Dysautonomia, Hypermobility Spectrum Disorders and Mast Cell Activation Syndrome as Migraine Comorbidities.

PURPOSE OF REVIEW: Dysautonomia refers to the dysfunction of the autonomic nervous system and encompasses a wide variety of autonomic symptoms and disorders. The most common autonomic disorders are postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope (NCS), and orthostatic hypotension (OH), which may be encountered in clinical practice as part of a triad of dysautonomia, hypermobility spectrum disorders (HSD), and mast cell activation syndrome (MCAS). Migraine is one of the most common comorbidities of POTS, HSD, and MCAS; conversely, these conditions are also prevalent in patients with migraine, especially in those with multiple systemic symptoms, such as chronic dizziness, lightheadedness, orthostatic intolerance, joint pain, and allergic symptoms. Diagnostic criteria, pathophysiologic mechanisms, and therapeutic considerations in patients with migraine and comorbid dysautonomia, HSD, and MCAS are reviewed. RECENT FINDINGS: Numerous studies indicate a significant overlap and shared pathophysiology in migraine, dysautonomia, HSD, and MCAS. In clinical setting, dysautonomia, HSD, and MCAS may present a diagnostic and therapeutic challenge in patients with migraine and require a high index of suspicion on the part of the neurologist. Diagnosis and treatment of these complex disorders in patients with migraine is essential to comprehensive patient-centric care, reduced symptom burden, and improved functional impairment secondary to both migraine and comorbidities.

Autonomic nervous system involvement in chronic inflammatory demyelinating polyradiculoneuropathy: a literature review.

BACKGROUND AND AIMS: Although dysautonomia is a well-recognized complication of acute demyelinating polyradiculoneuropathy, it is rarely reported and evaluated in chronic demyelinating neuropathies. The purpose of this review is to search and synthesize the current literature on the prevalence and type of autonomic dysfunction (AD) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: PubMed and Web of Science were searched for studies reporting AD in CIDP. RESULTS: Twelve studies, including 346 patients with CIDP, were found eligible for the review. Seven studies used autonomic tests only as an additional component of the comprehensive clinical evaluation, and found that dysautonomia in CIDP may indicate the presence of a comorbid disease (e.g., diabetes) and facilitate the differentiation of CIDP from other neuropathies (e.g., amyloid neuropathy). Five studies performed quantitative assessment of autonomic function in CIDP as a primary goal. Two studies have used the Composite Autonomic Severity Score (CASS) to assess severity and distribution of dysautonomia. The reported prevalence of dysautonomia in CIDP during quantitative assessment of autonomic function ranged from 25 to 89%, depending on the battery of tests used, with CASS not exceeding 4 points. The abnormalities in autonomic tests indicated both sympathetic and parasympathetic dysfunction and did not correlate with the duration, severity and variant of CIDP. CONCLUSIONS: Clinical or subclinical involvement of the ANS has been shown to be common and relatively mild in CIDP. The impact of autonomic impairment on disability and of its possible response to therapy in CIDP needs to be further investigated.

Prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome: A cross-sectional study.

BACKGROUND: The association between autonomic dysfunction and long-COVID syndrome is established. However, the prevalence and patterns of symptoms of dysautonomia in long-COVID syndrome in a large population are lacking. OBJECTIVE: To evaluate the prevalence and patterns of symptoms of dysautonomia in patients with long-COVID syndrome. METHODS: We administered the Composite Autonomic Symptom Score 31 (COMPASS-31) questionnaire to a sample of post-COVID-19 patients who were referred to post-COVID clinic in Assiut University Hospitals, Egypt for symptoms concerning for long-COVID syndrome. Participants were asked to complete the COMPASS-31 questionnaire referring to the period of more than 4 weeks after acute COVID-19. RESULTS: We included 320 patients (35.92 ± 11.92 years, 73% females). The median COMPASS-31 score was 26.29 (0-76.73). The most affected domains of dysautonomia were gastrointestinal, secretomotor, and orthostatic intolerance with 91.6%, 76.4%, and 73.6%, respectively. There was a positive correlation between COMPASS-31 score and long-COVID duration (p < 0.001) and a positive correlation between orthostatic intolerance domain score and post-COVID duration (p < 0.001). There was a positive correlation between orthostatic intolerance domain score and age of participants (p = 0.004). Two hundred forty-seven patients (76.7%) had a high score of COMPASS-31 >16.4. Patients with COMPASS-31 >16.4 had a longer duration of long-COVID syndrome than those with score <16.4 (46.2 vs. 26.8 weeks, p < 0.001). CONCLUSIONS: Symptoms of dysautonomia are common in long-COVID syndrome. The most common COMPASS-31 affected domains of dysautonomia are gastrointestinal, secretomotor, and orthostatic intolerance. There is a positive correlation between orthostatic intolerance domain score and patients' age.

Subtle differences in autonomic symptoms in people diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders.

The hypermobile Ehlers-Danlos syndrome (hEDS) GENE study is a multicenter, cohort study with the goal to identify genes associated with hypermobile EDS. Of the 148 people enrolled in the hEDS GENE study, 98 meet the 2017 hEDS criteria, 27 have a hypermobility spectrum disorder (HSD) and 23 are asymptomatic family members. More than 80% of participants are female with an average age of 41 years. Each participant has completed seven questionnaires to quantify disease-related symptomatology. People with hypermobility experience a variety of physical and somatic symptoms, especially in the areas of fatigue, kinesiophobia, gastrointestinal, and autonomic function. These cause a significant decrease in health-related quality of life. The frequency and severity of most symptoms were indistinguishable between participants with hEDS and HSD; however, there were significant differences in autonomic symptoms. Less than 20% of participants had autoantibodies known to be associated with dysautonomia. Subtle symptomatic differences in people meeting the 2017 diagnostic criteria suggest focusing further etiologic studies on autonomic pathways.

Neurologic Syndromes Predict Higher In-Hospital Mortality in COVID-19.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is protean in its manifestations, affecting nearly every organ system. However, nervous system involvement and its effect on disease outcome are poorly characterized. The objective of this study was to determine whether neurologic syndromes are associated with increased risk of inpatient mortality. METHODS: A total of 581 hospitalized patients with confirmed SARS-CoV-2 infection, neurologic involvement, and brain imaging were compared to hospitalized non-neurologic patients with coronavirus disease 2019 (COVID-19). Four patterns of neurologic manifestations were identified: acute stroke, new or recrudescent seizures, altered mentation with normal imaging, and neuro-COVID-19 complex. Factors present on admission were analyzed as potential predictors of in-hospital mortality, including sociodemographic variables, preexisting comorbidities, vital signs, laboratory values, and pattern of neurologic manifestations. Significant predictors were incorporated into a disease severity score. Patients with neurologic manifestations were matched with patients of the same age and disease severity to assess the risk of death. RESULTS: A total of 4,711 patients with confirmed SARS-CoV-2 infection were admitted to one medical system in New York City during a 6-week period. Of these, 581 (12%) had neurologic issues of sufficient concern to warrant neuroimaging. These patients were compared to 1,743 non-neurologic patients with COVID-19 matched for age and disease severity admitted during the same period. Patients with altered mentation (n = 258, p = 0.04, odds ratio [OR] 1.39, confidence interval [CI] 1.04-1.86) or radiologically confirmed stroke (n = 55, p = 0.001, OR 3.1, CI 1.65-5.92) had a higher risk of mortality than age- and severity-matched controls. CONCLUSIONS: The incidence of altered mentation or stroke on admission predicts a modest but significantly higher risk of in-hospital mortality independent of disease severity. While other biomarker factors also predict mortality, measures to identify and treat such patients may be important in reducing overall mortality of COVID-19.

Dysautonomia and Clinical Outcome in Vegetative State.

A dramatic disorder tentatively attributed to diencephalic-hypothalamic damage or dysfunction, dysautonomia, affects recovery from brain injury. Its incidence, correlation with etiology, and relevance as a predictor of outcome were retrospectively surveyed in 333 patients in vegetative state (VS) for more than 2 weeks at admission. Outcome was assessed according to the Glasgow Outcome Scale. Data were treated statistically by multi-variate analyses. Dysautonomia occurred in 26.1% of patients, with greater incidence among post-traumatic (31.9%) than non-traumatic (15.8%) patients. Outcome was worse among non-traumatic than post-traumatic patients irrespective of dysautonomia, and worst among non-traumatic patients with dysautonomia. Dysautonomia proved common among patients in VS (with incidence depending on etiology and age) and influenced the patients' outcome through mechanisms still to be defined, but conceivably mediated by diencephalic-hypothalamic unbalance.

Multifactorial Characteristics of Pediatric Dizziness and Imbalance.

OBJECTIVES: To examine the relative prevalence of individual diagnoses in children and adolescents presenting with dizziness and/or imbalance, and to assess the proportion of patients assigned multiple contributing diagnoses. STUDY DESIGN: Retrospective cohort study. METHODS: We retrospectively reviewed our internal database of all patients seen at our pediatric vestibular program between January 2012 and March 2019 to determine the incidence of common diagnoses and groups of diagnoses for patients ages 21 or younger. RESULTS: One thousand twenty-one patients were included with a mean age of 12.5 ± 4.9 years (range: 9 months-21 years). Of this total, 624 patients were female and 397 were male. Common diagnoses included vestibular migraine (VM; 35.0%), benign paroxysmal positional vertigo (BPPV; 21.6%), primary dysautonomia (15.7%), anxiety disorder (13.5%), and persistent postural perceptual dizziness (PPPD; 11.2%). A high proportion of patients (44.4%) received multiple contributing diagnoses. VM was frequently diagnosed with BPPV or PPPD, and 22 patients were diagnosed with all three concurrently. CONCLUSION: The causes of dizziness and imbalance in the pediatric population are diverse, and many patients have multiple diagnoses that are often interrelated. It is important that providers recognize that the causes of vestibular symptoms in children and adolescents may be multifactorial and may span across multiple specialties. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1308-E1314, 2021.

Family aggregation analysis shows a possible heritable background of equine grass sickness (dysautonomia) in a Hungarian stud population.

Equine grass sickness (also known as dysautonomia) is a life-threatening polyneuropathic disease affecting horses with approx. 80% mortality. Since its first description over a century ago, several factors, such as the phenotype, intestinal microbiome, environment, management and climate, have been supposed to be associated with the increased risk of dysautonomia. In this retrospective study, we examined the possible involvement of genetic factors. Medical and pedigree datasets regarding 1,233 horses with 49 affected animals born during a 23-year period were used in the analysis. Among the descendants of some stallions, the proportion of animals diagnosed with dysautonomia was unexpectedly high. Among males, the odds of dysautonomia were found to be higher, albeit not significantly, than among females. Significant familial clustering (genealogical index of familiality, P = 0.001) was observed among the affected animals. Further subgroups were identified with significant (P < 0.001) aggregation among close relatives using kinship-based methods. Our analysis, along with the slightly higher disease frequency in males, suggests that dysautonomia may have a genetic causal factor with an X-linked recessive inheritance pattern. This is the first study providing ancestry data and suggesting a heritable component in the likely multifactorial aetiology of the disease.

Association between quadrivalent human papillomavirus vaccination and selected syndromes with autonomic dysfunction in Danish females: population based, self-controlled, case series analysis.

OBJECTIVE: To evaluate the association between quadrivalent human papillomavirus vaccination and syndromes with autonomic dysfunction, such as chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome. DESIGN: Population-based self-controlled case series. SETTING: Information on human papillomavirus vaccinations and selected syndromes with autonomic dysfunction (chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome) identified using ICD-10 (international classification of diseases, revision 10) diagnostic codes from Danish nationwide registers. PARTICIPANTS: 869 patients with autonomic dysfunction syndromes from a cohort of 1 375 737 Danish born female participants aged 10 to 44 years during 2007-16. MAIN OUTCOME MEASURES: Self-controlled case series rate ratios (95% confidence intervals) of the composite outcome of chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome, adjusted for age and season, comparing female participants vaccinated and unvaccinated with the quadrivalent human papillomavirus vaccine. Chronic fatigue syndrome, complex regional pain syndrome, and postural orthostatic tachycardia syndrome were also considered separately in secondary analyses. RESULTS: During 10 581 902 person years of follow-up, 869 female participants with syndromes of autonomic dysfunction (136 with chronic fatigue syndrome, 535 with complex regional pain syndrome, and 198 with postural orthostatic tachycardia syndrome) were identified. Quadrivalent human papillomavirus vaccination did not statistically significantly increase the rate of a composite outcome of all syndromes with autonomic dysfunction in a 365 day risk period following vaccination (rate ratio 0.99, 95% confidence interval 0.74 to 1.32) or the rate of any individual syndrome in the risk period (chronic fatigue syndrome (0.38, 0.13 to 1.09), complex regional pain syndrome (1.31, 0.91 to 1.90), or postural orthostatic tachycardia syndrome (0.86, 0.48 to 1.54)). CONCLUSIONS: When vaccination is introduced, adverse events could occur in close temporal relation to the vaccine purely by chance. These results do not support a causal association between quadrivalent human papillomavirus vaccination and chronic fatigue syndrome, complex regional pain syndrome, or postural orthostatic tachycardia syndrome, either individually or as a composite outcome. An increased risk of up to 32% cannot be formally excluded, but the statistical power of the study suggests that a larger increase in the rate of any syndrome associated with vaccination is unlikely.

Gulf war illness, post-HPV vaccination syndrome, and Macrophagic Myofasciitis. Similar disabling conditions possibly linked to vaccine-induced autoimmune dysautonomia.

More than one-fourth of all Persian gulf war coalition soldiers remain seriously ill. Several epidemiological studies suggest a link between multiple vaccinations at the time of the military operation and the illness development. Macrophagic Myofasciitis and post-HPV vaccination syndrome are two newer controversial vaccine-related disabling ailments. OBJECTIVES: 1) To systematically review all original articles investigating the association of vaccines with gulf war illness, 2) To discuss gulf war illness, Macrophagic Myofasciitis, and post-HPV vaccination syndrome clinical similarities, 3) To discuss emergent pathogenetic mechanisms proposed for post-HPV vaccination syndrome that may be also relevant to gulf war illness and Macrophagic Myofasciitis. RESULTS: All original epidemiological studies (n = 11) found a positive association between vaccination and gulf war illness development. Chronic fatigue, widespread pain and cognitive impairment characterize the three syndromes under discussion. Anti-adrenergic receptor antibodies, dysautonomia and small fiber neuropathy have been recently described in patients with post-HPV vaccination syndrome. CONCLUSION: post-HPV vaccination syndrome, Macrophagic Myofasciitis, and gulf war illness analogy suggests that some vaccines or multiple vaccinations in a very short period of time may induce, in susceptible individuals, chronic pain, fatigue and dyscognition. Vaccine-induced autoimmune dysautonomia is hypothesized as the common pathogenetic mechanism for this symptom cluster. Further research on the presence of small fiber neuropathy, adrenergic receptor antibodies, and abnormal autonomic function tests in the three syndromes under discussion may help to elucidate this hypothesis.

Dysautonomia in 53 cats and dogs: retrospective review of clinical data and outcome.

BACKGROUND: Dysautonomia is a disease characterised by degeneration of autonomic neurons. METHODS: The aim of this study was to perform a retrospective multicentre review of clinical data relating to cats and dogs diagnosed with dysautonomia and to evaluate their outcome. RESULTS: Cats (n=34) and dogs (n=19) with clinical signs consistent with dysautonomia were considered for this retrospective study. Reported clinical findings included oesophageal and gastrointestinal dysmotility and distension, urinary retention, reduced or absent tear production, third eyelid protrusion and inappropriate mydriasis. Treatment was supportive and included gastrointestinal prokinetics, feeding tube placement (oesophageal and percutaneous endoscopic gastrostomy tubes) and medications to treat urinary retention. The survival to discharge was 29 per cent in cats and 47 per cent in dogs. The overall survival in cats was 21 per cent and that in dogs was 32 per cent. Survival of greater than 2 years was seen in six cats and in three dogs. CONCLUSION: This paper illustrates that some animals are able to survive this disease and can have a good long-term prognosis, which is an infrequently reported finding for this disease.

Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society.

INTRODUCTION: Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. OBJECTIVES: To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. METHODS: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. RESULTS: At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. CONCLUSION: Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

Alcohol-induced autonomic dysfunction: a systematic review.

PURPOSE: Autonomic dysfunction is a known consequence of chronic and excessive alcohol consumption. The aim of this systematic review was to characterise this phenomenon, describe the frequency at which it occurs and to explore the best management strategies. METHODS: A systematic, computer-based search was conducted using the PubMed database. All studies identified by the search were evaluated independently by at least three authors. For inclusion, studies had to report human subjects consuming ethanol in excess. Case reports and non-original studies were excluded from this review. RESULTS: A total of 55 studies were included in this review. According to cardiovascular reflex tests, 16-73% of chronic alcohol abusers suffer from autonomic dysfunction. The most commonly occurring symptom is erectile dysfunction, whilst other features such as postural dizziness are rare. The most important risk factor for this condition is total lifetime dose of ethanol, although there is mixed evidence supporting the role of other risk factors. The only management strategy currently explored in the literature is abstinence, which appears to lead to significant improvement in autonomic investigations. CONCLUSION: Current literature includes studies of highly heterogeneous populations, consuming differing volumes of alcohol over variable periods of time and utilising a number of different autonomic test batteries and criteria to diagnose autonomic dysfunction. Therefore, further research using homogeneous methods for measuring autonomic dysfunction in the field is needed. Despite this limitation, our review demonstrated that autonomic dysfunction is very common among alcohol abusers.

Dysautonomia and Headache in the Pediatric Population.

Dysautonomia and headache are 2 common diagnoses within pediatric neurology; in the case of dysautonomia, a lack of consideration may lead to misdiagnosis. Despite being common conditions, there is a lot to learn about each individually as well as collectively. Many of the symptoms between headache and dysautonomia patients overlap making the diagnosis difficult. Migraine patients often exhibit symptoms of dysautonomia, namely postural orthostatic tachycardia syndrome (POTS); yet these symptoms are overlooked or lumped in as a part of their migraine diagnosis. The distinction or coexistence between dysautonomia and headache is identified through a thorough history, a full exam, and an open mind. This is crucial for the treatment and outcomes of these patients. Struggles arise when critical treatment differences are overlooked because dysautonomia is not considered. In this review, we will look at the epidemiology of dysautonomia and headache with focus on POTS and migraine. We will then compare the clinical features of both conditions as well as some hypothesized pathophysiology overlaps. We will conclude by summarizing the diagnostic approach and multitiered treatment options for POTS and migraine.

Longitudinal assessment of autonomic dysfunction in early Parkinson's disease.

INTRODUCTION: Clinical correlates of autonomic nervous system (ANS) dysfunction in early Parkinson's disease (PD) have been addressed mainly in a cross-sectional way. METHODS: This is a combined cross-sectional and longitudinal prospective study of ANS dysfunction using the SCOPA-AUT in PD patients at the Hoehn and Yahr stage 1 with disease duration <2 years. PD patients (n = 107) were compared to healthy controls (HC, n = 79), and then followed-up for over 3 years. The severity of PD, depression, anxiety, apathy and cognitive impairment were evaluated using rating scales. RESULTS: At least one symptom of ANS dysfunction was present in 71% of PD patients in comparison to 30.4% of HC, and in all PD patients after three years. The overall severity of dysautonomia symptoms was mild (SCOPA-AUT mean ±â€¯SD; 4.16 ±â€¯5.0), but worsened by 23%, 86% and 0.3% during the 1st, 2nd and 3rd year respectively. Nighttime voiding (38.3%), constipation (30.8%) and straining for defecation (29%) were the most common symptoms. Prevalence and severity of urinary, gastrointestinal, and orthostatic symptoms increased, in contrast to thermoregulatory and pupillomotor symptoms. Frequency of symptoms suggestive of multi-domain ANS dysfunction rose from 49% to 79%. Psychiatric symptoms and age, but not motor impairment, were associated with dysautonomia symptoms. CONCLUSION: Symptoms of ANS dysfunction were frequent in the initial motor stage of PD and progressed, yet remaining mild, within 3 years. An independent progression of dysautonomia symptoms from motor disability and its associations with non-motor, mainly psychiatric symptoms and age support the non-motor clustering in PD.

Exploring hyperhidrosis and related thermoregulatory symptoms as a possible clinical identifier for the dysautonomic subtype of Parkinson's disease.

OBJECTIVE: To identify associated (non-)motor profiles of Parkinson's disease (PD) patients with hyperhidrosis as a dominant problem. METHODS: This is a cross-sectional, exploratory, analysis of participants enrolled in the Non-motor Longitudinal International Study (NILS; UKCRN No: 10084) at the Parkinson's Centre at King's College Hospital (London, UK). Hyperhidrosis scores (yes/no) on question 28 of the Non-Motor Symptom Questionnaire were used to classify patients with normal sweat function (n = 172) and excessive sweating (n = 56) (Analysis 1; n = 228). NMS scale (NMSS) question 30 scores were used to stratify participants based on hyperhidrosis severity (Analysis 2; n = 352) using an arbitrary severity grading: absent score 0 (n = 267), mild 1-4 (n = 49), moderate 5-8 (n = 17), and severe 9-12 (n = 19). NMS burden, as well as PD sleep scale (PDSS) scores were then analysed along with other correlates. RESULTS: No differences were observed in baseline demographics between groups in either analysis. Patients with hyperhidrosis exhibited significantly higher total NMSS burden compared to those without (p < 0.001). Secondary analyses revealed higher dyskinesia scores, worse quality of life and PDSS scores, and higher anxiety and depression levels in hyperhidrosis patients (p < 0.001). Tertiary analyses revealed higher NMSS item scores for fatigue, sleep initiation, restless legs, urinary urgency, and unexplained pain (p < 0.001). CONCLUSIONS: Chronic hyperhidrosis appears to be associated with a dysautonomia dominant subtype in PD patients, which is also associated with sleep disorders and a higher rate of dyskinesia (fluctuation-related hyperhidrosis). These data should prompt the concept of hyperhidrosis being used as a simple clinical screening tool to identify PD patients with autonomic symptoms.

Pediatric dysautonomia: Much-maligned, often overmedicated, but not as complex as you think.

Dysautonomia is an increasingly recognized yet still poorly understood disease within the field of pediatrics. Symptoms, including dizziness, headaches, fatigue, joint pain, anxiety, and intolerance of heat or cold, are often significant and difficult to sort, especially in terms of their relation to each other. This often leads to referral to multiple subspecialists, who then proceed to treat seemingly familiar symptoms in kind. In the authors' experience, this leads to more frustration on the part of the patients and their physicians when symptom improvement does not follow (or can even worsen). On the other hand, by understanding the pathophysiology, treatment success is possible by directing therapies toward the root causes and just as importantly, enlisting the patient in a daily treatment plan. In the text that follows, we hope to convey these viewpoints by highlighting an involved case, discussing the pathophysiology, outlining the usual evaluation, and finally describing our approach to treatment.

Reverse blood pressure dipping as marker of dysautonomia in Parkinson disease.

INTRODUCTION: We sought to evaluate if the presence of abnormal circadian loss of nocturnal blood pressure dipping (reverse dipping) is associated with cardiovascular dysautonomia, a major source of morbidity in Parkinson disease. METHODS: Consecutive Parkinson disease patients were enrolled in this cross-sectional study between January 2015 and June 2017. All subjects underwent same-day autonomic testing and 24-h ambulatory blood pressure monitoring. Cardiovascular dysautonomia was defined by the presence of at least one moderate or severe cardiovagal and adrenergic test abnormality. RESULTS: We recruited 114 PD patients (79 males; mean age 64 ±â€¯10 years; disease duration 6 ±â€¯4 years). Cardiovascular dysautonomia was present in 32% (36/114). The blood pressure patterns were normal dipping in 28.9% (n = 33), extreme dipping in 6.1% (n = 7), reduced dipping in 32.5% (n = 37), and reverse dipping in 32.5% (n = 37). Reverse dipping was disproportionately prevalent in subjects with cardiovascular dysautonomia (69% vs 15%, p < 0.001). The diagnostic accuracy of reverse dipping in discriminating cardiovascular dysautonomia (AUC 0.791, specificity 84%, sensitivity 69%) was higher than that of bedside blood pressure ascertainment of neurogenic orthostatic hypotension (0.681, 66%, 69%) and supine hypertension (0.641, 78%, 50%). CONCLUSIONS: Reverse nocturnal blood pressure dipping is a marker of cardiovascular dysautonomia in Parkinson disease, which can be screened for with ease and affordability using ambulatory blood pressure monitoring.

Stability of the HTLV-1 glycoprotein 46 (gp46) gene in an endemic region of the Brazilian Amazon and the presence of a significant mutation (N93D) in symptomatic patients.

BACKGROUND: The human T-lymphotropic virus type 1 (HTLV-1) affects 2-5 million people worldwide, and is associated with a number of degenerative and infectious diseases. The Envelope glycoproteins (gp) are highly conserved among the different HTLV-1 isolates, although nucleotide substitutions in the region that codifies these proteins may influence both the infectivity and the replication of the virus. The gp46 gene has functional domains which have been associated with the inhibition of the formation of the syncytium, cell-cell transmission, and the production of antibodies. The present study investigated the genetic stability of the gp46 gene of HTLV-1 in an endemic region of Brazilian Amazonia. METHODS: Index case (IC - a sample of a given family group) carriers of HTLV-1 were investigated in the metropolitan region of Belém (Pará, Brazil) between January 2010 (registered retrospectively) and December 2015. The sequences that codify the gp46 were amplified by PCR, purified and sequenced (MF084788-MF084825). The gene was characterized using bioinformatics and Bayesian Inference. RESULTS: The 40 patients analyzed had a mean age of 45.2 years and 70% presented some type of symptom, with a predominance of pain and sensitivity, dysautonomia, and motor disorders. All patients presented the aA (Transcontinental Cosmopolitan) genotype, with an extremely low mutation rate, which is characteristic of the codifying region (aA - 1.83 × 10-4 mutations per site per year). The gp46 gene had a nucleotide diversity of between 0.00% and 2.0%. Amino acid mutations were present in 66.6% of the samples of individuals with signs/symptoms or diseases associated with HTLV-1 (p = 0.0091). Of the three most frequent mutations, the previously undescribed N93D mutant was invariably associated with symptomatic cases. CONCLUSIONS: The aA HTLV-1 subtype is predominant in the metropolitan region of Belém and presented a high degree of genetic stability in the codifying region. The rare N93D amino acid mutation may be associated with the clinical manifestations of this viral infection. IMPORTANCE: Little is known of the phylogeny of HTLV-1 in the endemic region of Brazilian Amazonia, and few complete gene sequences are available for the gp46 glycoprotein from the local population. The nucleotide sequences of the viral gp46 gene recorded in the present study confirmed the genetic stability of the region, and pointed to a homogeneous viral group, with local geographic characteristics. Further research will be necessary to more fully understand the molecular diversity of this protein, given the potential of this codifying region as a model for an effective HTLV-1 vaccine. The identification of a rare mutation (N93D), present only in symptomatic patients, should also be investigated further as a potential clinical marker. TRIAL REGISTRATION: ISRCTN 12345678, registered 28 September 2014.