Obesity-related neuropathy: the new epidemic.

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.

Patient Travel Distance to Neurologist Visits.

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.

The effect of surgical weight loss on diabetes complications in individuals with class II/III obesity.

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/m2). 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.

Costs and Utilization of New-to-Market Neurologic Medications.

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.

Classification of painful or painless diabetic peripheral neuropathy and identification of the most powerful predictors using machine learning models in large cross-sectional cohorts.

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.

Comparison of the United Kingdom and United States approaches to approval of new neuromuscular therapies.

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.

Executive Functioning in Extreme Obesity: Contributions from Metabolic Status, Medical Comorbidities, and Psychiatric Factors.

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.

Chemotherapy-Induced Peripheral Neuropathy Detection via a Smartphone App: Cross-sectional Pilot Study.

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.

Central Obesity is Associated With Neuropathy in the Severely Obese.

OBJECTIVE: To determine the prevalence of neuropathy stratified by glycemic status and the association between extensive anthropometric measurements and neuropathy. PATIENTS AND METHODS: We performed a cross-sectional, observational study in obese individuals, before surgery, with body mass index (BMI) greater than 35 kg/m2. Lean controls were recruited from a research website. Neuropathy was defined by the Toronto consensus definition of probable neuropathy. We compared nine anthropometric measurements between obese participants with and without neuropathy. We used multivariable logistic regression to explore associations between these measures, and other metabolic risk factors, and neuropathy. RESULTS: We recruited 138 obese individuals and 46 lean controls. The mean age (SD) was 45.1 (11.3) years in the obese population (76.1% female, n=105) and 43.8 (12.1) years in the lean controls (82.2% female, n=37). The prevalence of neuropathy was 2.2% (n=1) in lean controls, 12.1% (n=4) in obese participants with normoglycemia, 7.1% (n=4) in obese participants with pre-diabetes, and 40.8% (n=20) in obese participants with diabetes (p≤.01). Waist circumference was the only anthropometric measure that was larger in those with neuropathy (139.3 cm vs 129.1 cm, p=.01). Hip-thigh (71.1 cm vs 76.6 cm, p<.01) and mid-thigh (62.2 cm vs 66.3 cm, p=.03) circumferences were smaller in those with neuropathy. The body mass index was comparable between patients who were obese with and without neuropathy (p=.86). Waist circumference (odds ratio [OR], 1.39; 95% CI, 1.10 to 1.75), systolic blood pressure (OR, 2.89; 95% CI, 1.49 to 5.61), and triglycerides (OR, 1.31; 95% CI, 1.00 to 1.70) were significantly associated with neuropathy. CONCLUSION: Normoglycemic obese patients have a high prevalence of neuropathy indicating that obesity alone may be sufficient to cause neuropathy. Waist circumference, but not general obesity, is significantly associated with neuropathy.

Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort.

OBJECTIVE: To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes. RESEARCH DESIGN AND METHODS: We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3). RESULTS: Among 5,249 patients with data on both DPN and pain, 17.9% (n = 938) had possible DPN, including 7.4% (n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain. CONCLUSIONS: Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.

The emerging role of dyslipidemia in diabetic microvascular complications.

PURPOSE OF REVIEW: To summarize recent advancements in our understanding of the impact of dyslipidemia on microvascular complications in type 2 diabetes (T2D), with an emphasis on peripheral neuropathy and nephropathy. RECENT FINDINGS: Mounting evidence suggests that rigorous glycemic control only mitigates certain microvascular complications in T2D patients. Particularly, well regulated blood glucose levels only marginally improve peripheral neuropathy in the T2D setting. Dyslipidemia, an abnormal lipid profile, is emerging as a key factor in peripheral neuropathy. Furthermore, although glycemic control may prevent or slow nephropathy, recent developments demonstrate that dyslipidemia can also affect kidney outcomes in normoglycemic patients. Transcriptomic, epigenomic, and lipidomic investigations, as well as integrative approaches, are shedding light on potential pathomechanisms. These molecular studies are identifying possible targets for therapeutic intervention. Complementing molecular research, lifestyle interventions are on-going to assess whether dietary choices and/or exercise, weight-loss, or surgical interventions, such as bariatric surgery, can ameliorate peripheral neuropathy and nephropathy in T2D patients. SUMMARY: Dyslipidemia is an emerging mechanism in microvascular complications in T2D. Elucidating the molecular pathomechanisms may pinpoint potential lipid-centric treatments. Interventional studies of dietary changes, exercise, or weight-loss surgery may also positively impact these highly prevalent and morbid complications.

Diabetic neuropathy: what does the future hold?

Frustratingly, disease-modifying treatments for diabetic neuropathy remain elusive. Glycaemic control has a robust effect on preventing neuropathy in individuals with type 1 but not in those with type 2 diabetes, which constitute the vast majority of patients. Encouragingly, recent evidence points to new metabolic risk factors and mechanisms, and thus also at novel disease-modifying strategies, which are desperately needed. Obesity has emerged as the second most important metabolic risk factor for neuropathy (diabetes being the first) from consensus findings of seven observational studies in populations across the world. Moreover, dyslipidaemia and altered sphingolipid metabolism are emergent novel mechanisms of nerve injury that may lead to new targeted therapies. Clinical history and examination remain critical components of an accurate diagnosis of neuropathy. However, skin biopsies and corneal confocal microscopy are promising newer tests that have been used as outcome measures in research studies but have not yet demonstrated clear clinical utility. Given the emergence of obesity as a neuropathy risk factor, exercise and weight loss are potential interventions to treat and/or prevent neuropathy, although evidence supporting exercise currently outweighs data supporting weight loss. Furthermore, a consensus has emerged advocating tricyclic antidepressants, serotonin-noradrenaline (norepinephrine) reuptake inhibitors and gabapentinoids for treating neuropathic pain. Out-of-pocket costs should be considered when prescribing these medications since their efficacy and tolerability are similar. Finally, the downsides of opioid treatment for chronic, non-cancer pain are becoming increasingly evident. Despite these data, current clinical practice frequently initiates and continues opioid prescriptions for patients with neuropathic pain before prescribing guideline-recommended treatments.

The Prevalence and Determinants of Cognitive Deficits and Traditional Diabetic Complications in the Severely Obese.

OBJECTIVE: To determine the prevalence of cognitive deficits and traditional diabetic complications and the association between metabolic factors and these outcomes. RESEARCH DESIGN AND METHODS: We performed a cross-sectional study in severely obese individuals before bariatric surgery. Lean control subjects were recruited from a research website. Cognitive deficits were defined by the National Institutes of Health (NIH) Toolbox (<5th percentile for lean control subjects). Cardiovascular autonomic neuropathy (CAN) was defined by an expiration-to-inspiration (E-to-I) ratio of <5th percentile for lean control subjects. Retinopathy was based on retinal photographs and nephropathy on the estimated glomerular filtration rate (<60 mg/dL) and/or the albumin-to-creatinine ratio (ACR) (≥30 mg/g). NIH Toolbox, E-to-I ratio, mean deviation on frequency doubling technology testing, and ACR were used as sensitive measures of these outcomes. We used multivariable linear regression to explore associations between metabolic factors and these outcomes. RESULTS: We recruited 138 severely obese individuals and 46 lean control subjects. The prevalence of cognitive deficits, CAN, retinopathy, and nephropathy were 6.5%, 4.4%, 0%, and 6.5% in lean control subjects; 22.2%, 18.2%, 0%, and 6.1% in obese participants with normoglycemia; 17.7%, 21.4%, 1.9%, and 17.9% in obese participants with prediabetes; and 25.6%, 31.9%, 6.1%, and 16.3% in obese participants with diabetes. Waist circumference was significantly associated with cognitive function (-1.48; 95% CI -2.38, -0.57) and E-to-I ratio (-0.007; 95% CI -0.012, -0.002). Prediabetes was significantly associated with retinal function (-1.78; 95% CI -3.56, -0.002). CONCLUSIONS: Obesity alone is likely sufficient to cause cognitive deficits but not retinopathy or nephropathy. Central obesity is the key metabolic risk factor.

Diabetic neuropathy.

The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.

Impact of early headache neuroimaging on time to malignant brain tumor diagnosis: A retrospective cohort study.

BACKGROUND: Neuroimaging for headaches is both common and costly. While the costs are well quantified, little is known about the benefit in terms of diagnosing pathology. Our objective was to determine the role of early neuroimaging in the identification of malignant brain tumors in individuals presenting to healthcare providers with headaches. METHODS: This was a retrospective cohort study using administrative claims data (2001-2014) from a US insurer. Individuals were included if they had an outpatient visit for headaches and excluded for prior headache visits, other neurologic conditions, neuroimaging within the previous year, and cancer. The exposure was early neuroimaging, defined as neuroimaging within 30 days of the first headache visit. A propensity score-matched group that did not undergo early neuroimaging was then created. The primary outcome was frequency of malignant brain tumor diagnoses and median time to diagnosis within the first year after the incident headache visit. The secondary outcome was frequency of incidental findings. RESULTS: 22.2% of 180,623 individuals had early neuroimaging. In the following year, malignant brain tumors were found in 0.28% (0.23-0.34%) of the early neuroimaging group and 0.04% (0.02-0.06%) of the referent group (P<0.001). Median time to diagnosis in the early neuroimaging group was 8 (3-19) days versus 72 (39-189) days for the referent group (P<0.001). Likely incidental findings were discovered in 3.17% (3.00-3.34%) of the early neuroimaging group and 0.66% (0.58-0.74%) of the referent group (P<0.001). CONCLUSIONS: Malignant brain tumors in individuals presenting with an incident headache diagnosis are rare and early neuroimaging leads to a small reduction in the time to diagnosis.

Claims data analyses unable to properly characterize the value of neurologists in epilepsy care.

OBJECTIVE: To determine the association of a neurologist visit with health care use and cost outcomes for patients with incident epilepsy. METHODS: Using health care claims data for individuals insured by United Healthcare from 2001 to 2016, we identified patients with incident epilepsy. The population was defined by an epilepsy/convulsion diagnosis code (ICD codes 345.xx/780.3x, G40.xx/R56.xx), an antiepileptic prescription filled within the succeeding 2 years, and neither criterion met in the 2 preceding years. Cases were defined as patients who had a neurologist encounter for epilepsy within 1 year after an incident diagnosis; a control cohort was constructed with propensity score matching. Primary outcomes were emergency room (ER) visits and hospitalizations for epilepsy. Secondary outcomes included measures of cost (epilepsy related, not epilepsy related, and antiepileptic drugs) and care escalation (including EEG evaluation and epilepsy surgery). RESULTS: After participant identification and propensity score matching, there were 3,400 cases and 3,400 controls. Epilepsy-related ER visits were more likely for cases than controls (year 1: 5.9% vs 2.3%, p < 0.001), as were hospitalizations (year 1: 2.1% vs 0.7%, p < 0.001). Total medical costs for epilepsy care, nonepilepsy care, and antiepileptic drugs were greater for cases (p ≤ 0.001). EEG evaluation and epilepsy surgery occurred more commonly for cases (p ≤ 0.001). CONCLUSIONS: Patients with epilepsy who visited a neurologist had greater subsequent health care use, medical costs, and care escalation than controls. This comparison using administrative claims is plausibly confounded by case disease severity, as suggested by higher nonepilepsy care costs. Linking patient-centered outcomes to claims data may provide the clinical resolution to assess care value within a heterogeneous population.

Unintended consequences of Mayo paraneoplastic evaluations.

OBJECTIVE: To determine the proportion of true and false positives from paraneoplastic panels and effects on downstream testing/treatment. METHODS: Using a retrospective cohort study design, we identified 500 consecutive patients with Mayo paraneoplastic autoantibody testing and performed chart abstraction. Paraneoplastic presentation types were categorized into probable, possible, and other by consensus. True positives were defined as a positive antibody titer with no other explanation found in addition to one of the following: syndrome known to be associated with the antibody, clinical improvement with treatment, and new malignancy. Comparisons of diagnostic testing and treatments between false and true positives were performed. Multivariable logistic regression was used to evaluate associations between patient-level factors and true positives. RESULTS: The mean (SD) age of the population was 55.4 (17.1) years, and 55.4% were female, with 1.3 (1.2) years of follow-up. Of the 500 tests, 87 (17.4%, 95% confidence interval [CI] 14.1%-20.7%) were positive and 62 (71.3%, 95% CI 61.8%-80.8%) of these were false positives. Of those with a possible/other presentation (n = 369), 2 (0.5%, 95% CI 0.0%-1.0%) were true positives. CT of the chest (30.7% vs 11.8%, p ≤ 0.01) was performed more often in false positives than true negatives. Probable presentation type (odds ratio [OR] 57.9, 95% CI 12.5-268.0) and outpatient setting (OR 8.7, 95% CI 2.4-31.8) were associated with true-positive results. CONCLUSION: Paraneoplastic tests result in a large proportion of false positives, particularly in those with clinical presentations that are not well established as paraneoplastic diseases. Future work should construct panels targeted to specific clinical presentations and ensure that tests are ordered in the appropriate clinical context.

Risk Factors for Incident Diabetic Polyneuropathy in a Cohort With Screen-Detected Type 2 Diabetes Followed for 13 Years: ADDITION-Denmark.

OBJECTIVE: To study incident diabetic polyneuropathy (DPN) prospectively during the first 13 years after a screening-based diagnosis of type 2 diabetes and determine the associated risk factors for the development of DPN. RESEARCH DESIGN AND METHODS: We assessed DPN longitudinally in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION) using the Michigan Neuropathy Screening Instrument questionnaire (MNSIQ), defining DPN with scores ≥4. Risk factors present at the diabetes diagnosis associated with the risk of incident DPN were estimated using Cox proportional hazard models adjusted for trial randomization group, sex, and age. RESULTS: Of the total cohort of 1,533 people, 1,445 completed the MNSIQ at baseline and 189 (13.1%) had DPN at baseline. The remaining 1,256 without DPN entered this study (median age 60.8 years [interquartile range 55.6; 65.6], 59% of whom were men). The cumulative incidence of DPN was 10% during 13 years of diabetes. Age (hazard ratio [HR] 1.03 [95% CI 1.00; 1.07]) (unit = 1 year), weight (HR 1.09 [95% CI 1.03; 1.16]) (unit = 5 kg), waist circumference (HR 1.14 [95% CI 1.05; 1.24]) (unit = 5 cm), BMI (HR 1.14 [95% CI 1.06; 1.23]) (unit = 2 kg/m2), log2 methylglyoxal (HR 1.45 [95% CI 1.12; 1.89]) (unit = doubling), HDL cholesterol (HR 0.82 [95% CI 0.69; 0.99]) (unit = 0.25 mmol/L), and LDL cholesterol (HR 0.92 [95% CI 0.86; 0.98]) (unit = 0.25 mmol/L) at baseline were significantly associated with the risk of incident DPN. CONCLUSIONS: This study provides further epidemiological evidence for obesity as a risk factor for DPN. Moreover, low HDL cholesterol levels and higher levels of methylglyoxal, a marker of dicarbonyl stress, are identified as risk factors for the development of DPN.