Novel CHRNA3 variants identified in a patient with bladder dysfunction, dysautonomia, and gastrointestinal dysmotility.

Congenital anomalies of the kidney and urinary tract (CAKUT) are estimated to be responsible for 20%-50% of congenital anomalies and are also a leading etiology of early-onset renal disease. Primary CAKUT are caused by genetic factors that impair proper in-utero genitourinary tract development and secondary CAKUT result from the influence of environmental factors. The CHRNA3 gene, which encodes the Alpha-3 subunit of the nicotinic acetylcholine receptor, is hypothesized to be associated with Megacystis-microcolon-intestinal hyperperistalsis syndrome. More recently, pathogenic variants in CHRNA3 have been identified in individuals with CAKUT as well as individuals with panautonomic failure. Here we present a patient with neurogenic bladder, vesicoureteral reflux, mydriasis, and gastrointestinal dysmotility found to have novel compound heterozygous variants in CHRNA3. These findings support the consideration of CHRNA3 disruption in the differential for CAKUT with dysautonomia and gastrointestinal dysmotility.

Standing gustatory papillae biopsy procedure for antemortem diagnosis of equine grass sickness.

OBJECTIVE: Diagnosing equine grass sickness (EGS) requires histopathological evidence of chromatolysis and/or neuronal loss in peripheral autonomic ganglia. Previous investigators performed postmortem biopsies of gustatory papillae located on the tongue and found chromatolytic subgemmal neurons in all 13 EGS horses. The present study aimed to design a standardized lingual biopsy sampling method through a transbuccal approach in healthy standing horses and assess the quality of the obtained samples, to allow antemortem diagnosis of EGS in clinical cases. ANIMALS: 6 healthy horses. METHODS: A transbuccal approach was performed bilaterally in 6 healthy standing horses. After having reached a deep level of sedation, horses were placed in stocks and a Günther mouth gag was inserted. Local anesthesia followed by a vertical full thickness incision was performed on both cheeks. Foliate papillae biopsies were carried out using an arthroscopic rongeur inserted through each incision site under oral endoscopic control. Tongue movements were restricted with diazepam. Histological assessment of taste buds and subgemmal plexi neurons was performed using H&E-stained longitudinal sections. RESULTS: The procedure was well tolerated in all horses. Minor complications observed were a transient facial paralysis, some incisional fluid collection, and abscesses. Ten samples (10/12) were suitable for assessment of neuronal perikarya. CLINICAL RELEVANCE: This procedure was safe for subgemmal plexus biopsy in healthy standing horses. The obtained samples were adequate as long as they were neatly cut lengthwise for inclusion. The technique was also used for 2 clinical cases and revealed the complete absence of neuronal perikarya, confirming chronic EGS.

Functional and structural markers of peripheral microvascular autonomic neuropathy.

INTRODUCTION/AIMS: Autonomic dysfunction is a common complication of small-fiber neuropathy (SFN). In this study we aimed to assess the applicability of autonomic microvascular indices as a potential marker for SFN assessment. METHODS: Fifteen patients with confirmed SFN (idiopathic neuropathy [n = 10], chemotherapy-induced peripheral neuropathy [n = 2], impaired glucose tolerance [n = 1], hereditary transthyretin amyloidosis (hATTR) [n = 1], pulmonary sarcoidosis [n = 1]) and 15 matched control subjects underwent assessment of vascular skin responses assessed through laser Doppler flowmetry and evaluation of microvascular vessel and nerve density in skin biopsies. All participants underwent peripheral autonomic evaluation by quantitative sudomotor axon reflex testing (QSART). RESULTS: We found no significant differences in vascular skin responses, or in any microvascular skin biopsy markers, when comparing SFN with control subjects. We found no correlation between vascular skin responses and skin biopsy indices. We saw no significant difference in any microvascular indices when comparing subjects with and without impaired sudomotor function. DISCUSSION: Our findings suggest markers of peripheral microvascular innervation and function are not associated with the diagnosis of SFN. Furthermore, we saw no association between microvascular markers and sudomotor function, suggesting that these are independent and unrelated components of the autonomic nervous system.

Non-invasive near-infrared spectroscopy assessment of the spinal neurovascular response in a patient with transverse myelitis: a case report.

BACKGROUND: Transverse myelitis (TM) is characterized by acute development of motor, sensory and autonomic dysfunctions due to horizontally diffused inflammation in one or more segments of the spinal cord in the absence of a compressive lesion. The not well-known inflammation process induces demyelination resulting in neurological dysfunction. CASE PRESENTATION: In this case report we used a functional Near-Infrared Spectroscopy (fNIRS) technique to evaluate changes in the peri-spinal vascular response induced by a peripheral median nerve electrical stimulation in a patient with chronic transverse myelitis (TM). fNIRS showed drastically reduced signal amplitude in the peri-spinal vascular response, compared to that obtained from a healthy control group throughout most of the C7-T1 and T10-L2 spinal cord segments. CONCLUSION: The potential use of this relatively non-invasive fNIRS technology support the potential clinical application of this method for functional test of the spinal cord through the assessment of the spinal neurovascular response.

Mini-Review on the Harlequin Syndrome-A Rare Dysautonomic Manifestation Requiring Attention.

Harlequin syndrome (HS) is a rare autonomic disorder. The causes and risk factors of the disease are not fully understood. Some cases of HS are associated with traumatic injuries, tumors, or vascular impairments of the head. Symptoms of HS can also occur in some autoimmune disorders, ophthalmic disorders, sleep disorders, and with certain organic lesions. In this context, a thorough review of the pathophysiology of HS in relation to neurological, ophthalmological, and dermatological conditions is necessary. In this mini-review, we aim to review the pathophysiological changes and underlying mechanisms in primary and secondary HS. Additionally, we discuss possible management approaches for patients with HS in light of the discussed pathological mechanisms. The main symptoms of HS that are correlated with autonomic nervous system impairments include sudden unilateral flushing of the face, neck, chest, and rarely arm, with concurrent contralateral anhidrosis. Despite reported co-occurring syndromes (such as cluster headaches), several studies have shown that HS could frequently overlap with other syndromes that are disruptive to the idiopathic nerve pathways. HS usually does not require any medical treatment. In some severe cases, symptomatic treatments could be needed. However, total symptomatic relief may not be achieved in many cases of HS. We therefore suggest an approach to comprehensive management of HS, which may lead to better long-term control of HS.

[Autonomic Dysfunction in Lewy Body Disease].

Lewy body disease is a clinicopathological entity that includes Parkinson's disease, dementia with Lewy bodies, and pure autonomic failure with Lewy bodies, all of which are characterized by varied degrees of autonomic dysfunction. Research in animal models has shown transmission of α-synuclein from peripheral autonomic nerves to the central nervous system via the autonomic nervous system, and the autonomic nervous system plays an important role in the study of Lewy body disease. This paper outlines the pathophysiology, characteristics, and treatment of typical autonomic dysfunction in patients with Lewy body disease.

Parkinson-like early autonomic dysfunction induced by vagal application of DOPAL in rats.

AIM: To understand why autonomic failures, a common non-motor symptom of Parkinson's disease (PD), occur earlier than typical motor disorders. METHODS: Vagal application of DOPAL (3,4-dihydroxyphenylacetaldehyde) to simulate PD-like autonomic dysfunction and understand the connection between PD and cardiovascular dysfunction. Molecular and morphological approaches were employed to test the time-dependent alternation of α-synuclein aggregation and the ultrastructure changes in the heart and nodose (NG)/nucleus tractus solitarius (NTS). RESULTS: Blood pressure (BP) and baroreflex sensitivity of DOPAL-treated rats were significantly reduced accompanied with a time-dependent change in orthostatic BP, consistent with altered echocardiography and cardiomyocyte mitochondrial ultrastructure. Notably, time-dependent and collaborated changes in Mon-/Tri-α-synuclein were paralleled with morphological alternation in the NG and NTS. CONCLUSION: These all demonstrate that early autonomic dysfunction mediated by vagal application of DOPAL highly suggests the plausible etiology of PD initiated from peripheral, rather than central site. It will provide a scientific basis for the prevention and early diagnosis of PD.

Neuroimaging and Pathology Findings Associated With Rapid Onset Obesity, Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) Syndrome.

Rapid onset Obesity, Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a rare syndrome whose underlying pathophysiology and etiology remain elusive. We present the case of a 36-month-old boy with the classic symptoms of ROHHAD and a neuroendocrine tumor, who progressed rapidly and subsequently succumbed to cardiorespiratory arrest because of hypoventilation. His magnetic resonance imaging findings at the initial diagnosis and the brain autopsy results are detailed. The literature was reviewed to summarize the current understanding of the underlying mechanism of this rare disorder.

Improvement in Cardiovascular Autonomic Neuropathy After High-Dose Vitamin D Supplementation in Patients With Type 1 Diabetes.

Background: Cardiovascular autonomic neuropathy (CAN) is associated with diabetes mellitus, increasing morbidity and mortality. Some cross-sectional studies associated CAN with low 25-hydroxyvitamin D levels. The aim of our study was to evaluate the effect of high-dose vitamin D (VD) supplementation on CAN in Type 1 Diabetes Mellitus (T1DM) patients. Methods: We performed a prospective study with 23 patients diagnosed with T1DM and CAN. Subjects with VD levels <30 ng/ml received 10,000 IU/day; the ones with VD levels between 30-60 ng/ml were given 4,000 IU/day for 12 weeks. Results: There was an improvement in CAN parameters related to resting heart rate variability, such as time domain parameters [Maximum RR interval (0.77 ± 0.11 vs 0.94 ± 0.51 s, p <0.05), Mean length of regular RR intervals (0.71 ± 0.10 vs 0.76 ± 0.09 s, p <0.05) and Standard deviation of all NN intervals (0.02 ± 0.01 vs 0.03 ± 0.02 s; p <0.01)] and frequency domain parameters [Low Frequency (1.9 ± 0.5 vs 2.5 ± 0.9 s, p < 0.001), Total Power (2.5 ± 0.4 vs 2.8 ± 0.6 s, p <0.05)]. In addition, there was a correlation between absolute VD level variation and posttreatment High Frequency (%), as well as among percent variation in VD level and end-of-study Low Frequency/High Frequency ratio (r=0.6, p<0.01; r= -0.5, p<0.05, respectively). Conclusion: Our pilot study is the first to suggest a strong association between high-dose vitamin D supplementation and improved cardiovascular autonomic neuropathy in T1DM patients. It occurred without any variation in HbA1C, blood pressure levels, lipids, and insulin dose. Clinical Trial Registration: http://www.isrctn.com/ISRCTN32601947, identifier ISRCTN32601947.

Afferent Baroreflex Dysfunction: Decreased or Excessive Signaling Results in Distinct Phenotypes.

Head and neck tumors can affect afferent baroreceptor neurons and either interrupt or intermittently increase their signaling, causing blood pressure to become erratic. When the afferent fibers of the baroreflex are injured by surgery or radiotherapy or fail to develop as in familial dysautonomia, their sensory information is no longer present to regulate arterial blood pressure, resulting in afferent baroreflex failure. When the baroreflex afferents are abnormally activated, such as by paragangliomas in the neck, presumably by direct compression, they trigger acute hypotension and bradycardia and frequently syncope, by a mechanism similar to the carotid sinus syndrome. We describe our observations in a large series of 23 patients with afferent baroreflex dysfunction and the cardiovascular autonomic features that arise when the sensory baroreceptor neurons are injured or compressed. The management of afferent baroreceptor dysfunction is limited, but pharmacological strategies can mitigate blood pressure swings, improve symptoms, and may reduce hypertensive organ damage. Although rare, the prevalence of afferent baroreflex dysfunction appears to be increasing in middle-aged men due to human papillomavirus related oropharyngeal cancer.

The impact of supine hypertension on target organ damage and survival in patients with synucleinopathies and neurogenic orthostatic hypotension.

INTRODUCTION: In addition to neurogenic orthostatic hypotension (nOH), patients with synucleinopathies frequently have hypertension when supine. The long-term consequences of both abnormalities are difficult to disentangle. We aimed to determine if supine hypertension is associated with target organ damage and worse survival in patients with nOH. METHODS: Patients with nOH due to multiple system atrophy (MSA), Parkinson disease (PD), or pure autonomic failure (PAF) were classified into those with or without supine hypertension (systolic BP of at least 140 mmHg or diastolic BP of at least 90 mmHg). Organ damage was assessed by measuring cerebral white matter hyperintensities (WMH), left ventricular hypertrophy (LVH), and renal function. We prospectively followed patients for 30 months (range: 12-66 months) and recorded incident cardiovascular events and all-cause mortality. RESULTS: Fifty-seven patients (35 with probable MSA, 14 with PD and 8 with PAF) completed all evaluations. In addition to nOH (average fall 35 ± 21/17 ± 14 mmHg, systolic/diastolic, mean ± SD), 38 patients (67%) had supine hypertension (systolic BP > 140 mmHg). Compared to those without hypertension, patients with hypertension had higher blood urea nitrogen levels (P = 0.005), lower estimated glomerular filtration rate (P = 0.008), higher prevalence of LVH (P = 0.040), and higher WMH volume (P = 0.019). Longitudinal follow-up of patients for over 2 years (27.1 ± 14.5 months) showed that supine hypertension was independently associated with earlier incidence of cardiovascular events and death (HR = 0.25; P = 0.039). CONCLUSIONS: Supine hypertension in patients with nOH was associated with an increased risk for target organ damage, cardiovascular events, and premature death. Defining management strategies and safe blood pressure ranges in patients with nOH remains an important research question.

Hypoglycemia unawareness and autonomic dysfunction in diabetes: Lessons learned and roles of diabetes technologies.

Impaired awareness of hypoglycemia (IAH) is a reduction in the ability to recognize low blood glucose levels that would otherwise prompt an appropriate corrective therapy. Identified in approximately 25% of patients with type 1 diabetes, IAH has complex pathophysiology, and might lead to serious and potentially lethal consequences in patients with diabetes, particularly in those with more advanced disease and comorbidities. Continuous glucose monitoring systems can provide real-time glucose information and generate timely alerts on rapidly falling or low blood glucose levels. Given their improvements in accuracy, affordability and integration with insulin pump technology, continuous glucose monitoring systems are emerging as critical tools to help prevent serious hypoglycemia and mitigate its consequences in patients with diabetes. This review discusses the current knowledge on IAH and effective diagnostic methods, the relationship between hypoglycemia and cardiovascular autonomic neuropathy, a practical approach to evaluating cardiovascular autonomic neuropathy for clinicians, and recent evidence from clinical trials assessing the effects of the use of CGM technologies in patients with type 1 diabetes with IAH.

Impaired orthostatic heart rate recovery is associated with smaller thalamic volume: Results from The Irish Longitudinal Study on Aging (TILDA).

The thalamus is a central hub of the autonomic network and thalamic volume has been associated with high-risk phenotypes for sudden cardiac death. Heart rate response to physiological stressors (e.g., standing) and the associated recovery patterns provide reliable indicators of both autonomic function and cardiovascular risk. Here we examine if thalamic volume may be a risk marker for impaired heart rate recovery in response to orthostatic challenge. The Irish Longitudinal Study on Aging involves a nationally representative sample of older individuals aged ≥50 years. Multimodal brain magnetic resonance imaging and orthostatic heart rate recovery were available for a cross-sectional sample of 430 participants. Multivariable regression and linear mixed-effects models were adjusted for head size, age, sex, education, body mass index, blood pressure, history of cardiovascular diseases and events, cardiovascular medication, diabetes mellitus, smoking, alcohol intake, timed up-and-go (a measure of physical frailty), physical exercise and depression. Smaller thalamic volume was associated with slower heart rate recovery (-1.4 bpm per 1 cm3 thalamic volume, 95% CI -2.01 to -0.82; p < .001). In multivariable analysis, participants with smaller thalamic volumes had a mean heart rate recovery -2.7 bpm slower than participants with larger thalamic volumes (95% CI -3.89 to -1.61; p < .001). Covariates associated with smaller thalamic volume included age, history of diabetes, and heavy alcohol consumption. Thalamic volume may be an indicator of the structural integrity of the central autonomic network. It may be a clinical biomarker for stratification of individuals at risk of autonomic dysfunction, cardiovascular events, and sudden cardiac death.

A novel method to quantify cutaneous vascular innervation.

INTRODUCTION: To develop a new method to quantify the density of nerves, vessels, and the neurovascular contacts, we studied skin biopsies in diabetes and control subjects. METHODS: Skin biopsies with dual immunofluorescent staining were used to visualize nerves and blood vessels. The density of nerves, vessels, and their neurovascular contacts were quantified with unbiased stereology. Results were compared with examination findings, validated questionnaires, and autonomic function. RESULTS: In tissue from 19 controls and 20 patients with diabetes, inter-rater and intra-rater intraclass correlation coefficients were high (>0.85; P < .001) for all quantitative methods. In diabetes, the nerve densities (P < .05), vessel densities (P < .01), and the neurovascular densities (P < .01) were lower compared with 20 controls. Results correlated with autonomic function, examination and symptom scores. DISCUSSION: We report an unbiased, stereological method to quantify the cutaneous nerve, vessel and neurovascular density and offer new avenues of investigation into cutaneous neurovascular innervation in health and disease.

The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: A systematic review.

Rigorous glycaemic control-reflected by low HbA1c goals-is of the utmost importance in the prevention and management of complications in patients with type 1 diabetes mellitus (T1DM). However, previous studies suggested that short-term glycaemic variability (GV) is also important to consider as excessive glucose fluctuations may have an additional impact on the development of diabetic complications. The potential relationship between GV and the risk of cardiovascular autonomic neuropathy (CAN), a clinical expression of cardiovascular autonomic dysfunction, is of increasing interest. This systematic review aimed to summarize existing evidence concerning the relationship between GV and cardiovascular autonomic dysfunction in T1DM. An electronic database search of Medline (PubMed), Web of Science and Embase was performed up to October 2019. There were no limits concerning year of publication. Methodological quality was evaluated using the Newcastle Ottawa Scale for observational studies. Six studies (four cross-sectional and two prospective cohorts) were included. Methodological quality of the studies varied from level C to A2. Two studies examined the association between GV and heart rate variability (HRV), and both found significant negative correlations. Regarding cardiovascular autonomic reflex tests (CARTs), two studies did not, while two other studies did find significant associations between GV parameters and CART scores. However, associations were attenuated after adjusting for covariates such as HbA1c, age and disease duration. In conclusion, this systematic review found some preliminary evidence supporting an association between GV and cardiovascular autonomic dysfunction in T1DM. Hence, uncertainty remains whether high GV can independently contribute to the onset or progression of CAN. The heterogeneity in the methodological approach made it difficult to compare different studies. Future studies should therefore use uniformly evaluated continuous glucose monitoring-derived parameters of GV, while standardized assessment of HRV, CARTs and other potential cardiac autonomic function parameters is needed for an unambiguous definition of CAN.

Lesion configuration effect on stroke-related cardiac autonomic dysfunction.

BACKGROUND: Autonomic nervous system (ANS) malfunction is a common sequel of stroke. The impact of lesion configuration on the expression of stroke-related ANS malfunction is largely unknown. OBJECTIVE: To examine the relationship between stroke location and ANS malfunction, as reflected in cardiac rhythm control. METHODS: 25 patients in the subacute phase post first-ever ischemic stroke were recruited for the study. Heart rate monitor (RS800CX) was used to record RR intervals analyzed as heart rate variability (HRV) parameters. Lesion data derived from follow-up CT scans of the brain was used for voxel-based lesion symptom mapping (VLSM) analysis (MEDx software, Medical Numerics) to identify voxels of the normalized brain where damage exerts a significant impact on the HRV scores. RESULTS AND CONCLUSION: ANS control of the cardiac rhythm, as expressed in the HRV, was affected by damage to a large array of cortical and subcortical structures in the right hemisphere. In the left hemisphere only damage confined to a small set of subcortical structures was shown to exert a significant impact on the recorded HRV measures. In addition, VLSM analysis disclosed a different pattern of cerebral control over two widely used standard time-dependent measures of the HRV - SDNN and RMSSD, with the former being sensitive to damage in a much larger array of structures in both hemispheres.

Skin Biopsy in Evaluation of Autonomic Disorders.

PURPOSE OF REVIEW: This article provides an up-to-date assessment of the role of skin biopsy in the evaluation of autonomic disorders. The standard methodology for completing a skin biopsy, the anatomic structures of interest detected within a skin biopsy, and the disease states in which skin biopsies may provide valuable information are reviewed. RECENT FINDINGS: Several recent advances in the studies of hereditary amyloidosis and the various degenerative synucleinopathies have demonstrated that simple skin biopsies can provide valuable pathologic evidence of neurologic disease. In addition to diagnosis of the underlying disorder, skin biopsies provide a quantitative structural measurement of the associated autonomic damage. SUMMARY: Skin biopsies are making great inroads into the study of autonomic and peripheral nerve disorders. Complex immunohistochemical staining protocols are challenging to complete, but the rich data derived from these studies in the diagnosis and monitoring of different disease states suggest that the role of skin biopsies in the study of the autonomic nervous system will continue to expand in the years to come.

Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction.

We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD-DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α-synuclein pathology. We found moderate-severe vascular changes and high-vascular pathology scores (P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub-set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life (P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α-synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging-related neurodegenerative disorders and characterize their end-stage clinical syndromes.