Delayed Orthostatic Hypotension 'Not Benign'

Pauline Anderson

September 23, 2015

Orthostatic hypotension (OH) that develops more than 3 minutes after standing progresses to OH in more than half of patients and carries a similar poor prognosis, including a high mortality rate, a 10-year follow-up study suggests.

"OH itself, whether delayed or not, is not a benign condition," said lead author Christopher Gibbons, MD, associate professor, neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

"Delayed OH is a real entity and has real complications and is largely unrecognized. If patients are complaining of lightheadedness and dizziness, particularly after standing for long periods of time, clinicians should definitely consider this as a possible diagnosis."

But it's not all "doom and gloom," said Dr Gibbons. Patients in the study who progressed from DOH to OH tended to have subtle abnormalities in parasympathetic functioning, suggesting that "we might be able to identify who would be progressing."

The results were published online September 23 in Neurology.

Neurogenic OH (nOH) is defined as a blood pressure fall of at least 20 mm Hg in systolic or 10 mm Hg in diastolic within 3 minutes of standing.

Delayed OH involves the same drop in blood pressure but occurs beyond 3 minutes after being tilted upright on tilt-table testing.

Researchers reviewed the medical records and test results of 230 individuals (mean age, 59 years; 49% female), who were referred for autonomic testing in 2002–2003. These patients had reported dizziness and feeling faint while standing — for example, waiting in a long line at the grocery store — and were being tested for OH, said Dr Gibbons.

At the time, 50 of the 230 were determined to have OH, 58 had delayed OH and 122 did not have OH, so their dizziness was related to something other than blood pressure, such as chronic fatigue.

Of the original 108 patients with OH or DOH, researchers had complete follow-up on 90 patients 10 years later. Of these, 42 of 50 had OH and 48 of 58 had DOH in the initial study.

Among patients with DOH initially, 26 (54%) developed OH during the follow-up period, 15 of whom developed a neurodegenerative synucleinopathy, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy.

"We seem to have two groups of people — some that progressed and some that did not — and it seemed that we could differentiate those that progressed because they tended to have other things that were wrong on their autonomic testing," said Dr Gibbons.

It's important to identify these people early on, he added. "We're actually capturing people years before they have a diagnosis of Parkinson disease. That could be a really important time in preventing the disease — if we have something that works."

Non-OH Controls

Of the 122 patients without OH in the original study, researchers had 75 age- and sex-matched controls for the 10-year follow-up. The researchers didn't use healthy controls because they were trying to link the timing of the test in people for whom dizziness was and was not related to blood pressure.

"We were looking for people who were tested at the same time in the same situation and on whom we had the same follow-up clinical data," explained Dr Gibbons.

Of the patients with OH on initial testing, the 10-year mortality rate was 64%. Of the patients with DOH who did not progress, the mortality rate was 5%, but in those who progressed to OH, the mortality rate was 50%.

The 10-year mortality rate of the controls was 9%, which, according to Dr Gibbons, approaches that of the national average for the same age group.

Having diabetes was associated with an even higher increase in mortality rate. Among those with diabetes and DOH on initial testing, the mortality rate was 80% in those who progressed to OH and 25% in those who did not progress to OH. In those with diabetes alone, without OH or DOH, the 10-year mortality rate was 13%.

"There is a clear association with autonomic neuropathy, and that is one of the causes of both delayed and orthostatic hypotension," commented Dr Gibbons. "The risk of that will be related to diabetes control and other risk factors like blood pressure and lipids."

The study doesn't "tell us everything we want to know, by any means," but it provides "a very clear understanding of the risks" of DOH, commented Dr Gibbons.

Sympathetic Degeneration

In an accompanying editorial, authors suggest the study findings support the concept that synucleinopathies are prion-like disorders that spread in a stepwise, pathway-specific fashion.

DOH may indicate not only less sympathetic degeneration than OH, but perhaps the location of additional pathways affected by the neurodegenerative process, write Horacio Kaufmann, MD, Department of Neurology, New York University School of Medicine, and Giris Jacob, MD, Tel Aviv Medical Center, Israel.

"It may be time to consider staging of nOH, to capture patients who are at risk of worsening and intervene sooner," they suggest.

DOH with parasympathetic impairment may turn out to be an early biomarker of synucleinopathy, they add. They note that in the study, abnormalities in parasympathetic (vagal) function were documented at the first visit in almost all patients with DOH who progressed to early OH and all those who turned out to have synucleinopathies.

Further, they point out that most of the patients with DOH who did not progress had no other abnormalities on autonomic testing and that two thirds were taking vasoactive medications that could potentially explain their OH.

Dr Kaufmann and Dr Jacob noted several limitations to the study. For example, the number of patients was small, the data were derived from a retrospective chart review, and some information, including the cause of death among those with DOH, was missing. It's not clear, for example, whether the deaths were related to the drop in blood pressure (syncope or falls) or to other unrelated reasons caused by the underlying pathological process.

"The take-home message," they concluded, "…is that it is useful to screen for OH for longer than 3 minutes. Delayed OH may explain a number of puzzling symptoms. It can be successfully treated and early recognition may prevent falls and their complications."

No targeted funding for the study was reported. Dr Gibbons has received personal compensation for serving on scientific advisory boards of Pfizer and Grifols. Dr Jacob has disclosed no relevant financial relationships. Dr Kauffman receives research support from the National Institutes of Health.

Neurology. Published online September 23, 2015. Abstract Editorial

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