Adverse effects of hypertension, supine hypertension, and perivascular space on cognition and motor function in PD

Dilated perivascular space (dPVS) has recently been reported as a biomarker for cognitive impairment in Parkinson’s disease (PD). However, comprehensive interrelationships between various clinical risk factors, dPVS, white-matter hyperintensities (WMH), cognition, and motor function in PD have not been studied yet. The purpose of this study was to test whether dPVS might mediate the effect of clinical risk factors on WMH, cognition, and motor symptoms in PD patients. A total of 154 PD patients were assessed for vascular risk factors (hypertension, diabetes mellitus, and dyslipidemia), autonomic dysfunction (orthostatic hypotension and supine hypertension [SH]), APOE ε4 genotype, rapid eye movement sleep-behavior disorder, motor symptoms, and cognition status. The degree of dPVS was evaluated in the basal ganglia (BG) and white matter using a 5-point visual scale. Periventricular, deep, and total WMH severity was also assessed. Path analysis was performed to evaluate the associations of these clinical factors and imaging markers with cognitive status and motor symptoms. Hypertension and SH were significantly associated with more severe BGdPVS, which was further associated with higher total WMH, consequently leading to lower cognitive status. More severe BGdPVS was also associated with worse motor symptoms, but without mediation of total WMH. Similar associations were seen when using periventricular WMH as a variable, but not when using deep WMH as a variable. In conclusion, BGdPVS mediates the effect of hypertension and SH on cognitive impairment via total and periventricular WMH, while being directly associated with more severe motor symptoms.

603 CHALLENGES IN THE MANAGEMENT OF SEVERE ORTHOSTATIC HYPOTENSION ASSOCIATED WITH SUPINE HYPERTENSION IN A PATIENT WITH AUTONOMIC DYSFUNCTION ON BACKGROUND OF NASOPHARYNGEAL CARCINOMA AND TYPE II DIABETES MELLITUS

Introduction Combined chemotherapy and radiotherapy increases long term survival in patients with nasopharyngeal carcinoma. However, radiotherapy of the carotid sinus or brain stem can evolve labile hypertension and orthostatic intolerance from chronic baroreflex failure. Diabetes would also cause this neuropathy. Management of patients with Supine hypertension-Orthostatic hypotension can be very challenging. Methods A case report was done on a 71-year-old man with metastatic nasopharyngeal carcinoma status post radiation therapy who was admitted with severe supine hypertension-orthostatic hypotension. Patient was managed with both non-pharmacological and pharmacological methods, and monitored for postural symptoms, complications of severe supine hypertension—which has been linked to left ventricular hypertrophy and kidney dysfunction, and placed on 24 hour ambulatory blood pressure monitoring to aid in management so as to prevent hypertension induced organ damage. Results This review outlines the pathophysiology of Supine hypertension-Orthostatic hypotension, treatment complications and potential management strategies recommendations for this group of patients. It revealed the benefit of having a 24 hour ambulatory blood pressure monitoring, which provides insight on the timing and magnitude of an individual’s blood pressure fluctuations throughout the day so as to further guide management. Conclusion Chronic baroreflex failure is a late sequela of neck irradiation for naso-pharyngeal carcinoma due to accelerated atherosclerosis in the region of the carotid sinus baroreceptor. Treatment goal is achieved with adequate control of pre-syncopal symptoms and prevention of long term complications. Non-pharmacological interventions remain the first line of therapy, followed by pharmacological interventions as necessary. Nonetheless, management of blood pressure in these elderly patients with baroreflex dysfunction remains challenging and should be individualized. Moving forward, a prospective study on the incidence of late onset, iatrogenic baroreflex failure as a late complication of neck irradiation and its particular relationship to carotid arterial rigidity should be conducted to increase awareness, timely diagnosis and management of the condition among physicians.

Supine Hypertension Is Associated With an Impaired Cerebral Oxygenation Response to Orthostasis: Finding From The Irish Longitudinal Study on Ageing

The cerebrovascular effects of supine hypertension (SH) are still poorly understood. With aging and atherosclerosis of the vascular system, it is not uncommon for SH and non-neurogenic orthostatic hypotension to co-occur. Given evidence for end organ damage and more extreme cerebral dysfunction in those with SH-orthostatic hypotension, we hypothesized that SH would be associated with impaired cerebral autoregulation. The aim of this study was to characterize the cerebrovascular response to orthostasis. Near-infrared spectroscopy was used to quantify the cerebrovascular response. We analyzed data from Wave 3 of TILDA (The Irish Longitudinal Study on Ageing; n=2750). Cerebral oxygenation and blood pressure (BP) were monitored continuously during an active stand. Responses were modeled using multilevel mixed-effects models and adjusted for important covariates such as age, sex, education, antihypertensive medications, and comorbidities. Forty-nine percent of the sample had SH. Those with SH demonstrated an impaired BP response and a slower recovery of BP after standing, graded by severity of SH. The cerebral oxygenation response was similar for both groups, but when standardized to mean arterial BP, the response was impaired in those with SH. A deficit of −0.83% (95% CI, −0.93 to −0.74) remained after 3 minutes of standing. Our study determined that cerebral oxygenation and cerebral autoregulation are impaired in those with SH. In older patients, consideration should be given to measuring SH and screening for orthostatic hypotension. Therapeutic studies are needed to better understand the relationship between cerebral oxygenation, medications, supine BP, and orthostatic hypotension.

Is orthostatic hypotension and co-existing supine and seated hypertension associated with future falls in community-dwelling older adults? Results from The Irish Longitudinal Study on Ageing (TILDA)

Orthostatic hypotension (OH) often co-exists with hypertension. As increasing age affects baroreflex sensitivity, it loses its ability to reduce blood pressure when lying down. Therefore, supine hypertension may be an important indicator of baroreflex function. This study examines (i) the association between OH and future falls in community-dwelling older adults and (ii) if these associations persist in those with co-existing OH and baseline hypertension, measured supine and seated. Data from 1500 community-dwelling adults aged ≥65 years from The Irish Longitudinal Study on Ageing (TILDA) were used. Continuous beat-to-beat blood pressure was measured using digital photoplethysmography during an active stand procedure with OH defined as a drop in systolic blood pressure (SBP) ≥20 mmHg and/or ≥10 mm Hg in diastolic blood pressure (DBP) within 3 minutes of standing. OH at 40 seconds (OH40) was used as a marker of impaired early stabilisation and OH sustained over the second minute (sustained OH) was used to indicate a more persistent deficit, similar to traditional OH definitions. Seated and supine hypertension were defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg. Modified Poisson models were used to estimate relative risk of falls (recurrent, injurious, unexplained) and syncope occurring over four year follow-up. OH40 was independently associated with recurrent (RR = 1.30, 95% CI = 1.02,1.65), injurious (RR = 1.43, 95% CI = 1.13,1.79) and unexplained falls (RR = 1.55, 95% CI = 1.13,2.13). Sustained OH was associated with injurious (RR = 1.55, 95% CI = 1.18,2.05) and unexplained falls (RR = 1.63, 95% CI = 1.06,2.50). OH and co-existing hypertension was associated with all falls outcomes but effect sizes were consistently larger with seated versus supine hypertension. OH, particularly when co-existing with hypertension, was independently associated with increased risk of future falls. Stronger effect sizes were observed with seated versus supine hypertension. This supports previous findings and highlights the importance of assessing orthostatic blood pressure behaviour in older adults at risk of falls and with hypertension. Observed associations may reflect underlying comorbidities, reduced cerebral perfusion or presence of white matter hyperintensities.

Local Passive Heat for the Treatment of Hypertension in Autonomic Failure

BackgroundSupine hypertension affects a majority of patients with autonomic failure; it is associated with end‐organ damage and can worsen daytime orthostatic hypotension by inducing pressure diuresis and volume loss during the night. Because sympathetic activation prevents blood pressure (BP) from falling in healthy subjects exposed to heat, we hypothesized that passive heat had a BP‐lowering effect in patients with autonomic failure and could be used to treat their supine hypertension.Methods and ResultsIn Protocol 1 (n=22), the acute effects of local heat (40–42°C applied with a heating pad placed over the abdomen for 2 hours) versus sham control were assessed in a randomized crossover fashion. Heat acutely decreased systolic BP by −19±4 mm Hg (versus 3±4 with sham,P<0.001) owing to decreases in stroke volume (−18±5% versus −4±4%,P=0.013 ) and cardiac output (−15±5% versus −2±4%,P=0.013). In Protocol 2 (proof‐of‐concept overnight study; n=12), we compared the effects of local heat (38°C applied with a water‐perfused heating pad placed under the torso from 10 pmto 6 am) versus placebo pill. Heat decreased nighttime systolic BP (maximal change −28±6 versus −2±6 mm Hg,P<0.001). BP returned to baseline by 8 am. The nocturnal systolic BP decrease correlated with a decrease in urinary volume (r=0.57,P=0.072) and an improvement in the morning upright systolic BP (r=−0.76,P=0.007).ConclusionsLocal heat therapy effectively lowered overnight BP in patients with autonomic failure and supine hypertension and offers a novel approach to treat this condition. Future studies are needed to assess the long‐term safety and efficacy in improving nighttime fluid loss and daytime orthostatic hypotension.RegistrationURL:https://www.clinicaltrials.gov; Unique identifiers: NCT02417415 and NCT03042988.

Management Strategies for Comorbid Supine Hypertension in Patients with Neurogenic Orthostatic Hypotension

Purpose of ReviewIn autonomic failure, neurogenic orthostatic hypotension (nOH) and neurogenic supine hypertension (nSH) are interrelated conditions characterized by postural blood pressure (BP) dysregulation. nOH results in a sustained BP drop upon standing, which can lead to symptoms that include lightheadedness, orthostatic dizziness, presyncope, and syncope. nSH is characterized by elevated BP when supine and, although often asymptomatic, may increase long-term cardiovascular and cerebrovascular risk. This article reviews the pathophysiology and clinical characteristics of nOH and nSH, and describes the management of patients with both nOH and nSH.Recent FindingsPressor medications required to treat the symptoms of nOH also increase the risk of nSH. Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other. The management of patients with nOH who also have nSH can be challenging and requires an individualized approach to balance the short- and long-term risks associated with these conditions.SummaryApproaches to manage neurogenic BP dysregulation include nonpharmacologic approaches and pharmacologic treatments. A stepwise treatment approach is presented to help guide neurologists in managing patients with both nOH and nSH.

Management of Orthostatic Hypotension, Postprandial Hypotension, and Supine Hypertension

This review provides recommendations for the treatment of neurogenic orthostatic hypotension (nOH), postprandial hypotension, and supine hypertension. It focuses on novel treatment strategies and new insights into the mechanism underlying these conditions. Our goal is to provide practical advice for clinicians on how to screen, diagnose, and treat these conditions with nonpharmacological and pharmacological approaches. For each disorder, we offered a stepwise recommendation on how to apply these new concepts to successfully ameliorate the symptoms associated with OH to prevent syncope and falls. The management of OH in patients who also have supine hypertension requires special considerations and pharmacotherapy. It is noteworthy that there are few therapeutic options for OH and only two Food and Drug Administration–approved drugs for the treatment of OH and nOH based on randomized clinical trials. We will use these studies to develop evidence-based guidelines for OH. The research is limited for postprandial hypotension and supine hypertension, and therefore the recommendations will be based on small studies, clinical expertise, and, above all, an understanding of the underlying pathophysiology.

Clinical Trials for Neurogenic Orthostatic Hypotension: A Comprehensive Review of Endpoints, Pitfalls, and Challenges

Neurogenic orthostatic hypotension (nOH) is among the most debilitating nonmotor features of patients with Parkinson's disease (PD) and other synucleinopathies. Patients with PD and nOH generate more hospitalizations, make more emergency room visits, create more telephone calls/mails to doctors, and have earlier mortality than those with PD but without nOH. Overall, the health-related cost in patients with PD and OH is 2.5-fold higher compared with patients with PD without OH. Hence, developing effective therapies for nOH should be a research priority. In the last few decades, improved understanding of the pathophysiology of nOH has led to the identification of therapeutic targets and the development and approval of two drugs, midodrine and droxidopa. More effective and safer therapies, however, are still needed, particularly agents that could selectively increase blood pressure only in the standing position because supine hypertension is the main limitation of available drugs. Here we review the design and conduct of nOH clinical trials in patients with PD and other synucleinopathies, summarize the results of the most recently completed and ongoing trials, and discuss challenges, bottlenecks, and potential remedies.

Management of Orthostatic Hypotension in Parkinson’s Disease

Orthostatic hypotension (OH) is a common non-motor feature of Parkinson’s disease that may cause unexplained falls, syncope, lightheadedness, cognitive impairment, dyspnea, fatigue, blurred vision, shoulder, neck, or low-back pain upon standing. Blood pressure (BP) measurements supine and after 3 minutes upon standing screen for OH at bedside. The medical history and cardiovascular autonomic function tests ultimately distinguish neurogenic OH, which is due to impaired sympathetic nerve activity, from non-neurogenic causes of OH, such as hypovolemia and BP lowering drugs. The correction of non-neurogenic causes and exacerbating factors, lifestyle changes and non-pharmacological measures are the cornerstone of OH treatment. If these measures fail, pharmacological interventions (sympathomimetic agents and/or fludrocortisone) should be introduced stepwise depending on the severity of symptoms. About 50% of patients with neurogenic OH also suffer from supine and nocturnal hypertension, which should be monitored for with in-office, home and 24 h-ambulatory BP measurements. Behavioral measures help prevent supine hypertension, which is eventually treated with non-pharmacological measures and bedtime administration of short-acting anti-hypertensive drugs in severe cases. If left untreated, OH impacts on activity of daily living and increases the risk of syncope and falls. Supine hypertension is asymptomatic, but often limits an effective treatment of OH, increases the risk of hypertensive emergencies and, combined with OH, facilitates end-organ damage. A timely management of both OH and supine hypertension ameliorates quality of life and prevents short and long-term complications in patients with Parkinson’s disease.