Delayed cerebral ischemia (DCI) is a feared and significant medical complication following aneurysmal subarachnoid hemorrhage (aSAH). It occurs in about 30% of patients surviving the initial hemorrhage, mostly between days 4 and 10 after aSAH. The known clinical symptoms such as decrease in the level of consciousness and focal signs such as aphasia and hemiparesis may be reversible or otherwise progress to cerebral infarction resulting in an unfavorable outcome or even death (1). Clinical deterioration attributable to DCI is a diagnosis after exclusion of other causes (such as infection, hypotension, hyponatremia, and others), and it is especially difficult to diagnose in patients who are comatose or sedated (1, 2). The latter are typically patients with a high grade on the World Federation of Neurosurgical Societies scale (3) (WFNS grade 4–5), which represent approximately 40–70% of the patient population with ruptured aneurysms. In this group of patients, the incidence of DCI is often underestimated (4) and higher when compared to low WFNS grade patients (5). As shown by Rabinstein and colleagues, as independent predictive factors of a very low risk to develop DCI at age 68 years or older, WFNS I–III at presentation and a modified Fisher grade 1–2 were identified, with specificity of 100% and positive predictive value of 100% (5). As mortality for high-grade patients remains high, efforts have been made to improve diagnosis and treatment of DCI-related damage and to identify a patient subgroup who can expect a better outcome (6).

Angiographic vasospasm can be associated with reductions in cerebral perfusion measured with 15O-positron emission tomographic imaging (7). However, regional hypoperfusion and oligemia frequently occurred in territories and patients with no angiographic vasospasm. Furthermore, the development of arterial spasm as diagnosed by angiography or transcranial Doppler (TCD) had no consistent relationship with 3-month outcome (8). Other factors in addition to large-vessel narrowing must contribute to critical reductions in perfusion. So far, because of the common association between clinical deterioration from DCI and angiographic vasospasm, arterial narrowing on angiography and increased blood flow velocities on TCD ultrasound examination are often used as surrogate diagnostic tool (2). This, however, is problematic as the old paradigm of “clinical deterioration due to DCI is equivalent to angiographic vasospasm” has changed in the last years (9). One of the landmarks was the clazosentan-study results (conscious-2), an endothelin-receptor antagonist that effectively resolves angiographic vasospasm, but failed to reduce mortality, DCI-related morbidity, or functional outcome in relation to aSAH (10). Patients with aSAH may have clinical deterioration attributable to DCI in the absence of radiologically confirmed vasospasm (11, 12). This may be the case because angiography is not obtained at the moment of clinical deterioration or because DCI is caused by other factors (2).

Throughout the literature, various means of defining vasospasm are used. To overcome difficulties to diagnose DCI, which is especially relevant in sedated and comatose patients, an excellent summary of possible definitions and their clinical impact, evaluated in 580 aSAH patients, was performed by Frontera and colleagues (8). More recently, to improve comparability of future SAH studies, two different definitions were reformulated by a multidisciplinary research group (2): (1) clinical deterioration caused by DCI and (2) cerebral infarction.

Delayed cerebral ischemia is defined as “the occurrence of focal neurological impairing (such as hemiparesis, aphasia, apraxia, hemianopsia, or neglect) or a decrease of at least two points on the Glasgow Coma Scale [either on the total score or one of its individual components (eye, motor on either side, verbal)]. This should last for at least 1 h, and is not apparent immediately after aneurysm occlusion and cannot be attributed to other causes by means of clinical assessments, cerebral CT or MRI scanning, and appropriate laboratory studies. Nevertheless, the diagnosis of DCI remains fairly subjective.

Cerebral infarction is defined as presence of cerebral infarction on CT or MRI scan of the brain within 6 weeks after SAH, or on the latest CT or MRI scan made before death within 6 weeks, or proven at autopsy, not present on the CT or MR scan between 24 and 48 h after early aneurysm occlusion, and not attributable to other causes (such as clipping or endovascular treatment). Hypodensities on CT imaging resulting from ventricular catheter or intraparenchymal hematoma should not be regarded as cerebral infarctions from DCI.

To remember, cerebral infarction correlates with the territory of angiographic vasospasm in only 25–81% of SAH patients (1, 13). The term “vasospasm” was recommended to be reserved for angiographic arterial narrowing. The occurrence of DCI should be described separately from the results of angiography as not all patients who experience DCI have angiographic vasospasm, and not all patients with angiographic spasm have DCI.

Though knowing that the simple association of radiographic evidence of vasospasm with clinical features of cerebral ischemia does not take into account the different factors that may contribute to DCI, most neurointensivist know a series of cases showing an excellent correlation between an observed clinical deterioration and angiographic narrowing, with deficits easily reversible with an increase of mean arterial blood pressure. In our view, these concern mainly low WFNS grade patients, while in high-WFNS grade patients, the large spectrum of difficult-to-diagnose DCI/infarction is common. The diagnosis of DCI is limited and the diagnosis of cerebral infarction possible only retrospectively once an infarct is found radiographically (8). Obviously, interobserver agreement rate is higher for cerebral infarction and easier to evaluate in high-WFNS grade patients. Nevertheless, a sophisticated evaluation is relevant also in this “difficult to evaluate and treat” patient group, e.g., the clinical course is often complicated by myocardial dysfunction, pneumonia, and acute respiratory distress syndrome secondary to the aneurysm ruptures that further complicate the “vasospasm” treatment and participates in the worst outcome of high WFNS. Some of the factors proceeding to infarction might be reversible if treated. The “infarction diagnosis” reflects an under treatment of ongoing not detected ischemia.

There are a series of worth-to-measure techniques, some of them shortly summarized in the following, aimed to detect “asymptomatic” ischemia in high-WFNS grade patients.

There are other potential mechanisms of primary and secondary brain injury events related to DCI (14), some of them detectable by neuromonitoring techniques. (1)

Intracranial pressure (ICP) and cerebral perfusion pressure (CPP): ICP and CPP monitoring, obviously important components of neurocritical care, are widely used in comatose aSAH patients. ICP is preferentially measured as external ventricular drainage (EVD), while in absence of hydrocephalus/slit ventricles, an ICP probe may be used instead, allowing continuous CPP monitoring. A high ICP (>20 mmHg) is considered as an indirect but unspecific warning sign, is associated with energy failure, high secretion of pro-inflammatory interleukins, and possibly aggravates vasospasm. Optimal CPP is targeted individually depending on several factors (ruptured aneurysm treated and presence of DCI). Since CPP might not be available in all patients, current guidelines (15) recommend (A) maintenance of euvolemia and normal circulating blood volume to prevent DCI (Class I; Level of Evidence B, revised recommendation from previous guidelines); (B) (new recommendation) induction of hypertension for patients with DCI unless blood pressure is elevated at baseline or cardiac status precludes it (Class I; Level of Evidence B); and (C) prophylactic hypervolemia before the development of angiographic spasm is not recommended (Class III; Level of Evidence B).

The finding that prevention of delayed vasospasm does not improve outcome in aSAH patients has brought into focus the influence of early brain injury on outcome of aSAH. A substantial amount of evidence indicates that brain injury begins at the aneurysm rupture, evolves with time, and plays an important role in patients’ outcome. It is postulated that intraparenchymal activation of the immune system after aSAH contributes to secondary brain injury. Intraparenchymal inflammation has been linked to progression of aSAH-induced secondary brain damage (30, 31). More specifically, leukocyte–endothelial cell interactions appear to play a critical role in vasospasm. It is hypothesized that the development of DCI is promoted by these inflammatory processes leading to a decreased immunocompetence and secondarily to infectious complications (32). Putative promising markers to indicate immunosuppression are low HLADR and high interleukin-6 levels (thresholds depending on laboratory).

Another point is the entity of patients “at high risk” presenting with acute focal neurological deficits (AFND) on admission (26). Most, but not all of them, are high-WFNS grade patients; however, presenting early brain damages, such as an intracerebral hemorrhage, edema, and high ICP not related to hydrocephalus. These patients show the most severe immunodepression and highest infection rate of the aSAH population (28, 32).

In conclusion, the use of clear definitions to classify: (1) occurring deficits such as AFND and DCI, (2) pathomechanisms such as CSD, cerebral hypoxia, disturbed cerebral autoregulation, cerebral metabolism, and inflammation alterations, and (3) resulting lesion using precise time windows and assessment techniques will allow to better share experiences on the disease and improve its understanding. Advanced neuromonitoring techniques may offer the neurointensivists complementary tools to better perceive the pathological condition and engage appropriate treatments that would otherwise lead to progressive, clinically not detectable ischemia, infarction, and unfavorable outcome in high-risk SAH population.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.