Central Autonomic Dysfunction Research Articles

Epilepsy and Cardiac Arrhythmias: A State-of-the-Art Review.

Epilepsy is an important cause of disability and mortality worldwide. It can be frequently misdiagnosed, and detailed history and relevant investigations are needed to differentiate epilepsy from syncope. Electroencephalogram is a key noninvasive assessment of neurological function, and the diagnostic yield is increased when performed for an extended period in the ambulatory setting with concurrent electrocardiogram and video monitoring. People living with epilepsy may be affected by a diverse range of ictal (seizure-associated) arrhythmias. The prevalence of detected arrhythmias in people living with epilepsy is anticipated to rise in the context of increasingly available wearable technology and improved survival. Ictal bradycardia and asystole sometimes observed in temporal lobe epilepsy may be associated with falls and injury that can be prevented by cardiac pacing; however, seizure control with medical therapy is still crucial. Sudden unexpected death in epilepsy is likely explained by a different mechanism, in particular central cardiorespiratory autonomic dysfunction sometimes associated with generalized tonic-clonic seizures. Channelopathies encompassing the heart-brain axis are increasingly recognized and may explain the overlap between certain epileptic and arrhythmogenic syndromes, with potential for targeted therapy in the future. The QT interval is prognostically significant in epilepsy, with various seizure types affecting the QT interval differently. Certain antiseizure medications may cause electrocardiogram abnormalities and arrhythmias although there remains limited clinical data. This State-of-the-Art Review describes our current understanding regarding the relationship between epilepsy and cardiac arrhythmias, as well as delineating areas of unmet need.

Central autonomic network dysfunction and plasma Alzheimer’s disease biomarkers in older adults

BackgroundHigher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer’s disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults.MethodsIndependently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aβ42, Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed.ResultsAll autonomic networks were positively associated with Aβ42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected.ConclusionThe present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aβ42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.

Tailored exercise programmes for fibromyalgia: a clinical practical guide.

To evaluate the role of exercise in the management of fibromyalgia syndrome (FM) by addressing its complex pathogenesis involving central sensitisation, autonomic dysfunction, inflammation, and neurological irregularities, and examining how exercise impacts symptom exacerbation caused by external stressors and comorbid conditions. This review synthesises evidence from current literature focusing on the benefits of structured and personalised exercise programmes in FM management. It discusses the importance of specifying exercise type, intensity, frequency, duration, and progression tailored to individual patient needs and clinical objectives. Regular physical activity effectively mitigates core aetiopathogenetic mechanisms of FM and improves associated conditions such as stress and obesity. It also provides benefits for preventing other chronic diseases, enhancing well-being, and promoting healthy ageing. Structured and personalised exercise programmes that start with a low-demand protocol and gradually increase exercise volume are most beneficial, by improving patient compliance and reducing the risk of adverse effects. Effective management of FM requires a patient-centred approach integrating both pharmacological and non-pharmacological treatments, with exercise playing a pivotal role. Personalised exercise prescriptions that consider FM patients' specific needs and limitations are crucial for optimising treatment outcomes and enhancing quality of life.

Neural correlate of reduced respiratory chemosensitivity during chronic epilepsy.

While central autonomic, cardiac, and/or respiratory dysfunction underlies sudden unexpected death in epilepsy (SUDEP), the specific neural mechanisms that lead to SUDEP remain to be determined. In this study, we took advantage of single-cell neuronal Ca2+ imaging and intrahippocampal kainic acid (KA)-induced chronic epilepsy in mice to investigate progressive changes in key cardiorespiratory brainstem circuits during chronic epilepsy. Weeks after induction of status epilepticus (SE), when mice were experiencing recurrent spontaneous seizures (chronic epilepsy), we observed that the adaptive ventilatory responses to hypercapnia were reduced for 5 weeks after SE induction with its partial recovery at week 7. These changes were paralleled by alterations in the chemosensory responses of neurons in the retrotrapezoid nucleus (RTN). Neurons that displayed adapting responses to hypercapnia were less prevalent and exhibited smaller responses over weeks 3-5, whereas neurons that displayed graded responses to hypercapnia became more prevalent by week 7. Over the same period, chemosensory responses of the presympathetic rostral ventrolateral medullary (RVLM) neurons showed no change. Mice with chronic epilepsy showed enhanced sensitivity to seizures, which invade the RTN and possibly put the chemosensory circuits at further risk of impairment. Our findings establish a dysfunctional breathing phenotype with its RTN neuronal correlate in mice with chronic epilepsy and suggest that the assessment of respiratory chemosensitivity may have the potential for identifying people at risk of SUDEP.

The Association of Nocturnal Seizures and Interictal Cardiac/Central Autonomic Function in Frontal Lobe Epilepsy: Heart Rate Variability and Central Autonomic Network Analysis.

Patients with epilepsy frequently experience autonomic dysfunction, closely related to sudden unexplained death in epilepsy (SUDEP). SUDEP occurs most often at night or during sleep, and frequent nocturnal seizures are an established risk factor. This study investigated the influence of nocturnal seizures on autonomic dysfunction in epilepsy. This retrospective study enrolled frontal lobe epilepsy (FLE) patients who performed 24-hour EEG monitoring. All participants were divided into nocturnal FLE (NFLE, > 90% of seizures occurring during sleep) or diurnal FLE (DFLE) groups. EEG and ECG signals were simultaneously obtained during waking and sleep stages. EEG current density source and connectivity analysis of the autonomic network were performed. ECG was analyzed across time and frequency domains heart rate variability (HRV) analysis method was used. The obtained parameters were compared between the NFLE and DFLE groups. Fifteen NFLE and 16 DFLE patients were enrolled with no significant difference in age, sex, disease duration, seizure frequency, or the number of anti-seizure medications between the two groups. During sleep, a decrease in HRV parameters and an increase of the beta-1 (13-22 Hz) current source density power in the bilateral paracentral lobule (BA4,5,6), precuneus (BA7), and cingulate (BA31) were observed in the NFLE group compared to DFLE group. The NFLE group also showed hyperconnectivity in the central autonomic (12 edges distributed over 10 nodes), sympathetic (2 edges distributed over 3 nodes), and parasympathetic (4 edges distributed over 6 nodes) beta-1 frequency band networks during sleep. During wakefulness, central and cardiac autonomic variables were not significantly different between the NFLE and DFLE groups. Interictal cardiac and central autonomic dysfunction occurred simultaneously and can be attributed to the brain-heart autonomic axis. Our findings suggest that nocturnal seizures may contribute to interictal autonomic dysfunction during sleep in people with epilepsy.

Control of Breathing and Central Hypoventilation Syndromes.

Control of breathing in children varies with age and sleep state. There is overlap between central hypoventilation, autonomic dysfunction, and hypothalamic dysfunction in the rare disorders (congenital central hypoventilation syndrome and rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation). Other, more common disorders that typically present in childhood also include central hypoventilation and disordered ventilatory responses.

Rapid-Onset Obesity with Hypoventilation, Hypothalamic Dysfunction, and Autonomic Dysregulation Neuroendocrine Tumor Syndrome

Background: Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) syndrome is a rare cause of obesity, characterized by early and rapid onset of obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysfunction. When there is an associated neuroendocrine tumor, (NET) it becomes ROHHAD NET. Hypothalamic dysfunction causes endocrine problems, respiratory dysfunction, and autonomic alterations. It is difficult to distinguish this clinically from other obesity syndromes of genetic origin unless an individualized strategic approach is used. Clinical Description: We present a case of a 5-year-old developmentally normal girl with excessive weight gain starting in early childhood and the development of a squint. The clinical phenotype of central hypoventilation and autonomic dysfunction, central hypothyroidism, and central precocious puberty satisfied the criteria for ROHHAD syndrome. Management: A right-sided paraspinal supradiaphragmatic mass was identified that was excised and diagnosed as neuroblastoma on histopathology. Since there was no evidence of metastases, chemotherapy was not indicated. Alpha and beta-blockers were started for autonomic dysfunction and high catecholamine levels. Lack of improvement in behavioral manifestations prompted a trial of immunosuppressive therapy, but yielded no results. She ultimately succumbed to a probable cardiorespiratory arrest during sleep. Conclusions: ROHHAD syndrome should be considered a differential diagnosis in rapid-onset monogenic obesity and should be managed with a multidisciplinary approach. Prognosis is guarded due to sudden life-threatening events secondary to autonomic dysfunction.

Down syndrome patients with normal hearts: are they really normal?

Even though congenital heart disease is a common finding in down syndrome (DS) patients, some of them have anatomically normal hearts. However, the term "normal" might not be suitable, as these patients usually suffer from functional cardiac dysfunction. Several research highlighted that despite the absence of anatomical heart defects, subtle cardiac function derangements are present in DS patients. We aim to assess cardiac functions by Two-dimensional echocardiography and tissue Doppler imaging (TDI) in pediatric DS patients who have anatomically normal hearts. One hundred seventy-two patients with karyotyping confirmed DS with anatomically normal hearts and 165 healthy normal control children were enrolled in the current study. Their cardiac functions were assessed using both 2-dimensional echocardiography and TDI. Both patients and controls had structurally and anatomically normal hearts. In DS patients, the right side of the heart showed a significant reduction in both systolic and diastolic functions. Systolic dysfunction was evident by significantly decreased levels of Tricuspid annular plane systolic excursion and systolic wave by TDI. Diastolic dysfunction of the right ventricle was evident by prolonged deceleration time by conventional echocardiography and a significant decrease in annular tissue doppler velocity during early diastole/late diastole ratio by TDI. The E/De ratio was significantly increased. Even with anatomically normal hearts, DS patients should undergo cardiac function assessment by echocardiography & TDI. TDI is superior to conventional echocardiography in detecting subtle cardiac dysfunction especially left ventricular diastolic dysfunction in DS patients. TDI showed a significant decrease in the early/atrial ratio of mitral valve annulus and prolongation of left ventricle isometric relaxation time in DS children. Also, the left ventricle E/De ratio was prolonged denoting elevated filling pressures and diastolic dysfunction. This indicates that the TDI has higher sensitivity to detect diastolic dysfunction than conventional Echocardiography. Biventricular TDI-derived myocardial performance index was found to be significantly increased in DS children.

Multiple sclerosis-related heat sensitivity linked to absence of DMT prescription and subjective hand impairment but not autonomic or corticospinal dysfunction.

Heat sensitivity (HS) describes a temporary worsening of multiple sclerosis (MS) symptoms with increased body temperature. The pathophysiology may relate to central nervous system conduction deficits and autonomic dysfunction. We conducted deep clinical phenotyping of a cohort of persons with MS to identify predictors of HS. We recruited 59 MS participants with HS or No HS. Participants self-reported symptom severity (Hospital Anxiety and Depression Scale, Multiple Sclerosis Impact Scale, and fatigue visual analog scale) and underwent maximal exercise and transcranial magnetic stimulation testing to characterize autonomic and corticospinal function. We examined associations with HS using binomial logistic regression. People with HS (36/59) had significantly greater disability, depression, fatigue, and physical and psychological functional effects of MS. They also had significantly lower corticospinal excitability but not conduction. After controlling for disease-modifying therapy (DMT), disability, and disease type, self-reported difficulty using hands in everyday tasks was significantly associated with a large increase in the odds of HS. Autonomic and corticospinal dysfunction were not associated with HS. Lack of DMT use alone was also associated with a large increase in the odds of HS. Following a comprehensive assessment of plausible contributors to HS, HS was most strongly associated with lack of a DMT prescription and self-reported hand dysfunction. Surprisingly, objective measurement of autonomic and corticospinal integrity did not contribute to HS.

Effects of Atomoxetine for the Treatment of Neurogenic Orthostatic Hypotension in Patients With Alpha-synucleinopathies: A Systematic Review of Randomized Controlled Trials and a Focus-Group Discussion.

Neurogenic orthostatic hypotension (nOH) is one of the most important nonmotor symptoms in patients with α-synucleinopathies. Atomoxetine is a selective norepinephrine transporter blocker that is a treatment option for nOH. This systematic review and expert focus-group study was designed to obtain evidence from published data and clinical experiences of Korean movement-disorder specialists about the efficacy and safety of atomoxetine for the pharmacological treatment of nOH in patients with α-synucleinopathies. The study comprised a systematic review and a focus-group discussion with clinicians. For the systematic review, multiple comprehensive databases including MEDLINE, Embase, Cochrane Library, CINAHL, PsycInfo, and KoreaMed were searched to retrieve articles that assessed the outcomes of atomoxetine therapy. A focus-group discussion was additionally performed to solicit opinions from experts with experience in managing nOH. The literature review process yielded only four randomized controlled trials on atomoxetine matching the inclusion criteria. Atomoxetine effectively increased systolic blood pressure and improved OH-related symptoms as monotherapy or in combination with other drugs. Its effects were pronounced in cases with central autonomic failure, including multiple-system atrophy (MSA). Atomoxetine might be a safe monotherapy regarding the risk of supine hypertension. Atomoxetine is an effective and safe option for short-term nOH management, which could be more evident in patients with central autonomic dysfunction such as MSA. However, there is a paucity of evidence in the literature, and data from the focus-group discussion were inadequate, and so further investigation is warranted.

Pre-pregnancy migraine diagnosis, medication use, and spontaneous abortion: a prospective cohort study

BackgroundMigraine is common among females of reproductive age (estimated prevalence:17–24%) and may be associated with reproductive health through underlying central nervous system excitability, autoimmune conditions, and autonomic dysfunction. We evaluated the extent to which pre-pregnancy migraine diagnosis and medication use are associated with risk of spontaneous abortion (SAB).MethodsWe analyzed data from a preconception study of pregnancy planners (2013–2021). Eligible participants self-identified as female, were aged 21–45 years, resided in the USA or Canada, and conceived during follow-up (n = 7890). Participants completed baseline and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever occurred first. Pregnant participants then completed questionnaires during early (~ 8–9 weeks) and late (~ 32 weeks) gestation. We defined migraineurs as participants who reported a migraine diagnosis or use of a medication to treat migraine. Preconception questionnaires elicited migraine medication use during the past 4 weeks, and SAB on follow-up and pregnancy questionnaires. We used Cox regression models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations among preconception migraine, migraine medication use, and SAB, controlling for potential demographic, medical, and lifestyle confounders.ResultsNineteen percent of study pregnancies ended in SAB. History of migraine before conception was not appreciably associated with SAB risk (HR = 1.03, 95% CI: 0.91–1.06). Use of any migraine medication was associated with a modest increase in SAB risk overall (HR = 1.14, 95% CI: 0.96–1.36). We observed the greatest increase in risk among those taking migraine medications daily (HR = 1.38, 95% CI: 0.81–2.35) and those taking prescription migraine prophylaxis (HR = 1.43, 95% CI: 0.72–2.84) or combination analgesic and caffeine medications (HR = 1.42, 95% CI: 0.99–2.04).ConclusionsMigraine medication use patterns suggesting greater underlying migraine severity were associated with increased risk of SAB. This research adds to the limited information available on the reproductive effects of migraine.

A Descriptive Investigation of the Prevalence of Neurological Disorders in People Treated Hemodialysis for End-Stage Renal Disease

Objectives: Patients with end-stage renal disease (ESRD) who were receiving hemodialysis were the subjects of a study to determine the neurological effects of the treatment. Methodology: ESRD patients at the Institute of kidney diseases hayatabad peshawar were the subjects of this descriptive research, which ran from jan to Dec 2021. Before participating in the trial, all Chronic Kidney Disease (CKD) patients had been on Hemodialysis (HD) for at least six months. HD patients were monitored for a total of six months in this study. Neurological events were observed and recorded at this period. All patients on HD, regardless of gender or age, were included in this research, which was conducted between the ages of 17 and 77. In this research, patients under the age of 15 years, those with acute renal failure, congestive cardiac failure, cirrhosis of the liver, malignancy, disseminated intravascular coagulation, sepsis, meningitis, or encephalitis, were all ruled out as candidates for inclusion. The data was analysed using SPSS version 2.2. Results: Intradialytic hypotension, Cerebrovascular accident, Encephalopathy, Dialysis dementia, Neuropathy, Dialysis disequilibrium, Reversible leukoencephalopathy, Central pontine myelinosis, Autonomic dysfunction, and Myopathy were the most common neurological consequences. Conclusions: Our patients on hemodialysis suffer from the most prevalent neurological complication: Intradialytic hypotension. While the long-term result and prognosis of this group may be affected by cerebrovascular illnesses and Dialysis dementias, it is important to examine them as soon as possible. Keywords: neurological problems, (ESRD),frequency, hemodialysis , end-stage renal disease.

Gastrointestinal and Autonomic Symptoms-How to Improve the Diagnostic Process in Panayiotopoulos Syndrome?

One of the most common epileptic disorders in the pediatric population is Panayiotopoulos syndrome. Clinical manifestations of this idiopathic illness include predominantly autonomic symptoms and dysfunction of the cardiorespiratory system. Another feature constitutes prolonged seizures that usually occur at sleep. It is crucial to differentiate the aforementioned disease from other forms of epilepsy, especially occipital and structural epilepsy and non-epileptic disorders. The diagnostic process is based on medical history, clinical examination, neuroimaging and electroencephalography—though results of the latter may be unspecific. Patients with Panayiotopoulos syndrome (PS) do not usually require treatment, as the course of the disease is, in most cases, mild, and the prognosis is good. The purpose of this review is to underline the role of central autonomic network dysfunction in the development of Panayiotopoulos syndrome, as well as the possibility of using functional imaging techniques, especially functional magnetic resonance imaging (fMRI), in the diagnostic process. These methods could be crucial for understanding the pathogenesis of PS. More data arerequired to create algorithms that will be able to predict the exposure to various complications of PS. It also concerns the importance of electroencephalography (EEG) as a tool to distinguish Panayiotopoulos syndrome from other childhood epileptic syndromes and non-epileptic disorders.

THE VIEW OF THE CLINICIAN ON THE PROBLEM OF COVID-19: review

The review article features the peculiarities in the epidemiological and clinical picture of a new coronavirus infection, COVID-19. The purpose of the review was to analyze the issues of the management. Pathogenetic relationships between SARS-CoV-2 virus, COVID-19 and angiotensin-converting enzyme 2 (ACE2) are assessed. Predisposing factors, which result in development of pneumonia and endothelial dysfunction, disorders in microcirculation, vasocon- striction, work of the renin-angiotensin system with subsequent development of ischemia in certain organs, inflammation and edema of tissues, are analyzed. Lung damage causes devel- opment of interstitial pneumonia, activation of the process of formation of fibrosis and de- creased pulmonary function. Accumulation of anti-inflammatory cytokines, which break the blood-brain barrier, in the CNS can cause dysregulation of central structures, autonomic dysfunction and severe asthenic syndrome, which can maintain low-grade inflammation for a long time. Opportune diagnosis and treatment of concomitant diseases in post-COVID-19 patients are of paramount significance for achieving a positive clinical outcome. The plan of rehabilitation treatment should be individualized according to the patient’s needs. In order to assess remote consequences of COVID-19 all patients require further follow-ups.

Gastroparesis.

This review highlights recent research advances regarding the pathophysiology and treatment of gastroparesis. Differences in brain activity have been identified on functional MRI imaging in gastroparesis patients with nausea. Abdominal pain is common in patients with gastroparesis and does not correlate with the severity of gastric emptying delay, though may be associated with depression and anxiety. Autonomic dysfunction may play an important role in the pathophysiology of gastroparesis. There is increasing sentiment that gastroparesis should be considered a part of the same spectrum of gastric neuromuscular disorders. The risk of tardive dyskinesia with metoclopramide has likely been significantly overestimated historically. Endoscopic BoTox injection of the pylorus and gastric electrical stimulation remain controversial treatments for gastroparesis. New, highly selective 5-hydroxytryptamine 4 (5-HT4) agonists appear safe and may be effective in improving symptoms of gastric emptying. Long-term data assessing the use of gastric peroral endoscopic myotomy (G-POEM) for the treatment of refractory gastroparesis suggest durable clinical improvement. Altered central processing and autonomic dysfunction may be important factors in the pathogenesis of gastroparesis. While the risk of tardive dyskinesia appears much lower than historically advertised, there is increasing hope for novel therapeutics with the advent of new 5-HT4 agonists, neurokinin-1 receptor (N1KR) antagonists, and G-POEM.

Understanding Seizures and Prognosis of the Extreme Delta Brush Pattern in Anti-N-Methyl-D-Aspartate (NMDA) Receptor Encephalitis: A Systematic Review.

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis (ANMDARE) is an autoimmune disorder with neurological and psychiatric features. The disease presents with a viral prodrome, followed by psychiatric manifestations. In the next phase, movement disorders or/and seizures occur. Finally, in the last phase, there is a decrease in the level of consciousness. Central hypoventilation and autonomic dysfunction can occur. Recently a unique EEG (electroencephalogram) pattern has been associated with anti-NMDA receptor encephalitis, the extreme delta brush (EDB). Although the association of the EDB with ANMDARE is known by the medical community, its significance is mainly unknown. A systematic review on NMDARE is also scarce. We decided to conduct a systematic review on this topic to consolidate the knowledge and establish the importance of the EDB as a prognostic factor. To conduct this systematic review, we used only studies conducted in humans, written in English, and published in the last 20 years. We used PubMed as a database and searched the following search terms: ("NMDA encephalitis"[Title/] AND "Epilepsy"[Title/]) OR (NMDA encephalitis"[Title/] AND "seizures" [Title/]) OR ("NMDA encephalitis"[Title/] AND "extreme delta brush"[Title/]). The protocol used for this systematic review was the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) protocol, and to analyze the bias of the studies, we used the ROBINS-1 tool.Eight studies were collected from our search strategy. Our data pulling showed that seizures were present in 178/249 (71.48%) patients. Status Epilepticus was reported in 29/96 (30.20%), and the EBD was seen in 30.89% (55/178) patients with seizures. The range of EDB was 5.9%-33% among the studies. Because the sample size was small, the statistical power was decreased. We had a low overall risk of bias. The wide range in the results could be related to the timing of the EEG recording. EDB was associated overall with increased length of hospital stay, increased ICU admission, and incidence of status epilepticus. The etiology of the EDB remains mainly unknown. However, it has been postulated that in NMDAR encephalitis, there is a disruption of the rhythmic neuronal activity. When antibodies block/target the NMDAR, the rhythmic neuronal activity is disrupted, leading to the unique EDB pattern. Another theory suggests that delta activity is caused because of focal abnormalities in the brain, and the superimposition of the beta waves is related to the alterations of the NMDA receptors.

Autonomic Dysfunction Contributes to Impairment of Cerebral Autoregulation in Patients with Epilepsy.

Patients with epilepsy frequently experience autonomic dysfunction and impaired cerebral autoregulation. The present study investigates autonomic function and cerebral autoregulation in patients with epilepsy to determine whether these factors contribute to impaired autoregulation. A total of 81 patients with epilepsy and 45 healthy controls were evaluated, assessing their sudomotor, cardiovagal, and adrenergic functions using a battery of autonomic nervous system (ANS) function tests, including the deep breathing, Valsalva maneuver, head-up tilting, and Q-sweat tests. Cerebral autoregulation was measured by transcranial Doppler examination during the breath-holding test, the Valsalva maneuver, and the head-up tilting test. Autonomic functions were impaired during the interictal period in patients with epilepsy compared to healthy controls. The three indices of cerebral autoregulation—the breath-holding index (BHI), an autoregulation index calculated in phase II of the Valsalva maneuver (ASI), and cerebrovascular resistance measured in the second minute during the head-up tilting test (CVR2-min)—all decreased in patients with epilepsy. ANS dysfunction correlated significantly with impairment of cerebral autoregulation (measured by BHI, ASI, and CVR2-min), suggesting that the increased autonomic dysfunction in patients with epilepsy may augment the dysregulation of cerebral blood flow. Long-term epilepsy, a high frequency of seizures, and refractory epilepsy, particularly temporal lobe epilepsy, may contribute to advanced autonomic dysfunction and impaired cerebral autoregulation. These results have implications for therapeutic interventions that aim to correct central autonomic dysfunction and impairment of cerebral autoregulation, particularly in patients at high risk for sudden, unexplained death in epilepsy.

Sympathetic nerve outflow to skin in a case with dentatorubral-pallidoluysian atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by slowly progressive cerebellar ataxia. Previously, autonomic symptoms or dysfunction have not been reported. To evaluate subclinical autonomic dysfunction regarding thermoregulatory function in SCA, we recorded sympathetic outflow to skin in a DRPLA patient confirmed by genetic analysis. We recorded skin sympathetic nerve activity (SSNA), which was elicited and recorded by using the microneurographical technique. In results, the resting frequency of SSNA bursts was very low (8.2 ± 0.4 bursts/min [institutional normal range: 20.8 ± 2.4 bursts/min]). However, acceleration of SSNA bursts induced by mental arithmetic stress was confirmed. The amplitude of reflex bursts induced by electrical stimuli was slightly low (9.6 ± 1.6 μV [institutional normal range: 10.9 ± 2.2 μV]), and the reflex latency was mildly prolonged (872 ± 23.7 msec [institutional normal range: 761.9 ± 51.7 msec]). These results suggest potentially central autonomic dysfunction in this patient with DRPLA. To our knowledge, this is the first report to record SSNA and confirm subclinical autonomic dysfunction in a case with DRPLA.

Characterization of Autonomic Dysfunction Among Migraineurs With and Without Complaints of Orthostatic Intolerance

Purpose and Hypothesis: To identify and distinguish central autonomic dysfunction from peripheral autonomic dysfunction (or both) in migraineurs suffering from orthostatic intolerance (OI) compared to migraineurs not suffering from OI. We hypothesize that OI manifests from a predominantly central autonomic component. Methods: We studied two populations of migraineurs, one group complaining of symptoms of OI for 6 months or longer and a group without OI symptoms, using a 70-degree, 45-minute passive head-up tilt-table test (HUT), R-R interval measurements during deep breathing, blood pressure and heart rate monitoring during Valsalva maneuver and release, Quantitative Sudomotor Axon Reflex Test (QSART), and skin biopsy for intraepidermal nerve fiber density. Categorical differences between the two populations were compared using exact likelihood ratio chi-square tests, and 95% confidence intervals for sensitivity, specificity, positive and negative predictive values were calculated. Results: Thirty-seven migraineurs with OI (Group 1) and 22 migraineurs without (Group 2) were studied and were demographically similar except for a greater representation of migraines with brainstem auras in Group 1 (27% v 5%; p= 0.032). Ninety-seven percent of Group 1 patients, versus 68% Group 2, manifested abnormal 45-minutes HUT, a significant difference (p=0.020, Fisher’s exact test). The first 5-minute evaluation of the HUT exhibited high specificity (1.00; 95% CI: 0.85-1.00) for the diagnosis of postural tachycardia syndrome (POTS) with a positive predictive value of 1.00 (0.59, 1.00; p=0.037). The HUT extended to 45-minutes however showed greater sensitivity compared with the 10-minute HUT (0.95; 95% CI:0.82-0.99; p=0.020). We found no differences between groups in autonomic laboratory or skin biopsy findings. Fifty-seven percent of Group 1 and 50% of Group 2 exhibited biopsy-proven small fiber neuropathy (SFN), a difference that did not reach statistical significance. Conclusions: We failed to confirm our hypothesis that OI is a manifestation of a central autonomic dysfunction in migraineurs. The finding of SFN in a majority of subjects points to peripheral autonomic contributions and raises the possibility of an underlying systemic disorder. Extending HUT table testing to 45-minutes increases diagnostic sensitivity and better reflects life events. Funding Statement: This study was supported by a grant from the Bakken Heart-Brain Institute, Cleveland Clinic, Cleveland, Ohio, USA. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study was approved by the Cleveland Clinic’s Institutional Review Board. Informed consent was obtained from all participants in the study.

A Cross-Sectional Study on Central Sensitization and Autonomic Changes in Fibromyalgia.

Fibromyalgia is a multi-symptomatic disorder characterized by generalized pain. The pathophysiology of fibromyalgia is supposedly an interplay between central nervous system hyper-responsiveness, autonomic dysfunction, and peripheral pain. In this cross-sectional study, the objective was to assess central sensitization and autonomic activity in patients with fibromyalgia compared with control. Fifty adults diagnosed with fibromyalgia by the modified American College of Rheumatology 2010 criteria and an equal number of age- and sex-matched controls participated in the study in an urban tertiary care hospital. Central sensitization was assessed by history and by evidence of increased prefrontal cortical activity as measured by cortical oxygenation using functional near-infrared spectroscopy. Autonomic activity was assessed by heart rate variability, electrodermal activity, and deep breathing test in three physiological states: rest, sympathetic stress (cold pressor test), and deep breathing. Mann–Whitney U-test, paired t-test, Wilcoxon test, and Friedman test with Bonferroni a priori were used to analyze the data. Cortical activity was significantly higher in the fibromyalgia group than control. There was no significant difference in autonomic activity between the fibromyalgia and control groups. In the fibromyalgia group, variable degrees of sympathetic hyperactivity and normal parasympathetic activity were observed. Central sensitization may be playing a primary role in the pathophysiology of generalized pain in fibromyalgia.