Mechanism-based therapy of non-cardiac syncope: a practical guide.

The term non-cardiac syncope includes all forms of syncope, in which primary intrinsic cardiac mechanism and non-syncopal transient loss of consciousness can be ruled out. Reflex syncope and orthostatic hypotension are the most frequent aetiologies of non-cardiac syncope. As no specific therapy is effective for all types of non-cardiac syncope, identifying the underlying haemodynamic mechanism is the essential prerequisite for an effective personalized therapy and prevention of syncope recurrences. Indeed, choice of appropriate therapy and its efficacy are largely determined by the syncope mechanism rather than its aetiology and clinical presentation. The two main haemodynamic phenomena leading to non-cardiac syncope include either profound hypotension or extrinsic asystole/pronounced bradycardia, corresponding to two different haemodynamic syncope phenotypes, the hypotensive and bradycardic phenotypes. The choice of therapy-aimed at counteracting hypotension or bradycardia-depends on the given phenotype. Discontinuation of blood pressure-lowering drugs, elastic garments, and blood pressure-elevating agents such as fludrocortisone and midodrine are the most effective therapies in patients with hypotensive phenotype. Cardiac pacing, cardioneuroablation, and drugs preventing bradycardia such as theophylline are the most effective therapies in patients with bradycardic phenotype of extrinsic cause.

Drug-induced orthostatic hypotension: Cluster analysis of co-prescription patterns in older people in UK primary care.

PURPOSE: Over 250 medications are reported to cause orthostatic hypotension, associated with serious adverse outcomes in older adults. Studies suggest a harmful cumulative risk of orthostatic hypotension with multiple medication use. However, there is limited evidence on the potential for harm in practice, particularly which drugs is co-prescribed and may increase risk of orthostatic hypotension. METHODS: Retrospective cohort study and cluster analysis using general practice data from IQVIA Medical Research Data (IMRD) in patients aged ≥50 contributing data between 1 January 2018 and 31 December 2018. Thirteen drug groups known to be associated with orthostatic hypotension by mechanism, were analyzed and clusters generated by sex and age-band. RESULTS: A total of 602 713 individuals aged ≥50 with 283 912 (47%) men and 318 801 (53%) women were included. The most prevalent prescriptions that might contribute to orthostatic hypotension were ACE inhibitors, calcium-channel blockers, beta-blockers, selective serotonin reuptake inhibitors and uroselective alpha-blockers. We identified distinct clusters of cardiovascular system (cardiovascular system) drugs in men and women at all ages. cardiovascular system plus psychoactive drug clusters were common in women at all ages, and in men aged ≤70. cardiovascular system plus uroselective alpha-blockers were identified in men aged ≥70. CONCLUSIONS: Distinct clusters of drugs associated with orthostatic hypotension exist in practice, which change over the life course. Our findings highlight potentially harmful drug combinations that may cause cumulative risk of orthostatic hypotension in older people. This may guide clinicians about the potential of synergistic harm and to monitor for orthostatic hypotension if using combinations of cardiovascular system drugs, cardiovascular system plus psychoactive drugs and/or alpha-blockers-particularly in patients aged ≥70 or at high-risk due to comorbidity. Future research should consider quantifying the risk of drug-induced orthostatic hypotension with such drug combinations.

Effect of levodopa on postural blood pressure changes in Parkinson disease: a randomized crossover study.

PURPOSE: We investigated the effect of levodopa on postural blood pressure changes in individuals with Parkinson disease (PD) with (PD+OH) and without neurogenic OH (PD-OH). METHODS: We performed a prospective randomized crossover study with autonomic testing performed ON and OFF levodopa. The primary outcome was the change in systolic blood pressure (SBP) from supine to 70° tilt at 3 min (ΔSBP-3'). Secondary outcomes included indices of baroreflex function and blood pressure and heart rate during tilt. RESULTS: We enrolled 40 individuals with PD (21 PD+OH, 19 PD-OH), mean age (SD) 73.2 years (7.9), 13 women (32.5%)). There was no difference in age, sex, disease duration, and severity between PD+OH and PD-OH. Mean difference in ΔSBP-3' ON versus OFF levodopa in the whole study population was - 3.20 mmHg [- 7.36 to 0.96] (p = 0.14). Mean difference in ΔSBP-3' was - 2.14 mmHg [- 7.55 to 3.28] (p = 0.45) in PD+OH and - 5.14 mmHg [- 11.63 to 1.35] (p = 0.14) in PD-OH. Mean difference in ΔSBP ON versus OFF levodopa was greater at 7 and 10 min (- 7.52 mmHg [- 11.89 to - 3.15], p = 0.002, and - 7.82 mmHg [- 14.02 to - 1.67], p = 0.02 respectively). Levodopa was associated with lower absolute values of blood pressure in both PD+OH and PD-OH and cardiovascular noradrenergic baroreflex impairment. CONCLUSION: Levodopa decreases blood pressure in both PD with and without autonomic failure, but it does not cause a greater fall in blood pressure from supine to standing at 3 min. Levodopa-induced baroreflex sympathetic noradrenergic impairment may contribute to lower blood pressure. Lower standing blood pressure with levodopa may increase the risks of fall and syncope.

[Afferent baroreflex failure with hyponatremia: A case report].

Afferent baroreflex failure (ABF) is a rare disease. It refers to the clinical syndrome caused by the impairment of the afferent limb of the baroreflex or its central connections at the level of the medulla. The recognized causes include trauma, surgery in related areas (radical neck tumor surgery, carotid endarterectomy), neck radiotherapy, brain stem stroke, tumor growth paraganglioma and hereditary diseases, among which the most common cause is extensive neck surgery or radiotherapy for neck cancer. The main manifestations are fluctuating hypertension, orthostatic hypotension, paroxysmal tachycardia and bradycardia. This case is a young man, whose main feature is blood pressure fluctuation, accom-panied by neurogenic orthostatic hypotension (nOH). After examination, the common causes of hypertension and nOH were ruled out. Combined with the previous neck radiotherapy and neck lymph node dissection, it was considered that the blood pressure regulation was abnormal due to the damage of carotid sinus baroreceptor after radiotherapy for nasopharyngeal carcinoma and neck lymph node dissection, which was called ABF. At the same time, the patient was complicated with chronic hyponatremia. Combined with clinical and laboratory examination, the final consideration was caused by syndrome of in- appropriate antidiuretic hormone (SIADH). Baroreceptors controlled the secretion of heart rate, blood pressure and antidiuretic hormone through the mandatory "inhibition" signal. We speculate that the carotid sinus baroreceptor was damaged after neck radiotherapy and surgery, which leads to abnormal blood pressure regulation and nOH, while the function of inhibiting ADH secretion was weakened, resulting in higher ADH than normal level and mild hyponatremia. The goal of treating ABF patients was to reduce the frequency and amplitude of sudden changes in blood pressure and heart rate, and to alleviate the onset of symptomatic hypotension. At present, drug treatment is still controversial, and non-drug treatment may alleviate some patients' symptoms, but long-term effective treatment still needs further study. The incidence of ABF is not high, but it may lead to serious cardiovascular and cerebrovascular events, and the mechanism involved is extremely complicated, and there are few related studies. The reports of relevant medical records warn that patients undergoing neck radiotherapy or surgery should minimize the da-mage to the baroreceptor in the carotid sinus in order to reduce the adverse prognosis caused by complications.

Orthostatic variation of pulmonary artery pressure in ambulatory heart failure patients.

AIM: To study effect of change in position (supine and standing) on pulmonary artery pressure (PAP) in ambulatory heart failure (HF) patients. METHODS: Seventeen patients with CardioMEMS® sensor and stable heart failure were consented and included in this single center study. Supine and standing measurements were obtained with at least 5 min interval between the two positions. These measurements included PAP readings utilizing the manufacturer handheld interrogator obtaining 10 s data in addition to the systemic blood pressure and heart rate recordings. RESULTS: Mean supine and standing readings and their difference (Δ) were as follows respectively: Systolic PAP were 33.4 (± 11.19), 23.6 (± 10) and Δ was 9.9 mmHg (p = 0.0001), diastolic PAP were 14.2 (± 5.6), 7.9 (± 5.7) and Δ was 6.3 mmHg (p = 0.0001) and mean PAP were 21.8 (± 7.8), 14 (± 7.2) and Δ was 7.4 mmHg (p = 0.0001) while the systemic blood pressure did not vary significantly. CONCLUSION: There is orthostatic variation of PAP in ambulatory HF patients demonstrating a mean decline with standing in diastolic PAP by 6.3 mmHg, systolic PAP by 9.9 mmHg and mean PAP by 7.4 mmHg in absence of significant orthostatic variation in systemic blood pressure or heart rate. These findings have significant clinical implications and inform that PAP in each patient should always be measured in the same position. Since initial readings at the time of implant were taken in supine position, it may be best to use supine position or to obtain a baseline standing PAP reading if standing PAP is planned on being used.

The 'Bermuda Triangle' of orthostatic hypotension, cognitive impairment and reduced mobility: prospective associations with falls and fractures in The Irish Longitudinal Study on Ageing.

BACKGROUND: Orthostatic hypotension (OH), cognitive impairment (Cog) and mobility impairment (MI) frequently co-occur in older adults who fall. This study examines clustering of these three geriatric syndromes and ascertains their relationship with future falls/fractures in a large cohort of community-dwelling people ≥ 65 years during 8-year follow-up. METHODS: OH was defined as an orthostatic drop ≥ 20 mmHg in systolic blood pressure (from seated to standing) and/or reporting orthostatic unsteadiness. CI was defined as Mini Mental State Examination ≤ 24 and/or self-reporting memory as fair/poor. MI was defined as Timed Up and Go ≥12 s. Logistic regression models, including three-way interactions, assessed the longitudinal association with future falls (explained and unexplained) and fractures. RESULTS: Almost 10% (88/2,108) of participants had all three Bermuda syndromes. One-fifth of participants had an unexplained fall during follow-up, whereas 1/10 had a fracture. There was a graded relationship with incident unexplained falls and fracture as the number of Bermuda syndromes accumulated. In fully adjusted models, the cluster of OH, CI and MI was most strongly associated with unexplained falls (odds ratios (OR) 4.33 (2.59-7.24); P < 0.001) and incident fracture (OR 2.51 (1.26-4.98); P = 0.045). Other clusters significantly associated with unexplained falls included OH; CI and MI; MI and OH; CI and OH. No other clusters were associated with fracture. DISCUSSION: The 'Bermuda Triangle' of OH, CI and MI was independently associated with future unexplained falls and fractures amongst community-dwelling older people. This simple risk identification scheme may represent an ideal target for multifaceted falls prevention strategies in community-dwelling older adults.

A framework to simplify paediatric syncope diagnosis.

This paper aims to improve the diagnosis of syncope and transient loss of consciousness (TLOC) in children. Diagnostic problems stem, first, from some causes spanning various disciplines, e.g. cardiology, neurology and psychiatry, while the most common cause, vasovagal syncope, is not embraced by any specialty. Second, clinical variability is huge with overlapping signs and symptoms. Third, the approach to TLOC/syncope of the European Society of Cardiology (ESC) is underused in childcare. We explain the ESC guidelines using an additional paediatric literature review. Classification of TLOC and syncope is hierarchic and based on history taking. Loss of consciousness (LOC) is defined using three features: abnormal motor control including falling, reduced responsiveness and amnesia. Adding a < 5 min duration and spontaneous recovery defines TLOC. TLOC simplifies diagnosis by excluding long LOC (e.g. some trauma, intoxications and hypoglycaemia) and focussing on syncope, tonic-clonic seizures and functional TLOC. Syncope, i.e. TLOC due to cerebral hypoperfusion, is divided into reflex syncope (mostly vasovagal), orthostatic hypotension (mostly initial orthostatic hypotension in adolescents) and cardiac syncope (arrhythmias and structural cardiac disorders). The initial investigation comprises history taking, physical examination and ECG; the value of orthostatic blood pressure measurement is unproven in children but probably low. When this fails to yield a diagnosis, cardiac risk factors are assessed; important clues are supine syncope, syncope during exercise, early death in relatives and ECG abnormalities.  Conclusions: In adults, the application of the ESC guidelines reduced the number of absent diagnoses and costs; we hope this also holds for children. What is Known: • Syncope and its mimics are very common in childhood, as they are at other ages. • Syncope and its mimics provide considerable diagnostic challenges. What is New: • Application of the hierarchic framework of transient loss of consciousness (TLOC) simplifies diagnosis. • The framework stresses history-taking to diagnose common conditions while keeping an eye on cardiac danger signs.

Exaggerated blood pressure response to standing in young-to-middle-age subjects: prevalence and factors involved.

PURPOSE: To investigate the prevalence of orthostatic hypertension and the association of the blood pressure (BP) level, supine BP decline, and white-coat effect with the orthostatic pressor response. METHODS: We studied 1275 young-to-middle-age individuals with stage-1 hypertension. Orthostatic response was assessed three times over a 3 month period. The white-coat effect was assessed at baseline and after 3 months, and was calculated as the difference between office and average 24 h BP. In 660 participants, urinary epinephrine and norepinephrine were also measured. RESULTS: An orthostatic systolic BP increase ≥ 20 mmHg was observed in 0.6-1.2% of the subjects during the three visits. Using the 20 mmHg cut-off, the prevalence of orthostatic hypertension was 0.6%. An orthostatic BP increase of ≥ 5 mmHg was found in 14.4% of participants. At baseline, the orthostatic response to standing showed an independent negative association with the supine BP level (p < 0.001), the supine BP change from the first to third measurement (p < 0.001), and the white-coat effect (p < 0.001). Similar results were obtained in the 1080 participants assessed at the third visit. Urinary epinephrine showed higher values in the top BP response decile (systolic BP increase ≥ 6 mmHg, p = 0.002 versus rest of the group). CONCLUSION: An orthostatic systolic BP reaction ≥ 20 mmHg is rare in young adults. However, even lower BP increases may be clinically relevant. The BP level, the supine BP decline over repeated measurement, and the white-coat effect can influence the estimate of the BP response to standing and should be considered in clinical and pathogenetic studies.

A systematic review and meta-analysis on the association between orthostatic hypotension and mild cognitive impairment and dementia in Parkinson's disease.

BACKGROUND: Cognitive impairment is a frequent disabling feature of Parkinson's disease (PD). Orthostatic hypotension (OH) is treatable and may be a risk factor for cognitive impairment. OBJECTIVE: We conducted a systematic review and meta-analysis to examine the relationship between OH with PD-associated minimal cognitive impairment (PD-MCI) and dementia (PDD) and assess the mitigating effects of potential confounding factors. METHODS: Observational studies published in English, Spanish, French, or Portuguese up to January 2022 were searched for in PubMed, EBSCO, and SciELO databases. The primary aim of this study was to revise the association between OH with PD-MCI and PDD. Alongside, we assessed OH as related to cognitive rating scales. Fixed and random models were fitted. Meta-regression was used to assess the mitigating effects of confounding variables. RESULTS: We identified 18 studies that reported OH association with PDD or PD-MCI, 15 of them reporting OH association with cognitive rating scales. OH was significantly associated with PDD/PD-MCI (OR, 95% CI: 3.31, 2.16-5.08; k = 18, n = 2251; p < 0.01). OH association with PDD (4.64, 2.68-8.02; k = 13, n = 1194; p < 0.01) was stronger than with PD-MCI (1.82, 0.92-3.58; k = 5, n = 1056; p = NS). The association between OH and PD-MCI/PDD was stronger in studies with a higher proportion of women and in those with a lower frequency of supine hypertension. Global cognition rating scale scores were lower in patients with OH (SMD, 95% CI: - 0.55, - 0.83/ - 0.26; k = 12, n = 1427; p < 0.01). CONCLUSIONS: Orthostatic hypotension shows as a significant risk factor for cognitive impairment in PD, especially in women and patients not suffering from hypertension.

Early and late-onset syncope: insight into mechanisms.

AIMS: Unexplained syncope is an important clinical challenge. The influence of age at first syncope on the final syncope diagnosis is not well studied. METHODS AND RESULTS: Consecutive head-up tilt patients (n = 1928) evaluated for unexplained syncope were stratified into age groups <30, 30-59, and ≥60 years based on age at first syncope. Clinical characteristics and final syncope diagnosis were analysed in relation to age at first syncope and age at investigation. The age at first syncope had a bimodal distribution with peaks at 15 and 70 years. Prodromes (64 vs. 26%, P < 0.001) and vasovagal syncope (VVS, 59 vs. 19%, P < 0.001) were more common in early-onset (<30 years) compared with late-onset (≥60 years) syncope. Orthostatic hypotension (OH, 3 vs. 23%, P < 0.001), carotid sinus syndrome (CSS, 0.6 vs. 9%, P < 0.001), and complex syncope (>1 concurrent diagnosis; 14 vs. 26%, P < 0.001) were more common in late-onset syncope. In patients aged ≥60 years, 12% had early-onset and 70% had late-onset syncope; older age at first syncope was associated with higher odds of OH (+31% per 10-year increase, P < 0.001) and CSS (+26%, P = 0.004). Younger age at first syncope was associated with the presence of prodromes (+23%, P < 0.001) and the diagnoses of VVS (+22%, P < 0.001) and complex syncope (+9%, P = 0.018). CONCLUSION: In patients with unexplained syncope, first-ever syncope incidence has a bimodal lifetime pattern with peaks at 15 and 70 years. The majority of older patients present only recent syncope; OH and CSS are more common in this group. In patients with early-onset syncope, prodromes, VVS, and complex syncope are more common.

A study of otolith function in patients with orthostatic dizziness.

BACKGROUND: Orthostatic dizziness (OD) is the dizziness that occurs when moving from a sitting or a supine to a standing position. It is typically thought to be connected to orthostatic hypotension (OH). The otolithic control of respiratory and cardiovascular system through vestibulosympathetic reflex has been the focus of considerable recent interest. This study aimed to evaluate the relationship between the orthostatic dizziness and otolith organ function. METHODS: This study was carried on 50 adults aged from 18 to 50 years with normal peripheral hearing. Subjects were divided into two groups: controls (GI): 20 healthy adults and study group (GII): 30 patients who were complaining of OD. Patients were submitted to; blood pressure measurement in sitting and standing positions, combined vestibular-evoked myogenic potentials (VEMPs) and subjective visual vertical and horizontal tests (SVV) and (SVH). RESULTS: The study group showed abnormal absent cVEMP, oVEMP. There were also statistically significant differences of P13 and N23 latencies and (P13N23) amplitudes between the two groups in the left ears. Both groups differed significantly in SVH values deviated to the left side. Study group were further subdivided into ten patients with OH and 20 patients with OD without OH. The both study subgroups showed abnormal absent cVEMP, oVEMP and abnormal SVH. OH patients showed statistically significant differences of cVEMP waves P13, N23 latencies in the left ears when compared with the control. CONCLUSIONS: Otolith malfunction may be the cause of orthostatic dizziness (OD) in patients with and without orthostatic hypotension.

Orthostatic Hypotension, Hypertension Treatment, and Cardiovascular Disease: An Individual Participant Meta-Analysis.

Importance: There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension. Objective: To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension. Data Sources: Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022. Study Selection: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with orthostatic hypotension assessments. Data Extraction and Synthesis: Individual participant data meta-analysis extracted following PRISMA guidelines. Effects were determined using Cox proportional hazard models using a single-stage approach. Main Outcomes and Measures: Main outcomes were CVD or all-cause mortality. Orthostatic hypotension was defined as a decrease in systolic BP of at least 20 mm Hg and/or diastolic BP of at least 10 mm Hg after changing position from sitting to standing. Standing hypotension was defined as a standing systolic BP of 110 mm Hg or less or standing diastolic BP of 60 mm Hg or less. Results: The 9 trials included 29 235 participants followed up for a median of 4 years (mean age, 69.0 [SD, 10.9] years; 48% women). There were 9% with orthostatic hypotension and 5% with standing hypotension at baseline. More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline orthostatic hypotension (hazard ratio [HR], 0.81; 95% CI, 0.76-0.86) similarly to those with baseline orthostatic hypotension (HR, 0.83; 95% CI, 0.70-1.00; P = .68 for interaction of treatment with baseline orthostatic hypotension). More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline standing hypotension (HR, 0.80; 95% CI, 0.75-0.85), and nonsignificantly among those with baseline standing hypotension (HR, 0.94; 95% CI, 0.75-1.18). Effects did not differ by baseline standing hypotension (P = .16 for interaction of treatment with baseline standing hypotension). Conclusions and Relevance: In this population of hypertension trial participants, intensive therapy reduced risk of CVD or all-cause mortality regardless of orthostatic hypotension without evidence for different effects among those with standing hypotension.

Tilt testing.

Tilt testing can help to diagnose unexplained syncope, by precipitating an episode during cardiac monitoring. The Italian protocol, now most widely used, involves giving sublingual nitroglycerine after 15 min, while monitoring beat-to-beat blood pressure (BP) and recording on video. Tilt testing is time-consuming but it is clinically useful and can guide therapy. Complications are rare. Syncope types include vasovagal syncope where BP falls after >3 min of tilt-up and later the heart rate falls; classic orthostatic hypotension where there is an immediate, progressive BP fall with minimal heart rate change; delayed orthostatic hypotension with a late BP fall after a stable phase but little or no heart rate rise; psychogenic pseudosyncope with apparent loss of consciousness, but no BP fall and a moderate heart rate rise; and postural orthostatic tachycardia syndrome where there is a significant heart rate rise but no BP fall.

Ambulatory blood pressure and drug treatment for orthostatic hypotension as predictors of mortality in patients with multiple system atrophy.

OBJECTIVES: Multiple system atrophy (MSA) is a rare fatal neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. This study was aimed at investigating possible associations between mortality, 24-h blood pressure (BP) level and variability, and drug treatments for orthostatic hypotension (OH) in MSA patients. METHODS: A total of 129 patients followed at the French Reference Center for MSA who underwent routine 24-h ambulatory BP monitoring were included. Unified MSA Rating Scale (UMSARS) scores, drug treatments and the occurrence and cause of death were recorded. RESULTS: Seventy patients died during follow-up (2.9 ± 1.8 years), mainly from terminal illness, pulmonary or sudden death. Multivariate Cox regression analysis, after adjustment for gender, disease duration and severity (UMSARS I+II score), showed that increased daytime systolic BP variability, OH severity and OH drug treatment were independently correlated with mortality. OH treatment was associated with the risk of cardiac causes and/or sudden death (p = 0.01). In a fully adjusted model, male gender [(female vs. male) hazard ratio (HR) 0.56, 95% CI 0.34-0.94, p = 0.03], UMSARS I+II score (HR 1.04, 95% CI 1.02-1.06, p < 0.01), systolic BP daytime variability (HR 3.66, 95% CI 1.46-9.17, p < 0.01) and OH treatment (HR: 2.13, 95% CI 1.15-3.94, p = 0.02) predicted mortality. CONCLUSIONS: Increased daytime BP variability and OH treatment were predictive of mortality in patients with MSA, independently from disease severity. Further studies are required to assess if these associations are explained by more severe autonomic dysfunction or if OH treatment exposes per se to a specific risk in this population.

Advances in the Pathophysiology and Management of Supine Hypertension in Patients with Neurogenic Orthostatic Hypotension.

PURPOSE OF REVIEW: Patients with neurogenic orthostatic hypotension (OH) frequently have hypertension in the supine position (sHTN). We review the controversies surrounding the need and safety of treating sHTN in patients with OH. RECENT FINDINGS: The presence of sHTN complicates the management of OH because treatment of one can worsen the other. New approaches have been developed to treat OH without worsening sHTN by preferentially improving standing blood pressure, such as medications that harness the patient's residual sympathetic tone like pyridostigmine and atomoxetine, and devices such as an automated abdominal binder that targets the inappropriate splanchnic venous pooling causing OH. There is a reluctance to treat sHTN for fear of increasing the risks of falls and syncope associated with OH, thought to be more immediate and dangerous than the late complications of organ damage associated with sHTN. This, however, does not take into account that nighttime sHTN induces natriuresis, volume loss, and begets daytime orthostatic hypotension. It is possible to treat sHTN in ways that reduce the risk of worsening OH. Furthermore, novel approaches, such as the use of local heat can control nighttime sHTN, reduce nocturia, and improve OH. Although continued progress is needed, recent findings offer hope that we can treat nocturnal sHTN and at the same time improve daytime OH, lessening the controversy whether to treat or not sHTN.

Orthostatic Hypotension and Antiparkinsonian Drugs: A Systematic Review and Meta-analysis.

BACKGROUND: Orthostatic hypotension (OH) is multifactorial in Parkinson's disease (PD). Antiparkinsonian medication can contribute to OH, leading to increased risk of falls, weakness and fatigue. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) of antiparkinsonian drugs associated with OH as an adverse effect, compared to placebo. We searched EMBASE, MEDLINE and Web of Science databases until November 2020. Analysis used fixed-effects models and the GRADE tool to rate quality of evidence. Meta-analysis was performed if 3 or more studies of a drug group were available. RESULTS: Twenty-one RCTs including 3783 patients were included comparing 6 PD drug groups to placebo (MAO-B inhibitors, dopamine agonists, levodopa, COMT inhibitors, levodopa and adenosine receptor antagonists). OH was recorded as an adverse event or measurement of vital signs, without further specification on how this was defined or operationalised. Meta-analysis was performed for MAO-B inhibitors and dopamine agonists, as there were 3 or more studies for these drug groups. In this analysis, compared with placebo, neither MAO-B inhibitors or dopamine agonists were associated with increased risk of OH, (OR 2.28 [95% CI:0.81-6.46]), (OR 1.39 [95% CI:0.97-1.98]). CONCLUSIONS: Most studies did not specifically report OH, or reporting of OH was limited, including how and when it was measured. Furthermore, studies specifically reporting OH included participants that were younger than typical PD populations without multimorbidity. Future trials should address this, for example,, by including individuals over the age of 75, to improve estimations of how antiparkinsonian medications affect risk of OH.

New horizons in the ageing autonomic nervous system: orthostatic hypotension and supine hypertension.

Blood pressure regulation is an automatic, moment-by-moment buffering of the blood pressure in response to physiological changes such as orthostasis, exercise and haemorrhage. This finely orchestrated reflex is called the baroreflex. It is a regulated arc of afferent, central and efferent arms. Multiple physiological changes occur with ageing that can disrupt this reflex, making blood pressure regulation less effective. In addition, multiple changes can occur with ageing-related diseases such as neurodegeneration, atherosclerosis, deconditioning and polypharmacy. These changes commonly result in orthostatic hypotension, hypertension or both, and are consistently associated with multiple adverse outcomes. In this article, we discuss the healthy baroreflex, and physiological and pathophysiological reasons for impaired baroreflex function in older people. We discuss why the common clinical manifestations of orthostatic hypotension and concomitant supine hypertension occur, and strategies for balancing these conflicting priorities. Finally, we discuss strategies for treating them, outlining our practice alongside consensus and expert guidance.

Independent effect of neurogenic orthostatic hypotension on mild cognitive impairment in Parkinson's disease.

PURPOSE: Orthostatic hypotension (OH) is an associative or causative factor of cognitive impairment in Parkinson's disease (PD). However, the association between mild cognitive impairment (MCI) and neurogenic OH directly associated with the presence of alpha-synuclein in PD remains unclear. We aimed to evaluate the relationship between MCI and neurogenic OH in patients with de novo PD. We also investigated the patterns of neuropsychological performance according to neurogenic OH. METHODS: A total of 456 patients with PD-normal cognition (PD-NC, n = 204) or PD-MCI (n = 252) were recruited from multiple centers in Korea. All patients underwent comprehensive neuropsychological tests and tilt-table tests to evaluate cognitive function and neurogenic OH. We used logistic regression analysis and multivariate analysis of covariance to determine the association between MCI and neurogenic OH and the pattern of neuropsychological performance according to neurogenic OH. RESULTS: Neurogenic OH (odds ratio = 3.66, 95% confidence interval 2.06 to 6.47) was independently associated with MCI in patients with de novo PD, regardless of orthostatic symptoms, while nonneurogenic OH was not. Patients with PD with neurogenic OH exhibited worse performance in frontal-executive function and visual memory function than those without neurogenic OH. CONCLUSION: Our findings provide insight into neurogenic OH as an important clinical factor with cognitive impairment in individuals with PD and vice versa. Therefore, the evaluation of cognitive function is necessary in PD patients with neurogenic OH.

Selected autonomic signs and symptoms as risk markers for phenoconversion and functional dependence in prodromal Parkinson's disease.

PURPOSE: To determine whether dysautonomia can stratify individuals with other prodromal markers of Parkinson's disease (PD) for risk of phenoconversion and functional decline, which may help identify subpopulations appropriate for experimental studies. METHODS: Data were obtained from Parkinson's Progression Markers Initiative. Cohorts without PD but with at-risk features were included (hyposmia and/or rapid-eye-movement-sleep behavior disorder, LRRK2 gene mutation, GBA gene mutation). Dysautonomia measures included Scales-for-Outcomes-in-Parkinson's-Disease Autonomic (SCOPA-AUT), seven SCOPA-AUT subscales, and cardiovascular dysfunction (supine hypertension, low pulse pressure, neurogenic orthostatic hypotension). Outcome measures were phenoconversion and Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤ 70, which indicates functional dependence. Cox proportional-hazards regression was used to evaluate survival to phenoconversion/SE-ADL ≤ 70 for each dysautonomia measure. If a significant association was identified, a likelihood-ratio test was employed to evaluate whether a significant interaction existed between the measure and cohort. If so, regression analysis was repeated stratified by cohort. RESULTS: Median follow-up was 30 months. On multivariable analysis, gastrointestinal and female sexual dysfunction subscales were associated with increased risk of phenoconversion, while the cardiovascular subscale and neurogenic orthostatic hypotension were associated with increased risk of SE-ADL ≤ 70; respective hazard ratios (95% confidence intervals) were 1.13 (1.01-1.27), 3.26 (1.39-7.61), 1.87 (1.16-2.99), 5.45 (1.40-21.25). Only the association between the cardiovascular subscale and SE-ADL ≤ 70 was modified by cohort. CONCLUSIONS: Symptoms of gastrointestinal and female sexual dysfunction predict phenoconversion in individuals with other risk markers for PD, while signs and symptoms of cardiovascular dysfunction may be associated with functional decline.

Faintly tired: a systematic review of fatigue in patients with orthostatic syncope.

BACKGROUND: Orthostatic syncope (transient loss of conscious when standing-fainting) is common and negatively impacts quality of life. Many patients with syncope report experiencing fatigue, sometimes with "brain fog", which may further impact their quality of life, but the incidence and severity of fatigue in patients with syncope remain unclear. In this systematic review, we report evidence on the associations between fatigue and conditions of orthostatic syncope. METHODS: We performed a comprehensive literature search of four academic databases to identify articles that evaluated the association between orthostatic syncope [postural orthostatic tachycardia syndrome (POTS), vasovagal syncope (VVS), orthostatic hypotension (OH)] and fatigue. Studies were independently screened using a multi-stage approach by two researchers to maintain consistency and limit bias. RESULTS: Our initial search identified 2797 articles, of which 13 met our inclusion criteria (POTS n = 10; VVS n = 1; OH n = 1; VVS and POTS n = 1). Fatigue scores were significantly higher in patients with orthostatic syncope than healthy controls, and were particularly severe in those with POTS. Fatigue associated with orthostatic syncope disorders spanned multiple domains, with each dimension contributing equally to increased fatigue. "Brain fog" was an important symptom of POTS, negatively affecting productivity and cognition. Finally, fatigue was negatively associated with mental health in patients with POTS. CONCLUSION: In conditions of orthostatic syncope, fatigue is prevalent and debilitating, especially in patients with POTS. The consideration of fatigue in patients with orthostatic disorders is essential to improve diagnosis and management of symptoms, thus improving quality of life for affected individuals.