Thomas Morrow, MD

If clinicians could get a earlier warning, there often would be time to forestall a full-blown ‘brain attack’

Thomas Morrow, MD

A stroke is one of the most feared medical conditions a person can face. About 2,400 years ago, Hippocrates provided what is most likely the earliest description of what we now term a stroke: a sudden onset of paralysis, which he called apoplexy, a Greek word meaning struck down with violence. About 700,000 strokes occur each year in the United States and account for about $58 billion in direct and indirect costs.

About 88 percent of acute strokes are ischemic, meaning that a lack of blood supply to an area of the brain has occurred because of thrombus formation, embolus, progressive atherosclerosis, break up of a plaque, or just generalized hypoperfusion such as in systemic shock. The other 12 percent are hemorrhagic, but there are theories that many of these are, in fact, the result of ischemia-induced necrosis where a bleed occurs because of previous silent ischemic stroke. Obviously, there is no accurate way to determine how many hemorrhagic strokes are initiated by ischemia.

Searching for a predictive test

Medical researchers have for some time been looking for a test that can predict a stroke beyond the known risk factors. The ideal biomarker would have several attributes including: rapid release from injured neurons and glial cells, ability to be rapidly measured in the blood, ability to discriminate between ischemic and hemorrhagic events, sensitivity to early ischemia, and finally, not be elevated in conditions presenting with similar symptoms and signs. Many have been postulated including homocysteine, antiphospholipid protein antibodies, glutamate, myelin basic protein, S-100b (a proteolytic enzyme), thrombomodulin, neuron-specific enolase, and others.

But by applying an understanding of exactly what occurs with an acute stroke, CIS Biotech may have come up with a test that can predict who will soon experience a stroke.

Biochemical cascade

When ischemia occurs, several biochemical cascades take place. A major excitatory neuroreceptor, the N-methyl-D-aspartate receptor (NMDAR), has been discovered to be one of the key regulators of transduction of neuronal electrical signals. NMDA receptors are localized on the surface of epithelia of microvessels that form the blood-brain barrier and they control microvessel function. Early on, several energy-dependent functions become disrupted. Membrane integrity is damaged and proteases are activated, which in turn cleave the NMDAR into fragments (NR2 peptides) that are released through the compromised blood-brain barrier into the bloodstream where they can be measured and provide evidence of neurotoxicity underlying ischemia. Antibodies to NMDAR peptides (NR2 Abs) develop in response to the release of NR2 peptide fragments and can be measured in the blood stream.

Studies conducted in Europe by Dambinova et al., 2003, reported that antibodies to NR2 peptide were an independent and sensitive serologic marker that correlates with recent stroke or transient ischemic attack (TIA). These antibodies may in fact be a neuroprotective response, as animal studies have demonstrated that autoantibodies to NMDAR were associated with neuroprotective effects in rats with induced cerebral ischemia. It has also been postulated that these antibodies may predict earlier damage and that the presence of NR2 Abs may predict near-term recurrent strokes or TIAs for up to six months in advance of an actual event, allowing physicians to institute preventive measures.

In a study published in 2006 in Stroke by Bokesch et al., the presence of NMDAR Abs predicted adverse neurological outcomes after cardiac surgery. This is an important finding as cerebral complications are the leading cause of disability after cardiopulmonary bypass.

CIS Biotech, a small company, has developed an enzyme-linked immunosorbent assay (ELISA) for the quantitative determination of antibodies to the NR2 subunit of NMDAR using serum. They have named this test the “Gold Dot NR2 Antibody Test.” Early studies have determined this test to have a high degree of sensitivity and specificity.

The test is intended to be used in conjunction with clinical evaluation and radiologic methods for diagnosis of TIA and ischemic stroke. It can also assist in differentiating ischemic and hemorrhagic stroke. The company has a CLIA certificate and Georgia State License for the Gold Dot NR2 Antibody test. Serum samples can be sent to the company’s facility for NR2 antibody testing upon a request by a medical doctor.

Risk factors

There are recognized risk factors for a stroke that include hypertension, atrial fibrillation, hyperlipidemia, diabetes, cigarette smoking, heavy alcohol consumption, obesity, drug use, and hypercoagulable states.

Hypertension accounts for 35–50 percent of all strokes and is by far the most important epidemiological factor in stroke prevention. Patients with atrial fibrillation have a 5 percent incidence of stroke per year. People with diabetes, in part because of other metabolic derangements such as hypertension and lipid abnormalities, are 2–3 times more likely to develop a stroke than people without diabetes.

Symptoms of a stroke include rapid onset of neurologic dysfunction that can involve virtually any area of the brain. The larger the area of the brain affected, the more the impairment. Most strokes are unilateral. If the symptoms last only a few hours and the absence of abnormalities is confirmed by brain MRI or CT scan, the event is termed TIA. Having had a TIA is a huge risk for a second ischemic event, including a completed stroke.

Once a stroke occurs, minutes count. In fact many people are suggesting that strokes be renamed “brain attacks” to impress upon the public the acute nature and importance of these episodes, in the way that the public has embraced “heart attack.” As is the case for heart attacks, several therapies are available to correct the ischemia of an acute brain attack. These therapies are beyond the scope of this article.

Implications for managed care

The development of a reliable test to predict the onset of a stroke would give physicians a powerful tool to change patient behavior and prescribe preventive measures. When the Gold Dot NR2 Antibody Test is released, it is likely to be added to the routine screening of patients along with the traditional lipid panel and other routine blood tests.

Will managed care cover this test? Will it require a nationally recognized technology assessment of this test or inclusion in national guidelines? Will it require an approval from the U.S. Preventive Services Task Force? Will it attempt to contract for this test on a national basis?

Obviously many other questions will arise. But an important scientific discovery may soon become part of Tomorrow’s Medicine.

Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. Contact him at

The author is a director in the value-based health department at Genentech Inc. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.

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