The initial issue is outcome assessment. Since 1938, when Dr. Walter Dandy clipped the first intracranial aneurysm (1), surgical and endovascular treatment has advanced dramatically because of the contributions of many neurosurgeons, such as the “giants” like Drs. G. Yasargil, V. Serbinienko, and G. Guglielmi, combined with the advances of technology (2). Nevertheless, since that time, intracranial aneurysm repair was, in the majority of cases, a lifesaving procedure. As a result, the goal of such treatment focused on assessing the patients’ physical well-being (Hunt and Hess, WFNS, Fisher, GOS; Tables 1–4) but not on their postoperative health, which the World Health Organization defined as “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.”

The mortality and morbidity related to treating intracranial aneurysms have declined significantly, establishing clipping and coiling as the standards of treatment (6). But a method of outcome assessment, e.g., the GOS, has remained the same for decades, despite a growing body of evidence that assessing patients’ mobility, speech, cranial nerves, short- and long-term memory, and/or sensory deficits (7) is inadequate for properly assessing the disease and its treatment impact on the patients’ fate (8, 9). Furthermore, the widely publicized advances of functional MRI and PET research focused on behavioral changes have brought an end to the myth of the “silent areas in the brain.” During the last 10 years, numerous studies have revealed that the brain regions regarded as “clinically silent” are not really silent. Nondominant hemisphere structures of the frontal, temporal lobes, and temporo-parietal junction and subcortical structures, such as the amygdala, striatum, etc., have been shown to regulate our social, moral, religious, and even political behaviors (10–12). These and other earlier observation of behavioral changes (13) after aneurysm treatment raised the question whether the GOS and the Quality Of Life (QOL) scale are proper tools to assess the outcome after this treatment. It becomes obvious that it is time to reevaluate these outcome measures and to develop more adequate tools allowing proper assessment consequences of both the surgical and endovascular treatments and vasospasm. This should facilitate a more accurate outcome prediction and allow for early intervention to prevent a poor outcome such as that of Ms. CD.

The second issue is that pathomechanisms that were responsible for such a dramatic difference in the outcome of these two relatively uncomplicated, successfully treated aneurysms remained undefined. For many years following the publication of the seminal paper by Weir (14), delayed cerebral vasospasm was recognized as “a single, more important cause of clinical deterioration and poor outcome after aneurismal SAH (aSAH) and successful treatment of intracranial aneurysm” (6, 15, 16). However, recently, there has been increased interest in other possible mechanisms that may contribute to the unsatisfactory results of the intracranial aneurysm treatment (17, 18). But, the question of what is the impact of initial rupture and subarachnoid clot formation on short- and long-term behavioral outcome remains unanswered. Also, it is still unclear how behavioral outcome is affected by surgery or endovascular treatment, whether there is a difference in the outcome between the patients who do or do not suffer SAH with or without ­vasospasm, as well as how the behavioral outcome is affected by development of postoperative delayed ischemic neurological deficits (DINDs) with or without coexisting vasospasm.

There are many mechanisms of brain injury that are unleashed by rupture of an intracranial aneurysm with violent high-pressure flow of highly oxygenated blood and formation of a blood clot in the subarachnoid space. Acutely, it is a dramatic increase of intracranial pressure (ICP) with a decrease of cerebral perfusion pressure (CPP) (19), with the possibility of developing acute hydrocephalus, intracerebral and intraventricular bleeding, “no-flow phenomenon,” as well as just recently confirmed development of early vasospasm (20). Subacutely, other insults to the brain occur as the result of different factors released locally from the blood, plasma, and clot, as well as the early inflammatory reaction, “no-reflow phenomenon,” electrolyte, and/or hormonal imbalance (e.g., the salt waste syndrome) (6, 21). The next aSAH-associated events occur in a delayed fashion (days 3–14) and these include delayed cerebral vasospasm (14, 22) and, for a long time considered being closely linked to it, clinical vasospasm (also referred to as DIND) (14). But, the findings of several recent studies revitalized interest in events other than vasospasm aSAH-related mechanisms (17, 18, 23) that can result in DINDs. Recently, this concept gained considerable interest after Dreier et al. (24, 25) proposed a new pathomechanism leading to DIND that does not require the presence of delayed cerebral vasospasm. These so-called spreading cortical ischemias (CSIs) that develop in the presence of blood in the subarachnoid space and decreased local availability of nitric oxide (NO) have recently been confirmed to exist in a patient after aSAH and are associated with clinical deterioration and the presence of CT-confirmed cortical infarctions (24–26). The chronic (occurring after more than 2 weeks after aSAH) reasons for clinical ­deterioration are hydrocephalus and emotional distress and/or depression. Of course, surgical trauma and blood flow changes evoked by the endovascular intervention add yet another insult due to decreased cerebral blood flow during cerebral arteriography (27) as well as an aneurysm repair both surgically or endovascularly (6, 13). However, the list of events that can affect the neurobehavioral outcome of aSAH and its treatments does not end here. The adjunct treatments of aSAH, such as CSF diversion via ventriculostomy, lumbar drainage or ventriculo-peritoneal shunt placement, administration of nimodipine, or triple H-therapy (28–31), may also impact neurobehavioral outcome.

There are also other issues that can influence outcome of the treatment, the neurobehavioral effects of which remain unknown. For instance, during the last 20 years, there has been increased success of treatment of aneurysms by endovascular therapies that lead to a decreased incidence of vasospasm. But most importantly, there is a significant increase of an incidental diagnosis of unruptured aneurysms, like in the case of AB (32–34), because of genetic studies as well as increased accessibility of CT/MRI. In the USA, even the slightest suspicion of intracranial disease leads to CT/MRI due to increased vigilance and awareness of symptoms of stroke after the successful “Brain is time” and “Decade of the brain” initiatives. This medically justifiable proactive attitude has significantly increased the number of patients whose aneurysms are treated before they rupture (34, 35). All these new developments have built new expectations from patients, their families, referring physicians, and rehabilitation therapist, especially with regard to outcome. Thus, it is clear that it is insufficient to assess only the patient after aneurysm repair by the GOS or even QOL scales. Patients and their families expect the patients’ posttreatment status to be adequately compared to “a state of complete physical, mental, and social well-being.” These expectations are shared also by the health providers building up a peer pressure to provide the outcome information addressing not only physical, but also social, behavioral, and economical aspects of life (6, 13).

Recent studies of neurobehavioralists and researchers, such as Hutter et al. (36), have brought the problem of neuropsychological consequences of aSAH to the forefront (9, 13, 37). Several studies have addressed (Table 5) this issue; nevertheless, no comprehensive and reliable conclusions can be drawn about the impact of acute, delayed, or chronic changes evoked by aSAH on neurobehavior.

Furthermore, most of these studies were focused on the presence of delayed vasospasm and its influence on neurobehavioral outcome (38, 40–43). They showed that 30–50% of all patients after aSAH suffer cognitive deficits, especially when tested for attention and memory (44), thus confirming a significant unfavorable effect of severe delayed cerebral vasospasm. But even the relatively simple issue of memory deficits in the setting of arteriographically confirmed delayed vasospasm after aSAH remains controversial because others (8, 39, 45) have not confirmed this observation. Of course, and it is not a surprise, there is no information about how early damage to the brain or endovascular and surgical aneurysm repair can affect neurobehavior. Nevertheless, as mentioned above, several factors beyond vasospasm have also been linked to the neurobehavioral deficits (Table 6).

There are several important conclusions emerging from these studies: (1) neuropsychological results predict the patient’s ability to resume work (47) and (2) the time frame of functional recovery remains unclear (44). Other important findings were (3) a significant discrepancy between a GOS 5 and poor neuropsychological results and (4) a lack of difference in the extent of neurobehavioral deficits between patients operated for aSAH and those with aSAH but without surgery (44). Furthermore, the International Study of Unruptured Aneurysms revealed that patients do better when operated upon before the aneurysm ruptures producing aSAH (49). These findings demonstrate the influence of early versus late aSAH-related events on outcome (17, 18, 20). Practical consequences of all these findings are difficult to overestimate. The patient whose clinical status was assessed at GOS 5 after aSAH and aneurysm treatment may still need significant neuropsychological diagnostics and rehabilitation. Thus, there is no doubt that establishing the cause and pathophysiology of reported neurobehavioral changes should facilitate the diagnostics and treatment options for aSAH. A properly designed experimental model could provide in-depth insight into causes, pathophysiology, and pathomechanisms of these deficits, thereby providing a tool to develop targeted treatments and rehabilitation.

For many years, we have developed excellent experimental models of SAH, but all were focused on studying the development, presence, and effects of delayed cerebral vasospasm (50). The focus was so narrow because these models were also supposed to address “vasospastic syndrome,” also known as “delayed cerebral dysfunction” (51) or DIND, since it was evoked by the presence of cerebral vasospasm (14). Recently, this dogma has been questioned and slowly abandoned (17, 18, 20). The new research approaches have refocused on the neurobehavioral changes evoked by aSAH acutely because of the severity of the initial SAH or the delayed development due to the prolonged presence of blood clot(s) on the surface of the brain. Both the acute and delayed mechanisms are at least as important as vasospasm and its neurological consequences in assessing the effects of treatment for intracranial aneurysms. Nevertheless, none of the models addresses the influence of these events on neurobehavior because all were developed to study delayed cerebral vasospasm (52).