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ICH Linked to Age-Related Macular Degeneration


THE FUNDUS showing intermediate age-related macular degeneration.

Investigators reported that older adults with stage 4 age-related macular degeneration (AMD) were nearly seven times more likely to suffer hemorrhagic stroke, compared with those that did not have AMD.

LOS ANGELES — There appears to be a strong association between advanced age-related macular degeneration (AMD) and intracerebral hemorrhage (ICH), according to new findings from the Rotterdam Study.

After adjustment for age, gender, and other risk factors, older adults with stage 4 AMD were nearly seven times more likely to suffer hemorrhagic stroke, compared with those that did not have AMD, reported Renske G. Wieberdink, MD, an epidemiologist at Erasmus Medical Center in Rotterdam, The Netherlands.

Both the wet and the dry forms of late AMD were independently associated with ICH, but not with cerebral infarction, she said here at the American Stroke Association International Stroke Conference 2011.

[Dry AMD occurs when the light-sensitive cells in the macula slowly break down, gradually blurring central vision in the affected eye. Wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula, leaking blood and fluid.]

Both AMD and stroke are frequent in the elderly. The two disorders share several underlying risk factors including hypertension, smoking, and elevated cholesterol levels, Dr. Wieberdink said.

Previous studies looking for an association between AMD and stroke have had inconsistent results. However, they were limited by the fact that they did not distinguish between early and late AMD or between cerebral infarction and ICH, she said.


The new study investigated whether AMD was associated with the risk of stroke and stroke subtypes among 6,207 people enrolled in the Rotterdam Study. All were aged 55 years or older and free of stroke at baseline between 1990 and 1993.

AMD was assessed using fundus photographs at baseline and at follow-up visits every three to four years. Severity of AMD was classified into five mutually exclusive stages, ranging from stage 0, or absence of AMD, to stage 4, or extensive AMD, with stage 4 further divided into “dry,” or atrophic AMD, and “wet,” or neovascular AMD.

Participants were continuously followed for stroke using general practitioners' and nursing home records. Strokes were classified into stroke subtypes — cerebral infarction, ICH, or unspecified — using neuroimaging results obtained from hospital records.

Over a median follow-up period of 13.6 years, there were 726 strokes, including 397 cerebral infarctions, 59 ICHs, and 270 unspecified strokes.

After adjustment for age, sex, diabetes, systolic blood pressure, antihypertensive medication use, current smoking, total cholesterol, HDL cholesterol, carotid artery plaque, body mass index, alcohol intake, and C-reactive protein, stage 4 AMD predicted a 1.56-fold higher risk (95% CI, 1.08-2.26) of any stroke.

When stroke was looked at by subtype, stage 4 AMD was associated with a 6.11-fold increased risk (95% CI, 2.34-15.98) of ICH. The link was stronger for wet AMD; it predicted a more than eight-fold increased risk of hemorrhagic stroke. However, the link between dry AMD and ICH also reached statistical significance.

There was no association between late AMD and cerebral infarction. Also, there was no association between Stage 1 to 3 AMD and stroke or any subtype of stroke.

While calling the association between advanced AMD and ICH “remarkable,” Dr. Wieberdink urged caution in interpreting the results due to the small numbers of people with late AMD and brain hemorrhage in the study.

Also, the mechanism of the association is unknown, she said. “We don't think AMD causes stroke. Instead, we think that AMD and bleeding stroke may result from a common underlying disease process,” she said.

Among the shared mechanisms that have been proposed to explain the link are atherosclerosis, apolipoprotein E, and inflammation, with complement activation, Dr. Wieberdink said.

Vascular integrity problems could also be at play, she said. In wet AMD, there is leakage of fragile, abnormal blood vessels behind the retina, she explained.

A limitation of the study is that patients were only followed up to 2007, before use of some of the newer AMD drugs, such as the vascular endothelial growth factor blockers bevacizumab and ranibizumab, that may raise stroke risk, Dr. Wieberdink said.


Asked to comment on the findings, Philip B. Gorelick, MD, the John S. Garvin Professor and Chair of the Department of Neurology and Rehabilitation and Director of the Center for Stroke Research at the University of Illinois College of Medicine in Chicago, said that the findings need to be replicated.

“It's too soon to conclude that advanced stages of AMD are associated with brain hemorrhage. That said, the cardiovascular risk factors for advanced AMD are also the risk factors for brain hemorrhage.

“Even as we await further validation of this relationship and mechanism studies, it would pay to prevent and control these risk factors. That may reduce the risk of both disorders,” Dr. Gorelick said.