Bladder dysfunction in adolescents with type 1 diabetes.

BACKGROUND: It is increasingly significant that adults with diabetes experience lower urinary tract symptoms, however, there has been limited research in younger individuals with type 1 diabetes. OBJECTIVE: To investigate bladder function using non-invasive urodynamics as a potential indicator of autonomic neuropathy in adolescents with type 1 diabetes. This involved examining the association between urinary flow disturbances, reported symptoms, and results from other autonomic tests. STUDY DESIGN: Cross-sectional study enrolling 49 adolescents with type 1 diabetes and 18 control subjects. All participants underwent uroflowmetry and ultrasound scanning, completed the Composite Autonomic Symptom Score (COMPASS)-31 questionnaire, and were instructed to record their morning urine volume and voiding frequencies and report them back. Cardiovascular reflex tests (CARTs) and the quantitative sudomotor axon reflex test (QSART) were performed. RESULTS: The main results are shown in the Summary figure. DISCUSSION: In this study, urological abnormalities were not significantly more frequent in adolescents with diabetes, however, urological issues were observed. This is supported by previous findings of Szabo et al. who found that adolescents with type 1 diabetes had reduced flow acceleration and time to maximum flow compared to control subjects. In our study, we observed cases with reduced acceleration and prolonged uroflow curves, possibly indicating detrusor underactivity. People with diabetes had a higher risk of nocturia than healthy controls, which our results supported. Some adolescents reported urination twice per night. Based on these findings, it is considered beneficial to ask about urological symptoms annually to determine if more examinations (frequency-volume charts and uroflowmetry) are necessary and/or if any opportunities for treatment optimization exist. However, uroflowmetry has limitations, as bladder filling and emptying is a complex process involving multiple pathways and neurological centers, making it difficult to standardize and evaluate. Another limitation of this study was that our control group was smaller and consisted of fewer males than females, which could affect the results due to differences in anatomy and physiology in the lower urinary tract system. CONCLUSION: In conclusion, adolescents with type 1 diabetes, as well as healthy adolescents, frequently experience urological symptoms. Although urological abnormalities were not significantly more frequent in adolescents with diabetes in this study, the focus on nocturia and risk for bladder dysfunction seems relevant, even in adolescents without any other tests indicating autonomic dysfunction.

A rare case of sarcoid myelitis complicating Löfgren's syndrome.

Neurosarcoidosis is a rare and serious condition. Rapid diagnosis and treatment are crucial to prevent morbidity and mortality. When neurological symptoms are not present at the time of diagnosis, CNS involvement can be undetected. We present a case of neurosarcoidosis complicating Löfgren's syndrome and discus the challenges in diagnostics and treatment, that can be encountered.

Sweat gland nerve fiber density and association with sudomotor function, symptoms, and risk factors in adolescents with type 1 diabetes.

PURPOSE: To quantify sweat gland nerve fiber density in adolescents with diabetes. Additionally, to investigate associations between sudomotor innervation, sweat responses, and possible risk factors for sudomotor neuropathy. METHODS: Cross-sectional study where 60 adolescents with type 1 diabetes (duration > 5 years) and 23 control subjects were included. Clinical data, quantitative sudomotor axon reflex test, and skin biopsies were obtained. Skin tissue was immunostained and imaged by confocal microscopy. Quantification of the sweat gland volume and three-dimensional reconstruction of the nerve fibers was performed using a design-unbiased technique. RESULTS: Adolescents with diabetes had a significant reduction of maximum and mean values of nerve fiber length and nerve fiber density in sweat glands compared to controls (p values < 0.05). No association between nerve fiber density and sweat responses was found (p = 0.21). In cases with reduced sweat gland nerve fiber length, nerve fiber density, and volume, the sweat response was reduced or absent. Height, systolic blood pressure, time in hypoglycemia, and total daily and basal/total insulin dose were positively correlated to sweat response, while low-density lipoprotein, and HbA1c were negatively correlated with sweat response (p values < 0.05). Other microvascular complications and high cholesterol levels increased the relative risk for reduced sweat gland nerve fiber density. CONCLUSION: Our findings of reduced sweat gland innervation in a selected group of adolescents add new knowledge about the structural changes that occur in autonomic nerves due to diabetes. Evaluating both the sweat gland innervation and sweat gland volume was important for understanding the association with sweat responses. Further research is needed to understand its clinical relevance.

Cardiovascular autonomic neuropathy in patients with type 2 diabetes with and without sensorimotor polyneuropathy.

BACKGROUND AND AIMS: Cardiovascular autonomic neuropathy (CAN) in patients with diabetes is associated with poor prognosis. We aimed to assess signs of CAN and autonomic symptoms and to investigate the impact of sensorimotor neuropathy on CAN by examining type 2 diabetes patients with (DPN [distal sensorimotor polyneuropathy]) and without distal sensorimotor polyneuropathy (noDPN) and healthy controls (HC). Secondarily, we aimed to describe the characteristics of patients with CAN. METHODS: A population of 374 subjects from a previously described cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) were included. Subjects were examined with the Vagus™ device for the diagnosis of CAN, where two or more abnormal cardiovascular autonomic reflex tests indicate definite CAN. Autonomic symptoms were assessed with Composite Autonomic Symptom Score 31 (COMPASS 31) questionnaire. DPN was defined according to the Toronto consensus panel definition. RESULTS: Definite CAN was present in 22% with DPN, 7% without DPN and 3% of HC, and 91% of patients with definite CAN had DPN. Patients with DPN and definite CAN reported higher COMPASS 31 scores compared to patients with noDPN (20.0 vs. 8.3, p < 0.001) and no CAN (22.1 vs. 12.3, p = 0.01). CAN was associated with HbA1c and age in a multivariate logistic regression analysis but was not associated with IEFND or triglycerides. INTERPRETATION: One in five patients with DPN have CAN and specific CAN characteristics may help identify patients at risk for developing this severe diabetic complication. Autonomic symptoms were strongly associated with having both DPN and CAN, but too unspecific for diagnosing CAN.

Neuropathy in adolescents with type 1 diabetes: Confirmatory diagnostic tests, bedside tests, and risk factors.

AIMS: To estimate the prevalence of large fiber (LFN), small fiber (SFN), and autonomic neuropathy in adolescents with type 1 diabetes using confirmatory tests known from adults and to identify risk factors and bedside methods for neuropathy. METHODS: Sixty adolescents with type 1 diabetes (diabetes duration > five years) and 23 control subjects underwent neurological examination and confirmatory diagnostic tests for neuropathy, including nerve conduction studies, skin biopsies determining intraepidermal nerve fiber density, quantitative sudomotor axon reflex test (QSART), cardiovascular reflex tests (CARTs), and tilt table test. Possible risk factors were analyzed. Bedside tests (biothesiometry, DPNCheck®, Sudoscan, and Vagus®device) were compared with the confirmatory tests using ROC analysis. RESULTS: The prevalence of neuropathies in the adolescents with diabetes (mean HbA1c 7.6% (60 mmol/mol)) was as follows: 14% confirmed/26% subclinical LFN, 2% confirmed/25% subclinical SFN, 20% abnormal QSART, 8% abnormal CARTs, and 14% orthostatic hypotension. Higher age, higher insulin dose, previous smoking, and higher triglycerides level were found to increase the relative risk for neuropathy. The bedside tests showed poor to acceptable concordance with the confirmatory tests (all, AUC ≤ 0.75). CONCLUSIONS: The diagnostic tests confirmed the presence of neuropathy in adolescents with diabetes and underscore the importance of prevention and screening.

Early Gastrointestinal Neuropathy Assessed by Wireless Motility Capsules in Adolescents with Type 1 Diabetes.

BACKGROUND: To assess the prevalence of objective signs of gastrointestinal (GI) autonomic neuropathy (AN) in adolescents with type 1 diabetes (T1D). In addition, to investigate associations between objective GI findings and self-reported symptoms or other findings of AN. METHODS: Fifty adolescents with T1D and 20 healthy adolescents were examined with a wireless motility capsule to assess the total and regional GI transit times and motility index. GI symptoms were evaluated with the GI Symptom Rating Scale questionnaire. AN was evaluated with cardiovascular and quantitative sudomotor axon reflex tests. RESULTS: There was no difference in GI transit times in adolescents with T1D and healthy controls. Adolescents with T1D had a higher colonic motility index and peak pressure than the controls, and GI symptoms were associated with low gastric and colonic motility index (all p < 0.05). Abnormal gastric motility was associated with the duration of T1D, while a low colonic motility index was inversely associated with "time in target range" for blood glucose (all p < 0.01). No associations were found between signs of GI neuropathy and other measures of AN. CONCLUSIONS: Objective signs of GI neuropathy are common in adolescents with T1D and it seems to require early interventions in patients at high risk of developing GI neuropathy.

Complex Regional Pain Syndrome or Limb Pain: A Plea for a Critical Approach.

Most frequently, complex regional pain syndrome (CRPS) develops after a trauma and affects distal parts of the limbs. Early recognition and initiation of adequate treatment is crucial for a favorable outcome. On the other hand, misdiagnosing other disorders as CRPS is detrimental because more appropriate treatment may be withheld from the patients. Despite intensive research, a specific biomarker or paraclinical measure for CRPS diagnosis is still lacking. Instead, clinical criteria approved by the International Association for the Study of Pain (IASP) and latest adapted in 2019 are central for diagnosing CPRS. Thus, the CRPS diagnosis remains challenging with the risk of a "deliberate diagnosis" for unexplained pain, while at the same time a delayed CRPS diagnosis prevents early treatment and full recovery. CRPS is a diagnosis of exclusion. To clinically diagnose CRPS, a vigorous exclusion of "other diseases that would better explain the signs and symptoms" are needed before the patients should be referred to tertiary centers for specific pain treatment. We highlight red flags that suggest "non-CRPS" limb pain despite clinical similarity to CRPS. Clinical and neurological examination and paraclinical evaluation of a probably CRPS patient are summarized. Finally, we pinpoint common differential diagnoses for CRPS. This perspective might help CRPS researchers and caregivers to reach a correct diagnosis and choose the right treatment, regardless whether for CRPS mimics or CRPS itself.

Treatment-induced neuropathy of diabetes in an adolescent with rapid reduction in HbA1c and weight loss: Persistent neuropathic findings at follow-up after 1.5 years.

Treatment-induced neuropathy of diabetes (TIND) is a condition occurring within weeks after a rapid decline in blood glucose. This case report illustrates consequences in an adolescent with TIND. Gold standard methods diagnosing large fiber, small fiber, and autonomic neuropathy were abnormal at 1.5 years of follow-up. Awareness of TIND is important.

Large fibre, small fibre and autonomic neuropathy in adolescents with type 1 diabetes: A systematic review.

AIMS: To estimate the prevalence of neuropathy in adolescents with type 1 diabetes. METHODS: Systematic collection of published studies exploring the prevalence of large fibre neuropathy (LFN), small fibre neuropathy (SFN), and autonomic neuropathy in adolescents with type 1 diabetes. Following prospective registration (Prospero CRD42020206093), PubMed, EMBASE, and Cochrane Library were searched for studies from 2000 to 2020. PICO framework was used in the selection process (Population: adolescents aged 10-19 years with type 1 diabetes; Intervention: diagnostic methods for neuropathy; Comparison: reference data; Outcome: data on prevalence or comparison). Data were extracted concerning study quality based on available data and established methods for determining and diagnosing various neuropathy types. RESULTS: From 2,017 initial citations, 27 studies (7589 participants) fulfilled eligibility criteria. The study population (47% males) had a diabetes duration between 4.0 and 10.6 years, and HbA1c level between 7.3 and 10.8%, 56-95 mmol/mol. The prevalence of LFN, based on nerve conduction studies, was 10-57%. Based on other tests for neuropathy, the prevalence of LFN and SFN was 12-62%, and that of cardiac autonomic neuropathy was 12-75%. CONCLUSION: The described prevalence of neuropathy in adolescents with type 1 diabetes varied, which can be methodological due to different screening methods and classifications of neuropathy.

Spinal cord stimulation in severe cases of complex regional pain syndrome: A retrospective cohort study with long-term follow-up.

BACKGROUND: Complex regional pain syndrome (CRPS) is a debilitating pain condition often resistant to standard treatment modalities. In these cases, spinal cord stimulation (SCS) can be an option, but the effect on CRPS remains disputed. We aimed to assess the long-term effect of SCS on CRPS. METHODS: We retrospectively analysed 51 CRPS patients implanted with an SCS system at the University Hospitals in Aarhus or Odense, Denmark, with a median follow-up time of 4.4 years. Primary outcomes were pain intensity on a numeric rating scale (NRS) and the Patients' Global Impression of Change (PGIC). Secondary outcomes were patient satisfaction, work status, consumption of pain medication, the Major Depression Inventory (MDI), Pain Catastrophizing Scale (PCS) and quality of life (QoL) measured using the Short-Form Health Survey (SF-36). For each outcome measure, baseline data were compared to the latest collected data point. RESULTS: A significant pain relief was found with a mean reduction in NRS score of 2.4 (95% CI: 1.7-3.0, p < 0.0001). 68.8% reported 'much improved' or 'very much improved' on the PGIC scale. 87.5% would choose SCS again for the same outcome. A significant beneficial impact was found on MDI score, PCS, SF-36 summary scores and consumption of tricyclic antidepressants, antiepileptic drugs and opioids. No statistical effect was found on work status. CONCLUSION: Pain intensity, depression, pain catastrophizing, pain medication use and QoL were significantly improved after SCS implantation, with high patient satisfaction rates in CRPS patients. This study supports the continued use of SCS in the treatment of severe CRPS. SIGNIFICANCE: This study presents detailed data from a large, well-characterized cohort of Danish CRPS patients treated with SCS, analyzing several outcome measures. The results serve to document SCS as an effective treatment for severe CRPS and expands the cumulative level of evidence in favor of its use. Additionally, analysis of preoperative patient characteristics suggests that SCS treatment should not be withheld in patients with a high degree of psychological distress or high consumption of analgesics.

Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats.

Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson's disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson's disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson's disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson's disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson's disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions.

[Diabetic neuropathy caused by too rapid downregulation of blood glucose].

Treatment-induced neuropathy of diabetes is an iatrogenic acute painful sensory and autonomic neuropathy. The condition is caused by rapid downregulation of blood glucose after a long period of hyperglycaemia. In this case report, a 43-year-old man with Type 1 diabetes and severe metabolic dysregulation had downregulated his blood glucose level with 3.8% over ten weeks through optimised insulin treatment and weight loss. He developed severe neuropathic pain due to small fiber neuropathy and neurogenic autonomic dysfunction with erectile dysfunction, urine retention and cardiovagal and enteric dysfunction.

Translation and linguistic validation of the Composite Autonomic Symptom Score COMPASS 31 in Danish.

INTRODUCTION: The Composite Autonomic Symptom Score (COMPASS 31) is a validated self-assessment questionnaire quantifying the severity and distribution of autonomic symptoms across six domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder and pupillomotor functions) by scoring 31 clinically selected questions. The aim of this study was to translate into Danish and validate the Danish version of COMPASS 31. METHODS: The original (US) English version of the COMPASS 31 questionnaire was translated into Danish via forward/backward translation and validated in accordance with a protocol set forth by the Autonomic Group at the Mayo Clinic. Ten healthy controls and 20 patients with disorders associated with a variable degree of autonomic dysfunction were enrolled - all bilingual (Danish mother tongue, proficiency in English). RESULTS: A total of 20 patients (16 women, aged 48 + 17 years) and ten healthy controls (six women, aged 40 + 19 years) were included. Test-retest reliability was high with no consistent bias, and the Danish version of the COMPASS 31 significantly correlated with the English version of the COMPASS 31 in both total score and all sub-scores. Patients scored significantly higher on the COMPASS 31 questionnaire than healthy controls (34.0 (26.5-49.2) versus 2.3 (1.6-24.3) (median (interquartile ranges); p = 0.01). CONCLUSIONS: We present a Danish version of the COMPASS 31 - a validated self-reported questionnaire allowing for the quantification of autonomic dysfunction. We hope this Danish version will be implemented in both clinical practice and research settings in Denmark. FUNDING: none. TRIAL REGISTRATION: not relevant.

Skin Temperature in Parkinson's Disease Measured by Infrared Thermography.

BACKGROUND: Patients with Parkinson's disease (PD) often show peripheral autonomic dysfunction and depositions of pathological alpha-synuclein aggregates in the skin. However, functional consequences of this skin involvement have received little attention. OBJECTIVE: To determine thermographic differences in the skin between healthy controls (HCs) and PD patients on hands, feet, and trunk and to correlate findings with symptoms and signs of dysautonomia. Between-group differences in autonomic parameters and questionnaires were explored. METHODS: Twenty-one PD patients and 19 HCs were examined by thermographic infrared imaging of standardized anatomical locations on the trunk and upper and lower extremities at baseline and after exposure to cold stress test (CST). Thermal recovery rates (RRs) were determined on the basis of thermograms. Correlation analyses between alterations in skin temperature and autonomic dysfunction were performed. RESULTS: The most significant RR difference between PD patients and HCs was seen on the fifth distal phalanx 10 minutes post-CST (mean RR ± SD: 51 ± 18% vs. 70 ± 23%, p = 0.003). No between-group differences were seen in baseline or post-CST values of the feet. No correlations were seen between thermal parameters and clinical and autonomic data. In the HC group, a positive, moderate correlation was seen between post-CST recovery values on the 3rd and 5th phalanx and body mass index (BMI) (r = 0.661, p = 0.002). CONCLUSIONS: The PD patients exhibited significant reduction in RR compared to HC and patients also displayed altered thermal responses in multiple anatomical locations. Thus, infrared thermography could become an important future tool in investigation of autonomic deficiency in PD.

Region-Specific Effects of Trigeminal Capsaicin Stimulation.

AIMS: To investigate the region-specific effects of painful trigeminal capsaicin stimulation in healthy participants. METHODS: Twenty healthy participants (10 men and 10 women) participated in four sessions in which they received application of 0.05 mL Vaseline (placebo) or capsaicin cream (0.1%) to a different area innervated by the three branches of the trigeminal nerve: the supraorbital area (V1), the nasal mucosa (V1/V2), and the maxillary (V2) and mandibular (V3) oral mucosa. The participants rated their perceived sensations on a 0-50-100 numeric rating scale (NRS). Thermal (5°C, 23°C, and 50°C) and mechanical (32 mN and 256 mN) sensitivities were assessed. The Schirmer tearing test was used to monitor the lacrimation level as a local measure of autonomic activity, and the Task Force Monitor was used to record systemic autonomic activity. Data were analyzed using repeated measures analysis of variance. RESULTS: Capsaicin application evoked significantly higher overall NRS scores (P < .001) and induced significantly higher ratings to the heat stimuli (P < .009) in all sessions compared to control. For lacrimation level, capsaicin stimulation resulted in a significant increase compared to control (P < .0002) only in the nasal mucosa session. CONCLUSION: Topical application of capsaicin cream to the different branches of the trigeminal nerve caused higher NRS scores along with an altered somatosensory sensitivity. Furthermore, in the nasal mucosa session, a robust local and generalized parasympathetic activation appeared following capsaicin application.

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy.

INTRODUCTION: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. METHODS: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. RESULTS: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. DISCUSSION: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59:354-357, 2019.

[Neurogenic autonomic dysfunction in adults].

Neurogenic autonomic dysfunction (NAD) is underdiagnosed, and it is likely in patients, who have orthostatic hypotension and symptoms from multiple organ systems as well as abnormal results from a neurological examination. A clinical and neurophysiological examination of the autonomic nervous system combined with a standardised paraclinical evaluation should be performed. NAD may be present in neurodegenerative disorders, vitamin deficiency, toxicity, infection, and in paraneoplastic, metabolic, hereditary and immune-mediated conditions.

[Neurogenic autonomic dysfunction in primary amyliodosis].

Neurogenic autonomic dysfunction (NAD) and polyneuropathy occur in common conditions like diabetes and alcoholism. However, it can also be seen in rare diseases like in this case report of amyloid light-chain amyloidosis: primary amyloidosis. A 56-year-old man presented with polyneuropathy, a sympathetic dysfunction causing orthostatic intolerance, syncope, parasympathetic dysfunction and involvement of the enteric nervous system. The report illustrates, that routine screening can be insufficient in diagnosing amyloidosis. NAD and polyneuropathy without clear aetiology may require a multidisciplinary elucidation of more rare diseases.

Autonomic function testing: Compliance and consequences.

BACKGROUND: The deep breathing test (DB) and Valsalva maneuver (VM) are used to detect autonomic dysfunction. The VM induces sympathetically mediated changes in blood pressure (phase II late, phase IV, and recovery time) and both tests induce vagally mediated heart rate changes. There is limited information on effects of key variables, compliance with testing and the effects of non-compliance This study has twin goals of evaluating compliance with standard instructions and the effects of changes in key variables. We also evaluated the effect of position on the VM. MATERIAL AND METHODS: Forty healthy males performed DB at air exchange volumes of 50, 80, and 100% of vital lung capacity (VLC). The VM was performed at 40 and 30mmHg expiratory pressure for 15 and 10s in sitting and supine position, respectively. RESULTS: Participants performed DB at lower volumes than intended and were not able to maintain 100% VLC for the duration of the test. The DB heart rate response decreased 6.3beats/min per liter below VLC. During the VM, subjects blew at lower pressures than instructed. The VM responses were significantly larger with longer expiration durations, higher expiratory pressures and when performed sitting. Performing the VM at 40mmHg for 10s in supine position increased the odds ratio of experiencing flat-top responses. CONCLUSION: The ability of subjects to strictly comply with methodological guidelines significantly improves results. Recording of both test parameters and ensuing results is suggested.