Infectious diseases causing autonomic dysfunction

Objectives

To review infectious diseases that may cause autonomic dysfunction.

Methods

Review of published papers indexed in medline/embase.

Results

Autonomic dysfunction has been reported in retrovirus (human immunodeficiency virus (HIV), human T-lymphotropic virus), herpes viruses, flavivirus, enterovirus 71 and lyssavirus infections. Autonomic dysfunction is relatively common in HIV-infected patients and heart rate variability is reduced even in early stages of infection. Orthostatic hypotension, urinary dysfunction and hypohidrosis have been described in tropical spastic paraparesis patients. Varicella zoster reactivation from autonomic ganglia may be involved in visceral disease and chronic intestinal pseudo-obstruction. Autonomic and peripheral nervous system dysfunction may happen in acute tick-borne encephalitis virus infections. Hydrophobia, hypersalivation, dyspnea, photophobia, and piloerection are frequently observed in human rabies. Autonomic dysfunction and vagal denervation is common in Chagas disease. Neuronal depopulation occurs mainly in chagasic heart disease and myenteric plexus, and megacolon, megaesophagus and cardiomyopathy are common complications in the chronic stage of Chagas disease. Parasympathetic autonomic dysfunction precedes left ventricle systolic dysfunction in Chagas disease. A high prevalence of subclinical autonomic neuropathy in leprosy patients has been reported, and autonomic nerve dysfunction may be an early manifestation of the disease. Autonomic dysfunction features in leprosy include anhidrosis, impaired sweating function, localised alopecia ,and reduced heart rate variability. Urinary retention and intestinal pseudo-obstruction have been described in Lyme disease. Diphtheritic polyneuropathy, tetanus and botulism are examples of bacterial infections releasing toxins that affect the autonomic nervous system.

Conclusions

Autonomic dysfunction may be responsible for additional morbidity in some infectious diseases.

     

Autonomic function and brain volume

Objective

The aim of this study is to review the evidence on the role of the autonomic nervous system as a determinant of brain volume. Brain volume measures have gained increasing attention given its biological importance, particularly as a measurement of neurodegeneration.

Methods

Using an integrative approach, we reviewed publications addressing the anatomical and physiological characteristics of brain autonomic innervation focusing on evidence from diverse clinical populations with respect to brain volume.

Results

Multiple mechanisms contribute to changes in brain volume. Autonomic influence on cerebral blood volume is of significant interest.

Conclusion

We suggest a role for the autonomic innervation of brain vessels in fluctuations of cerebral blood volume. Further investigation in several clinical populations including multiple sclerosis is warranted to understand the specific role of parenchyma versus blood vessels changes on final brain volume.

     

Relationships between autonomic nerve function and gastric emptying in patients with autoimmune gastritis

Purpose

Autonomic nervous system dysfunction exists in autoimmune diseases. Symptoms of autoimmune gastritis are not specific, and some patients may present symptoms suggestive of delayed gastric emptying. This study aims to investigate whether any autonomic dysfunction exists in autoimmune gastritis patients, and if so, to clarify the relationship between the autonomic nervous dysfunction, delayed gastric emptying, and gastrointestinal symptoms.

Methods

75 patients (50 women, mean age 56.73 ± 11.77) diagnosed with autoimmune gastritis were investigated by means of autonomic nervous system and gastric emptying tests. All patients underwent a standardized scintigraphic gastric emptying study and five tests evaluating autonomic nervous system. Patients with autonomic nervous system dysfunction were then analyzed and compared by means of existence of delayed gastric emptying and gastrointestinal symptoms.

Results

62 patients had autonomic nervous system dysfunction (14 mild, 40 moderate, and 8 severe autonomic dysfunction). The mean total score of autonomic tests was 3.85 ± 2.35. Total autonomic score of patients (n = 60) with delayed gastric emptying was significantly higher than patients (n = 15) with normal gastric emptying (4.68 ± 1.7 vs. 1.53 ± 0.58, p < 0.001). Mean gastroparesis cardinal symptom index was significantly higher in patients (n = 60) with delayed gastric emptying half-time compared to patients (n = 15) with normal gastric emptying half-time (1.89 ± 1.16 vs 0.4 ± 0.3, p < 0.001).

Conclusions

Most of patients with autoimmune gastritis also have autonomic nerve dysfunction. There is a close relationship between autonomic nervous system dysfunction and delayed gastric emptying. Gastroparesis cardinal symptom index has a high sensitivity and specificity in predicting both autonomic nerve function and delay in gastric emptying.

     

Autonomic dysfunction in pediatric patients with headache: migraine versus tension-type headache

Purpose

To examine symptoms indicating central nervous system (CNS) autonomic dysfunction in pediatric patients with migraine and tension-type headache.

Methods

A retrospective chart review assessed six symptoms (i.e. constipation, insomnia, dizziness, blurry vision, abnormal blood pressure, and cold and clammy palms and soles) indicating central nervous system (CNS) autonomic dysfunction in 231 patients, ages 5–18 years, diagnosed with migraine, tension-type headache (TTH), or Idiopathic Scoliosis (IS).

Results

Higher frequencies of “insomnia,” “dizziness,” and “cold and clammy palms and soles” were found for both migraine and TTH patients compared to the IS control group (P < 0.001). Frequencies of all six symptoms were greater in TTH than migraine patients with “cold and clammy palms and soles” reaching significance (P < 0.001).

Conclusions

The need for prospective research investigating autonomic dysfunction in pediatric headache patients is discussed.

     

The symptoms of autonomic dysfunction in HIV-positive Africans

Background

Human immunodeficiency virus (HIV) infection is associated with autonomic neuropathy. The resultant autonomic dysfunction impairs quality of life and can have fatal consequences. Our aim was to clearly define the symptoms of autonomic dysfunction in African HIV-positive patients and determine whether these symptoms were related with (a) autonomic reflex responses (b) the degree of immunosupression.

Methods

Thirty-one HIV-positive treatment-naïve African patients (mean CD4 cell count 269.5 ± 253.4/mm³) and 12 healthy controls completed a detailed questionnaire (Autonomic System Profile, Mayo Clinic, Rochester, MN) relating to specific symptoms of autonomic dysfunction. After completion of the questionnaire, subjects underwent a standard battery of autonomic reflex tests.

Results

The autonomic symptom score was higher in the male HIV-positive patients (26.7 ± 14.7 points) and female patients with CD4 <200/mm³ (24.7 ± 18.0) than sex-matched controls (male controls, 9.9 ± 6.8, P < 0.05; female controls, 8.8 ± 10.1; P < 0.05). Six patients had scores indicative of severe autonomic dysfunction (>43.8 points). The most common autonomic symptoms were: orthostatic intolerance, secretomotor and gastrointestinal dysfunction. There was no relationship between CD4 cell counts and autonomic symptom scores. The blood pressure response to sustained handgrip was blunted, but all other cardiovascular reflex tests were within the normal range or borderline.

Conclusion

African HIV-positive patients report symptoms of autonomic dysfunction, despite normal or borderline autonomic reflex responses.

     

Pupillary autonomic dysfunction in patients with ANCA-associated vasculitis

Objective

To assess autonomic function by infrared dynamic pupillometry in patients with ANCA-vasculitis (AAV) in correlation to autonomic symptoms, disease specific clinical parameters and cardiovascular reflex tests.

Methods

Patients with AAV and healthy controls underwent pupillometry at rest and after sympathetic stimulation (cold pressor test). Three parasympathetic parameters (amplitude, relative amplitude, maximum constriction velocity) and one sympathetic parameter (late dilatation velocity) were assessed. Results were correlated with clinical parameters, symptoms of autonomic dysfunction (COMPASS31 questionnaire), heart rate variability during deep breathing test and blood pressure response to pain.

Results

23 patients and 18 age-matched controls were enrolled. Patients had a smaller amplitude (1.44 vs. 1.70 mm; p = 0.009) and a slower constriction velocity (4.15 vs. 4.71 mm/s; p = 0.028) at baseline and after sympathetic stimulation (1.47 vs. 1.81 mm, p = 0.001; 4.38 vs. 5.19 mm/s, p = 0.006, respectively). Relative amplitude was significantly smaller in patients after sympathetic stimulation (28.6 vs. 32.5%; p = 0.043), but not at baseline. There was no difference in sympathetic pupillary response between the groups. In patients, parasympathetic pupil response was correlated negatively with age and positively with parasympathetic cardiac response. After adjusting for age, no significant correlation was observed with clinical parameters. However, there was a trend towards a negative correlation with disease duration, vasculitis damage index and CRP.

Conclusion

Patients with AAV exhibit parasympathetic pupillary autonomic dysfunction. Although correlations were weak and not significant, pupillary autonomic dysfunction is rather linked to chronic damage than to active inflammation or symptoms of autonomic dysfunction.

     

Seronegative autoimmune autonomic neuropathy: a distinct clinical entity

Purpose

Autoimmune autonomic ganglionopathy (AAG) is associated with ganglionic acetylcholine receptor (gAChR) antibodies. We describe a similar but distinct series of patients with autoimmune autonomic failure lacking this antibody.

Methods

Retrospective chart review.

Results

Six patients presented with subacute autonomic failure, seronegative for gAChR antibodies. Orthostatic hypotension and gastrointestinal complaints were common. Autonomic testing revealed predominant sympathetic failure and no premature pupillary redilation. All patients had sensory symptoms and/or pain, which was severe in three. Immunotherapy with plasma exchange, intravenous immunoglobulin, and rituximab was ineffective. Three patients responded to intravenous steroids.

Conclusion

In these cases of autoimmune autonomic failure, key differences from seropositive AAG emerge. Testing showed prominent sympathetic (rather than cholinergic) failure, specific pupillary findings of AAG were absent, and sensory symptoms were prominent. AAG responds to antibody-targeted immunotherapy, while these patients responded best to steroids. This seronegative autoimmune autonomic neuropathy is a distinct clinical entity requiring a different treatment approach from AAG.

     

Autonomic symptoms following Zika virus infection

Purpose

To determine if autonomic symptoms are associated with previous Zika virus infection.

Methods

Case–control study including 35 patients with Zika virus infection without evidence of neurological disease and 105 controls. Symptoms of autonomic dysfunction were assessed with the composite autonomic symptom scale 31 (COMPASS-31).

Results

Patients with previous Zika virus infection had significantly higher COMPASS-31 score than controls regardless of age and sex (p = 0.007). The main drivers for the higher scores where orthostatic intolerance (p = 0.003), secretomotor (p = 0.04) and bladder symptoms (p < 0.001).

Conclusion

Zika virus infection is associated with autonomic dysfunction. The mechanisms remain to be elucidated.

     

Autonomic Cardiovascular Control and Executive Function in Chronic Hypotension

Background

Chronic low blood pressure (hypotension) is characterized by complaints such as fatigue, reduced drive, dizziness, and cold limbs. Additionally, deficits in attention and memory have been observed. Autonomic dysregulation is considered to be involved in the origin of this condition.

Purpose

The study explored autonomic cardiovascular control in the context of higher cognitive processing (executive function) in hypotension.

Methods

Hemodynamic recordings were performed in 40 hypotensive and 40 normotensive participants during execution of four classical executive function tasks (number-letter task, n-back task, continuous performance test, and flanker task). Parameters of cardiac sympathetic control, i.e., stroke volume, cardiac output, pre-ejection period, total peripheral resistance, and parasympathetic control, i.e., respiratory sinus arrhythmia and baroreflex sensitivity, were obtained.

Results

The hypotensive group exhibited lower stroke volume and cardiac output, as well as higher pre-ejection period and baroreflex sensitivity during task execution. Increased error rates in hypotensive individuals were observed in the n-back and flanker tasks. In the total sample, there were positive correlations of error rates with pre-ejection period, baroreflex sensitivity and respiratory sinus arrhythmia, and negative correlations with cardiac output.

Conclusions

Group differences in stroke volume, cardiac output, and pre-ejection period suggest diminished beta-adrenergic myocardial drive during executive function processing in hypotension, in addition to increased baroreflex function. Although further research is warranted to quantify the extent of executive function impairment in hypotension, the results from correlation analysis add evidence to the notion that higher sympathetic inotropic influences and reduced parasympathetic cardiac influences are accompanied by better cognitive performance.

     

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

Purpose

Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood.

Methods

Routine histology and immunohistochemistry was performed on GAN KO mouse specimens taken at various ages. Enteric dysfunction was assessed by quantifying the frequency, weight, and water content of defecation in GAN KO mice.

Results

Histological examination of the enteric, parasympathetic and sympathetic ANS of GAN KO mice revealed pronounced and widespread neuronal perikaryal intermediate filament inclusions. These neuronal inclusions served as an easily identifiable, early marker of GAN in young GAN KO mice. Functional studies identified an age-dependent alteration in fecal weight and defecation frequency in GAN KO mice.

Conclusions

For the first time in the GAN KO mouse model, we described the early, pronounced and widespread neuropathologic features involving the ANS. In addition, we provided evidence for a clinical autonomic phenotype in GAN KO mice, reflected in abnormal gastrointestinal function. These findings in GAN KO mice suggest that consideration should be given to ANS involvement in human GAN, especially when considering treatments and patient care.

     

Multiple sclerosis incidence in Tuscany from administrative data

Background

Italy is a high-risk area for multiple sclerosis with 110,000 prevalent cases estimated at January 2016 and 3400 annual incident cases. To study multiple sclerosis epidemiology, it is preferable to use population-based studies, e.g., with a registry. A valid alternative to obtain data on entire population is from administrative sources.

Objective

To estimate the incidence of multiple sclerosis in Tuscany using a case-finding algorithm based on administrative data.

Methods

In a previous study, we calculated the prevalence in Tuscany using a validated case-finding algorithm based on administrative data. Incident cases were identified as a subset of prevalent cases among those patients not traced in the years before the analysis period, and the date of the first multiple sclerosis-related claim was considered the incidence date of multiple sclerosis diagnosis. We examined the period 2011–2015.

Results

We identified 1147 incident cases with annual rates ranged from 5.60 per 100,000 in 2011 to 6.58 in 2015.

Conclusions

We found a high incidence rate, similarly to other Italian areas, especially in women, that may explain the increasing prevalence in Tuscany. To confirm this data and to calculate the possible bias caused by our inclusion method, we will validate our algorithm for incident cases.

     

Influence of sex,menstrual cycle,and oral contraceptives on the cerebrovascular response to paced deep breathing

Purpose

Deep breathing assesses autonomic function; however, many researchers/clinicians do not account for hyperventilation, brain blood flow or blood pressure.

Methods

Men and women (with/without oral contraceptives) participated. women participated during low and high hormone phases of the menstrual cycle. Blood pressure, end-tidal carbon dioxide, middle cerebral artery velocity and cerebrovascular resistance were assessed.

Results

Deep breathing decreased end-tidal carbon dioxide and middle cerebral artery velocity while increasing cerebrovascular resistance in all participants; blood pressure decreased in men. There were no influences of menstrual cycle or oral contraceptives.

Conclusions

Men have different autonomic responses to deep breathing compared to women.

     

Heart rate variability during sleep in children with autism spectrum disorder

Purpose

Autonomic dysfunction has been reported in autism spectrum disorders (ASD). Less is known about autonomic function during sleep in ASD. The objective of this study is to provide insight into the autonomic cardiovascular control during different sleep stages in ASD. We hypothesized that patients with ASD have lower vagal and higher sympathetic modulation with elevated heart rate, as compared to typical developing children (TD).

Methods

We studied 21 children with ASD and 23 TD children during overnight polysomnography. Heart rate and spectral parameters were calculated for each vigilance stage during sleep. Data from the first four sleep cycles were used to avoid possible effects of different individual sleep lengths and sleep cycle structures. Linear regression models were applied to study the effects of age and diagnosis (ASD and TD).

Results

In both groups, HR decreased during non-REM sleep and increased during REM sleep. However, HR was significantly higher in stages N2, N3 and REM sleep in the ASD group. Children with ASD showed less high frequency (HF) modulation during N3 and REM sleep. LF/HF ratio was higher during REM. Heart rate decreases with age at the same level in ASD and in TD. We found an age effect in LF in REM different in ASD and TD.

Conclusion

Our findings suggest possible deficits in vagal influence to the heart during sleep, especially during REM sleep. Children with ASD may have higher sympathetic dominance during sleep but rather due to decreased vagal influence.

     

Insights into the Mechanisms That May Clarify Obesity as a Risk Factor for Multiple Sclerosis

Purpose of Review

The proportion to which genetic and environmental factors contribute to the etiology of multiple sclerosis (MS) is still incompletely understood. An interesting association between MS etiology and obesity has recently been shown although the mechanisms underlying this association are still unknown. We propose deregulated gut microbiota and increased leptin levels as possible mechanisms underlying MS etiology in obese individuals.

Recent Findings

Alterations in the human gut microbiota and leptin levels have recently been established as immune modulators in both MS patients and obese individuals. A resemblance between pro-inflammatory bacterial profiles in MS and obese individuals was observed. Furthermore, elevated leptin levels push the immune system towards a more pro-inflammatory state and inhibit the regulatory immune response.

Summary

Deregulated gut microbiota and elevated leptin levels may explain the increased risk of developing MS in obese individuals. Further research to confirm causality is warranted.

     

Post-ganglionic autonomic neuropathy associated with anti-glutamic acid decarboxylase antibodies

Purpose

Antibodies to glutamic acid decarboxylase (GAD-Abs) have been associated with several conditions, rarely involving the autonomic nervous system. Here, we describe two patients complaining of autonomic symptoms in whom a post-ganglionic autonomic neuropathy has been demonstrated in association with significantly elevated serum and CSF GAD-Abs levels.

Methods

Patients underwent nerve conduction studies, sympathetic skin response testing, evaluation of autonomic control of the cardiovascular system and skin biopsy. Also, serum screening to exclude predisposing causes of peripheral neuropathy was performed. Anti-GAD65 antibodies were evaluated in serum and CSF.

Results

GAD-Abs titer was increased in both serum and CSF in both patients. Sympathetic skin response was absent and skin biopsy revealed a non-length-dependent small-fiber neuropathy with sympathetic cholinergic and adrenergic post-ganglionic damage in both patients. Nerve conduction studies and evaluation of autonomic control of the cardiovascular system were normal in both patients. Both patients were treated with steroids with good, but partial, (patient 2) recovery of the autonomic dysfunctions.

Conclusions

Although the pathophysiological mechanisms involved are not fully defined, GAD-abs positivity in serum and CSF should be searched in patients with autonomic neuropathy when no other acquired causes are evident. This positivity may help to clarify autoimmune etiology and, subsequently, to consider immunomodulatory treatment.

     

Assessment of autonomic function in a cohort of patients with ANCA-associated vasculitis

Objective

To assess symptoms and objective parameters of autonomic dysfunction (AD) in patients with ANCA-associated vasculitides.

Methods

Symptoms and objective parameters of AD were assessed in patients with ANCA-associated vasculitis and in age-matched healthy controls. Autonomic symptoms were explored by COMPASS31, a validated questionnaire addressing symptoms of six autonomic domains (orthostatic, vasomotor, secretomotor, gastrointestinal, pupillomotor, and bladder dysfunction). Objective autonomic parameters consisted of expiratory/inspiratory (E/I) ratio during the deep breathing test (DBT), blood pressure response to cold pressor test (CPT), and skin conductance changes during mental arithmetic.

Results

27 patients and 27 healthy controls have been enrolled. 27 patients and 27 controls completed COMPASS31. 21 patients and 18 controls underwent objective autonomic testing. Vasculitis patients had significantly higher COMPASS31 total scores than controls (median 10.4 vs 3.0; p = 0.005). In the sub-domain analysis, significant differences were seen in the vasomotor and the bladder domain (p = 0.004; p < 0.001, respectively). No correlation was found between COMPASS31 score and disease duration, number of affected organs, or Birmingham vasculitis activity score (BVAS). There was no significant difference in any of the objective autonomic parameters between patients and controls. In a subgroup analysis, no difference in objective autonomic parameters was found between patients with active disease (n = 12) and patients in remission (n = 7).

Conclusion

Patients with ANCA-associated vasculitides commonly have symptoms of autonomic dysfunction that are independent of disease duration and disease severity. However, at least in this single-centre observation, there was no evidence of impaired autonomic regulation in three autonomic function tests in vasculitis patients.

     

Attachment Orientations,Respiratory Sinus Arrhythmia,and Stress Are Important for Understanding the Link Between Childhood Socioeconomic Status and Adult Self-Reported Health

Background

Low childhood socioeconomic status (SES) is reliably associated with poor adult health. Social environments early in life and physiological stress responses are theorized to underlie this link; however, the role of attachment orientations is relatively unknown.

Purpose

In this study, we examined whether attachment orientations (i.e., attachment anxiety and attachment avoidance) and self-reported stress were mediators of the association between childhood SES and self-reported health in adulthood. Furthermore, we examined whether parasympathetic nervous system functioning was a moderator of associations between attachment orientations and self-reported stress.

Methods

Participants (N = 213) provided self-reports of childhood SES, attachment orientations, general stress, and self-rated health. Respiratory sinus arrhythmia (RSA) was measured at rest, as well as during an acute social stressor.

Results

Low childhood SES was associated with poor self-reported health via the serial pathway from attachment anxiety to general stress. Moreover, attachment avoidance was associated with self-reported health via general stress, but only among those with high stress-induced RSA. Findings were independent of participant age, sex, race, body mass index, baseline RSA, and adult SES.

Conclusions

Attachment theory is useful for understanding why those from low SES backgrounds are at greater risk of negative health outcomes in adulthood. Findings extend our knowledge of how interpersonal relationships in childhood can shape emotional and physical health outcomes in adulthood.

     

Does fatigue in Parkinson’s disease correlate with autonomic nervous system dysfunction?

Background

Despite its negative impact on quality of life, fatigue in Parkinson’s disease (PD) remains an under-recognized issue and the underlying pathology is undetermined.

Objective

To contribute at understanding the pathogenesis of fatigue in a naturalistic cohort of cognitively intact PD patients.

Methods

In a Caucasian population of PD patients (n?=?27), we evaluated to what extent fatigue (quantified as PFS-16 score) is associated with PD duration and with autonomic dysfunction, studied by both MIBG scintigraphy and autonomic nervous system testing. The latter included the head-up tilt test, Valsalva maneuver, deep breathing, and handgrip tests.

Results

PFS-16 score correlated with disease duration (R?=?0.57, p?=?0.002). Fatigue showed a clear correlation with deep breathing test (R?=???0.53, p?=?0.004) but not with the MIBG H/M ratios.

Conclusions

Our data are consistent with a multifactorial pathogenesis of fatigue and with effects of dopamine depletion in PD-related fatigue; on the other hand, our findings do not support a role for sympathetic denervation in PD-related fatigue.

     

Mitochondrial Dysfunction in Parkinson’s Disease: New Mechanistic Insights and Therapeutic Perspectives

Purpose of Review

Parkinson’s disease (PD) is a complex neurodegenerative disorder, the aetiology of which is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we review recent developments around mitochondrial dysfunction in familial and sporadic PD, with a brief overview of emerging therapies targeting mitochondrial dysfunction.

Recent Findings

Increasing evidence supports the critical role for mitochondrial dysfunction in the development of sporadic PD, while the involvement of familial PD-related genes in the regulation of mitochondrial biology has been expanded by the discovery of new mitochondria-associated disease loci and the identification of their novel functions.

Summary

Recent research has expanded knowledge on the mechanistic details underlying mitochondrial dysfunction in PD, with the discovery of new therapeutic targets providing invaluable insights into the essential role of mitochondria in PD pathogenesis and unique opportunities for drug development.