Diagnosing and Treating Neurogenic Orthostatic Hypotension: A Case Study

Transcription

1 Diagnosing and Treating Neurogenic Orthostatic Hypotension: A Case Study Learning Objectives: Illustrate how to accurately diagnose noh Employ scales and questionnaires in combination with cardiovascular measures to accurately evaluate the impact of disease on patient functioning Examine how to tailor therapy for noh according to a patient s disease characteristics Design treatment plans to manage patient-specific factors and improve QoL

2 Diagnosis Julie is a 65-year old female who was diagnosed with Parkinson s disease (PD) two years ago. In the last two months, she has noticed issues when trying to stand up from a seated position--- she feels lightheaded and dizzy. Recently, when trying to stand up and walk to answer the door, Julie stumbled and almost fell. She has noticed that the dizziness and feeling faint lasts for a few minutes and she must hold onto something before they pass and she feels stable enough to walk. She currently takes an immediate-release form of carbidopa/levodopa, 25/100 mg, TID, for her PD. Julie s only other significant health condition is arthritis in her hands which was present before the onset of PD symptoms. To help with her morning arthritis pain, Julie takes 2 naproxen sodium tablets in the morning for a total dose of 440 mg; this seems to help with the pain. Julie decides to see her physician about these new symptoms as she is worried her PD may be progressing. When Julie arrives at her physician s office, she is weighed and her blood pressure (BP) is taken. The LPN asks Julie about the reason for her visit and lets her know that the doctor will be with her shortly. Julie feels comfortable talking with her physician, Dr. Northrup. Dr. Northrup greets Julie and listens to her concerns about her worsening PD. Her physician looks at the BP that his LPN recorded and reviews her list of current medications. He asks her if she has changed anything with her medications, diet, physical activity, and sleep. He asks her about her mood and probes to see if she is still active with her social circle a small group of retired women she has become close to in her retirement community. While she is answering his questions, Dr. Northrup is watching Julie for possible tremors at rest, changes in facial expression, dyskinesias, and other symptoms that may indicate a worsening of her PD. He doesn t notice anything different from Julie s usual baseline so he asks her to stand and walk. Upon standing, Julie wobbles and reaches down to hold onto the chair arms. Dr. Northrup steadies her. He decides to measure her BP, first in the supine position, and then while standing, as he has a suspicion that Julie s problems are related to neurogenic orthostatic hypotension (noh). After about five minutes in the supine position, Julie s BP is 120/80 mm Hg. Dr. Northrop then has Julie stand and starts a timer to count to 1 minute. After 1 minute of standing, Julie s BP is 85/70 mm Hg and she reports that she feels lightheaded. Dr. Northrup has her sit down and Julie notes that the lightheadedness resolves. Neurogenic orthostatic hypotension is a disorder that results in a drop in blood pressure, when going from a supine or seated position to a standing position. The decrease in BP may be either systolic (>20 mm Hg) or diastolic (>10 mm Hg). The second factor that defines noh and differentiates it from other types of orthostatic hypotension is an impairment of the sympathetic nervous system resulting in decreased release of norepinephrine from the postganglionic cells onto their targets (ie, blood vessels). Approximately 40% of patients with PD have OH, and when examined closely, it is almost always neurogenic. (Goldstein 2009) Other causes of OH should be excluded, the most common of which is iatrogenic OH caused by antihypertensive medications. Because noh is commonly comorbid with a neurologic disorder, patients frequently assume its symptoms are attributable to the primary neurologic disorder, when in fact they constitute a separate diagnosis and are manageable via a different therapy class. Patients with other forms of synucleinopathies also may suffer from noh: multiple system atrophy (MSA), Shy-Drager syndrome, autonomic neuropathy, and those with pure autonomic failure (PAF). A simple way to diagnose noh in the clinic is to measure BP while the patient is supine and then after one (initial OH) and three minutes of standing (delayed OH). In fact, many expert centers obtain orthostatic blood pressures on every Parkinson s disease patient because some patients may not report or recognize symptoms of noh.

3 Patients with symptomatic noh may be susceptible to injury from falls due presyncope and syncope. Receiving treatment for noh may help to prevent falls, and patients may be more confident in their ability to ambulate. This is currently an active area of research. Patients who do not experience symptoms (ie, do not feel dizzy, light-headed, faint, or experience vertigo upon standing) may not need treatment but should be monitored for the appearance of symptoms or BP worsening. Measuring orthostatic BPs and screening for symptoms remains the gold standard for detecting noh. Although not commonly used in clinical practice, assessment tools can help clinicians start gauge the impact of the disease on patient functioning. For instance, the Orthostatic Hypotension Daily Activity Scale assesses the interference of noh on daily activities: standing for short or long periods of time, and walking for short or long periods of time. Patients score items on a scale of 0 to 10 for the average severity of symptoms over the past week. (Low 2015) The Orthostatic Grading Scale (OGS) can help clinicians gauge the extent and type of symptoms a patient may be experiencing as well as their impact on daily living activities. (Schrezenmaier 2005) This scale is composed of five items that address the severity and frequency of orthostatic symptoms, the impact of symptoms on activities of daily living and standing time, and assesses the relationship of symptoms to orthostatic stressors. (Low 2015) In the interest of time, physicians may have patients complete the scales while they wait and then review the results together. Patient diaries may also help patients be more consistent in noting their symptoms and may help clinicians observe how standing blood pressures vary throughout the day in addition to helping determine stressors that patients may need to minimize or avoid. Thus, these scales and assessment tools provide a more objective means for clinicians to visualize the impact of symptoms on patients functioning as well as their relationship to blood pressure changes.

4 Treatment Dr. Northrup reviewed Julie s medication history and noted that her PD medication appeared appropriate as motor symptoms of the disease were under control and the dose was not excessive nor causing side effects. Julie does not take any anti-hypertensives, so this is a noncontributing factor which also can be excluded. Julie s only other issue is arthritis in her hands, which is most noticeable in the morning. Dr. Northrup diagnoses noh based on her blood pressure readings and her symptoms. He considers possible treatments as she lives alone in her condominium. Goals of treatment involve improving orthostatic hypotension without inducing excessive supine hypertension, relieving orthostatic symptoms, and improving standing time. Pharmacological treatments for orthostatic hypotension exist. These therapies may include fludrocotisone, midodrine, or droxidopa. Both fludrocortisone and midodrine are approved to treat orthostatic hypotension but are not specifically indicated for symptomatic noh. Fludrocortisone is a mineralocorticoid. Clinicians have to be cautious when prescribing this drug as there is cardiotoxicity data showing that high drug doses can result in myocardial fibrosis and renal fibrosis. Additionally, patients should be monitored for the following since the drug is a volume expander: supine hypertension, edema, congestive heart failure, cardiotoxicity, and hypokalemia. (Hauser 2014, Metzler 2013) Midodrine is a direct α1-agonist (vasopressor). Use is cautioned and clinicians should monitor for: supine hypertension, paresthesias, pruritus, urinary retention, piloerection, and chills. It has a history of use to help correct for drops in blood pressure in patients receiving dialysis. (Hauser 2014) Droxidopa, a precursor of norepinephrine, was approved specifically for the treatment of symptomatic noh in 2014; to date, it is the only FDA-approved therapy for symptomatic noh. In one of the trials used for the basis of drug approval by the FDA (trial 301), patients had PD, MSA, PAF, or nondiabetic autonomic neuropathies. The primary endpoint in this trial was improvement in the symptoms of symptomatic noh for the group of patients receiving drug. To this end, there was a mean decrease of 1.83 points on the composite symptom score of the Orthostatic Hypotension Questionnaire (1 point over placebo) and an increase of about 8 points over placebo was observed in standing BP (11. 2 mm Hg vs 3.9 mm Hg for placebo). (Kaufmann 2014) The symptoms which patients noted the most improvement on included dizziness, lightheadedness, feeling faint, or a feeling like you might black out. Additionally, patients reported a significant improvement in the tolerance to stand for a long time. The most frequently reported side effects in the drug group included headache, dizziness, or nausea, and palpitations. About 5% of patients in the drug group experienced adverse events leading to discontinuation (ie, most commonly nausea or hypertension). Data released at AAN 2016 demonstrated that droxidopa efficacy was similar across a range of ages: <65 years, 65 years, or <75 years. Furthermore, incidences of side effects were also similar across these same age groups, with the incidence of supine hypertension being higher in patients taking droxidopa as compared with those given placebos; however, this difference dissipated if stable treatment was given beyond one week. (Han 2016) The approved starting dose of droxidopa is 100 mg, three times daily with a maximum daily dose of up to 600 mg. Clinicians are recommended to titrate patients drug doses until they exhibit a symptomatic response. Additionally, the drug s efficacy beyond two weeks has yet to be established, and clinicians are requested to monitor patients periodically. Some clinicians may continue to use droxidopa beyond the two-week indication, however, they should

5 periodically monitor their patients for adverse events; patients are also encouraged to monitor their blood pressure. The prescribing information for droxidopa states that if supine hypertension cannot be managed by head elevation, the droxidopa dose may need to be either reduced or the drug discontinued. The RESTORE study is currently underway to examine the long-term efficacy of the drug in patients with PD, MSA, or PAF. (ClinicalTrials.gov. NCT ) It is recommended that patients take their last droxidopa dose at least three hours prior to bedtime to reduce the likelihood of overnight supine hypertension. Additionally, clinicians may choose to prescribe a low dose, short-acting antihypertensive at bedtime to manage nighttime supine hypertension, if necessary. (Hauser 2014) It is noteworthy that patients who are on the more severe spectrum of those with symptomatic noh, tend to have a relatively poor prognosis, with increased cardiovascular and noncardiovascular morbidity and mortality, in spite of optimal treatment. Nondrug therapies are also recommended for use as first-line treatments for noh. Strategies can include: Rehydration (not just water as patients can get hyponatremic)/increased salt intake; these procedures may help to maintain a higher salt level in the brain. However, clinicians should be aware that it may be hard to convince patients that they need a higher salt diet as it s very much opposite to the advice given to the majority of Americans, Compression garments, and Resting/sleeping with the patient s head up (30 degrees). Dr. Northrup provides Julie with a prescription and schedule to introduce droxidopa she is both symptomatic and experiences significant decreases in her BP. She is to start at 100 mg TID with doses in the morning upon awakening, midday, and late afternoon. The schedule calls for her to increase her dose by 100 mg TID every other day if she is not experiencing side effects and is still getting lightheaded upon standing. He also teaches her how to take her own BP at home, supine and after standing for 1 minute. He requests that she measure her BPs every morning when she first gets up and every night when she is ready for bed, and to keep a log of her BPs for him to review at their next visit. He also tells her not to increase her droxidopa dose if her BP reading is higher than 180/90. Dr. Northrup also talks to Julie about getting enough water, not cutting salt from her diet, wearing compression stockings, and sleeping with her head elevated.

6 Follow-up Julie returns to see Dr. Northrup a month after she started taking droxidopa. She reports that one she increased her droxidopa dose to 300 mg TID her lightheadedness resolved and therefore she didn t increase the dose any further. She says she is more stable when she stands up, and hasn t had any recent falls. She denies any side effects, including headache., Dr. Northrup reviews Julie s BP log and sees that her morning blood pressures generally show reduction in orthostatic drop, consistent with her symptomatic improvement, and her bedtime supine BPs do not show concerning supine hypertension. Orthostatic BPs in the office are 130/85 mm Hg supine and 115/78 mm Hg after standing for 1 minute. On examination, Dr. Northrup finds that Julie s Parkinson disease signs are unchanged. She still has mild bradykinesia and a slight rest tremor in the left hand, but she does not need an increase in her levodopa dosage. Dr. Northrup makes a mental note that in the future, when she does need an increase in Parkinson medications, this could cause lowering of Julie s BP and an increase in treatment for OH may be required if she becomes symptomatic again. Through all of this, Julie has done exceptionally well at remembering to take all her medications: her Parkinson s, droxidopa, and arthritis medications in the morning; droxidopa in the afternoon; and her Parkinson s and droxidopa therapies again in the late afternoon/early evening. Julie says that she keeps her large weekly pill box on the dining table which serves as a visual reminder to take her therapies with meals. Finally, before concluding the appointment, Dr. Northrup also reiterates the need for Julie to monitor her supine and standing blood pressure about once a week in the morning and at bedtime now that her droxidopa dose is stable. He asks her to record these measurements in a notebook and show them to him at her next appointment.

7 References ClinicalTrials.gov Sustained effect of droxidopa in symptomatic neurogenic orthostatic hypotension (RESTORE). NCT Goldstein DS, Sharabi DS. Neurogenic orthostatic hypotension. A pathophysiological approach. Circulation. 2009;119: Han DH for MPR. Droxidopa effective, safe for symptomatic noh across age groups. April 20, Available at April, Hauser RA, Kaufmann H, White WB for Medscape. Neurogenic orthostatic hypotension: expert perspectives on diagnosis and treatment strategies. December, Kaufmann H, Freeman R, Biaggiioni I, et al. Droxidopa for neurogenic orthostatic hypotension. Neurology. 2014;83(4): Low PA. Neurogenic orthostatic hypotension: pathophysiology and diagnosis. Am J Manag Care. 2015;S248-S257. Metzler M, Duerr S, Granata R, et al. Neurogenic orthostatic hypotension: pathophysiology, evaluation, and management. J Neurol. 2013;260: Schrezenmaier C, Gebrking JA, Hines SM, et al. Evaluation of orthostatic hypotension: relationship of a new self-report instrument to laboratory-based measures. Mayo Clin Proc. 2005;80: