Cerebral vasospasm

Author: Danilo Ravazza
Date: 01/04/2012



“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 fig. 1). 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. 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, 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 (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, 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 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:

  • Subangiographic vasospasm is the type that cannot be detected by the "gold standard" imaging method for vasospasm detection known as cerebral angiography. 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. 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), or to differences in the "road-maps" of their brain circulation (presence of 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.

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 (in the subarachnoid space (SAS) surrounding brain arteries) 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 or up to 14 days later. 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.

Genetic predisposition to develop cerebral vasospasm

For a long time it has been known that the amount of blood seen on a TC scan after a bleed from a brain aneurysm (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. 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 genetic polymorphisms. Researchers from Japan first identified a link between polymorphic eNOS and susceptibility 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. Note that such studies will need to be groups before becoming a benchmark for clinical-genetic screening.

Mechanism of Cerebral Vasospasm at molecular level

Growing factors are secreted polypeptides that regulate the growth of normal and pathological cells. Today the family of EGF growing factors consists of seven members, including the Heparin Binding EGF-like factor (HB-EGF). A feature of the EGF family is the presence of six-spaced residues of cysteines in the EGF domain. The six residues of cysteines create three disulfide bonds that allow the formation of a secondary structure, required for the biological activity of polypeptides.
The mRNA of HB-EGF is commonly expressed in many mammals tissues. The HB-EGF is synthesized in form of a forerunner; it contains an EGF-like domain binding heparin. The HB-EGF exists in forms from 19 to 23 kD, this is due to different N-terminal cleavage and in different glycosylation during processing. The HB-EGF is O-glycosylated and different from EGF has no site of N-linked glycosylation. The HB-EGF has two families of receptors, the EGF receptor and HER4 receptor.
Oxyhemoglobin and HB-EGF are booth protagonists in a process bringing to the suppression of voltage dependent potassium channels. The majority of voltage dependent channels open after a membrane depolarization. They are a very important group, membrane excitability is based on their functions.The suppression of KV channels is a multiphase process with both activators and inhibitors elements.
The oxyhemoglobin activate a metalloprotease (MMP9/ADAM) which protealised a membrane protein called proHB-EGF. This metalloprotease is inhibited by GM6001;
HB-EGF now active, binds and activates it’s receptor, the transmembrane tyrosine kinase protein EGFR. HB-EGF is inactivated by heparine and CRM 197.
The tyrosine kinase intrinsec activity of EGFR bring to inclusion of Kv channels in membrane of endocitotic vesicles, breaking out the suppression of those activity.


The reduction of presence of Kv channels on membrane brings to the alteration of natural membrane potential in muscolar cells, that induces an increase of Ca++ passage through Cav channels that breaks out to cellular contraction, the result is a reduction of vascular caliber (vasospasm).
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), 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. These changes, in addition to the functional changes described above, serve to maintain cerebral vasospasm in the longer term.

This figure illustrates the basic mechanism underlying cerebral vasospasm. 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.


A classic picture of a "stroke" may involve one or more of the features below, and is usually a most severe event.
Symptoms include: fever, neck stiffness, mild confusion, dysphagia, hemiplegia, and severely impaired consciousness. Symptoms may be specific for the artery territory interested. For example if vasospasm concern to medium cerebral artery or his branches, we will have contralateral hemiparesis, dysphagia, anosognosia, aprattognosia. Nevertheless even high-grade vasospasm could not bring to ischemia if a collateral circulation is present.These symptoms and signs may "wax and wane" (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.

Detection of cerebral vasospasm

Vasospasm can be detected by the signs observed on physical examination of the patient and by radiological methods such as cerebral angiography, and transcranial Doppler (TCD) ultrasound.
The gold standard radiological method for detecting vasospasm is cerebral angiography.
A brain TC 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 may more precisely show the extent of brain tissue damaged
TCD 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.
The localization and the extension of blood in the basal cisterns and in fissures in subarachnoid space is detected with TC to prevalence, localization, and importance of vasospasm. The incidence is particularly high in subject with a detected subarachnoid mass sized 5×3 mm in basal cisterns, or thicker than 1 mm in fissures. Vasospasm is less prevertable in posterior cerebral arteries.


Unfortunately, the cure remains elusive. At present, two very important aspects of medical management of a patient at risk of, or suffering, from vasospasm are.

  • Nimodipine is a calcium channel blocker; it dilates or relaxes arteries by blocking the entry of calcium ions into vascular smooth muscle cells.
  • HHH therapy stands for hypervolemic-hypertensive-hemodilution therapy; basically this means keep the fluids of a vasospasm patient up, and the concentration (or viscosity) of the patient's blood down. Remembering that the flux (F) is equal to blood pressure (P) divided by resistance it’s possible increase the flux through a vessel with a restrict caliber by changing blood pressure, increasing blood volume, or by lowing resinstence reducing blood density. Together, this pattern of blood properties (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 (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.


A Video clipping of a middle cerebral artery aneurysm


  • "HB-EGF mediates OxyHb-induced KV suppression". Masayo Koide, Paul L. Penar, Bruce I.Tranmer and George C. Wellman
  • Early brain injury or cerebral Vasospasm Di Ying Mao,John H. Zhang
  • "Harrison's Principles of Internal Medicine" Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.
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