Brain aneurysm, cerebral vasospasm, arteriovenous malformation (AVM) information

"Cerebral vasospasm" is a term that refers to physical narrowing of the central "lumen" of a brain blood vessel due to overcontraction of the vessel wall (see Figure 1, below). Here, "cerebral" refers to the brain, while "vaso" refers to blood vessel and "spasm" refers to the vessel's "spastic" or "shut down" or "constricted" physical state. In the worst-case scenario, a vasospastic brain artery is so shut down it no longer permits blood flow as its central "lumen" no longer exists, a state that can be likened to a tightly clenched fist.

Figure 1 shows how, in cerebral vasospasm, a brain artery which was once normal in terms of its diameter, ends up overcontracting, i.e., becoming "spastic". The central lumen of the artery which normally permits the free flow of blood becomes very narrow and may even entirely shut down in vasospasm.

Cerebral vasospasm generally occurs due to a ruptured brain aneurysm, or (very rarely) hemorrhage from another blood vessel abnormality such as an arteriovenous malformation (AVM). The common factor here is the abnormal presence of a substantial amount of blood on the outer ("subarachnoid" or "adventitial") surface of the blood vessel. This can particularly affect arteries at the base of the brain, i.e., around the Circle of Willis. In theory, blood from any cause of subarachnoid hemorrhage (SAH) can trigger vasospasm. It should be noted that cerebral vasospasm is also known to occur in patients who suffer SAH from traumatic brain injury (say, in motor vehicle or sporting accidents). Here, the amount of blood in the subarachnoid space may be less compared with patients experiencing aneurysmal rupture. Nonetheless, vasospasm may still occur, and its occurrence may negatively influence "outcome" in patients with significant traumatic SAH.

Vasospasm is generally thought to occur only in arteries and not in smaller arterioles or capillaries or veins. The reason for this is at least partly related to physical differences in the wall structure between these types of vessels; arteries have thicker walls (especially due to a thicker smooth muscle layer) and can clamp down (or contract) harder than, say, a vein or capillary. There are also molecular differences between these vessels that may partly explain why vasospasm occurs selectively in arteries. Vasospasm is certainly known to occur in the large arteries comprising the Circle of Willis (

go to the section on Brain Arteries) and the main branches arising from this vascular ring; it even occurs in small "pial" arteries that course over the surface of the brain.

Cerebral vasospasm can be classified into three types, namely, "subangiographic", "angiographic", and "clinical" vasospasm:

Subangiographic vasospasm is the type that cannot be detected by the "gold standard" (i..e., best) imaging method for vasospasm detection known as cerebral angiography (see 5., below). This means that vasospasm is actually occurring at a physical level, but we just can't see it due to limitations of available imaging methods. Specifically, either the narrowing is too mild to detect, or the spasm is happening in a part of the arterial tree which is most difficult to look at using angiography - this part involves the smaller of the brain arteries. The patient may or may not be "clinically affected" by subangiographic vasospasm; that is, at the bedside, a physician may or may not be able to detect its presence. Surprisingly, some patients with subangiographic spasm still suffer symptoms that, to the exclusion of all other causes, are thought to be due to the vasospastic process taking place in their brain arteries, albeit beyond the level of angiographic detection.
Angiographic vasospasm is the type that can be detected by cerebral angiography (see 5., below). Again, surprisingly, the patient may or may not be clinically affected by angiographic vasospasm. Generally, it is thought that if one can detect spasm angiographically, then the patient should be affected in such a way that it can be picked up by a physician at the patient's bedside. However, there are exceptions to this rule. The reasons for this are unknown, but may relate to differences between individuals in terms of the unique capacities of their brains to tolerate the same degree of arterial spasm (this may have a genetic basis; see 2., below), or to differences in the "road-maps" of their brain circulation (e.g., presence of back-up routes of blood supply or "collateral circulation"). In general, in vasospasm due to aneurysmal bleeding, the vasospastic arteries (if detected) tend to be close to the site of the aneurysm rupture. However, more distant or remote arteries can also be affected in a "diffuse" or "generalized" manner.
Clinical vasospasm is the type that, regardless of the angiographic findings, can be detected by a physician on physical examination of a patient (see 4., below).

In terms of the occurrence of vasospasm following aneurysmal rupture, it is likely that in most, if not all, patients suffering a "subarachnoid hemorrhage" (SAH) there would be some degree of subangiographic vasospasm triggered by the presence of blood on the outer surface of the vessels [i.e., in the "subarachnoid space" (SAS) surrounding brain arteries;

take me to Brain Aneurysms]. Angiographic spasm tends to be most readily detected (by cerebral angiography) at about 7 days after the SAH, although it may be detected even as early as 3 days after the hemorrhage. It occurs in between half to two-thirds of all aneurysm patients depending on the time at which angiography was carried out. Clinical vasospasm occurs in approximately one-third of all patients suffering aneurysmal SAH.

The arterial narrowing that occurs in cerebral vasospasm is typically a transient or temporary event, naturally lasting from a few days up to 3 weeks. However, despite the reversible nature of this condition, its occurrence may still be harmful, or even fatal (see 4., below).

For a long time it has been known that the amount of blood seen on a CAT scan after a bleed from a brain aneurysm (i.e., the radiological amount of subarachnoid hemorrhage/blood on the imaging) correlates with the risk of developing cerebral vasospasm. That is, the more the blood, the higher the risk of developing cerebral vasospasm. However, it has also been regularly observed that different patients with similar amounts of blood on the CAT scan may or may not share the same susceptibility to, or effects of, cerebral vasospasm. Perhaps more clearly, patient A and patient B both have ruptured brain aneurysms, and also happen to have the same amount of blood on the CT scan (per a radiologist or neurosurgeon's estimation as they scroll through the brain imaging), but patient A develops cerebral vasospasm, while patient B does not or (alternatively), patient A develops only angiographic vasospasm, while patient B develops angiographic and clinical vasospasm. In the absence of significant differences between their ages, race, gender, medical illnesses, etc., then this paradox can perhaps be explained by differences in certain vasoregulatory or vasoresponsive genes/proteins between patient A and patient B. One such candidate is the key vasoregulatory molecule, endothelial nitric oxide synthase (eNOS). Such differences between patients are called genetic polymorphisms, they are not mutations, but rather more frequent genetic variations noted across the population. Researchers from Japan first identified a link between polymorphic eNOS and susceptibiltiy to coronary (heart vessel) vasospasm (the particular polymorphism they reported was the T-786C eNOS promoter single nucleotide polymorphism). Polymorphisms such as this also predict susceptibility to cerebral vasospasm following brain aneurysm rupture (

see Key References). Note that such studies will need to be confirmed by other groups before becoming a benchmark for clinical-genetic screening.

The precise mechanism underlying cerebral vasospasm is not known. What is known, however, is that the cascade of events leading to abnormal constriction of the artery (see Figure 2, below) begins with oxyhemoglobin, a breakdown product of red blood cells. Oxyhemoglobin, derived from the blood clot now present in the SAS following, e.g., rupture of an aneurysm, leads to the generation of so-called "reactive oxygen species" (ROS; akin to "oxygen-derived free-radicals") such as superoxide (O₂.). These toxic species damage cells throughout the neighboring blood vessel wall including endothelial cells, smooth muscle cells, and adventitial fibroblasts and nerve fibers. In so doing, the artery's "vasomotor function" (i.e., normal relaxation-contraction cycling) is considerably disturbed, and it reacts by shutting down or contracting in an abnormal manner. This represents the functional component of cerebral vasospasm, and it is triggered by oxyhemoglobin. There is a known association between the severity of the hemorrhage (i.e., related to the amount of oxyhemoglobin which ends up accumulating in the clot), and the occurrence and severity of cerebral vasospasm.

The functional component of vasospasm really amounts to loss of the artery's natural relaxation mechanisms, and a now exaggerated contraction mechanism. At a molecular level, relaxation and contraction are governed by different but inter-related "mediators" or "agents"(

see a list of relevant articles in the Key References section). It therefore follows that the molecular basis of cerebral vasospasm is closely related to impairments in the function of these mediators, or the "signaling systems" which they comprise. Key mediators which have been implicated in the functional component of cerebral vasospasm include the vasodilators nitric oxide (NO) and prostacyclin (PGI₂) which become underactive, and the vasoconstrictors endothelin-1 (ET-1) and thromboxane A₂ (TXA₂) which become overactive. Potassium channels are also thought to play an important role, as is the enzyme heme oxygenase [

see articles in the Key References section].

There is also a structural component to cerebral vasospasm. This takes the form of an inflammatory reaction in the vessel wall. In addition to the destruction of the vessel wall cells [especially the endothelial cells and adventitial nerve fibers which normally play a key role in relaxing the artery (i.e., in vasodilatation)], the vessel wall is invaded by white blood cells ("white cell infiltration"), while the smooth muscle layer can actually become thickened ("myoproliferation") and the adventitial and smooth muscle layers can even become more stiff or fibrotic ("fibrosis"). These changes, in addition to the functional changes described above, serve to maintain cerebral vasospasm in the longer term [

see articles in the Key References section].

Figure 2 illustrates the basic mechanism underlying cerebral vasospasm. A section of the artery wall is shown, similar to the cross-section seen elsewhere (

take me to Brain Artery Structure right now). Say the part of the wall shown above represents the wall of a brain aneurysm that has just ruptured. Blood (shown in red-brown) now gushes from its normal compartment in the lumen of the blood vessel through the ruptured wall (see 1 in the figure) and into the space surrounding the brain artery known as the subarachnoid space. Here it forms a clot (2) which contains a lot of red blood cells and, eventually, their breakdown products. A key breakdown product is oxyhemoglobin, and when it forms, it generates free radicals (curved black arrows originating from 2) which damage cells in all layers of the blood vessel wall, including the endothelium (3), smooth muscle (4), and adventitia. In the adventitia, fibroblasts (5) and nerve fibers (6) are damaged. A brisk inflammatory reaction follows. Overall, the blood vessel overcontracts, its lumen shuts down, and local blood flow is impaired. This entire process culminates in cerebral vasospasm.

The essential problem with vasospasm is that it causes an artery to shut down. Since a brain artery's function is to transport blood (and all its nutrients) to a specific part of the brain, then it follows that vasospasm leads to loss of the ability of the artery to carry out its normal function. As a result, the part of the brain formerly supplied by that artery effectively starves (ischemia) and may die ("infarction" or "stroke"). As mentioned above, although cerebral vasospasm is a transient (or temporary) phenomenon, which occurs clinically in about one-third of all aneurysm patients, it may cause irreversible brain damage, including death. Overall, cerebral vasospasm accounts for approximately 20% of the severe disability and death associated with ruptured aneurysms. Aneurysmal rebleeding is the most dreaded complication in patients surviving a ruptured aneurysm (

take me to Aneurysmal Rebleeding right now) but the next most feared complication is vasospasm.

The symptoms (what a patient describes) and signs (what a physician observes on physical examination) of cerebral vasospasm are listed in the table below. They are listed in the order of least threatening to most threatening. Note that dysphasia refers to impaired language comprehension and communication (including speech) while hemiplegia refers to profound weakness down one side of the body. A classic picture of a "stroke" may involve one or more of the features below, and is usually a most severe event.

These symptoms and signs may "wax and wane" (i.e., come and go with different degrees of severity) for days. Their onset is usually at a time point at least 3 days after the bleed. They last up to 3 weeks.

Vasospasm can be detected by the signs observed on physical examination of the patient (see 5., above) and by radiological methods such as cerebral angiography, and transcranial Doppler (TCD) ultrasound.

The gold standard (i.e., best) radiological method for detecting vasospasm is cerebral angiography. Basically, this involves injection of an opaque dye into the blood stream of a patient; the dye eventually reaches the brain circulation, and X-rays are taken at this point. The dye is "radio-opaque" in that X-rays don't pass as easily through it as they do through neighboring brain tissue, so the dye stands out. This way, a road-map of the brain circulation is obtained, telling a physician about the state of the arteries in terms of their course, their pattern of communication, their diameters and lengths, and any other abnormalities. Vasospastic arteries on a cerebral angiogram appear to have abnormally thin columns of blood in their lumens, almost string-like in their width.

A brain CAT scan in a patient suspected of having vasospasm may show new strokes in the distribution of the vasospastic artery or arteries.

An MRI of the brain (especially in its Diffusion Weighted Image, DWI, and FLAIR sequences) may more precisely show the extent of brain tissue damaged (infarcted) by vasospasm. Vasospasm in larger vessels may also be seen using magnetic resonance angiography (MRA), but at present cerebral angiography is a more reliable tool for this.

TCD is a bedside test that relies on ultrasound waves generated from a probe placed on the skin of the head and/or neck region to detect the flow of blood in a cerebral artery. It is a convenient, safe, and frequently effective method that can be used to rapidly confirm the clinical findings, and is certainly much less "invasive" than cerebral angiography. It has numerous technical limitations, however, and the information gleaned from TCD is typically not of the same caliber as that derived from angiography. Nonetheless, we use it regularly to follow ruptured aneurysm patients for the development and progression of spasm.

Over the last 40 years, there has been an array of "silver bullets" proposed to be the "cure" (or definitive treatment) for cerebral vasospasm. Unfortunately, however, to this day, the cure remains elusive. This is most likely because we do not as yet know the precise cause of cerebral vasospasm at a molecular level.

At present, two very important aspects of medical management of a patient at risk of, or suffering, from vasospasm are: (1) commence Nimodipine early; and (2) adhere where possible to the principles of hyperdynamic (HHH) therapy.

Nimodipine is a calcium channel blocker; it dilates or relaxes arteries by blocking the entry of calcium ions into vascular smooth muscle cells (Ca²⁺ entry normally stimulates their contraction). It may also be neuroprotective, i.e., offering direct protection to brain neurons.
HHH therapy stands for hypervolemic-hypertensive-hemodilution therapy; basically this means keep the fluids (and therefore blood pressure or, more correctly, the mean arterial pressure) of a vasospasm patient up, and the concentration (or viscosity) of the patient's blood down. Together, this pattern of blood properties (i.e., this rheologic and hemodynamic profile) is associated with improved brain blood flow. This form of therapy, however, is not without risks, particularly if the patient's aneurysm has not been surgically clipped or endovascularly coiled, in which case HHH therapy can increase the risk of aneurysmal rebleeding.

Other methods used to emergently dilate or relax a vasospastic artery are based on using a catheter either to deliver a strong vasodilating agent (e.g., phosphodiesterase inhibitor papaverine, or the calcium channel blockers nimodipine, nicardipine and verapamil, via selective INTRA-ARTERIAL infusion) directly into the territory of the vasospastic artery in order to "pharmacologically dilate" it, or to physically wedge a balloon-tip catheter in the vasospastic artery itself and use the balloon (expanded from the catheter-tip) to "mechanically dilate" the artery - a technique referred to as mechanical angioplasty. Papaverine therapy often works, but its effects are very short-lived. Mechanical angioplasty also works, but the artery can rupture during angioplasty, and normal arterial function is never really restored. Catheter-based techniques are reserved for severe vasospasm emergencies and for optimal results require an experienced interventional neuroradiologist or endovascular neurosurgeon.

Surgically, perhaps the most helpful thing to do to prevent vasospasm is to clip the aneurysm early and remove as much of the subarachnoid blood products as possible (since these are known to trigger vasospasm). That is, thorough cisternal irrigation intraoperatively. However, excessive mechanical manipulation of blood vessels intraoperatively can increase their risk of going into spasm. The author also believes in aggressive CSF blood clearance using an external ventricular drain (EVD) (and/or a lumbar drain) in patients with high Fisher grade SAH (i.e., lots of hemorrhage).

On an experimental front, gene therapy is being explored as a potential treatment option for cerebral vasospasm. Here, an engineered vector carrying the gene for nitric oxide synthase (which produces the strong vasodilator molecule, nitric oxide), is delivered into a vasospastic territory, with the intention being to dilate the artery by causing the local overproduction of nitric oxide (

take me to Gene Therapy right now; for further information, see the Key References section). Another method is to directly infuse lots of nitric oxide-containing solution (i.e., a liquid nitric oxide donor compound) into brain circulation either via the traditional intravascular approach, or via the perivascular (adventitial) approach. These experimental procedures are still being evaluated, but appear promising.

It is expected that once we know the precise cause of vasospasm, the most appropriate therapy will also then be known. In the meantime, careful monitoring, oral Nimodipine and HHH therapy (with selective intraarterial infusions and/or mechanical angioplasty as last resorts) are the best we can do.