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Purpose: We previously reported that single doses of the norepinephrine transporter inhibitor, atomoxetine, increased standing blood pressure (BP) and ameliorated symptoms in patients with neurogenic orthostatic hypotension (nOH). We aimed to evaluate the effect of atomoxetine over four weeks in patients with nOH., Methods: A randomized, double-blind, placebo-controlled crossover clinical trial between July 2016 and May 2021 was carried out with an initial open-label, single-dose phase (10 or 18 mg atomoxetine), followed by a 1-week wash-out, and a subsequent double-blind 4-week treatment sequence (period 1: atomoxetine followed by placebo) or vice versa (period 2). The trial included a 2-week wash-out period. The primary endpoint was symptoms of nOH as measured by the orthostatic hypotension questionnaire (OHQ) assessed at 2 weeks., Results: A total of 68 patients were screened, 40 were randomized, and 37 completed the study. We found no differences in the OHQ composite score between atomoxetine and placebo at 2 weeks (-0.3 ± 1.7 versus -0.4 ± 1.5; P = 0.806) and 4 weeks (-0.6 ± 2.4 versus -0.5 ± 1.6; P = 0.251). There were no differences either in the OHSA scores at 2 weeks (3 ± 1.9 versus 4 ± 2.1; P = 0.062) and at 4 weeks (3 ± 2.2 versus 3 ± 2.0; P = 1.000) or in the OH daily activity scores (OHDAS) at 2 weeks (4 ± 3.0 versus 5 ± 3.1, P = 0.102) and 4 weeks (4 ± 3.0 versus 4 ± 2.7, P = 0.095). Atomoxetine was well-tolerated., Conclusions: While previous evidence suggested that acute doses of atomoxetine might be efficacious in treating nOH; results of this clinical trial indicated that it was not superior to placebo to ameliorate symptoms of nOH., Trial Registration: ClinicalTrials.gov; NCT02316821., (© 2024. The Author(s).)

Familial dysautonomia (FD) is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN, type 3) expressed at birth with profound sensory loss and early death. The FD founder mutation in the ELP1 gene arose within the Ashkenazi Jews in the sixteenth century and is present in 1:30 Jews of European ancestry. The mutation yield a tissue-specific skipping of exon 20 and a loss of function of the elongator-1 protein (ELP1), which is essential for the development and survival of neurons. Patients with FD produce variable amounts of ELP1 in different tissues, with the brain producing mostly mutant transcripts. Patients have excessive blood pressure variability due to the failure of the IXth and Xth cranial nerves to carry baroreceptor signals. Neurogenic dysphagia causes frequent aspiration leading to chronic pulmonary disease. Characteristic hyperadrenergic "autonomic crises" consisting of brisk episodes of severe hypertension, tachycardia, skin blotching, retching, and vomiting occur in all patients. Progressive features of the disease include retinal nerve fiber loss and blindness, and proprioceptive ataxia with severe gait impairment. Chemoreflex failure may explain the high frequency of sudden death in sleep. Although 99.5% of patients are homozygous for the founder mutation, phenotypic severity varies, suggesting that modifier genes impact expression. Medical management is currently symptomatic and preventive. Disease-modifying therapies are close to clinical testing. Endpoints to measure efficacy have been developed, and the ELP1 levels are a good surrogate endpoint for target engagement. Early intervention may be critical for treatment to be successful., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Objective: Familial dysautonomia (FD) is a rare inherited autosomal recessive disorder with abnormal somatosensory, enteric, and afferent autonomic neurons. We aimed to define the incidence of gastrointestinal bleeding and its associated risk factors in patients with FD., Methods: In this retrospective case-control study, we identified all episodes of gastrointestinal bleeding in patients with FD, occurring over four decades (January 1980-December 2017), using the New York University FD registry., Results: We identified 104 episodes of gastrointestinal bleeding occurring in 60 patients with FD. The estimated incidence rate of gastrointestinal bleeds in the FD population rate was 4.20 episodes per 1000 person-years. We compared the 60 cases with 94 age-matched controls. Bleeding in the upper gastrointestinal tract from gastric and duodenal ulcers occurred most frequently (64 bleeds, 75.6%). Patients were more likely to have a gastrostomy (G)-tube and a Nissen fundoplication [odds ratio (OR) 3.73, 95% confidence interval (CI) 1.303-13.565] than controls. The mean time from G-tube placement to first gastrointestinal bleed was 7.01 years. The mean time from Nissen fundoplication to bleed was 7.01 years. Cases and controls had similar frequency of intake of nonsteroidal antiinflammatory drugs (NSAID) and selective serotonin reuptake inhibitors (SSRI)., Conclusion: The incidence of gastrointestinal bleeding in the pediatric FD population was estimated to be 4.20 per 1000 person-years, 21 times higher than in the general pediatric population (0.2 per 1000 person-years). Patients with FD with a G-tube and a Nissen fundoplication had a higher risk of a subsequent gastrointestinal bleeding., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Pure autonomic failure (PAF) is a rare disease in which chronic neurogenic orthostatic hypotension (nOH) dominates the clinical picture. Longitudinal studies have reported that PAF can phenoconvert to a central synucleinopathy with motor or cognitive involvement-i.e., to Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). These studies have classified patients clinically as having PAF based on nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration. This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA. Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA. Conversely, PAF without these features leaves open the possibility of premotor MSA., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Purpose: In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective norepinephrine reuptake inhibitor, increases circulating norepinephrine levels. This study explored the safety of ampreloxetine and its effect on blood pressure and symptoms in patients with neurogenic orthostatic hypotension., Methods: A multicenter ascending-dose trial (range 1-20 mg, Part A) was followed by a 1 day, double-blind, randomized, placebo-controlled study (median dose 15 mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10 mg, Part C) followed by a 4-week withdrawal. Assessments included the Orthostatic Hypotension Symptom Assessment Scale (item 1), supine/seated/standing blood pressure, and safety., Results: Thirty-four patients (age 66 ± 8 years, 22 men) were enrolled. Part A: The proportion of participants with a positive response (i.e., increase from baseline in seated systolic blood pressure of ≥ 10 mmHg) was greater with the 5 and 10 mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6-52.3); P = 0.0112]. Part C: Symptoms of dizziness/lightheadedness improved 3.1 ± 3.0 points from baseline and standing systolic blood pressure increased 11 ± 12 mmHg. After 4 weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration., Conclusion: Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure., Trial Registration: NCT02705755 (first posted March 10, 2016)., (© 2021. The Author(s).)

Purpose: The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA., Methods: Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations., Results: The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others., Conclusions: Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.

Purpose: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (HSAN-3) that is clinically characterized by impaired pain and temperature perception and abnormal autonomic function. Patients with FD have gastrointestinal dysmotility and report a range of gastrointestinal symptoms that have yet to be systematically evaluated. The aim of this study was to establish the frequency and severity of gastrointestinal symptoms in patients with FD., Methods: The validated National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) survey questionnaire, together with additional FD-specific questions, were distributed to 202 living patients with genetically confirmed FD who had been identified from the New York University FD Patient Registry or, when relevant, to their respective caretaker. As a comparison group, we used a general US adult population for whom PROMIS scores were available (N = 71,812)., Results: Of the 202 questionnaires distributed, 77 (38%) were returned, of which 53% were completed by the patient. Median age of the respondents was 25 years, and 44% were male. Gastrostomy tube was the sole nutrition route for 25% of the patients, while 53% were reliant on the gastrostomy tube only for liquid intake. The prevalence of gastrointestinal symptoms was significantly higher in each of the eight domains of PROMIS in patients with FD than in the controls. Gastrointestinal symptoms as measured by raw scores on the PROMIS scale were significantly less severe in the FD patient group than in the control population in all domains with the exception of the abdominal pain domain. The surveys completed by caregivers reported the same burden of symptoms as those completed only by patients., Conclusion: Gastrointestinal symptoms affect nearly all patients with FD. Gastrointestinal symptoms are more prevalent in adult patients with FD than in the average US adult population but are less severe in the former.

Purpose: To assess the relationship between depressive symptoms and self-perceived severity of autonomic dysfunction in patients with multiple system atrophy (MSA)., Methods: Cross-sectional evaluation of patients with MSA who underwent autonomic testing, Unified MSA Rating Scale (UMSARS)-1 and -2, rating of the presence and severity of depressive symptoms (Zung scale), quality of life (SF-36), body vigilance, anxiety (Spielberger's anxiety scale), severity of autonomic dysfunction with the Composite Autonomic Symptoms Score (COMPASS-31), and severity of orthostatic hypotension (OH) symptoms with the Orthostatic Hypotension Questionnaire (OHQ)., Results: Fifty-eight patients (32 women) with probable MSA (aged 61.8 ± 8.6 years; disease duration 4.3 ± 2.1 years) were studied. Forty patients (69%) had symptoms of depression in the Zung scale. Age, disease duration, and motor disability were similar in those with and without symptoms of depression. Despite a similar orthostatic blood pressure fall, the severity of orthostatic symptoms was higher in patients with symptoms of depression (p = 0.004). Depression scores were associated with higher burden of autonomic symptoms (R = 0.401, p = 0.02), specifically with the COMPASS-31 items related to orthostatic intolerance (R = 0.337, p = 0.045), and with the OHQ (R = 0.529; p < 0.001). A multivariable regression model including age, sex, UMSARS, and drop in systolic blood pressure upon head-up tilt as covariates showed that the burden of depressive symptoms was independently associated with the OHQ score: for every 1-unit increase in the Zung depression score, there was a 1.181-point increase in the total OHQ score., Conclusions: In patients with MSA, depressive symptoms worsen the perceived severity of autonomic symptoms in general and orthostatic hypotension in particular. Our findings have implications for clinical trial design.

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.

Purpose: Neurogenic orthostatic hypotension is a prominent and disabling manifestation of autonomic dysfunction in patients with hereditary transthyretin (TTR) amyloidosis affecting an estimated 40-60% of patients, and reducing their quality of life. We reviewed the epidemiology and pathophysiology of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis, summarize non-pharmacologic and pharmacological treatment strategies and discuss the impact of novel disease-modifying treatments such as transthyretin stabilizers (diflunisal, tafamidis) and RNA interference agents (patisiran, inotersen)., Methods: Literature review., Results: Orthostatic hypotension in patients with hereditary transthyretin amyloidosis can be a consequence of heart failure due to amyloid cardiomyopathy or volume depletion due to diarrhea or drug effects. When none of these circumstances are apparent, orthostatic hypotension is usually neurogenic, i.e., caused by impaired norepinephrine release from sympathetic postganglionic neurons, because of neuronal amyloid fibril deposition., Conclusions: When recognized, neurogenic orthostatic hypotension can be treated. Discontinuation of potentially aggravating medications, patient education and non-pharmacologic approaches should be applied first. Droxidopa (Northera ® ), a synthetic norepinephrine precursor, has shown efficacy in controlled trials of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis and is now approved in the US and Asia. Although they may be useful to ameliorate autonomic dysfunction in hereditary TTR amyloidosis, the impact of disease-modifying treatments on neurogenic orthostatic hypotension is still uninvestigated.

Purpose: Familial dysautonomia (FD) is a rare autosomal recessive disease that affects the development of sensory and autonomic neurons, including those in the cranial nerves. We aimed to determine whether conventional brain magnetic resonance imaging (MRI) could detect morphologic changes in the trigeminal nerves of these patients., Methods: Cross-sectional analysis of brain MRI of patients with genetically confirmed FD and age- and sex-matched controls. High-resolution 3D gradient-echo T1-weighted sequences were used to obtain measurements of the cisternal segment of the trigeminal nerves. Measurements were obtained using a two-reader consensus., Results: Twenty pairs of trigeminal nerves were assessed in ten patients with FD and ten matched controls. The median (interquartile range) cross-sectional area of the trigeminal nerves in patients with FD was 3.5 (2.1) mm 2 , compared to 5.9 (2.0) mm 2 in controls (P < 0.001). No association between trigeminal nerve area and age was found in patients or controls., Conclusions: Using conventional MRI, the caliber of the trigeminal nerves was significantly reduced bilaterally in patients with FD compared to controls, a finding that appears to be highly characteristic of this disorder. The lack of correlation between age and trigeminal nerve size supports arrested neuronal development rather than progressive atrophy.

Purpose: Patients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure., Methods: As a first and preparatory step, a systematic search of PubMed-indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension., Results: In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management., Conclusions: The establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment.

Purpose: To report the use of intranasal dexmedetomidine, an α 2 -adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia., Methods: Case series., Results: Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises., Conclusions: Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

Objective: Adrenergic crises are a cardinal feature of familial dysautonomia (FD). Traditionally, adrenergic crises have been treated with the sympatholytic agent clonidine or with benzodiazepines, which can cause excessive sedation and respiratory depression. Dexmedetomidine is a centrally-acting α 2 -adrenergic agonist with greater selectivity and shorter half-life than clonidine. We evaluated the preliminary effectiveness and safety of intravenous dexmedetomidine in the treatment of refractory adrenergic crisis in patients with FD., Methods: Retrospective chart review of patients with genetically confirmed FD who received intravenous dexmedetomidine for refractory adrenergic crises. The primary outcome was preliminary effectiveness of dexmedetomidine defined as change in blood pressure (BP) and heart rate (HR) 1 h after the initiation of dexmedetomidine. Secondary outcomes included incidence of adverse events related to dexmedetomidine, hospital and intensive care unit (ICU) length of stay, and hemodynamic parameters 12 h after dexmedetomidine cessation., Results: Nine patients over 14 admissions were included in the final analysis. At 1 h after the initiation of dexmedetomidine, systolic BP decreased from 160 ± 7 to 122 ± 7 mmHg (p = 0.0005), diastolic BP decreased from 103 ± 6 to 65 ± 8 (p = 0.0003), and HR decreased from 112 ± 4 to 100 ± 5 bpm (p = 0.0047). The median total adverse events during dexmedetomidine infusion was 1 per admission. Median hospital length of stay was 9 days [interquartile range (IQR) 3-11 days] and median ICU length of stay was 7 days (IQR 3-11 days)., Conclusions: Intravenous dexmedetomidine is safe in patients with FD and appears to be effective to treat refractory adrenergic crisis. Dexmedetomidine may be considered in FD patients who do not respond to conventional clonidine and benzodiazepine pharmacotherapy., Competing Interests: Dr. Dillon has nothing to disclose. Ms. Spalink has nothing to disclose. Dr. Altshuler has nothing to disclose. Dr. Fridman has nothing to disclose. Dr. Papadopoulos has nothing to disclose.

Here we report the case of a patient with familial dysautonomia (a genetic form of afferent baroreflex failure), who had severe hypertension (230/149 mmHg) induced by the stress of his mother taking his blood pressure. His hypertension subsided when he learnt to measure his blood pressure without his mother's involvement. The case highlights how the reaction to maternal stress becomes amplified when catecholamine release is no longer under baroreflex control.

Objective: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia frequently affecting patients with synucleinopathies, but its exact prevalence in multiple system atrophy (MSA) is unclear. Whether questionnaires alone are sufficient to diagnose RBD is also unknown., Methods: We performed a cross-sectional study of patients with probable MSA from six academic centers in the US and Europe. RBD was ascertained clinically and with polysomnography; we also performed a meta-analysis according to PRISMA guidelines for studies published before September 2014 that reported the prevalence of RBD in MSA. A random-effects model was constructed using weighted prevalence proportions. Only articles in English were included. Studies were classified into those that ascertained the presence of RBD in MSA clinically and with polysomnography. Case reports or case series (≤ 5 patients) were not included., Results: Forty-two patients completed questionnaires and underwent polysomnography. Of those, 32 (76.1%) had clinically suspected RBD and 34 (81%) had polysomnography-confirmed RBD. Two patients reported no symptoms of RBD but had polysomnography-confirmed RBD. The primary search strategy yielded 374 articles of which 12 met the inclusion criteria. The summary prevalence of clinically suspected RBD was 73% (95 % CI, 62-84%) in a combined sample of 324 MSA patients. The summary prevalence of polysomnography-confirmed RBD was 88 % (95% CI, 79-94%) in a combined sample of 217 MSA patients., Interpretation: Polysomnography-confirmed RBD is present in up to 88% of patients with MSA. RBD was present in some patients that reported no symptoms. More than half of MSA patients report symptoms of RBD before the onset of motor deficits.

Multiple system atrophy (MSA) is a sporadic, adult onset, relentlessly progressive neurodegenerative disease characterized by autonomic abnormalities associated with parkinsonism, cerebellar dysfunction, pyramidal signs, or combinations thereof. Treatments that can halt or reverse the progression of MSA have not yet been identified. MSA is neuropathologically defined by the presence of α-synuclein-containing inclusions, particularly in the cytoplasm of oligodendrocytes (glial cytoplasmic inclusions, GCIs), which are associated with neurodegeneration. The mechanisms by which oligodendrocytic α-synuclein inclusions cause neuronal death in MSA are not completely understood. The MSA neurodegenerative process likely comprises cell-to-cell transmission of α-synuclein in a prion-like manner, α-synuclein aggregation, increased oxidative stress, abnormal expression of tubulin proteins, decreased expression of neurotrophic factors, excitotoxicity and microglial activation, and neuroinflammation. In an attempt to block each of these pathogenic mechanisms, several pharmacologic approaches have been tried and shown to exert neuroprotective effects in transgenic mouse or cellular models of MSA. These include sertraline, paroxetine, and lithium, which hamper arrival of α-synuclein to oligodendroglia; rifampicin, lithium, and non-steroidal anti-inflammatory drugs, which inhibit α-synuclein aggregation in oligodendrocytes; riluzole, rasagiline, fluoxetine and mesenchymal stem cells, which exert neuroprotective actions; and minocycline and intravenous immunoglobulins, which reduce neuroinflammation and microglial activation. These and other potential therapeutic strategies for MSA are summarized in this review.

Management of blood pressure (BP) abnormalities in patients with autonomic failure is usually based on office BP readings. It is uncertain, whether office readings reflect actual BP's [corrected] during a typical day. Therefore, in 45 patients with autonomic failure, we compared office BP values during a tilt test with those captured on a 24-h BP [corrected] ambulatory monitor. Office BP values while supine predicted well the level of nighttime hypertension. However, in only 33% of patients, office values during tilt test accurately reflected hypotension during a typical day. Therefore, BP [corrected] ambulatory monitoring is useful to gauge the true severity of hypotension in patients with autonomic failure.

Background: There is no widely accepted validated scale to assess the comprehensive symptom burden and severity of neurogenic orthostatic hypotension (NOH). The Orthostatic Hypotension Questionnaire (OHQ) was developed, with two components: the six-item symptoms assessment scale and a four-item daily activity scale to assess the burden of symptoms. Validation analyses were then performed on the two scales and a composite score of the OHQ., Methods: The validation analyses of the OHQ were performed using data from patients with NOH participating in a phase IV, double blind, randomized, cross over, placebo-controlled trial of the alpha agonist midodrine. Convergent validity was assessed by correlating OHQ scores with clinician global impression scores of severity as well as with generic health questionnaire scores. Test-retest reliability was evaluated using intraclass correlation coefficients at baseline and crossover in a subgroup of patients who reported no change in symptoms across visits on a patient global impression scores of change. Responsiveness was examined by determining whether worsening or improvement in the patients' underlying disease status produced an appropriate change in OHQ scores., Results: Baseline data were collected in 137 enrolled patients, follow-up data were collected in 104 patients randomized to treatment arm. Analyses were conducted using all available data. The floor and ceiling effects were minimal. OHQ scores were highly correlated with other patient reported outcome measures, indicating excellent convergent validity. Test-retest reliability was good. OHQ scores could distinguish between patients with severe and patients with less severe symptoms and responded appropriately to midodrine, a pressor agent commonly used to treat NOH., Conclusion: These findings provide empirical evidence that the OHQ can accurately evaluate the severity of symptoms and the functional impact of NOH as well as assess the efficacy of treatment.

We report the case of a woman with Münchausen syndrome who surreptitiously injected epinephrine causing recurrent ventricular tachyarrhythmias accompanied by dramatically high plasma levels of epinephrine and normal norepinephrine levels.

Objective: To determine whether the heart rate changes during tilt table testing could be used in the differential diagnosis between vasovagal syncope and chronic autonomic failure., Methods: We compared the relationship between electrocardiographic R-R intervals and beat-to-beat blood pressure in 43 patients with typical vasovagal responses and 30 patients with chronic autonomic failure (6 pure autonomic failure, 23 multiple system atrophy, and 1 Parkinson's disease)., Results: In every patient with vasovagal syncope, at the time when the blood pressure was falling, it was possible to identify at least 12 successive heart beats (mean 33 +/- 2 heart beat, range 12-57) when blood pressure and heart rate fell in parallel, i.e., there was a negative relationship between blood pressure and R-R intervals (P < 0.001). In contrast, the relationship between blood pressure and R-R intervals in patients with chronic autonomic failure was never negative, i.e., heart rate always increased, albeit less than expected for the given fall in blood pressure, or remained unchanged., Interpretation: The heart rate changes during the fall in blood pressure can distinguish patients with vasovagal responses from those with chronic autonomic failure.

Neurogenic orthostatic hypotension results from failure to release norepinephrine, the neurotransmitter of sympathetic postganglionic neurons, appropriately upon standing. In double blind, cross over, placebo controlled trials, administration of droxidopa, a synthetic amino acid that is decarboxylated to norepinephrine by the enzyme L: -aromatic amino acid decarboxylase increases standing blood pressure, ameliorates symptoms of orthostatic hypotension and improves standing ability in patients with neurogenic orthostatic hypotension due to degenerative autonomic disorders. The pressor effect results from conversion of droxidopa to norepinephrine outside the central nervous system both in neural and non-neural tissue. This mechanism of action makes droxidopa effective in patients with central and peripheral autonomic disorders.

Background: Oral L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic catechol amino acid, increases standing blood pressure and improves standing ability in patients with neurogenic orthostatic hypotension, by conversion of L-DOPS to norepinephrine (NE) outside the brain. This study assessed the pharmacokinetics of L-DOPS, NE, and dihydroxyphenylglycol (DHPG), the main neuronal metabolite of NE, in patients with primary chronic autonomic failure from pure autonomic failure (PAF) or multiple system atrophy (MSA)., Methods: In 5 MSA and 4 PAF patients, antecubital venous blood was drawn during supine rest and plasma levels of catechols measured at various times for 48 hours after a single oral dose of 400 mg of L-DOPS., Results: Plasma L-DOPS peaked at 1.9 microg/ml (9 micromol/L) about 3 hours after drug administration, followed by a monoexponential decline with a half-time of 2-3 hours in both patient groups. Plasma NE and DHPG also peaked at about 3 hours, but at much lower concentrations (4 and 42 nmol/L). Compared to the MSA group, the PAF group had a smaller calculated volume of distribution of L-DOPS and up to 10-fold lower plasma NE levels at all time points. Plasma NE was above baseline in MSA even at 48 hours after L-DOPS., Conclusions: The relatively long half-time for disappearance of L-DOPS compared to that of NE explains their very different attained plasma concentrations. The similar NE and DHPG responses in PAF and MSA suggests production of NE from LDOPS mainly in non-neuronal cells. Persistent elevation of plasma NE in MSA suggests residual release of NE from sympathetic nerves.

Cost-effective diagnostic approaches to reflex syncope require knowledge of its frequency and causes in different age groups. For this purpose we reviewed the available literature dealing with the epidemiology of reflex syncope. The incidence pattern of reflex syncope in the general population and general practice is bimodal with peaks in teenagers and in the elderly. In the young almost all cases of transient loss of consciousness are due to reflex syncope. The life-time cumulative incidence in young females ( congruent with 50 %) is about twice as high as in males ( congruent with 25 %). In the elderly, cardiac causes, orthostatic and postprandial hypotension, and the effects of medications are common, whereas typical vasovagal syncope is less frequent. In emergency departments, cardiac causes and orthostatic hypotension are more frequent especially in elderly subjects. Reflex syncope, however, remains the most common cause of syncope, but all-cause mortality in subjects with reflex syncope is not higher than in the general population. This knowledge about the epidemiology of reflex syncope can serve as a benchmark to develop cost-effective diagnostic approaches.

There is no widely adopted definition or classification of syncope and related disorders. This lack of uniformity harms patient care, research, and medical education. In this article, syncope is defined as a form of transient loss of consciousness (TLOC) due to cerebral hypoperfusion. Differences between syncope and other causes of TLOC such as epilepsy, and disorders mimicking TLOC are described. A pathophysiological classification of syncope is proposed.

The initial evaluation of a patient with syncope should include a thorough clinical history, physical examination and 12 lead electrocardiogram (ECG). The history is the best diagnostic tool. Clinical findings guide further testing. Patients with syncope and heart disease require echocardiography, Holter monitoring or exercise testing. The tilt test and carotid sinus massage are useful to reproduce reflex syncope. An insertable subcutaneous loop recorder can provide prolonged ECG monitoring.

The medical history, in combination with the physical examination and a 12-lead electrocardiogram, plays a key role in the diagnosis and risk stratification of patients with syncope. However, diagnostic clinical criteria are not uniformly applied. In older studies, the diagnostic criteria for vasovagal or reflex syncope often included typical precipitating events and warning symptoms. More recent studies have documented that a variety of unrecognized stressors can trigger reflex syncope and that warning signs and symptoms may be minimal. A characteristic medical history (a trigger and/or prodromi) is enough to diagnose reflex syncope if the risk for a cardiac cause of syncope is low (e. g. patients < 65 yrs, without a history of heart disease and no ECG abnormalities). In elderly subjects with a higher risk of cardiac syncope, the yield of the medical history is lower. However, a prospective study of the value of the medical history for the diagnosis of syncope with long-term follow-up has not been performed.

Patient education, identification of possible triggers of syncope and reassurance are a central feature of the management of patients with reflex syncope. Patients should be advised as to the importance of adequate hydration and taught physical countermaneuvers to enhance cardiac venous return. These maneuvers are sufficient for most patients, however, for a small number of patients who continue to have recurrent syncopal events, pharmacological intervention may be considered. Volume expansion can be enhanced with salt and fludrocortisone. Agents from diverse pharmacological classes have been used to attenuate the reflex response, enhance vasoconstriction and attenuate vagal outflow. Alpha adrenoreceptor agonists, anticholinergic agents, theophylline, beta adrenoreceptor antagonists, serotonin reuptake inhibitors and disopyramide are the most widely studied. None of these agents has shown a consistent therapeutic benefit in clinical trials.