A heart attack can actually be subtle

Subtle signs - the brain before the infarction

Anyone who survives severe brain damage as a result of an accident, bleeding or a stroke is still at risk despite all medical skills. Delayed brain damage often occurs, which destroys the initial success of the treatment. They include "vasospasm", a vascular spasm that typically occurs a week after the acute event and can be fatal for patients. Oliver Sakowitz, Daniel Haux and Andreas Unterberg from the Neurosurgical University Clinic Heidelberg research early changes that indicate the impending danger in good time. The aim of the scientists is to develop new therapeutic approaches with which the dangerous vascular changes can be treated causally.

Friday, February 24, 2006, 9:30 p.m., Head Clinic of the University of Heidelberg: The emergency doctor brings a 46-year-old patient. At home she complained of severe, sudden headaches, vomited several times and then fell into a coma. Computed tomography of the head shows extensive bleeding. It is not located in the brain tissue itself, but below the spider tissue or "arachnoid", the last covering that surrounds the brain. The cause of such spontaneously occurring "subarachnoid hemorrhages", or SAB for short, are usually congenital bulges in the cerebral vessels, so-called aneurysms. These changes can be detected by vascular imaging using X-ray contrast media (angiography) and are responsible for about a quarter of all cerebral circulation deaths.

It is estimated that every hundredth German citizen lives with such a cerebral artery aneurysm, but initially does not notice it. The risk of actual bleeding from the aneurysm is statistically cumulative at ten percent over a decade of life. Despite intensive efforts, the death rate after the occurrence of an SAB is still alarmingly high at 25 to 50 percent. Disastrous secondary bleeding often occurs within a few days of the acute event. Such bleeding can be prevented by switching off the aneurysm at an early stage with a small metal clip surgically placed from the outside (microsurgical procedure) or by stuffing it with fine metal spirals using an arterial catheter (endovascular procedure).

But even patients who are spared rebleeding are still at risk. In the period after the surgical aneurysm has been closed, this is primarily due to a delayed onset of vasoconstriction. This "vasospasm" (VSP; vascular spasm) typically does not occur until one week after the bleeding and subsides again during the second and third weeks. The vasospasm, the causes of which are still unknown, is usually found in the vicinity of the aneurysm. It is believed to be set in motion by substances produced during the breakdown of the clotted subarachnoid blood. From an evolutionary point of view, the temporary narrowing of the vessel may once have served as protection against rebleeding. Unfortunately, vasospasm can reduce cerebral blood flow to such an extent that the symptoms of a stroke occur and, in the worst case, the patient dies from it.

The therapy of such circulatory disorders consists, among other things, in an increase in blood pressure, which, however, is not without risk. Since not all SAB patients are equally affected by vasospasm, this therapy should not be used prophylactically. So it is important to look for harbingers of vasospasm. Repeatedly displaying the blood vessels in order to detect vessel congestion, for example by means of angiography, is not practical and also does not say anything about whether there is actually a deficient blood flow. The measurement of the flow velocity in the basal cerebral arteries with the help of ultrasound correlates well with the result of the vascular imaging (angiography), but does not allow precise information on whether the blood flow is sufficient to optimally supply the brain tissue.

If the cerebral blood flow falls below a critical threshold, there are initially temporary functional failures, which can be detected by a clinical-neurological examination. Most neurosurgeons see the occurrence of these functional failures as the ultimate argument for promptly starting therapy. However, this assumes that the patient can be examined properly. Patients who are already in a coma, as in the case described above, cannot be adequately monitored.

When the brain chemistry is no longer right

Since the mid-1990s, microcatheters have been used to measure metabolic parameters that are important for blood circulation. For example, the local cerebral blood flow and oxygen supply, the electrical function of the brain and the biochemical metabolic processes can be monitored. The "brain chemistry" is accessible for measurement through polymer membranes in the sub-millimeter range (microdialysis), which are placed in the endangered brain area. A continuous flow of liquid along these semipermeable membranes collects ions and substrates which, following the concentration gradient, diffuse from the spaces surrounding the nerve cells via the membrane into the catheter. At the end of the flow of liquid, a solution is collected whose biochemical composition largely corresponds to the external environment of the cells.

In an analysis device at the bedside, measurements of the energy-supplying fructose glucose and its metabolic products lactate and pyruvate can then be carried out in these microdialysates once or several times per hour. Lactate increases in the tissue when there is insufficient blood flow and reduced oxygen tension, when the physiological path of glucose metabolism is blocked by oxygen-dependent cell organelles.

The same applies to the amino acid glutamate, which serves healthy nerve cells as a messenger substance at the cell contacts and is normally quickly removed from the intercellular space by energy-dependent processes. This recycling should allow a concerted function of the nerve cells among each other and avoid overexcitation. To what extent the high glutamate concentrations released from damaged cells themselves affect the environment has not yet been fully clarified.

In the Neurosurgical Clinic of the University of Heidelberg, all of the above diagnostic procedures are used to detect vasospasm. The first test results on the value of the microdialysis method in the clinic show that the diagnostic reliability for a clinically relevant vasospasm could be increased as a result. However, caution should be exercised not to rely solely on one measurement. On the one hand, these are only regional measurements; on the other hand, in some patients these metabolic changes only occur in the late course. Therefore, several parameters (electrical brain activity, absolute cerebral blood flow, brain oxygen supply and brain metabolism) are monitored in parallel in the case of corresponding risk patients.

Destructive waves of excitation

One of the current study projects of the Neurosurgical Clinic is supported by the "ZNS Hannelore-Kohl-Stiftung" (www.kuratorium-zns.de) and is dedicated to the electrical brain activity in the area surrounding acute brain injuries, for example in SAB patients. In neurophysiology, excitation waves of the cerebral mantle zone followed by "silence" (cortical spreading depression; CSD) have been known for a long time. CSD was recently seen in patients for the first time. In the patient, voltage potentials are derived directly from the surface of the brain using flat strip electrodes. CSD are found in the central nervous system of mammals in response to pathological stimuli (chemical, electrical, mechanical). It propagates through the cerebral cortex at a characteristic speed of one to five millimeters per minute. At the beginning of the wave front there is an increase in activity to 200 to 300 percent of the resting value. After that, the spontaneous electrical activity under the respective electrodes reaches a minimum within 30 seconds, where it lingers for two to three minutes, and then slowly fully recovers within five to ten minutes.

In healthy, normally perfused brain tissue, CSD does not cause sustained metabolic stress or cellular damage. The situation in the injured brain tissue is less harmless. In order to regain the equilibrium that has collapsed in the CSD, the cells have to expend a great deal of additional energy, which is reflected in increased oxygen and glucose consumption. Whether irreversible tissue destruction occurs in the event of insufficient blood flow depends on how the brain with its limited resources can react to further energetic loads. If there is no therapeutic intervention here, previously healthy brain tissue may be included in the affected area. As part of an international study group (www.cosbid.org), CSD are now being clinically investigated for the first time and could offer new approaches in the pharmacological therapy of brain injuries in the future.

Changed protein pattern

Whether changes in the protein composition, the so-called proteome, of the brain tissue may initiate vasospasm and allow risk patients to be recognized even earlier is currently being examined together with associate professor Dr. Martin Maurer from the Institute for Physiology and Pathophysiology.

Little is known about the entire spectrum of proteins and their function in SAB. With microdialysis it is now possible, in addition to metabolic products, to collect and analyze proteins that diffuse through the pores of the catheter membrane. If you separate the proteins according to their charge and size (two-dimensional gel electrophoresis) and then identify them with the help of mass spectrometry, you will find several proteins that are synthesized in different amounts in patients with vasospasm compared to patients without vasospasm. In the future, patients with an increased risk of developing vasospasm could be identified and treated preventively on the basis of altered proteome patterns.

The role of the corresponding proteins in the development of vasospasm is currently unclear. Since the analyzes are still very time-consuming at the moment, a rapid test method for the proteome analysis is to be developed. The aim is to develop new therapeutic approaches for vasospasm through further studies of the corresponding proteins. In contrast to the previous symptomatic therapy for vasospasm, hopefully a causal treatment will soon become possible.

Authors:
Dr. Oliver Sakowitz, Dr. Daniel Haux and Prof. Dr. Andreas Unterberg
Neurosurgical Clinic of the Heidelberg University Hospital
Im Neuenheimer Feld 400, 69120 Heidelberg
Telephone (0 62 21) 5 63 61 72, email: [email protected]