Triggers, Risk Factors, and the Prevalence of Syncope Among Domestic Hajj Pilgrims, 2023: A Cross-Sectional Study.

BACKGROUND: Syncope and other transient loss of consciousness episodes in crowded and unfamiliar environments may lead to major health hazards. Despite numerous publications, data on syncope among Hajj pilgrims in Makkah is lacking. OBJECTIVES: To identify the triggers, risk factors, and prevalence of syncope and other transient loss of consciousness episodes among domestic pilgrims. METHODOLOGY: This cross-sectional study included a convenient sample of domestic pilgrims who performed Hajj in July 2023 using an online Google Forms questionnaire (Alphabet Inc., Mountain View, CA). RESULTS: Out of 388 participants, 69 (18.1%) reported a history of syncope during the Hajj pilgrimage. Among these, 57 (82.6%) reported complete loss of consciousness, and 56 (81.2%) noted warning symptoms preceding the episode. The syncopal attack occurred once in 49 respondents (71%). Several triggers for syncope were identified, with sudden standing from a sitting position being the most prevalent (100%). Additional co-triggers were crowding (n=43; 62.3%), stressful conditions (n=30; 43.2%), prolonged standing (n=21; 30.4%), and walking (n=11; 15.9%). Traumatic injuries were reported in 33 (47.8%) as a result of syncope. Standing for long periods of time on the day of Arafat (Arafat standing) emerged as the most common triggering situation (n=48; 69.6%). There were multiple medical factors contributing to syncopal episodes; the most common medical explanations were heat exhaustion (n=48; 69.6%), dehydration (n=24; 34.8%), over-exertion (n=48; 69.6%), low blood sugar (n=10; 14.5%), and low blood pressure (n=17; 24.6%). Significant predictors were the presence of cardiac disease (odd ratio (OR) 7.6, 95% confidence interval (CI) 2.71-21.45, p<0.001), anemia (OR 2.5, 95% CI 1.01-6.09, p=0.049), previous syncope (OR 2.5, 95% CI 1.02-6.27, p=0.049, and family history of syncope (OR 10.1, 95% CI 2.08-49.32, p=0.004). CONCLUSION: Syncope during the domestic Hajj pilgrimage is frequent, especially on the day of Arafat, and carries the risk of traumatic injury. People with previous episodes of syncope and comorbidities, especially cardiac patients and those who have a family history of syncope, are particularly prone to this risk. Healthcare should focus on at-risk patients, particularly on critical pilgrimage days, and increase pilgrims' awareness about triggers of syncope including sudden and prolonged standing, exertion, and heat exposure.

Dizziness in a tertiary neurological department: A cross-sectional study.

BACKGROUND AND OBJECTIVE: Dizziness is a common and challenging symptom, which can be caused by different pathophysiological mechanisms and might affect a large number of population. However, up to now, there have been limited research on the characteristics of dizziness as the chief complaint in hospitalized patients in the Department of Neurology. Thus, the aim of this study was to investigate the hospitalized patients with dizziness as their chief complaint in the Department of Neurology. METHODS: In this cross-sectional study, we conducted a retrospective document analysis of hospitalized patients admitted to a tertiary neurological department with the symptom of dizziness during the period of September 2019 to December 2020. We included 211 patients with dizziness as their chief complaint from 1841 patients admitted to this tertiary neurological department during that period. RESULTS: Of all 1841 hospitalized patients, those with dizziness as the chief complaint accounted for 11.5% and most of their past medical history included hypertension, diabetes, cerebrovascular diseases, dyslipidemia, and coronary heart disease. Among these 211 patients, dizziness was more common in women than in men (p = .004). More patients presented with vertigo (40.8%) and light-headedness (39.8%) than disequilibrium (17.1%) and pre-syncope (2.4%). Nausea (48.3%), vomiting (34.1%), headache (13.3%), walking unsteadily (13.3%), and ear symptoms (12.8%) were the most common concomitant symptoms. Dix-Hallpike test (24.6%) and Romberg's sign (11.4%) were positive in these dizzy patients. Nystagmus (2.4%), vision changes (1.4%), and hearing disorders (8.5%) were relatively rare symptoms. Common auxiliary examinations were performed, such as magnetic resonance imaging (60.2%), computed tomography (31.8%), carotid duplex ultrasound (30.8%), and echocardiography (28.0%). Benign paroxysmal positional vertigo (24.2%) and stroke/transient ischemic attack (19.0%) were confirmed to be common causes of dizziness. Note that 97.2% of dizzy patients were in improved recovery after treatment. CONCLUSION: The diagnosis and management of dizziness remain a challenge for clinicians. Vertigo and light-headedness were the most common symptoms among different types of dizziness. Benign paroxysmal positional vertigo and stroke/transient ischemic attack were among the leading causes for common dizziness disorders. The prognosis of most dizzy patients was good.

Relief of postural orthostatic tachycardia syndrome with chiropractic rehabilitation.

Postural orthostatic tachycardia syndrome (POTS) is a form of dysautonomia that's characterised by an abnormal heart rate response to a positional change. A 50-year-old female presented with lightheadedness, palpitation, and neck pain for 3 years. Lightheadedness and palpitation occurred when shifting from a prolonged seated or lying position. Standing radiographs showed spinal misalignment with cervical kyphosis and thoracic scoliosis. Continuous static stress on these minor variants could aggravate biomechanical and autonomic disorder like POTS. After ruling out cardiovascular, neurological, or vestibular pathophysiology, a multicomponent treatment approach was adopted including the use of thermal ultrasound therapy, cervical and thoracic spinal manipulation, and intermittent motorized cervicothoracic traction to manage her neck pain complaints. Following 3 months of regular treatment, the patient reported a full resolution of neck pain, dizziness, and POTS. At 12-month follow-up, all radiographic metrics showed improvement, including improvement of cervical alignment and thoracic curvature. POTS is a prevalent, under-diagnosed dysautonomia. This study might arouse the alertness of clinicians that symptoms related to POTS may be erroneously attributed to other neuro-cardiovascular disorders.

Comparison of supine and seated orthostatic hypotension assessments and their association with falls and orthostatic symptoms.

BACKGROUND: Orthostatic hypotension (OH) based on a change from seated-to-standing blood pressure (BP) is often used interchangeably with supine-to-standing BP. METHODS: The Study to Understand Fall Reduction and Vitamin D in You (STURDY) was a randomized trial of vitamin D3 supplementation and fall in adults aged ≥70 years at high risk of falls. OH was defined as a drop in systolic or diastolic BP of at least 20 or 10 mmHg, measured at pre-randomization, 3-, 12-, and 24-month visits with each of 2 protocols: seated-to-standing and supine-to-standing. Participants were asked about orthostatic symptoms, and falls were ascertained via daily fall calendar, ad hoc reporting, and scheduled interviews. RESULTS: Among 534 participants with 993 paired supine and seated assessments (mean age 76 ± 5 years, 42% women, 18% Black), mean baseline BP was 130 ± 19/68 ± 11 mmHg; 62% had a history of high BP or hypertension. Mean BP increased 3.5 (SE, 0.4)/2.6 (SE, 0.2) mmHg from sitting to standing, but decreased with supine to standing (mean change: -3.7 [SE, 0.5]/-0.8 [SE, 0.3] mmHg; P-value < 0.001). OH was detected in 2.1% (SE, 0.5) of seated versus 15.0% (SE, 1.4) of supine assessments (P < 0.001). While supine and seated OH were not associated with falls (HR: 1.55 [0.95, 2.52] vs 0.69 [0.30, 1.58]), supine systolic OH was associated with higher fall risk (HR: 1.77 [1.02, 3.05]). Supine OH was associated with self-reported fainting, blacking out, seeing spots and room spinning in the prior month (P-values < 0.03), while sitting OH was not associated with any symptoms (P-values ≥ 0.40). CONCLUSION: Supine OH was more frequent, associated with orthostatic symptoms, and potentially more predictive of falls than seated OH.

Lower body muscle preactivation and tensing mitigate symptoms of initial orthostatic hypotension in young females.

BACKGROUND: Initial orthostatic hypotension (IOH) is a form of orthostatic intolerance defined by a transient decrease in blood pressure upon standing. Current clinical recommendations for managing IOH includes standing up slowly or lower body muscle tensing (TENSE) after standing. Considering that IOH is likely due to a large muscle activation response resulting in excessive vasodilation with a refractory period (<2 minutes), we hypothesized that preactivating lower body muscles (PREACT) before standing would reduce the drop in mean arterial pressure (MAP) upon standing and improve presyncope symptoms. OBJECTIVE: The purpose of this study was to provide IOH patients with effective symptom management techniques. METHODS: Study participants completed 3 sit-to-stand maneuvers, including a stand with no intervention (Control), PREACT, and TENSE. Continuous heart rate and beat-to-beat blood pressure were measured. Stroke volume and cardiac output were then estimated from these waveforms. RESULTS: A total of 24 female IOH participants (mean ± SD: 32 ± 8 years) completed the study. The drops in MAP following PREACT (-21 ± 8 mm Hg; P <.001) and TENSE (-18 ± 10 mm Hg; P <.001) were significantly reduced compared to Control (-28 ± 10 mm Hg). The increase in cardiac output was significantly larger following PREACT (2.6 ± 1 L/min; P <.001) but not TENSE (1.9 ± 1 L/min; P = .2) compared to Control (1.4 ± 1 L/min). The Vanderbilt Orthostatic Symptom Score following PREACT (9 ± 8 au; P = .033) and TENSE (8 ± 8 au; P = .046) both were significantly reduced compared to Control (14 ± 9 au). CONCLUSION: Both the drop in MAP and symptoms upon standing improved with either PREACT or TENSE. These maneuvers provide novel symptom management techniques for patients with IOH.

Safety of low-dose oral minoxidil for hair loss: A multicenter study of 1404 patients.

BACKGROUND: The major concern regarding the use of low-dose oral minoxidil (LDOM) for the treatment of hair loss is the potential risk of systemic adverse effects. OBJECTIVE: To describe the safety of LDOM for the treatment of hair loss in a large cohort of patients. METHODS: Retrospective multicenter study of patients treated with LDOM for at least 3 months for any type of alopecia. RESULTS: A total of 1404 patients (943 women [67.2%] and 461 men [32.8%]) with a mean age of 43 years (range 8-86) were included. The dose of LDOM was titrated in 1065 patients, allowing the analysis of 2469 different cases. The most frequent adverse effect was hypertrichosis (15.1%), which led to treatment withdrawal in 14 patients (0.5%). Systemic adverse effects included lightheadedness (1.7%), fluid retention (1.3%), tachycardia (0.9%), headache (0.4%), periorbital edema (0.3%), and insomnia (0.2%), leading to drug discontinuation in 29 patients (1.2%). No life-threatening adverse effects were observed. LIMITATIONS: Retrospective design and lack of a control group. CONCLUSION: LDOM has a good safety profile as a treatment for hair loss. Systemic adverse effects were infrequent and only 1.7% of patients discontinued treatment owing to adverse effects.

Chronic isolated lightheadedness is a sign of abnormal plasma levels of phospholipids.

OBJECTIVE: To evaluate whether Chronic Isolated Light-headedness (CIL) commonly manifested in elderly patients is related with cerebral oxygen insufficiency. METHODS: In this case-control study, 462 patients (aged 40-83 years) with CIL and 238 clinical data matched controls were enrolled consecutively from January 2011 to September 2014. The plasma levels of "phospholipids with solubility similar to that of lysophosphatidic acid" (PSS-LPA), a surrogate marker for cerebral oxygen insufficiency, were assayed for all subjects to compare the occurrence and severity of CIL with the values of PSS-LPA. RESULTS: Patients with CIL had significantly higher plasma levels of PSS-LPA than controls, regardless of having or having not psychogenic abnormalities, χ2 = 448, odds ratio (95% CI) = 140 (72-260), P < 0.001; the mean plasma levels, 0.573 vs. 0.290 mmol/L respectively (P < 0.001). Receiver operator characteristic (ROC) analyses showed plasma PSS-LPA was both sensitive and specific for CIL. The area under ROC curve (AUC) was as high as 0.953 (0.938-0.968). The changes in severity of CIL between two separate assays of one month apart were correlated closely with the changes in plasma levels of PSS-LPA for the same patients, correlation coefficient (Spearman) = 0.90, p < 0.001. CONCLUSIONS: CIL is a manifestation of abnormal plasma levels of phospholipids which suggests cerebral oxygen insufficiency. This new finding shows that cerebral oxygen insufficiency is not rare especially in elderly persons.

Predictors of Intradialytic Symptoms: An Analysis of Data From the Hemodialysis Study.

BACKGROUND: Most patients receiving maintenance hemodialysis (HD) experience adverse symptoms, which are associated with decreased quality of life. Despite decades of experience, our understanding of causes of HD symptoms remains limited. We aimed to identify modifiable patient- and HD-related predictors of intradialytic symptoms. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: We leveraged patient-level (n=1,838) and HD session-level (n=64,797) data from the Hemodialysis Trial. EXPOSURE: Pre-HD serum urea nitrogen (SUN) level, pre-HD systolic blood pressure (SBP), intradialytic SBP decline, and ultrafiltration rate (UFR). OUTCOMES: Intra-HD symptoms, including cramps, nausea, chest pain, headache, and lightheadedness. ANALYTICAL APPROACH: Random-effects logistic regression models. RESULTS: Overall, symptoms occurred in 10.7% of HD sessions. Higher pre-HD SUN level (per 10 mg/dL) was associated with higher adjusted odds of muscle cramping and lightheadedness (adjusted ORs [aORs] of 1.20 [95% CI, 1.17-1.22] and 1.13 [95% CI, 1.08-1.18], respectively). SBP decline (from the predialysis value to the dialysis session nadir, per each 10-mm Hg decrease) was associated with greater risk for muscle cramping, headache, chest pain, vomiting, and lightheadedness (the largest aORs were for the 2 latter symptoms: 1.24 [95% CI, 1.20-1.28] and 1.37 [95% CI, 1.33-1.42], respectively). Higher UFR (per 1 mL/kg/h) was associated with greater odds of cramping (aOR, 1.03; 95% CI, 1.02-1.03). Conversely, higher pre-HD SBP (per 10 mm Hg) was associated with reduced risk for vomiting (aOR, 0.88; 95% CI, 0.85-0.92) and lightheadedness (aOR, 0.82; 95% CI, 0.80-0.85). LIMITATIONS: Measured osmolality, dialysate prescription data, and time stamps for symptom occurrence were not available. Clinical trial data may not be broadly generalizable. CONCLUSIONS: Higher pre-HD SUN level, UFR, pre-HD SBP, and SBP decline are independently associated with different patterns of adverse intradialytic symptoms. Recognition that different symptoms may have variable causes may allow tailoring of personalized treatments in future interventional studies.

A Single-institution Study on Predictors of Short-term Progression from Mild Cognitive Impairment in Parkinson's Disease to Parkinson's Disease with Dementia.

BACKGROUND: Patients with non-demented Parkinson's disease (PD) sometime have mild cognitive impairment (MCI), and mild cognitive impairment in Parkinson's disease (PD-MCI) may convert to Parkinson's disease with dementia (PDD) within several years. Cognitive impairment also occurs in the early stages of the disease, gradually progressing to lower quality of life and instrumental activities of daily living. It is important to elucidate the predictors of progression from PD-MCI to PDD via longitudinal studies. METHODS: This was a single center, case-control study. We analysed data from 49 patients with PD-MCI diagnosed as level I using the Movement Disorder Society PD-MCI criteria at baseline who had completed 1.5 years of follow-up. We defined patients who progressed to PDD as patients with progressive PD-MCI and patients who did not progress to PDD as patients with non-progressive PD-MCI. Depression, apathy, sleep disorders, constipation, light-headedness, hallucinations, impulse control disorders (ICDs) and impulsive-compulsive behaviors (ICBs) at baseline were statistically analysed as predictors of progression. RESULTS: Of the 49 PD-MCI patients, 33 did not convert to PDD (non-progressive PD-MCI), and 16 converted to PDD (progressive PD-MCI). The Mini-Mental State Examination (MMSE) score, light-headedness and ICDs were elucidated as predictors of progressive PD-MCI via a multivariate logistic regression model. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for each item were MMSE score, OR 0.324, 95% CI 0.119-0.882, P = 0.027; light-headedness, OR 27.665, 95% CI 2.263-338.185, P= 0.009; and ICDs, OR 53.451, 95% CI 2.298-291.085, P = 0.010. CONCLUSION: Cognitive function, ICDs and light-headedness may be risk factors for the development of PDD in PD-MCI patients.

Theoretical framework for "unexplained" dizziness in the elderly: The role of small vessel disease.

In this paper we postulate that disruption of connectivity in the human brain can lead to dizziness, a symptom normally associated with focal disease of the vestibular system. The specific case that we will examine is the development of "unexplained" dizziness in the elderly-an extremely common clinical problem. Magnetic resonance imaging of the brain in the elderly usually show variable degrees of multifocal micro-angiopathy (small vessel white matter disease, SVD); thus, we review the literature, present a conceptual model and report preliminary quantitative EEG data in support of the hypothesis that such hemispheric SVD leads to central nervous system disconnection that elderly patients report as dizziness. Loss of connectivity by age-related build-up of SVD could lead to dizzy feelings through one or more of the following mechanisms: disconnection of cortical vestibular centers, disconnection between frontal gait centers and the basal ganglia, and disconnection between intended motor action (efference copy) and sensory re-afference. Finally, we propose that SVD-mediated dysregulation of cerebral blood pressure is linked to dizziness during standing and walking in elderly patients with "unexplained" dizziness.

Association of Orthostatic Hypotension Timing With Clinical Events in Adults With Diabetes and Hypertension: Results From the ACCORD Trial.

OBJECTIVE: To determine the effects of orthostatic hypotension (OH) measurement timing on its associations with dizziness, falls, fractures, cardiovascular disease (CVD), and mortality. METHODS: We analyzed OH measurements from the Action to Control Cardiovascular Risk in Diabetes BP trial, which evaluated two blood pressure (BP) goals (systolic BP [SBP] < 120 mm Hg vs. SBP < 140 mm Hg) and incident CVD among adults with diabetes and hypertension. Seated BP was measured after 5 minutes of rest at baseline and follow-up visits (12 months, 48 months, and exit). Standing BP was measured 3 consecutive times (M1-M3) after standing, starting at 1 minute with each measurement separated by 1 minute. Consensus OH was defined as a drop in SBP ≥ 20 mm Hg or diastolic BP (DBP) ≥ 10 mm Hg. Participants were asked about orthostatic dizziness, recent falls, and recent fractures, and underwent surveillance for CVD events and all-cause mortality. RESULTS: There were 4,268 participants with OH assessments over 8,450 visits (mean age 62.6 years [SD = 6.6]; 46.6% female; 22.3% black). Although all measures of consensus OH were significantly associated with dizziness, none were associated with falls, and only M2 (~3 minutes) was significantly associated with fractures. No measurements were associated with CVD events, but later measurements were significantly associated with mortality. BP treatment goal did not increase risk of OH regardless of timing. Associations were not consistently improved by the mean or minimum of M1-M3. CONCLUSION: In this population of adults with hypertension and diabetes, neither single time nor set of measurements were clearly superior with regard to outcomes. These findings support the use of a flexibly timed, single measurement to assess OH in clinical practice. CLINICAL TRIALS REGISTRATION: Trial Number NCT00000620.

Effects of sodium intake on postural lightheadedness: Results from the DASH-sodium trial.

Lightheadedness after standing contributes to adverse clinical events, including falls. Recommendations for higher sodium intake to treat postural lightheadedness have not been evaluated in a trial setting. The Dietary Approaches to Stop Hypertension (DASH)-Sodium trial (1998-1999) tested the effects of the DASH diet and sodium reduction on blood pressure (BP). Participants were randomly assigned to DASH or a typical Western diet (control). During either diet, participants ate three sodium levels (50, 100, 150 meq/d at 2100 kcal) in random order for 30-days, separated by 5-day breaks. Participants reported the presence and severity of postural lightheadedness at baseline and after each feeding period. There were 412 participants (mean age 48 years; 57% women; 57% black). Mean baseline SBP/DBP was 135/86 mm Hg; 9.5% reported baseline lightheadedness. Among those consuming the DASH diet, high vs low sodium increased lightheadedness (OR 1.71; 95% CI: 1.01, 2.90; P = 0.047) and severity of lightheadedness (P = 0.02), but did not affect lightheadedness in those consuming the control diet (OR 0.77; 95% CI: 0.46, 1.29; P = 0.32). Among those consuming high vs low sodium in the context of the DASH diet, adults <60 vs ≥60 years old experienced more lightheadedness (P-interaction = 0.04), along with obese vs non-obese adults (P-interaction = 0.01). In the context of the DASH diet, higher sodium intake was associated with more frequent and severe lightheadedness. These findings challenge traditional recommendations to increase sodium intake to prevent lightheadedness.

Utilisation of medications to reduce symptoms in children with postural orthostatic tachycardia syndrome.

BACKGROUND: Postural orthostatic tachycardia syndrome encompasses multiple disabling symptoms that interfere with daily activities. Non-pharmacologic approaches can be insufficient and can require adjunctive medications to manage symptoms. Minimal data exist in the literature on medication outcomes in these patients. We reviewed our database for medication management outcomes.Materials and MethodsPatients aged 18 years and younger at initial diagnosis met the inclusion criteria. All prescribed patient medications were extracted from the electronic health record, excluding medications for unrelated symptoms or comorbid diseases. Medications were grouped by symptom class consistent with our programme utilisation protocol. Within symptom classification, therapy was deemed successful when a specific dose was prescribed at least five consecutive times without changes; this was confirmed by chart review. Individual medications and overall percentage of successful therapies within symptom classifications were assessed, with further analysis by gender. t-Test, χ2, and Mann-Whitney U-test were used to assess for differences in specific variables, as appropriate. RESULTS: A total of 708 patients met the study criteria. The percentage of patients with effective therapy by symptom includes light-headedness (52.2%), headache (48.2%), nausea (39.1%), dysmotility (43.4%), pain (53.4%), and insomnia (42.8%). Insomnia therapy was better for females; all other therapies showed no gender difference. The median number of therapies prescribed per patient per symptom was 2 for light-headedness, headache, and insomnia, and 1 for nausea, dysmotility, and pain.DiscussionSymptoms associated with this disorder can be effectively managed with various medications. Further randomised studies are needed to better ascertain true efficacy compared with placebo.

High Grade Atrioventricular Block in Von Recklinghausen Disease: A Rare Phenomenon.

A case of a 73-year-old woman with a history of von Recklinghausen disease (neurofibromatosis type 1) who presented initially with a gradual onset of shortness of breath and lightheadedness with no associated fever, chills, angina, palpitations, cough, weight loss, night sweats, nausea, vomiting, or constipation. She was found to be severely bradycardic and in third degree atrioventricular block by her primary care physician. She was admitted in the hospital because of intermittent bouts of lightheadedness and progression of the shortness of breath. Twelve-lead electrocardiogram documented the high grade atrioventricular block. Chest radiograph showed subtle mild pulmonary congestion. Transthoracic echocardiogram revealed mild concentric hypertrophy and normal systolic function with no regional wall motion abnormalities or evidence of significant valvular disease. Pacemaker was inserted and her symptoms improved significantly.

Tailored multifactorial intervention to improve dizziness symptoms and quality of life, balance and gait in dizziness sufferers aged over 50 years: protocol for a randomised controlled trial.

BACKGROUND: Dizziness is a frequently reported symptom in older people that can markedly impair quality of life. This manuscript presents the protocol for a randomised controlled trial, which has the main objective of determining the impact of comprehensive assessment followed by a tailored multifaceted intervention in reducing dizziness episodes and symptoms, improving associated impairments to balance and gait and enhancing quality of life in older people with self-reported significant dizziness. METHODS: Three hundred people aged 50 years or older, reporting significant dizziness in the past year will be recruited to participate in the trial. Participants allocated to the intervention group will receive a tailored, multifaceted intervention aimed at treating their dizziness symptoms over a 6 month trial period. Control participants will receive usual care. The primary outcome measures will be the frequency and duration of dizziness episodes, dizziness symptoms assessed with the Dizziness Handicap Inventory, choice-stepping reaction time and step time variability. Secondary outcomes will include health-related quality of life measures, depression and anxiety symptoms, concern about falling, balance and risk of falls assessed with the physiological fall risk assessment. Analyses will be by intention-to-treat. DISCUSSION: The study will determine the effectiveness of comprehensive assessment, combined with a tailored, multifaceted intervention on dizziness episodes and symptoms, balance and gait control and quality of life in older people experiencing dizziness. Clinical implications will be evident for the older population for the diagnosis and treatment of dizziness. TRIAL REGISTRATION: The study is registered with the Australia New Zealand Clinical Trials Registry ACTRN12612000379819 .

Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B).

Neurogenic orthostatic hypotension (nOH) results from failure of norepinephrine responses to postural change to maintain standing systolic blood pressure (s-SBP). Droxidopa is an oral prodrug of norepinephrine. Study nOH306 enrolled patients with Parkinson's disease (PD) and symptomatic nOH. Subjects underwent up to 2 weeks of double-blind titration of droxidopa or placebo, followed by 8 weeks of double-blind maintenance treatment (100-600 mg thrice-daily). For the initial 51 subjects (study nOH306A, previously reported), the primary efficacy measure, Orthostatic Hypotension Questionnaire (OHQ) composite score, did not demonstrate significant change versus placebo at maintenance week 8. For the subsequent 171 subjects (study nOH306B, reported here), the primary efficacy measure was change versus placebo on item 1 ("dizziness, lightheadedness, feeling faint, or feeling like you might black out") of the Orthostatic Hypotension Symptom Assessment (OHSA) subsection of the OHQ at maintenance week 1. At week 1, mean (standard deviation) improvement on OHSA item 1 was 2.3 (2.95) for droxidopa versus 1.3 (3.16) for placebo (P = 0.018). In addition, mean increase in s-SBP at week 1 was 6.4 (18.85) for droxidopa versus 0.7 (20.18) mmHg for placebo (nominal P value: 0.032). Differences in change in OHSA item 1 scores from baseline to maintenance weeks 2, 4, and 8 were not statistically significant. Adverse-event (AE) incidence was similar across groups, but 12.4% of droxidopa and 6.1% of placebo subjects withdrew because of AEs. The most common AEs on droxidopa (vs. placebo) were headache (13.5% vs. 7.3%) and dizziness (10.1% vs. 4.9%). Study nOH306B demonstrated subjective (OHSA item 1) and objective (s-SBP) evidence of short-term droxidopa efficacy (vs. placebo) for symptomatic nOH in PD.

Neurogenic orthostatic hypotension in Parkinson's disease: evaluation, management, and emerging role of droxidopa.

Neurogenic orthostatic hypotension (nOH) is due to failure of the autonomic nervous system to regulate blood pressure in response to postural changes due to an inadequate release of norepinephrine, leading to orthostatic hypotension and supine hypertension. nOH is common in Parkinson's disease (PD). Prevalence varies throughout the course of PD, ranging from 40% to 60%, and resulting in symptomatic nOH in approximately half. Symptomatic nOH, including lightheadedness, can limit daily activities and lead to falls. Symptomatic nOH can also limit therapeutic options for treating PD motor symptoms. Clinical evaluation should routinely include symptom assessment and blood pressure measurement of supine, sitting, and 3-minute standing; 24-hour ambulatory blood pressure monitoring can also be helpful. Non-pharmacological management of symptomatic nOH involves education, physical maneuvers, and adequate hydration. Current pharmacological treatment of symptomatic nOH includes salt supplement, fludrocortisone, midodrine, pyridostigmine, and other empiric medications. Despite these options, treatment of symptomatic nOH remains suboptimal, often limited by severe increases in supine blood pressure. Droxidopa, an oral prodrug converted by decarboxylation to norepinephrine, is a promising therapeutic option for symptomatic nOH in PD, improving symptoms of nOH, daily activities, falls, and standing systolic blood pressure in several recent trials. These trials demonstrated short-term efficacy and tolerability, with comparable increases in standing and supine blood pressures. Longer-term studies are ongoing to confirm durability of treatment effect.