), and thymectomy were defined using drug names or CPT codes. Steroid use was defined using AHFS class codes. We also determined whether an individual had a visit to a neurologist and the time between primary care and neurologist visits. Logistic regression determined associations between sex and race/ethnicity and testing, treatments, and access to neurologists., Results: Female patients were less likely to get a computed tomography (CT) chest (odds ratio (OR) 0.73, 95% confidence interval (CI): 0.64-0.83), receive steroids (OR: 0.85, 95% CI: 0.75-0.97), steroid-sparing agents (OR: 0.84, 95% CI: 0.72-0.97), and IVIG or PLEX (OR: 0.80, 95% CI: 0.67-0.95). Black patients were less likely to receive steroids (OR: 0.78, 95% CI: 0.63-0.96). No significant disparities were seen in access to neurologists., Discussion: We found healthcare disparities in MG treatment with female and Black patients receiving less treatment than men and those of other races/ethnicities. Further research and detailed assessments accounting for individual patient factors are needed to confirm these apparent disparities., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Purpose of Review: To examine the evidence evaluating the association between obesity and neuropathy as well as potential interventions., Recent Findings: Although diabetes has long been associated with neuropathy, additional metabolic syndrome components, including obesity, are increasingly linked to neuropathy development, regardless of glycemic status. Preclinical rodent models as well as clinical studies are shedding light on the mechanisms of obesity-related neuropathy as well as challenges associated with slowing progression. Dietary and surgical weight loss and exercise interventions are promising, but more data is needed., Summary: High-fat-diet rodent models have shown that obesity-related neuropathy is a product of excess glucose and lipid accumulation leading to inflammation and cell death. Clinical studies consistently demonstrate obesity is independently associated with neuropathy; therefore, likely a causal risk factor. Dietary weight loss improves neuropathy symptoms but not examination scores. Bariatric surgery and exercise are promising interventions, but larger, more rigorous studies are needed. Further research is also needed to determine the utility of weight loss medications and ideal timing for obesity interventions to prevent neuropathy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine bidirectional associations between the timing of chronic diabetes complications (CDCs) and mental health disorders (MHDs) in individuals with type 1 or type 2 diabetes., Research Design and Methods: We used a nationally representative health care claims database to identify matched individuals with type 1 or 2 diabetes or without diabetes using a propensity score quasirandomization technique stratified by age (0-19, 20-39, 40-59, and ≥60 years). CDCs and MHDs were identified using ICD-9/10 codes. We fit Cox proportional hazards models with time-varying diagnoses of CDCs or MHDs to investigate their association with the hazard of developing MHDs or CDCs, respectively., Results: From 2001 to 2018, a total of 553,552 individuals were included (44,735 with type 1 diabetes, 152,187 with type 2 diabetes, and 356,630 without diabetes). We found that having a CDC increased the hazard of developing an MHD (hazard ratio [HR] 1.9-2.9; P < 0.05, with higher HRs in older age strata), and having an MHD increased the hazard of developing a CDC (HR 1.4-2.5; P < 0.05, with the highest HR in age stratum 0-19 years). In those aged <60 years, individuals with type 1 diabetes were more likely to have CDCs, whereas individuals with type 2 diabetes were more likely to have MHDs. However, the relationship between CDCs and MHDs in either direction was not affected by diabetes type (P > 0.05 for interaction effects)., Conclusions: We found a consistent bidirectional association between CDCs and MHDs across the life span, highlighting the important relationship between CDCs and MHDs. Prevention and treatment of either comorbidity may help reduce the risk of developing the other., (© 2024 by the American Diabetes Association.)

Introduction/aims: Randomized controlled trials show that repeat intravenous immunoglobulin (IVIG) dosing and plasma exchange (PLEX) followed by IVIG (combination therapy) have no additional therapeutic benefit in Guillain-Barre Syndrome (GBS) non-responders. Furthermore, the delineation between GBS and Acute Onset CIDP (A-CIDP) can be particularly challenging and carries therapeutic implications. We aimed to evaluate the presence of repeat IVIG, combination therapy, and diagnostic reclassification from GBS to CIDP., Methods: We performed a retrospective study of a large healthcare database for patients with GBS in the US from 2001 to 2018. We identified individuals initially diagnosed with GBS and later re-classified as CIDP. Multivariable logistic regression models were developed to determine associations between patient factors and repeat IVIG dosing, combination therapy, and diagnostic re-classification from GBS to CIDP., Results: We identified 2325 patients with GBS. A total of 39.7% received repeat IVIG and 6.1% received combination therapy. The proportion of individuals initially diagnosed with GBS and then re-classified as CIDP was 32.0%. Repeat IVIG, combination therapy, and diagnostic reclassification remained stable over time. Female sex (OR 0.79, 95% CI 0.65-0.96) and medium-high net worth (OR 0.64, 95% CI 0.45-0.90) associated with repeat IVIG therapy, while Asian ethnicity associated with diagnostic re-classification from GBS to CIDP (OR 1.77, 95% CI 1.09-2.86)., Discussion: Repeat IVIG dosing was quite common in GBS before newer trials suggesting harm in non-responders, and IVIG/PLEX combination therapy continues to persist despite strong evidence against use in non-responders. Further, nearly one in three patients initially diagnosed with GBS is subsequently diagnosed with CIDP, but the reasons are unclear., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Background and Objectives: Reduction of blood lipids may aid in preventing diabetic polyneuropathy (DPN), but evidence remains conflicting. We investigated the association between lipid parameters and DPN risk in individuals with type 2 diabetes mellitus (T2DM)., Methods: We conducted a population-based cohort study of individuals with newly diagnosed T2DM and a cross-sectional study using a clinically recruited T2DM cohort. Triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and non-HDL cholesterol were measured in routine diabetes care. Each lipid parameter was categorized according to the latest cutoffs in clinical guidelines on dyslipidemia. DPN was assessed with validated hospital diagnosis codes in the population-based cohort and with the Michigan Neuropathy Screening Instrument questionnaire in the clinical cohort. We calculated hazard ratios (HRs) using Cox regression and prevalence ratios (PRs) using Poisson regression., Results: We included 61,853 individuals in the population-based cohort (median age 63 [quartiles 54-72] years) and 4,823 in the clinical cohort (median age 65 [quartiles 57-72] years). The incidence rate of hospital-diagnosed DPN in the population-based cohort was 3.6 per 1000 person-years during a median follow-up of 7.3 years. Achieving guideline targets for HDL, LDL, and non-HDL cholesterol showed no association with DPN risk. By contrast, adjusted HRs (95% CI) for DPN were 1.02 (0.89-1.18) for triglyceride levels between 150 and 204 mg/dL (1.7-2.3 mmol/L) and 1.28 (1.13-1.45) for levels >204 mg/dL (2.3 mmol/L). In the clinical cohort with a DPN prevalence of 18%, DPN associated strongly with triglycerides >204 mg/dL (2.3 mmol/L) with an adjusted PR (95% CI) of 1.40 (1.21-1.62). The prevalence of DPN was modestly elevated for individuals with HDL cholesterol <39 mg/dL (1.0/1.3 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women (PR 1.13 [0.99-1.28]) and for individuals with non-HDL cholesterol >131 mg/dL (3.4 mmol/L) (PR 1.27 [1.05-1.52]). In both cohorts, spline models showed an increasing risk of DPN starting from triglyceride levels >124 mg/dL (1.4 mmol/L). All results were similar among statin users., Discussion: High triglyceride levels are a strong DPN risk factor. Future intervention studies shall determine whether triglyceride reduction is more important for DPN prevention than reduction of other lipids.

Background and Objectives: Distal symmetric polyneuropathy (DSP) is a disabling, often painful condition associated with falls and reduced quality of life. Non-Hispanic Black people and people with low income are underrepresented in existing DSP studies; therefore, it is unknown whether data accurately reflect the prevalence, risk factors, and burden of disease in these populations., Methods: Patients older than 40 years presenting to an outpatient internal medicine clinic predominantly serving Medicaid patients in Flint, Michigan, were enrolled in a cross-sectional study. Demographics, clinical characteristics, including medication use, anthropomorphic measurements, fasting lipids, and hemoglobin A1c were collected. DSP was defined using the modified Toronto Clinical Neuropathy Score (mTCNS). Multivariable logistic regression was performed to model DSP and undiagnosed DSP as a function of potential risk factors age, metabolic syndrome, and race. DSP burden was measured using Peripheral Neuropathy Quality of Life Instrument-97., Results: Two hundred participants were enrolled, and 169 (85%) completed all data collection. The population was 55% female of mean age (SD) 58.2 years (10.4) and 69% non-Hispanic Black. Among the population, 50% had diabetes, 67% had metabolic syndrome, and 47% had a household income <$20,000. DSP was present in 73% of the population, of which 75% were previously undiagnosed. Neuropathic pain was documented in 57% of participants with DSP. DSP based on mTCNS criteria was associated with older age (odds ratio [OR] 1.1 [95% confidence interval (CI) 1.03-1.2]) and metabolic syndrome (OR 4.4 [1.1-18.1]). Non-Hispanic Black participants had lower odds of DSP (OR 0.1 [0.01-0.4]) than non-Hispanic White and Hispanic participants. DSP burden was high, including increased pain, health-related worry, and poorer quality of life (all p < 0.001)., Discussion: DSP is extremely common and often underrecognized in this predominantly non-Hispanic Black, low-income population and leads to substantial disease burden. Metabolic syndrome is a highly prevalent, modifiable risk factor in this population that should be managed to lower DSP prevalence.

Background and Objective: Following the outbreak of viral infections from the severe acute respiratory syndrome coronavirus 2 virus in 2019 (coronavirus disease 2019 [COVID-19]), reports emerged of long-term neurologic sequelae in survivors. To better understand the burden of neurologic health care and incident neurologic diagnoses in the year after COVID-19 vs influenza, we performed an analysis of patient-level data from a large collection of electronic health records (EMR)., Methods: We acquired deidentified data from TriNetX, a global health research network providing access to EMR data. We included individuals aged 18 years or older during index event, defined as hospital-based care for COVID-19 (from April 1, 2020, until November 15, 2021) or influenza (from 2016 to 2019). The study outcomes were subsequent health care encounters over the following year for 6 neurologic diagnoses including migraine, epilepsy, stroke, neuropathy, movement disorders, and dementia. We also created a composite of the 6 diagnoses as an incident event, which we call "incident neurologic diagnoses." We performed a 1:1 complete case nearest-neighbor propensity score match on age, sex, race/ethnicity, marital status, US census region patient residence, preindex years of available data, and Elixhauser comorbidity score. We fit time-to-event models and reported hazard ratios for COVID-19 vs influenza infection., Results: After propensity score matching, we had a balanced cohort of 77,272 individuals with COVID-19 and 77,272 individuals with influenza. The mean age was 51.0 ± 19.7 years, 57.7% were female, and 41.5% were White. Compared with patients with influenza, patients with COVID-19 had a lower risk of subsequent care for migraine (HR 0.645, 95% CI 0.604-0.687), epilepsy (HR 0.783, 95% CI 0.727-0.843), neuropathies (HR 0.567, 95% CI 0.532-0.604), movement disorders (HR 0.644, 95% CI 0.598-0.693), stroke (HR 0.904, 95% CI 0.845-0.967), or dementia (HR 0.931, 95% CI 0.870-0.996). Postinfection incident neurologic diagnoses were observed in 2.79% of the COVID-19 cohort vs 4.91% of the influenza cohort (HR 0.618, 95% CI 0.582-0.657)., Discussion: Compared with a matched cohort of adults with a hospitalization or emergency department visit for influenza infection, those with COVID-19 had significantly fewer health care encounters for 6 major neurologic diagnoses over a year of follow-up. Furthermore, we found that COVID-19 infection was associated with a lower risk of an incident neurologic diagnosis in the year after infection.

Neuropathy, headache, and low back pain (LBP) are common conditions requiring pain management. Yet little is known regarding whether access to specialists impacts opioid prescribing. We aimed to identify factors associated with opioid initiation among opioid-naïve older adults and evaluate how access to particular specialists impacts prescribing. This retrospective cohort study used a 20% Medicare sample from 2010 to 2017. Opioid initiation was defined as a first opioid prescription filled within 12 months after a diagnosis encounter. Disease-related opioid initiation was defined as a first opioid prescription filled within 7 days following a disease-specific claim. Logistic regression using generalized estimating equations was used to determine the association of patient demographics, provider types, and regional physician specialty density with disease-related opioid initiation, accounting for within-region correlation. We found opioid initiation steadily declined from 2010 to 2017 (neuropathy: 26-19%, headache: 31-20%, LBP: 45-32%), as did disease-related opioid initiation (4-3%, 12-7%, 29-19%) and 5 to 10% of initial disease-related prescriptions resulted in chronic opioid use within 12 months of initiation. Certain specialist visits were associated with a lower likelihood of disease-related opioid initiation compared with primary care. Residence in high neurologist density regions had a lower likelihood of disease-related opioid initiation (headache odds ratio [OR] .76 [95% CI: .63-.92]) and LBP (OR .7 [95% CI: .61-.81]) and high podiatrist density regions for neuropathy (OR .56 [95% CI: .41-.78]). We found that specialist visits and greater access to specialists were associated with a lower likelihood of disease-related opioid initiation. These data could inform strategies to perpetuate reductions in opioid use for these common pain conditions. PERSPECTIVE: This article presents how opioid initiation for opioid-naïve patients with newly diagnosed neuropathy, headache, and LBP varies across providers. Greater access to certain specialists decreased the likelihood of opioid initiation. Future work may consider interventions to support alternative treatments and better access to specialists in low-density regions., (Copyright © 2023 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Aims: Describe and compare healthcare costs and utilization for insured persons with type 1 diabetes (T1D), type 2 diabetes (T2D), and without diabetes in the United States., Methods: Using a nationally representative healthcare claims database, we identified matched persons with T1D, T2D, and without diabetes using a propensity score quasi-randomization technique. In each year between 2009 and 2018, we report costs (total and out-of-pocket) and utilization for all healthcare services and those specific to medications, diabetes-related supplies, visits to providers, hospitalizations, and emergency department visits., Results: In 2018, we found out-of-pocket costs and total costs were highest for persons with T1D (out-of-pocket: $2,037.2, total: $25,652.0), followed by T2D (out-of-pocket: $1,543.3, total: $22,408.1), and without diabetes (out-of-pocket: $1,122.7, total: $14,220.6). From 2009 to 2018, out-of-pocket costs were increasing for persons with T1D(+6.5 %) but decreasing for T2D (-7.5 %) and without diabetes (-2.3 %). Medication costs made up the largest proportion of out-of-pocket costs regardless of diabetes status (T1D: 51.4 %, T2D: 55.4 %,without diabetes: 51.1 %)., Conclusions: Given the substantial out-of-pocket costs for people with diabetes, especially for those with T1D, providers should screen all persons with diabetes for financial toxicity (i.e., wide-ranging problems stemming from healthcare costs). In addition, policies that aim to lower out-of-pocket costs of cost-effective diabetes related healthcare are needed with a particular focus on medications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Reynolds, Putnam, Banerjee, Mizokami-Stout, Albright, Ang). The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Lee is on the medical advisory board for GoodRx. Dr. Pop-Busui receives research support from Metronic, Novo Nordisk, and consults for Novo Nordisk, Regenacy, Roche, Procter &Gamble, Averitas and Nevro. Dr. Feldman consults for Biogen. Dr. Callaghan consults for DynaMed, receives research support from the American Academy of Neurology and performs medical legal consultations including consultations for the Vaccine Injury Compensation Program.]., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Objectives: The density of neurologists within a given geographic region varies greatly across the United States. We aimed to measure patient travel distance and travel time to neurologist visits, across neurologic conditions and subspecialties. Our secondary goal was to identify factors associated with long-distance travel for neurologic care., Methods: We performed a cross-sectional analysis using a 2018 Medicare sample of patients with at least 1 outpatient neurologist visit. Long-distance travel was defined as driving distance ≥50 miles 1-way to the visit. Travel time was measured as driving time in minutes. Multilevel generalized linear mixed models with logistic link function, which accounted for clustering of patients within hospital referral region and allowed modeling of region-specific random effects, were used to determine the association of patient and regional characteristics with long-distance travel., Results: We identified 563,216 Medicare beneficiaries with a neurologist visit in 2018. Of them, 96,213 (17%) traveled long distance for care. The median driving distance and time were 81.3 (interquartile range [IQR]: 59.9-144.2) miles and 90 (IQR: 69-149) minutes for patients with long-distance travel compared with 13.2 (IQR: 6.5-23) miles and 22 (IQR: 14-33) minutes for patients without long-distance travel. Comparing across neurologic conditions, long-distance travel was most common for nervous system cancer care (39.6%), amyotrophic lateral sclerosis [ALS] (32.1%), and MS (22.8%). Many factors were associated with long-distance travel, most notably low neurologist density (first quintile: OR 3.04 [95% CI 2.41-3.83] vs fifth quintile), rural setting (4.89 [4.79-4.99]), long-distance travel to primary care physician visit (3.6 [3.51-3.69]), and visits for ALS and nervous system cancer care (3.41 [3.14-3.69] and 5.27 [4.72-5.89], respectively). Nearly one-third of patients bypassed the nearest neurologist by 20+ miles, and 7.3% of patients crossed state lines for neurologist care., Discussion: We found that nearly 1 in 5 Medicare beneficiaries who saw a neurologist traveled ≥50 miles 1-way for care, and travel burden was most common for lower-prevalence neurologic conditions that required coordinated multidisciplinary care. Important potentially addressable predictors of long-distance travel were low neurologist density and rural location, suggesting interventions to improve access to care such as telemedicine or neurologic subspecialist support to local neurologists. Future work should evaluate differences in clinical outcomes between patients with long-distance travel and those without., (© 2023 American Academy of Neurology.)

We performed a cross-sectional study to determine associations between cognition and MRI-derived brain outcomes, with obesity, diabetes duration, and metabolic risk factors in 51 Pima American Indians with longstanding type 2 diabetes (T2d) (mean [SD] age: 48.4 [11.3] years, T2d duration: 20.1 [9.1] years). Participants had similar cognition (NIH Toolbox Cognition Battery composite: 45.3 [9.8], p = 0.64, n = 51) compared to normative data. T2d duration, but not other metabolic risk factors, associated with decreased cortical thickness (Point Estimate (PE): -0.0061, 95%CI: -0.0113, -0.0009, n = 45), gray matter volume (PE: -830.39, 95%CI: -1503.14, -157.64, n = 45), and increased white matter hyperintensity volume (PE: 0.0389, 95%CI: 0.0049, 0.0729, n = 45)., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Objective: This article provides an up-to-date review of the diagnosis and management of the most common neuropathies that occur in patients with diabetes., Latest Developments: The prevalence of diabetes continues to grow worldwide and, as a result, the burden of diabetic neuropathies is also increasing. Most diabetic neuropathies are caused by hyperglycemic effects on small and large fiber nerves, and glycemic control in individuals with type 1 diabetes reduces neuropathy prevalence. However, among people with type 2 diabetes, additional factors, particularly metabolic syndrome components, play a role and should be addressed. Although length-dependent distal symmetric polyneuropathy is the most common form of neuropathy, autonomic syndromes, particularly cardiovascular autonomic neuropathy, are associated with increased mortality, whereas lumbosacral radiculoplexus neuropathy and treatment-induced neuropathy cause substantial morbidity. Recent evidence-based guidelines have updated the recommended treatment options to manage pain associated with distal symmetric polyneuropathy of diabetes., Essential Points: Identifying and appropriately diagnosing the neuropathies of diabetes is key to preventing progression. Until better disease-modifying therapies are identified, management remains focused on diabetes and metabolic risk factor control and pain management., (Copyright © 2023 American Academy of Neurology.)

Objective: Metabolic syndrome components may cumulatively increase the risk of diabetic polyneuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients, driven by insulin resistance and hyperinsulinemia. We investigated the prevalence of DPN in three T2DM subgroups based on indices of β-cell function and insulin sensitivity., Research Design and Methods: We estimated β-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) in 4,388 Danish patients with newly diagnosed T2DM. Patients were categorized into subgroups of hyperinsulinemic (high HOMA2-B, low HOMA2-S), classical (low HOMA2-B, low HOMA2-S), and insulinopenic (low HOMA2-B, high HOMA2-S) T2DM. After a median follow-up of 3 years, patients filled the Michigan Neuropathy Screening Instrument questionnaire (MNSIq) to identify DPN (score ≥ 4). We used Poisson regression to calculate adjusted prevalence ratios (PRs) for DPN, and spline models to examine the association with HOMA2-B and HOMA2-S., Results: A total of 3,397 (77%) patients filled in the MNSIq. The prevalence of DPN was 23% among hyperinsulinemic, 16% among classical, and 14% among insulinopenic patients. After adjusting for demographics, diabetes duration and therapy, lifestyle behaviors, and metabolic syndrome components (waist circumference, triglycerides, HDL cholesterol, hypertension, and HbA1c), the PR of DPN was 1.35 (95% CI 1.15-1.57) for the hyperinsulinemic compared with the classical patients. In spline analyses, we observed a linear relation of higher DPN prevalence with increasing HOMA2-B, independent of both metabolic syndrome components and HOMA2-S., Conclusions: Hyperinsulinemia marked by high HOMA2-B is likely an important risk factor for DPN beyond metabolic syndrome components and insulin resistance. This should be considered when developing interventions to prevent DPN., (© 2023 by the American Diabetes Association.)

Aims/hypothesis: The aim of this study was to determine the effect of bariatric surgery on diabetes complications in individuals with class II/III obesity (BMI > 35 kg/m 2 )., Methods: We performed a prospective cohort study of participants with obesity who underwent bariatric surgery. At baseline and 2 years following surgery, participants underwent metabolic phenotyping and diabetes complication assessments. The primary outcomes for peripheral neuropathy (PN) were a change in intra-epidermal nerve fibre density (IENFD, units = fibres/mm) at the distal leg and proximal thigh, the primary outcome for cardiovascular autonomic neuropathy (CAN) was a change in the expiration/inspiration (E/I) ratio, and the primary outcome for retinopathy was a change in the mean deviation on frequency doubling technology testing., Results: Among 127 baseline participants, 79 completed in-person follow-up (age 46.0 ± 11.3 years [mean ± SD], 73.4% female). Participants lost a mean of 31.0 kg (SD 18.4), and all metabolic risk factors improved except for BP and total cholesterol. Following bariatric surgery, one of the primary PN outcomes improved (IENFD proximal thigh, +3.4 ± 7.8, p<0.01), and CAN (E/I ratio -0.01 ± 0.1, p=0.89) and retinopathy (deviation -0.2 ± 3.0, p=0.52) were stable. Linear regression revealed that a greater reduction in fasting glucose was associated with improvements in retinopathy (mean deviation point estimate -0.7, 95% CI -1.3, -0.1)., Conclusions/interpretation: Bariatric surgery may be an effective approach to reverse PN in individuals with obesity. The observed stability of CAN and retinopathy may be an improvement compared with the natural progression of these conditions; however, controlled trials are needed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetic retinopathy, neuropathy, and nephropathy occur in more than 50% of people with diabetes, contributing substantially to morbidity and mortality. Patient understanding of these microvascular complications is essential to ensure early recognition and treatment of these sequalae as well as associated symptoms, yet little is known about patient knowledge of microvascular sequalae. In this comprehensive literature review, we provide an overview of existing knowledge regarding patient knowledge of diabetes, retinopathy, neuropathy, and nephropathy. We also discuss health care provider's knowledge of these sequalae given that patients and providers must work together to achieve optimal care. We evaluated 281 articles on patient and provider knowledge of diabetic retinopathy, neuropathy, and nephropathy as well as predictors of improved knowledge and screening practices. Results demonstrated that patient and provider knowledge of microvascular sequalae varied widely between studies, which may reflect sociocultural or methodologic differences. Knowledge assessment instruments varied between studies with limited validation data and few studies controlled for confounding. Generally, improved patient knowledge was associated with greater formal education, longer diabetes duration, and higher socioeconomic status. Fewer studies examined provider knowledge of sequalae, yet these studies identified multiple misconceptions regarding appropriate screening practices for microvascular complications and the need to screen patients who are asymptomatic. Further investigations are needed that use well validated measures, control for confounding, and include diverse populations. Such studies will allow identification of patients and providers who would benefit from interventions to improve knowledge of microvascular complications and, ultimately, improve patient outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: The objective of this study was to compare the utilization and costs (total and out-of-pocket) of new-to-market neurologic medications with existing guideline-supported neurologic medications over time., Methods: We used a healthcare pharmaceutical claims database (from 2001 to 2019) to identify patients with both a diagnosis of 1 of 11 separate neurologic conditions and either a new-to-market medication or an existing guideline-supported medication for that condition. Neurologic conditions included orthostatic hypotension, spinal muscular atrophy, Duchenne disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, Huntington disease, tardive dyskinesia, transthyretin amyloidosis, and migraine. New-to-market medications were defined as all neurologic medications approved by the US Food and Drug Administration (FDA) between 2014 and 2018. In each year, we determined the median out-of-pocket and standardized total costs for a 30-day supply of each medication. We also measured the proportion of patients receiving new-to-market medications compared with all medications specific for the relevant condition., Results: We found that the utilization of most new-to-market medications was small (<20% in all but 1 condition), compared with existing, guideline-supported medications. The out-of-pocket and standardized total costs were substantially larger for new-to-market medications. The median (25th percentile, 75th percentile) out-of-pocket costs for a 30-day supply in 2019 were largest for edaravone ($712.8 [$59.8-$802.0]) and eculizumab ($91.1 [$3.0-$3,216.4]). For new-to-market medications, the distribution of out-of-pocket costs was highly variable and the trends over time were unpredictable compared with existing guideline-supported medications., Discussion: Despite the increasing number of FDA-approved neurologic medications, utilization of newly approved medications in the privately insured population remains small. Given the high costs and similar efficacy for most of the new medications, limited utilization may be appropriate. However, for new medications with greater efficacy, future studies are needed to determine whether high costs are a barrier to utilization., (© 2022 American Academy of Neurology.)

Introduction/aims: In vasculitic neuropathy (VN), a 50% side-to-side difference in the amplitude of compound muscle action potentials and sensory nerve action potentials is considered meaningful, but unequivocal evidence is lacking. The aim of this study is to characterize electrodiagnostic features that best distinguish VN from other axonal polyneuropathies., Methods: We conducted a case-control study between January 2000 and April 2021. We reviewed the records of patients with VN who had bilateral nerve conduction studies (NCS) and evaluated different electrodiagnostic models to help distinguish VN from non-inflammatory axonal polyneuropathies., Results: We identified 82 cases, and 174 controls with non-inflammatory axonal neuropathies. The amplitude percent difference Z-score model showed the best discriminatory capability between cases and controls (area under the curve [AUC] 0.87; 95% confidence interval [CI] 0.82, 0.93), and the number of nerves tested did not significantly influence the model. Individually, the ulnar motor nerve (AUC 0.86; 95% CI 0.77, 0.94) and median motor nerve (AUC 0.85; 95% CI 0.77, 0.94) showed the best discriminatory capability. A 50% amplitude difference between at least two bilateral nerves, either in the upper (AUC 0.85; 95% CI 0.77, 0.93) or lower (AUC 0.79; 95% CI 0.71, 0.87) extremity showed good discriminatory threshold for detecting VN., Discussion: The best electrodiagnostic criteria for VN utilizes z-scores of percent differences in nerve amplitudes, but this approach may be difficult to implement at the bedside. Alternately, a 50% amplitude difference in at least two nerves is a reasonable approximation., (© 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Obesity is a global epidemic and is associated with cognitive impairment and dementia. It remains unknown whether weight loss interventions, such as bariatric surgery, can mitigate cognitive impairment., Objectives: We aimed to determine the effect of surgical weight loss on cognition in individuals with class II/III obesity., Design: We performed a prospective cohort study of participants who underwent bariatric surgery. At baseline and two years following surgery, participants completed metabolic risk factor and neuropsychological assessments., Setting: Participants were enrolled from an academic suburban bariatric surgery clinic., Participants: There were 113 participants who completed baseline assessments and 87 completed two-year follow-up assessments (66 in-person and 21 virtual) after bariatric surgery. The mean (SD) age was 46.8 (12.5) years and 64 (73.6%) were female., Intervention: Bariatric surgery. There were 77 (88.5%) participants that underwent sleeve gastrectomy and 10 (11.5%) that underwent gastric bypass surgery., Measurements: Cognition was assessed using the NIH toolbox cognitive battery (NIHTB-CB) and the Rey Auditory Verbal Learning Test (AVLT). The primary outcome was the change in NIHTB-CB fluid composite score before and after surgery., Results: The primary outcome, NIHTB-CB composite score, was stable following bariatric surgery (-0.4 (13.9), p=0.81,n=66). Among secondary outcomes, the NIHTB-CB dimensional card sorting test (executive function assessment), improved (+6.5 (19.9),p=0.01,n=66) while the Rey AVLT delayed recall test (memory assessment) declined (-0.24 (0.83),p=0.01,n=87) following surgery. Improvements to metabolic risk factors and diabetes complications were not associated with improvements to NIHTB-CB composite score. The other 4 NIHTB-CB subtests and Rey AVLT assessments of auditory learning and recognition were stable at follow-up., Conclusions: Following bariatric surgery, the age-adjusted composite cognitive outcome did not change, but an executive subtest score improved. These results suggest that bariatric surgery may mitigate the natural history of cognitive decline in individuals with obesity, which is expected to be faster than normal aging, but confirmatory randomized controlled trials are needed. The decline in delayed recall also warrants further studies to determine potential differential effects on cognitive subtests., Competing Interests: Dr. Reynolds reports no disclosures. Dr. Votruba reports no disclosures.Ms. Watanabe reports no disclosures. Dr. Banerjee reports no disclosures. Dr. Elafros reports no disclosures. Ms. Chant reports no disclosures. Ms. Villegas-Umana reports no disclosures. Dr. Giordani reports no disclosures. Dr. Feldman reports no disclosures. Dr. Callaghan consults for DynaMed, receives research support from the American Academy of Neurology and performs medical legal consultations including consultations for the Vaccine Injury Compensation Program.

Diabetic peripheral neuropathy (DPN) occurs in up to half of individuals with type 1 or type 2 diabetes. DPN results from the distal-to-proximal loss of peripheral nerve function, leading to physical disability and sometimes pain, with the consequent lowering of quality of life. Early diagnosis improves clinical outcomes, but many patients still develop neuropathy. Hyperglycaemia is a risk factor and glycaemic control prevents DPN development in type 1 diabetes. However, glycaemic control has modest or no benefit in individuals with type 2 diabetes, probably because they usually have comorbidities. Among them, the metabolic syndrome is a major risk factor for DPN. The pathophysiology of DPN is complex, but mechanisms converge on a unifying theme of bioenergetic failure in the peripheral nerves due to their unique anatomy. Current clinical management focuses on controlling diabetes, the metabolic syndrome, and pain, but remains suboptimal for most patients. Thus, research is ongoing to improve early diagnosis and prognosis, to identify molecular mechanisms that could lead to therapeutic targets, and to investigate lifestyle interventions to improve clinical outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: The serum lipidomic profile associated with neuropathy in type 2 diabetes is not well understood. Obesity and dyslipidemia are known neuropathy risk factors, suggesting lipid profiles early during type 2 diabetes may identify individuals who develop neuropathy later in the disease course. This retrospective cohort study examined lipidomic profiles 10 years prior to type 2 diabetic neuropathy assessment., Methods: Participants comprised members of the Gila River Indian community with type 2 diabetes (n = 69) with available stored serum samples and neuropathy assessment 10 years later using the combined Michigan Neuropathy Screening Instrument (MNSI) examination and questionnaire scores. A combined MNSI index was calculated from examination and questionnaire scores. Serum lipids (435 species from 18 classes) were quantified by mass spectrometry., Results: The cohort included 17 males and 52 females with a mean age of 45 years (SD = 9 years). Participants were stratified as with (high MNSI index score > 2.5407) versus without neuropathy (low MNSI index score ≤ 2.5407). Significantly decreased medium-chain acylcarnitines and increased total free fatty acids, independent of chain length and saturation, in serum at baseline associated with incident peripheral neuropathy at follow-up, that is, participants had high MNSI index scores, independent of covariates. Participants with neuropathy also had decreased phosphatidylcholines and increased lysophosphatidylcholines at baseline, independent of chain length and saturation. The abundance of other lipid classes did not differ significantly by neuropathy status., Interpretation: Abundance differences in circulating acylcarnitines, free fatty acids, phosphatidylcholines, and lysophosphatidylcholines 10 years prior to neuropathy assessment are associated with neuropathy status in type 2 diabetes., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Objective: To characterize trends in antiseizure medication (ASM) fills and total prescription costs in people with epilepsy., Methods: This was a retrospective cohort study of beneficiaries with epilepsy (ASM, plus ICD codes) in a 20% random Medicare sample, with continuous Fee-For-Service coverage (Parts A, B, and D) in 2008-2018. We summed the number of pill days and costs (adjusted to 2018 dollars) per person-year for each ASM. ASMs were categorized into brand vs generic, first vs newer generation, and enzyme inducers vs noninducers., Results: There were 77,000-133,000 beneficiaries with epilepsy per year. The most common ASM was phenytoin in 2008, which shifted to levetiracetam in 2018 (2008: phenytoin 25%, levetiracetam 14%; 2018: phenytoin 9%, levetiracetam 27%). Brand name (2008: 56%; 2018: 14%), first-generation (2008: 55%; 2018: 32%), and enzyme-inducing ASMs (2008: 44%; 2018: 24%) each decreased over time as a proportion of pill days. The number of brand pill days per person-year initially decreased (e.g., 2008: 250; 2009: 121; 2010: 96) but then plateaued (2013-2018: between 66 and 69) given a notable increase in lacosamide pill days per person (2008: 0; 2018: 20). Total brand name costs per year initially decreased 2008-2010 (2008: $150 million; 2010: $72 million) but then increased after 2010 (2018: $256 million). In 2018, brand name ASMs represented 79% of costs despite representing only 14% of pill days, a 1-year pill supply became 277% more expensive for brand name medications but 42% less expensive for generic medications over time (2008: brand ∼$2,800 vs generic ∼$800; 2018: brand ∼$10,700 vs generic ∼$460), and many common brand name ASMs cost approximately 10-fold more per pill day than their generic equivalents., Discussion: First-generation and enzyme-inducing ASMs waned from 2008 to 2018. Although brand name ASMs initially waned translating into lower costs and potentially higher value care, after 2010, brand name costs markedly increased because of increasing use of lacosamide plus a 277% increase in per-pill cost of brand name ASMs. Brand name ASMs represented a minority of prescriptions, but the majority of costs., (© 2022 American Academy of Neurology.)

Background: To improve the treatment of painful Diabetic Peripheral Neuropathy (DPN) and associated co-morbidities, a better understanding of the pathophysiology and risk factors for painful DPN is required. Using harmonised cohorts (N = 1230) we have built models that classify painful versus painless DPN using quality of life (EQ5D), lifestyle (smoking, alcohol consumption), demographics (age, gender), personality and psychology traits (anxiety, depression, personality traits), biochemical (HbA1c) and clinical variables (BMI, hospital stay and trauma at young age) as predictors., Methods: The Random Forest, Adaptive Regression Splines and Naive Bayes machine learning models were trained for classifying painful/painless DPN. Their performance was estimated using cross-validation in large cross-sectional cohorts (N = 935) and externally validated in a large population-based cohort (N = 295). Variables were ranked for importance using model specific metrics and marginal effects of predictors were aggregated and assessed at the global level. Model selection was carried out using the Mathews Correlation Coefficient (MCC) and model performance was quantified in the validation set using MCC, the area under the precision/recall curve (AUPRC) and accuracy., Results: Random Forest (MCC = 0.28, AUPRC = 0.76) and Adaptive Regression Splines (MCC = 0.29, AUPRC = 0.77) were the best performing models and showed the smallest reduction in performance between the training and validation dataset. EQ5D index, the 10-item personality dimensions, HbA1c, Depression and Anxiety t-scores, age and Body Mass Index were consistently amongst the most powerful predictors in classifying painful vs painless DPN., Conclusions: Machine learning models trained on large cross-sectional cohorts were able to accurately classify painful or painless DPN on an independent population-based dataset. Painful DPN is associated with more depression, anxiety and certain personality traits. It is also associated with poorer self-reported quality of life, younger age, poor glucose control and high Body Mass Index (BMI). The models showed good performance in realistic conditions in the presence of missing values and noisy datasets. These models can be used either in the clinical context to assist patient stratification based on the risk of painful DPN or return broad risk categories based on user input. Model's performance and calibration suggest that in both cases they could potentially improve diagnosis and outcomes by changing modifiable factors like BMI and HbA1c control and institute earlier preventive or supportive measures like psychological interventions., (© 2022. The Author(s).)

Context: Peripheral neuropathy (PN) is a frequent prediabetes and type 2 diabetes (T2D) complication. Multiple clinical studies reveal that obesity and dyslipidemia can also drive PN progression, independent of glycemia, suggesting a complex interplay of specific metabolite and/or lipid species may underlie PN., Objective: This work aimed to identify the plasma metabolomics and lipidomics signature that underlies PN in an observational study of a sample of individuals with average class 3 obesity., Methods: We performed plasma global metabolomics and targeted lipidomics on obese participants with (n = 44) and without PN (n = 44), matched for glycemic status, vs lean nonneuropathic controls (n = 43). We analyzed data by Wilcoxon, logistic regression, partial least squares-discriminant analysis, and group-lasso to identify differential metabolites and lipids by obesity and PN status. We also conducted subanalysis by prediabetes and T2D status., Results: Lean vs obese comparisons, regardless of PN status, identified the most significant differences in gamma-glutamyl and branched-chain amino acid metabolism from metabolomics analysis and triacylglycerols from lipidomics. Stratification by PN status within obese individuals identified differences in polyamine, purine biosynthesis, and benzoate metabolism. Lipidomics found diacylglycerols as the most significant subpathway distinguishing obese individuals by PN status, with additional contributions from phosphatidylcholines, sphingomyelins, ceramides, and dihydroceramides. Stratifying the obese group by glycemic status did not affect discrimination by PN status., Conclusion: Obesity may be as strong a PN driver as prediabetes or T2D in a sample of individuals with average class 3 obesity, at least by plasma metabolomics and lipidomics profile. Metabolic and complex lipid pathways can differentiate obese individuals with and without PN, independent of glycemic status., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine the prevalence of neuropsychological outcomes in individuals with type 1 diabetes compared to individuals with type 2 diabetes or without diabetes, and to evaluate the association of diabetes status and microvascular/macrovascular complications with neuropsychological outcomes., Patients and Methods: We used a nationally representative healthcare claims database of privately insured individuals (1/1/2001-12/31/2018) to identify individuals with type 1 diabetes. Propensity score matching was used as a quasi-randomization technique to match type 1 diabetes individuals to type 2 diabetes individuals and controls. Diabetes status, microvascular/macrovascular complications (retinopathy, neuropathy, nephropathy, stroke, myocardial infarction, peripheral vascular disease, amputations), and neuropsychological outcomes (mental health, cognitive, chronic pain, addiction, sleep disorders) were defined using ICD-9/10 codes. Logistic regression determined associations between diabetes status, microvascular/macrovascular complications, and neuropsychological outcomes., Results: We identified 184,765 type 1 diabetes individuals matched to 524,602 type 2 diabetes individuals and 522,768 controls. With the exception of cognitive disorders, type 2 diabetes individuals had the highest prevalence of neuropsychological outcomes, followed by type 1 diabetes, and controls. After adjusting for the presence of microvascular/macrovascular complications, type 1 diabetes was not significantly associated with a higher risk of neuropsychological outcomes; however, type 2 diabetes remained associated with mental health, cognitive, and sleep disorders. The presence of microvascular/macrovascular complications was independently associated with each neuropsychological outcome regardless of diabetes status., Conclusion: Microvascular/macrovascular complications are associated with a high risk of neuropsychological outcomes regardless of diabetes status. Therefore, preventing microvascular and macrovascular complications will likely help reduce the likelihood of neuropsychological outcomes either as the result of similar pathophysiologic processes or by preventing the direct and indirect consequences of these complications. For individuals with type 2 diabetes, risk factors beyond complications (such as obesity) likely contribute to neuropsychological outcomes., Competing Interests: JL is on the medical advisory board for GoodRx. RP-B consults for Novo Nordisk, Boehringer Ingelheim, Regenacy, Averitas and Nevro. EF consults for Novartis. BC consults for a PCORI grant, DynaMed, receives research support from the American Academy of Neurology and performs medical legal consultations including consultations for the Vaccine Injury Compensation Program. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer [SB] declared a shared affiliation with the authors to the handling editor at time of review., (Copyright © 2022 Putnam, Reynolds, Banerjee, Mizokami-Stout, Albright, Lee, Pop-Busui, Feldman and Callaghan.)

Objective: To update the 2011 American Academy of Neurology (AAN) guideline on the treatment of painful diabetic neuropathy (PDN) with a focus on topical and oral medications and medical class effects., Methods: The authors systematically searched the literature from January 2008 to April 2020 using a structured review process to classify the evidence and develop practice recommendations using the AAN 2017 Clinical Practice Guideline Process Manual., Results: Gabapentinoids (standardized mean difference [SMD] 0.44; 95% confidence interval [CI], 0.21-0.67), serotonin-norepinephrine reuptake inhibitors (SNRIs) (SMD 0.47; 95% CI, 0.34-0.60), sodium channel blockers (SMD 0.56; 95% CI, 0.25-0.87), and SNRI/opioid dual mechanism agents (SMD 0.62; 95% CI, 0.38-0.86) all have comparable effect sizes just above or just below our cutoff for a medium effect size (SMD 0.5). Tricyclic antidepressants (TCAs) (SMD 0.95; 95% CI, 0.15-1.8) have a large effect size, but this result is tempered by a low confidence in the estimate., Recommendations Summary: Clinicians should assess patients with diabetes for PDN (Level B) and those with PDN for concurrent mood and sleep disorders (Level B). In patients with PDN, clinicians should offer TCAs, SNRIs, gabapentinoids, and/or sodium channel blockers to reduce pain (Level B) and consider factors other than efficacy (Level B). Clinicians should offer patients a trial of medication from a different effective class when they do not achieve meaningful improvement or experience significant adverse effects with the initial therapeutic class (Level B) and not use opioids for the treatment of PDN (Level B)., (© 2021 American Academy of Neurology.)

Objective: The objective of this study was to understand current practice, clinician understanding, attitudes, barriers, and facilitators to optimal headache neuroimaging practices., Background: Headaches are common in adults, and neuroimaging for these patients is common, costly, and increasing. Although guidelines recommend against routine headache neuroimaging in low-risk scenarios, guideline-discordant neuroimaging is still frequently performed., Methods: We administered a 60-item survey to headache clinicians at the Veterans Affairs health system to assess clinician understanding and attitudes on headache neuroimaging and to determine neuroimaging practice patterns for three scenarios describing hypothetical patients with headaches. Descriptive statistics were used to summarize responses, stratified by clinician type (physicians or advanced practice clinicians [APCs]) and specialty (neurology or primary care)., Results: The survey was successfully completed by 431 of 1426 clinicians (30.2% response rate). Overall, 317 of 429 (73.9%) believed neuroimaging was overused for patients with headaches. However, clinicians would utilize neuroimaging a mean (SD) 30.9% (31.7) of the time in a low-risk scenario without red flags, and a mean 67.1% (31.9) of the time in the presence of minor red flags. Clinicians had stronger beliefs in the potential benefits (268/429, 62.5%) of neuroimaging compared to harms (181/429, 42.2%) and more clinicians were bothered by harms stemming from the omission of neuroimaging (377/426, 88.5%) compared to commission (329/424, 77.6%). Additionally, APCs utilized neuroimaging more frequently than physicians and were more receptive to potential interventions to improve neuroimaging utilization., Conclusions: Although a majority of clinicians believed neuroimaging was overused for patients with headaches, many would utilize neuroimaging in low-risk scenarios with a small probability of changing management. Future studies are needed to define the role of currently used red flags given their importance in neuroimaging decisions. Importantly, APCs may be an ideal target for future optimization efforts., (© 2022 American Headache Society.)

Many novel therapies are now available for rare neuromuscular conditions that were previously untreatable. Hereditary transthyretin amyloidosis and spinal muscular atrophy are two examples of diseases with new medications that have transformed our field. The United States and the United Kingdom have taken disparate approaches to the approval and coverage of medications, despite both providing incentives to develop therapies targeting rare diseases. The US requires less evidence for approval when compared with medications for common diseases and does not have a mechanism to ensure or even encourage cost-effectiveness. The Institute of Clinical and Economic Review provides in-depth cost-effectiveness analyses in the US, but does not have the authority to negotiate drug costs. In contrast, the UK has maintained a similar scientific threshold for approval of all therapies, while requiring negotiation with National Institute for Health and Care Excellence to ensure that medications are cost-effective for rare diseases. These differences have led to approval of medications for rare diseases in the US that have less evidence than required for common diseases. Importantly, these medications have not been approved in the UK. Even when medications meet traditional scientific thresholds, they uniformly arrive with high list prices in the US, whereas they are available at cost-effective prices in the UK. The main downsides to the UK approach are that cost-effective medications are often available months later than in the US, and some medications remain unavailable., (© 2021 Wiley Periodicals LLC.)

Objective: The aim of this study was to determine the effect of dietary weight loss on neuropathy outcomes in people with severe obesity., Methods: A prospective cohort study of participants attending a medical weight-management program was followed. Weight loss was achieved with meal replacement of 800 kcal/d for 12 weeks and then transitioning to 1,200 to 1,500 kcal/d. The coprimary outcomes were changes in intraepidermal nerve fiber density (IENFD) at the distal leg and proximal thigh. Secondary outcomes included nerve conduction studies, Michigan Neuropathy Screening Instrument questionnaire and exam, Quality of Life in Neurological Disorders, and quantitative sensory testing., Results: Among 131 baseline participants, 72 (mean [SD] age: 50.1 [10.5] years, 51.4% female) completed 2 years of follow-up. Participants lost 12.4 (11.8) kg. All metabolic syndrome components improved with the exception of blood pressure. IENFD in the distal leg (0.4 [3.3], p = 0.29), and proximal thigh (0.3 [6.3], p = 0.74) did not significantly change. Improvements were observed on the Michigan Neuropathy Screening Instrument questionnaire, two Quality of Life in Neurological Disorders subdomains, and quantitative sensory testing cold threshold., Conclusions: Dietary weight loss was associated with improvements in all metabolic parameters except blood pressure, and both IENFD outcomes remained stable after 2 years. Given that natural history studies reveal decreases in IENFD over time, dietary weight loss may halt this progression, but randomized controlled trials are needed., (© 2021 The Obesity Society.)

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30-40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Severe chemotherapy-induced peripheral neuropathy (CIPN) can cause long-term dysfunction of the hands and feet, interfere with activities of daily living, and diminish the quality of life. Monitoring to identify CIPN and adjust treatment before it progressing to a life-altering severity relies on patients self-reporting subjective symptoms to their clinical team. Objective assessment is not a standard component of CIPN monitoring due to the requirement for specially trained health care professionals and equipment. Smartphone apps have the potential to conveniently collect both subjective and objective CIPN data directly from patients, which could improve CIPN monitoring., Objective: The objective of this cross-sectional pilot study was to assess the feasibility of functional CIPN assessment via a smartphone app in patients with cancer that have received neurotoxic chemotherapy., Methods: A total of 26 patients who had completed neurotoxic chemotherapy were enrolled and classified as CIPN cases (n=17) or controls (n=9) based on self-report symptoms. All participants completed CIPN assessments within the NeuroDetect app a single time, including patient-reported surveys (CIPN20 [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Chemotherapy-induced Peripheral Neuropathy 20-item scale] and PRO-CTCAE [Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events]) and functional assessments (Gait and Balance and 9-Hole Peg Test). Functional assessment data were decomposed into features. The primary analysis was done to identify features indicative of the difference between CIPN cases and controls using partial least squares analyses. Exploratory analyses were performed to test if any features were associated with specific symptom subtypes or patient-reported survey scores. Patient interviews were also conducted to understand the challenges they experienced with the app., Results: Comparisons between CIPN cases and controls indicate that CIPN cases had shorter step length (P=.007), unique swaying acceleration patterns during a walking task, and shorter hand moving distance in the dominant hands during a manual dexterity task (variable importance in projection scores ≥2). Exploratory analyses showed similar signatures associated with symptoms subtypes, CIPN20, and PRO-CTCAE. The interview results showed that some patients had difficulties due to technical issues, which indicated a need for additional training or oversight during the initial app download., Conclusions: Our results supported the feasibility of remote CIPN assessment via a smartphone app and suggested that functional assessments may indicate CIPN manifestations in the hands and feet. Additional work is needed to determine which functional assessments are most indicative of CIPN and could be used for CIPN monitoring within clinical care., (©Ciao-Sin Chen, Judith Kim, Noemi Garg, Harsha Guntupalli, Reshma Jagsi, Jennifer J Griggs, Michael Sabel, Michael P Dorsch, Brian C Callaghan, Daniel L Hertz. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 05.07.2021.)

Objective: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown., Methods: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION-Denmark) with and without diabetic polyneuropathy versus lean control participants., Results: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids., Interpretation: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Extreme obesity has been associated with cognitive deficits across the lifespan and may be a risk factor for dementia in later life. However, the relationship between obesity and domain-specific cognitive deficits is complicated by a body of literature that often fails to adequately account for medical and psychiatric conditions frequently co-occurring with extreme obesity., Materials and Methods: The present study included a cross-sectional evaluation of adults with extreme obesity (n=117) compared to lean control (n=46) participants on a brief cognitive battery using the NIH Toolbox and Rey Auditory Verbal Learning Test. Specifically, this study evaluated measures of executive functioning, attention, processing speed, learning, and memory while accounting for many common obesity-related medical and psychiatric comorbidities with known cognitive effects., Results: Results revealed group differences with lower performances on measures of executive functioning, processing speed, and learning (ps<0.01) for participants with obesity. Reduced executive functioning was associated with abdominal obesity and medication use (ps<0.01) and together contributed significantly to overall modeling of cognition in individuals with obesity., Conclusion: Individuals with extreme obesity in this sample showed lower cognitive performance on measures of executive functioning, processing speed, and learning compared to lean controls. Abdominal obesity was associated with executive functioning deficits independent of many common medical and psychiatric factors.

Introduction: It is unknown how often patients with electrodiagnostic evidence of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a potentially treatable condition, present with a distal symmetric polyneuropathy (DSP) phenotype., Methods: We reviewed the records of patients who presented to our electrodiagnostic laboratory between January 1, 2011, to December 31, 2019, and fulfilled electrodiagnostic criteria for CIDP to identify those who presented with a sensory predominant DSP phenotype., Results: One hundred sixty-two patients had a chronic acquired demyelinating neuropathy, of whom 138 met criteria for typical or atypical CIDP. Nine of these patients presented with a sensory predominant DSP phenotype, among whom six were eventually diagnosed with distal acquired demyelinating symmetric (DADS) neuropathy; one with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes (POEMS) syndrome; and two with idiopathic DSP. The prevalence of acquired chronic demyelinating neuropathies among all patients presenting with a DSP phenotype was estimated to be 0.34%., Discussion: Patients who meet electrodiagnostic criteria for CIDP rarely present with a sensory predominant DSP phenotype, and electrodiagnostic testing rarely identifies treatable demyelinating neuropathies in patients who present with a DSP phenotype., (© 2021 Wiley Periodicals LLC.)