Pharmacological and Nonpharmacological Treatments for Painful Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most prevalent chronic complications of diabetes. The lifetime prevalence of DPN is thought to be >50%, and 15%–25% of patients with diabetes experience neuropathic pain, referred to as “painful DPN.” Appropriate treatment of painful DPN is important because this pain contributes to a poor quality of life by causing sleep disturbance, anxiety, and depression. The basic principle for the management of painful DPN is to control hyperglycemia and other modifiable risk factors, but these may be insufficient for preventing or improving DPN. Because there is no promising diseasemodifying medication for DPN, the pain itself needs to be managed when treating painful DPN. Drugs for neuropathic pain, such as gabapentinoids, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, alpha-lipoic acid, sodium channel blockers, and topical capsaicin, are used for the management of painful DPN. The U.S. Food and Drug Administration (FDA) has approved pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch as drugs for the treatment of painful DPN. Recently, spinal cord stimulation using electrical stimulation is approved by the FDA for the treatment for painful DPN. This review describes the currently available pharmacological and nonpharmacological treatments for painful DPN.

Prevalence of Diabetic Retinopathy in Undiagnosed Diabetic Patients: A Nationwide Population-Based Study

Background@#We investigated the prevalence of diabetic retinopathy (DR) in patients with undiagnosed diabetes through a nationwide survey, compared to those with known diabetes. @*Methods@#Among the participants of the Korean National Health and Nutrition Examination Surveys (KNHANES) from 2017 to 2018, individuals aged ≥40 years with diabetes and fundus exam results were enrolled. Sampling weights were applied to represent the entire Korean population. Newly detected diabetes patients through KNHANES were classified under “undiagnosed diabetes.” @*Results@#Among a total of 9,108 participants aged ≥40 years, 951 were selected for analysis. Of them, 31.3% (standard error, ±2.0%) were classified under “undiagnosed diabetes.” The prevalence of DR in patients with known and undiagnosed diabetes was 24.5%±2.0% and 10.7%±2.2%, respectively (P<0.001). The DR prevalence increased with rising glycosylated hemoglobin (HbA1c) levels in patients with known and undiagnosed diabetes (P for trend=0.001 in both). Among those with undiagnosed diabetes, the prevalence of DR was 6.9%±2.1%, 8.0%±3.4%, 5.6%±5.7%, 16.7%±9.4%, and 42.6%±14.8% for HbA1c levels of <7.0%, 7.0%–7.9%, 8.0%–8.9%, 9.0%–9.9%, and ≥10.0% respectively. There was no difference in the prevalence of hypertension, dyslipidemia, hypertriglyceridemia, or obesity according to the presence or absence of DR. @*Conclusion@#About one-third of patients with diabetes were unaware of their diabetes, and 10% of them have already developed DR. Considering increasing the prevalence of DR according to HbA1c level was found in patients with undiagnosed diabetes like those with known diabetes, screening and early detection of diabetes and DR are important.

Adrenal Morphology as an Indicator of Long-Term Disease Control in Adults with Classic 21-Hydroxylase Deficiency

Background@#Monitoring adults with classical 21-hydroxylase deficiency (21OHD) is challenging due to variation in clinical and laboratory settings. Moreover, guidelines for adrenal imaging in 21OHD are not yet available. We evaluated the relationship between adrenal morphology and disease control status in classical 21OHD. @*Methods@#This retrospective, cross-sectional study included 90 adult 21OHD patients and 270 age- and sex-matched healthy controls. We assessed adrenal volume, width, and tumor presence using abdominal computed tomography and evaluated correlations of adrenal volume and width with hormonal status. We investigated the diagnostic performance of adrenal volume and width for identifying well-controlled status in 21OHD patients (17α-hydroxyprogesterone [17-OHP] <10 ng/mL). @*Results@#The adrenal morphology of 21OHD patients showed hypertrophy (45.6%), normal size (42.2%), and hypotrophy (12.2%). Adrenal tumors were detected in 12 patients (13.3%). The adrenal volume and width of 21OHD patients were significantly larger than those of controls (18.2±12.2 mL vs. 7.1±2.0 mL, 4.7±1.9 mm vs. 3.3±0.5 mm, P<0.001 for both). The 17-OHP and androstenedione levels were highest in patients with adrenal hypertrophy, followed by those with normal adrenal glands and adrenal hypotrophy (P<0.05 for both). Adrenal volume and width correlated positively with adrenocorticotropic hormone, 17-OHP, 11β-hydroxytestosterone, progesterone sulfate, and dehydroepiandrosterone sulfate in both sexes (r=0.33–0.95, P<0.05 for all). For identifying well-controlled patients, the optimal cut-off values of adrenal volume and width were 10.7 mL and 4 mm, respectively (area under the curve, 0.82–0.88; P<0.001 for both). @*Conclusion@#Adrenal volume and width may be reliable quantitative parameters for monitoring patients with classical 21OHD.

Effect of Vitamin D Supplementation on Risk of Fractures and Falls According to Dosage and Interval: A Meta-Analysis

Background@#Although recent studies comparing various dosages and intervals of vitamin D supplementation have been published, it is yet to be elucidated whether there is an appropriate dose or interval to provide benefit regarding fracture risk. We aimed to assess the published evidence available to date regarding the putative beneficial effects of vitamin D supplements on fractures and falls according to various dosages and intervals. @*Methods@#We performed a meta-analysis of randomized controlled studies reporting associations between vitamin D supplementation and the risks of fractures and falls in PubMed, EMBASE, and Cochrane library. Studies with supplements of ergocalciferol or calcitriol, those with a number of event ≤10, or those with a follow-up duration of less than 6 months were also excluded. @*Results@#Thirty-two studies were included in the final analysis. Vitamin D supplementation with daily dose of 800 to 1,000 mg was associated with lower risks of osteoporotic fracture and fall (pooled relative risk [RR], 0.87; 95% confidence interval [CI], 0.78 to 0.97 and RR, 0.91; 95% CI, 0.85 to 0.98), while studies with 1,000 mg/day did not. Also, among intervals, daily administration of vitamin D was associated with the reduced risk of falls, while intermittent dose was not. Also, patients with vitamin D deficiency showed a significant risk reduction of falls after vitamin D supplementation. @*Conclusion@#Daily vitamin D dose of 800 to 1,000 IU was the most probable way to reduce the fracture and fall risk. Further studies designed with various regimens and targeted vitamin D levels are required to elucidate the benefits of vitamin D supplements.

Lipid Profiles in Primary Aldosteronism Compared with Essential Hypertension: Propensity-Score Matching Study

Background@#There has been controversy regarding the association between primary aldosteronism (PA) and dyslipidemia and few studies considered the effects of diabetes and renal function on lipid metabolism. We analyzed lipid profiles of PA patients and compared them to propensity-score (PS)-matched essential hypertension (EH) patients adjusting for glycemic status and renal function. @*Methods@#Patients who were diagnosed with PA using a saline-infusion test at Seoul National University Hospital from 2000 to 2018 were retrospectively analyzed. EH patients who had aldosterone-renin ratio (ARR) results were selected as controls. Covariates, including diabetes, were PS-matched for patients with PA, lateralized PA, non-lateralized PA, and high ARR to EH patients, respectively. @*Results@#Among a total of 80 PA and 80 EH patients, total cholesterol (TC) and triglyceride (TG) levels were significantly lower in the PA patients than in the EH patients (least-squares mean±standard error: 185.5±4.4 mg/dL vs. 196.2±4.4 mg/dL, P=0.047, for TC; and 132.3±11.5 mg/dL vs. 157.4±11.4 mg/dL, P=0.035, for TG) in fully adjusted model (adjusting for multiple covariates, including diabetes status, glycosylated hemoglobin level, and estimated glomerular filtration rate). There were no significant differences in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol levels between the two groups. According to increments in aldosterone levels, an increasing tendency of HDL-C and decreasing tendencies of TG and non-HDL-C were observed. @*Conclusion@#PA patients had lower TC and TG levels than EH patients, independent of glycemic status and renal function.

Lipid Profiles in Primary Aldosteronism Compared with Essential Hypertension: Propensity-Score Matching Study

Background@#There has been controversy regarding the association between primary aldosteronism (PA) and dyslipidemia and few studies considered the effects of diabetes and renal function on lipid metabolism. We analyzed lipid profiles of PA patients and compared them to propensity-score (PS)-matched essential hypertension (EH) patients adjusting for glycemic status and renal function. @*Methods@#Patients who were diagnosed with PA using a saline-infusion test at Seoul National University Hospital from 2000 to 2018 were retrospectively analyzed. EH patients who had aldosterone-renin ratio (ARR) results were selected as controls. Covariates, including diabetes, were PS-matched for patients with PA, lateralized PA, non-lateralized PA, and high ARR to EH patients, respectively. @*Results@#Among a total of 80 PA and 80 EH patients, total cholesterol (TC) and triglyceride (TG) levels were significantly lower in the PA patients than in the EH patients (least-squares mean±standard error: 185.5±4.4 mg/dL vs. 196.2±4.4 mg/dL, P=0.047, for TC; and 132.3±11.5 mg/dL vs. 157.4±11.4 mg/dL, P=0.035, for TG) in fully adjusted model (adjusting for multiple covariates, including diabetes status, glycosylated hemoglobin level, and estimated glomerular filtration rate). There were no significant differences in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol levels between the two groups. According to increments in aldosterone levels, an increasing tendency of HDL-C and decreasing tendencies of TG and non-HDL-C were observed. @*Conclusion@#PA patients had lower TC and TG levels than EH patients, independent of glycemic status and renal function.

The Early Response to Dietary Therapy can Predict the Late Outcome in Children with Intractable Epilepsy

Background@#and Purpose Dietary therapy (DT), including the ketogenic diet (KD), is one of the nonpharmacological treatment options for patient with drug-resistant epilepsy. However, maintaining DT in patients without seizure reduction is very difficult, so it is critical for clinicians to decide when to stop this intervention. @*Methods@#We retrospectively analyzed early clinical and laboratory findings and the clinical characteristics of children who received DT. The maintenance of DT and the clinical seizure frequency were assessed at 1, 3, 6, 12, and 24 months after KD initiation. Responders were defined as patients showing an overall reduction in seizure frequency of >50% relative to the baseline. @*Results@#We included 67 patients who received DT, but only 23 (34.3%) of these patients remained on DT at 6 months. Only 1 (5%) of the 20 responders at 1 month became a nonresponder at 6 months. The response rate at 6 months was significantly higher among patients under 2 years of age (15/17, 88.2%) than older patients (2/6, 33.3%; p=0.021). Moreover, the 6-month responders were significantly younger (29.4±38.6 months, mean±SD) than the nonresponders (98.9±84.6 months, p=0.012) at the initiation of the diet. A high blood β-hydroxybutyrate (BHB) level at 1 month predicted a good DT response at 6 months. @*Conclusions@#Most 1-month responders maintained their response on DT for up to 6 months.The blood BHB level at 1 month was significantly correlated with the 6-month seizure outcome.Confirming clinical and laboratory biomarkers for the efficacy of DT requires further studies with larger cohorts.

Response: Favorable Glycemic Control with Once-Daily Insulin Degludec/Insulin Aspart after Changing from Basal Insulin in Adults with Type 2 Diabetes (Endocrinol Metab 2019; 34:382-9, Han Na Jang et al.)

No abstract available.

Favorable Glycemic Control with Once-Daily Insulin Degludec/Insulin Aspart after Changing from Basal Insulin in Adults with Type 2 Diabetes

BACKGROUND: Conflicting results have been reported on the efficacy of insulin degludec/insulin aspart (IDegAsp) compared to basal insulin in type 2 diabetes. We investigated the effects of changing basal insulin to IDegAsp on glycemic control and sought to identify factors related to those effects.METHODS: In this retrospective study of patients from three referral hospitals, patients with type 2 diabetes using basal insulin with hemoglobin A1c (HbA1c) levels less than 11.0% were enrolled. Basal insulin was replaced with IDegAsp, and data were analyzed from 3 months before to 3 months after the replacement.RESULTS: Eighty patients were recruited (52.5% male; mean age, 67.0±9.8 years; mean duration of diabetes, 18.9±8.5 years; mean HbA1c, 8.7%±1.0%). HbA1c levels increased during 3 months of basal insulin use, but significantly decreased after changing to IDegAsp (8.28%±1.10%, P=0.0001). The reduction was significant at 6 months in 35 patients whose longer-term data were available. Patients with a measured fasting plasma glucose (m-FPG) lower than their predicted FPG (p-FPG) by regression from HbA1c showed a significant HbA1c reduction caused by the change to IDegAsp, even without a significantly increased insulin dose. However, patients whose m-FPG was higher than their p-FPG did not experience a significant HbA1c reduction, despite a significantly increased insulin dose. Furthermore, the HbA1c reduction caused by IDegAsp was significant in patients with low fasting C-peptide levels and high insulin doses.CONCLUSION: We observed a significant glucose-lowering effect by replacing basal insulin with IDegAsp, especially in patients with a lower m-FPG than p-FPG.

Efficacy and Tolerability of Low-Dose Perampanel in Patients with Childhood-Onset Intractable Epilepsy / 대한소아신경학회지

PURPOSE@#The aim of this study was to evaluate the efficacy and tolerability of perampanel as adjunctive therapy in childhood-onset refractory epilepsy.@*METHODS@#We retrospectively reviewed the medical records of 110 patients who were treated with perampanel in Asan Medical Center children's hospital. Two patients with poor compliance were excluded and 108 patients were enrolled. The clinical characteristics were reviewed, and the total seizure frequency before and after the add-on of perampanel was analyzed.@*RESULTS@#The mean age of the patients (64 males) was 20.2 years (range, 10.5 to 35.6). The mean maintenance dose was 4.8 mg/day (2 to 10 mg). Eight patients (7.4%) achieved seizure freedom and 35 (32.4%) achieved a seizure reduction of ≥50%. Among them, three patients achieved seizure freedom with only 2 mg/day of perampanel. There was no significant difference in sex, age at seizure onset, duration of epilepsy, use of concomitant enzyme-inducing antiepileptic drugs, number of concomitant antiepileptic drugs, and adverse events between responders and non-responders. The retention rate was up to 68.0% in the first year and 59.5% in the second year of the study. Thirty-four patients (31.5%) reported adverse events: violence, somnolence, dizziness, drooling, weight gain, insomnia, and vomiting. There was no contributing factor for the adverse events, including sex, age, and the number of concomitant antiepileptic drugs and enzyme-inducing antiepileptic drugs when comparing the adverse event present group with the adverse event absent group.@*CONCLUSION@#Low-dose perampanel showed reasonable efficacy and tolerability in patients with refractory childhood-onset epilepsy. Further validation with pharmacokinetic studies is needed.

Management of Spontaneous Spinal Epidural Hematoma Developed in Children with Hemophilia / 임상소아혈액종양

Spinal epidural hematoma (SEH) is a rare neurosurgical emergency in which pressure on the spinal cord leads to acute neurological deficits, and is a rare complication in children with hemophilia. We report three cases of SEH in severe hemophilia A. An 8-month-old boy who presented with non-traumatic acute-onset irritability was found to have SEH and was later diagnosed with hemophilia. The two other patients presented with neck pain and magnetic resonance imaging confirmed the diagnosis of SEH. Two patients who received conservative management fully recovered, however the patient who presented with progressive neurological abnormalities at the time of diagnosis, received surgery but later developed breathing difficulties and quadriplegia. Early diagnosis and immediate, aggressive, clotting factor replacement therapy are crucial when managing SEH in children with hemophilia. Immediate and aggressive factor replacement, accompanied by both neurological monitoring and early imaging, are essential for hemophiliac with suspected SEH.

Impact of Influenza Infection on Febrile Seizures: Clinical Implications / 대한소아신경학회지

PURPOSE: Febrile seizures (FSs) are the most common type of seizure in the first 5 years of life and are frequently associated with viral infections. Influenza infection is associated with a variety of neurological conditions, including FSs. The purpose of this study was to evaluate the clinical implications of influenza infection in FSs. METHODS: In total, 388 children with FS were divided into two groups: FS with influenza infection (n=75) and FSs without influenza infection (n=313). Their medical records, including seizure type, frequency, duration, and familial history of FSs or epilepsy, were retrospectively reviewed and the clinical characteristics of the two groups were compared. RESULTS: In total, 75 of the 388 children (19.3%) had FSs associated with influenza infection; such children were significantly older than those with FSs without influenza infection (34.9±22.3 months vs. 24.4±14.2 months; P < 0.001). The children who had more than two febrile seizures episodes were more prevalent in children with FS with influenza infection [40/75 (53.3%) vs. 92/313 (29.4%); P < 0.01]. Children older than 60 months were more likely to have influenza infection compared to those aged less than 60 months [11/22 (50%) vs. 64/366 (17.5%); P=0.001]. CONCLUSION: Influenza infection may be associated with FSs in older children, and with recurrence of FSs. Its role in the development of afebrile seizures or subsequent epilepsy requires further investigation with long-term follow-up.