Intracranial Aneurysms

Intracranial aneurysms are not rare, with an overall prevalence of around 3% of the population, which means that there are around 15 million people in the European Union who have an intracranial aneurysm [1]. Most of these aneurysms are very small (Box 13.1), with inherent very small risk of rupture if found incidentally [2]. Also, two-thirds of the unruptured aneurysms are located at the middle cerebral or internal carotid arteries, which are the sites with the lowest risk of rupture [2]. Risk factors for aneurysms can be divided into environmental and non-modifiable factors. Women have a slightly higher risk, which is more pronounced after the sixth decade [1]. The most important modifiable risk factors for intracranial aneurysms are smoking and hypertension [3]. The risk in persons who smoke and have hypertension is higher than the sum of each of these risks separately, which suggests an additive effect [3]. Physical exercise seems to lower the risk. Data for hypercholesterolemia are conflicting, with some studies showing an increased prevalence for aneurysms [4], and others not [5]. Intracranial aneurysms are not present during life, and are extremely rare in the first two decades of life, but after the third decade of life the prevalence is comparable between the different age strata [1]. The prevalence is particularly high in patients with autosomal dominant polycystic kidney disease and persons with a positive family history of intracranial aneurysm or ASAH. Intracranial aneurysms have also been linked to connective tissue disorders such as Ehlers-Danlos disease type IV, Marfan syndrome, or neurofibromatosis, but good data supporting these associations are lacking [6]. For Marfan syndrome two older cohort studies did not find an increased prevalence of intracranial aneurysms or ASAH [7, 8], and for neurofibromatosis a recent population-based study from East Finland provides good evidence against an association [9].

Aneurysmal Subarachnoid Hemorrhage

Compared to other stroke types, ASAH occurs at an earlier age, with a mean age of onset of around 55 years [10]. The incidence of ASAH has declined slightly over the last decades, and overall the incidence is now around 9 per 100 000 patient-years [10]. There are, however, striking regional differences in the incidence of ASAH, with incidences ranging from around 20 per 100 000 patient-years in Finland and Japan to around 4 in Central and South America. The incidence is higher in women, but this difference between sexes starts only in the sixth decade, and increases thereafter [10]. The reason for this higher incidence in women is unknown [11]. Obviously, risk factors for aneurysms and those for ASAH show overlap. Smoking and hypertension are established risk factors for ASAH [12]; the case for hypercholesterolemia is less certain [13].

In population-based studies, case fatality rates have decreased by 17% over the last three decades [14], which is an impressive reduction because one per six to eight patients with ASAH die before reaching the hospital and therefore cannot be salvaged [15, 16]. Despite this improved case fatality, still around one-third of patients die within the first month after the hemorrhage [14].

Because of the young age and poor outcome, the economic and disease burden of ASAH is considerable. The loss of productive life years from ASAH is as large as that from ischemic stroke [17], and the total economic burden in the UK has been estimated to be more than £500 million per year [18].

Symptoms and Signs

Almost all patients with ASAH complain of the most severe headache ever; the rare exceptions being patients who lose consciousness before being able to complain of headache and who die without regaining consciousness, or patients who are in a confusional or agitated state [21]. Such patients may have aggressive behavior, with kicking, spitting, yelling, or screaming, making a proper history-taking impossible. The hallmark of the headache in patients with ASAH is, however, not the severity, but the speed at which it develops. Although textbooks usually describe the onset in a split second, such an onset is reported by only half the patients. The other half gives a history of onset in a few seconds, or even a few minutes, but no more than 5 [22]. How long headache lasts in subarachnoid hemorrhage is not exactly known. In a series of more than 100 patients who were and remained conscious during the initial 48 hours, the shortest period wherein headache had disappeared was 10 hours [23], but we have one patient on record with a ruptured aneurysm of the posterior communicating artery who was reading Dostojewski, without complaining of headache, already 6 hours after the ASAH.

Loss of consciousness occurs in around half the patients with ASAH at the time of aneurysmal rupture or shortly thereafter [24], 5–10% have a seizure at onset [25, 26], and one-third report transient focal deficits, usually lasting only a few minutes [22]. These transient focal deficits are probably caused by transient ischemia from acute vasoconstriction after aneurysmal rupture.

Aneurysmal rupture can occur when patients are in complete rest, but established trigger factors for aneurysmal rupture are coffee and cola consumption, anger, startling, straining for defecation, sexual intercourse, nose blowing, and vigorous physical exercise [27]. These triggers have in common that they induce a sudden and short increase in blood pressure, which seems a possible common cause for aneurysmal rupture. This does not mean, however, that patients with unruptured aneurysms that are not occluded should be advised to refrain from such activities. Let alone the chance that patients with unruptured aneurysm will follow advice to, for example, refrain from sexual intercourse, such advice would not decrease the risk of rupture to a meaningful extent: it has been estimated that patients with a small aneurysm that is not occluded need to avoid 1.3 million episodes of sexual intercourse (that is, 20 000 years of sexual activity) to avoid one episode of subarachnoid hemorrhage [28].

On admission, almost all patients with ASAH have a high blood pressure, but often this is a reactive phenomenon caused by the raised intracranial pressure and pain, and usually the blood pressure returns to normal within a few days.

Neck stiffness is a well-known finding in patients with SAH, but it may take several hours to develop. In a series of patients with a clinical suspicion of SAH, a normal level of consciousness, and no focal neurologic deficits, absence of neck stiffness at neurological examination performed within 6 hours after headache onset had a negative predictive value of 69%, but for patients admitted and examined between 6 and 72 hours after headache onset, negative predictive value was 91% [29].

Intraocular hemorrhages (Terson’s syndrome), in one or both eyes, are often overlooked, but occur in approximately one of every five to six patients with ASAH [30, 31]. These hemorrhages give rise to disabling scotomas, and if there is no spontaneous recovery after the initial months, vitrectomy is indicated and results in good recovery [31]. In most instances there in no need to perform vitrectomy in the acute phase; the exception may be patients with bilateral vitreous hemorrhages [32]. The most common cranial nerve deficit in patients with ASAH is a third nerve deficit, usually with a dilated and non-reactive pupil. It is usually caused by rupture of an aneurysm at the origin of the posterior communicating artery, but can also be caused by rupture of a large aneurysm of the basilar artery, or even the superior cerebellar artery. Non-reactive pupils can also occur in Parinaud’s syndrome caused by acute hydrocephalus. In Parinaud’s syndrome, the pupils are, however, small, and patients have impaired consciousness and vertical eye movements, although the last sign often is difficult to assess. Sixth nerve palsy usually occurs during the clinical course, but can be present from the outset.

One of six patients with ASAH has focal signs on admission, usually from an intraparenchymal extension of the hemorrhage from an aneurysm at the middle cerebral artery or at the anterior communicating artery.

Ancillary Investigations for Diagnosing Subarachnoid Hemorrhage

For decades, the diagnosis of SAH has rested on computed tomography (CT) scans, and if CT was negative on lumbar puncture to assess bilirubin or other blood degradation products. The reason for doing a lumbar puncture is that CT can be false negative, and not making the diagnosis puts the patient with a ruptured aneurysm at a high risk of rebleeding in the initial hours to days after the hemorrhage. For patients presenting in the initial hours after the onset of headache, lumbar puncture had to be postponed if the CT scan was negative, because it takes 6–12 hours before blood degradation products are formed and can be detected in the cerebrospinal fluid (CSF). To investigate whether nowadays examination of the CSF is still needed, a large collaborative Canadian study group assessed the negative predictive value of CT scans in patients presenting at an emergency department of university-affiliated, tertiary care teaching hospitals with acute onset of severe headache within the last 2 weeks. In this study, the overall sensitivity of CT was 92.9% (95% confidence interval [CI] 89.0–95.5%), and for patients with CT scan done <6 hours after onset of the headache the negative predictive value of CT was 100% (95% CI 99.5–100%), if CT was interpreted by a neuroradiologist or general radiologist who routinely reports head CT images [33]. This study clearly showed the importance of the reader of the CT scan, because some instances of SAH were missed when the CT scans were interpreted by residents or non-radiologists. To assess the generalizability of these results to general hospitals, to where most patients with acute headache go, a large Dutch multicenter study group reviewed a consecutive series of 760 patients with CT performed within 6 hours after onset of headache and read by staff radiologists in 11 non-academic hospitals. CT scans of patients with a positive lumbar puncture were re-read by two neuroradiologists and one stroke neurologist from two academic tertiary care centers independently from each other. The negative predictive value in this study was very high and, accordingly, the number of patients needed to be punctured to prevent missing the diagnosis in one patient with ASAH was extremely high: 15 200 patients presenting within 6 hours with acute headache and a negative CT scan have to undergo examination of the CSF to prevent missing ASAH in one of them [34]. In contrast to the negligible yield of CSF examination in patients who present early after the onset of headache, the yield is considerable in patients who present more than 3 days after headache onset. In a series of 30 patients with sudden headache, with a negative CT scan but positive CSF examination (defined as detection of bilirubin >0.05 at wavelength 458 nm), half the patients who presented between 4 and 10 days after headache onset had an aneurysm [35].

In clinical practice, we therefore refrain from lumbar puncture in patients with acute, severe headache who present within 6 hours after onset and have a negative CT. If such patients present in the evening or early night, we admit them, re-examine them the next morning, and review the CT scan. In our experience, the history the next morning is often less alarming, with less acute onset of headache. If the clinical examination is normal (no fever or neck stiffness, and normal consciousness) and CT indeed negative, we discharge patients without further lumbar puncture. Since the negative predictive value of MR imaging for ruling out SAH in case of a negative CT is unknown, we do not routinely proceed to MR in such patients. We also do not advocate to proceeding with CT angiography or MR angiography in case of a negative CT scan. Because 3% of the population has an intracranial aneurysm, one may run into the problem of finding an intracranial aneurysm in a patient with acute headache and a negative CT scan. In such instances, it is unknown whether the aneurysm is an incidental finding, or the cause of a not yet detected SAH. Thus, it is pivotal to first making the diagnosis of SAH, and only if this is established to proceed for looking for the cause of the SAH.

Ancillary Investigations for Diagnosing Aneurysms

If a CT scan shows blood in the basal cisterns, the next step is to find its cause. Since a ruptured aneurysm is by far the most common cause of SAH and has a high risk of rebleeding, this means that an aneurysm should be ruled in (or out) as soon as possible. CT angiography is a sensible first-line investigation in this respect [36, 37]. CT angiography can usually be made immediately after the CT has demonstrated subarachnoid blood, and has a high sensitivity and specificity [36]. Moreover, CT angiography can visualize the configuration of the aneurysm and surrounding vessels properly [38, 39], which is helpful in the decision as to whether the aneurysm can be clipped or coiled. If CT angiography is negative, it is pivotal to assess the pattern of hemorrhage on CT. If the pattern is a typical perimesencephalic one (Figure 13.1), and the CT angiogram is of good quality, according to several decision analyses based on all available literature, no further vascular imaging is needed [40–43]. In patients with an aneurysmal pattern of hemorrhage but a negative CT angiogram, a catheter angiography has additional value in detecting aneurysms, and should be considered in all such patients who are eligible for aneurysm occlusion [44–47]. If even this catheter angiography is negative, repeated imaging 1 week later still can find an aneurysm in up to 5% of patients according to two single-center studies [44, 48]. A repeated CT angiography several weeks after a negative CT angiogram and negative catheter angiogram detected a vascular lesion (one aneurysm and one small AVM) in 2 out of 25 patients (8%) in a single-center study using a standardized diagnostic approach [49].

Figure 13.1 Typical perimesencephalic pattern of hemorrhage.

Our current approach in patients with an aneurysmal pattern of hemorrhage and a negative CT angiogram is to repeat the CT angiography after 1 or 2 days, and if still negative after 2 weeks and 3 months. We reserve catheter angiography mostly for patients with focal accumulation of blood (e.g. in the Sylvian or anterior interhemispheric fissure). The local protocols depend, however, on the quality and experience with CT angiography.

Initial Assessment

The neurological condition should preferably be assessed according to a scoring system based on the Glasgow Coma Scale. The advantage of such scales over the commonly used Hunt and Hess scale is that the items in the Hunt and Hess scale are rather vague. It uses descriptions as “minimal” versus “moderate to severe” headache and “slight nuchal rigidity” versus “nuchal rigidity” to discriminate between grades 1 and 2, and uses terms such as “drowsy,” “stupor,” and “deep coma” for the higher grades. In patients with an impaired level of consciousness on admission it is pivotal to ascertain the cause of the poor outcome. There are several causes for a poor neurological condition, which need separate treatment. A starting point for assessing the cause of the poor neurological condition is careful history-taking, to find out whether the poor condition existed from the outset, or whether there was a secondary deterioration after the onset of symptoms. In case of a secondary deterioration, one needs to assess whether the secondary deterioration occurred suddenly, or whether there was a gradual decline in level of consciousness. In case of a sudden deterioration an episode of rebleeding (Figure 13.2) is most likely. Even in the era of early aneurysm occlusion, rebleeding still occurs in around 15% of patients with a median time after the initial rupture of 180 minutes [19]. Early rebleeding usually results in loss of consciousness and can even result in loss of all brainstem reflexes. However, even if all brainstem reflexes have been lost shortly after rebleeding, resuscitation should immediately be applied, because a minority of such patients can ultimately have a good outcome. A second diagnosis to consider in patients with a sudden deterioration is an epileptic seizure, but many patients with a loss of consciousness and jerky limb movements have an episode of rebleeding, and not epilepsy. In case of a gradual decline in consciousness over the initial hours after onset, an acute hydrocephalus (Figure 13.3) should be suspected and treated. The clinical hallmark of an acute hydrocephalus is, apart from a decreased level of consciousness, the presence of small, non-reactive pupils and impaired upward gaze with otherwise intact brainstem reflexes (the so-called Parinaud syndrome). CSF drainage can lead to rapid improvement of consciousness. Another cause to consider in patients with a gradually declining consciousness in the initial hours after aneurysmal rupture are cardiopulmonary complications, such as cardiac stunning or pulmonary edema, which often go together. Usually patients with ASAH have a (very) high blood pressure on admission, but cardiac stunning with ventricular failure can result in low blood pressures, necessitating inotropic agents. Pulmonary edema results in dyspnea and cyanosis, and in pink sputum. Thus, in patients in poor clinical condition after ASAH, it is important not only to run to the CT scanner for (repeated) brain imaging, but also to assess blood pressure, pulse rate, blood oxygenation, and to order an X-ray of the lungs (Figure 13.4). If coma exists from the outset, this may be caused by global perfusion failure from high intracranial pressure during the intracranial arterial bleeding, but also by treatable conditions such as large intraventricular hemorrhage (hematocephalus), a subdural hematoma, or an intraparenchymal hematoma. Hematocephalus may be treated with extraventricular drainage combined with fibrinolysis [60, 61]. A subdural hematoma after aneurysmal rupture is associated with intracerebral and intraventricular extension of the hemorrhage, and is an independent risk factor for poor outcome, but still 25% of patients with ASAH and a subdural hematoma achieve a good outcome at 3 months [62]. Thus, even in patients admitted in a poor condition not all may be lost and such patients should immediately be transferred to a tertiary care center as soon as possible.

Figure 13.2 Patient with two episodes of rebleeding within 3 hours after admission from an aneurysm proximal on the middle cerebral artery. The patient was alert on admission (left panel), suddenly lapsed into coma (middle panel), and obeyed commands (right panel). In particular the intracerebral hematoma increased during the subsequent episodes of bleeding.

Figure 13.3 Acute hydrocephalus. A 75-year-old woman who was alert but disoriented on admission (upper panel). Within several hours she gradually deteriorated and lapsed into coma (lower panel).

Figure 13.4 Pulmonary edema. A 31-year-old man who presented with acute headache and short loss of consciousness. Left panel shows X-rays of lungs on admission. Right panel shows repeated X-rays a few hours later when he had developed dyspnea with low oxygen saturation and low blood pressure.

General Management

Patients with ASAH should be treated in tertiary care centers with ample experience of both micro-neurosurgical and endovascular treatment options. A recent North American study showed that even within the group of tertiary care centers the number of patients who are treated per center matters (Table 13.1) [63]. An international study including 8 525 patients from centers in Europe, the USA, and Australia found similar results. Case fatality rates dropped from 10.4% in centers with 40 patients per year or fewer, to 7.0% in centers with 41–70 patients per year, and to 5.4% in centers with more than 70 patients per year, with comparable results after clipping and coiling [64].

After aneurysm occlusion, there is no reason to treat high blood pressures, unless the blood pressure is extreme or in case of end-organ deterioration. “Extreme high blood pressure” is hard to define and should be decided upon on individual basis. It makes a difference whether the patient is young and has no other risk factors than a positive family history, or is over 70 years of age, has a long-lasting history of smoking and hypertension, and has a myocardial infarction in the past medical history.

Although seizures occur in around 10% of patients during the clinical course, there is no indication for prophylactic treatment with anti-epileptic drugs. Besides lack of evidence of improved outcome after prophylactic treatment, this may even lead to worse outcome [65–67].

Many patients with ASAH develop hyponatremia, which is most often caused by so-called “cerebral salt wasting” and associated with high levels of brain natriuretic peptide [68], and not by inappropriate secretion of anti-diuretic hormone. The therapeutic implication is that if hyponatremia occurs, it should not be treated with fluid restriction, because fluid restriction increases the risk of delayed cerebral ischemia.

Management to Prevent or Treat Delayed Cerebral Ischemia

Delayed cerebral ischemia (DCI) is a complication occurring a couple of days after aneurysmal rupture, hence the term “delayed” (Figure 13.5). Depending on the definition used, it occurs in around 20–40% of patients and is an important contributor to poor outcome after ASAH [69]. Most often it starts 4–10 days after the ASAH, with a gradual decline in level of consciousness, combined with focal deficits. The symptoms and signs are initially waxing and waning, may resolve spontaneously, or may progress into multifocal areas of infarction that are not confined to the territory of the artery with the ruptured aneurysm. Traditionally, vasospasm has been linked to DCI and often the term “vasospasm” has been used to describe the clinical syndrome of DCI. For proper understanding of the clinical syndrome, and for the development of new therapies, it is essential to discriminate between DCA and vasospasm. Vasospasm of larger intracranial arteries occurs in the same time frame as DCI – roughly 4–10 days after aneurysmal rupture – but is neither a sufficient nor an essential factor in the development of DCI, because not all patients with vasospasm develop DCI and not all patients with DCI have vasospasm. Moreover, none of the therapies that (aimed to) ameliorate vasospasm, including prophylactic balloon angioplasty [70], results in better clinical outcome, despite improved size of arteries. Thus, new treatment strategies should no longer aim to prevent or treat vasospasm, but to prevent or combat the cerebral ischemia.

Figure 13.5 Delayed cerebral ischemia. The upper row shows the ASAH shortly after admission, when the patient was alert and oriented. Four days after the hemorrhage and clipping of the ruptured middle cerebral artery aneurysm on the left side, she gradually developed dysphasia, a right-sided hemiparesis, and decreased level of consciousness.

The only proven therapy to decrease the risk of DCI and to improve clinical outcome is oral administration of nimodipine [71]. Other extensively studied medical therapies, such as statins, endothelin antagonists, and magnesium sulfate, all failed to improve outcome [72–74]. Another approach for preventing DCI is continuous lumbar drainage, aiming to increase clearance of blood from the CSF, and thereby decreasing the thromboembolic and inflammatory effects of blood degradation products. Several groups have studied this approach, and according to two systematic reviews on the effectiveness of continuous lumbar drainage, this strategy reduces the risk of DCI. However, in only one of the reviews a reduction in poor outcome was found, and both reported a poor methodological quality of the included studies and considerable heterogeneity between the included studies [75, 76].

For patients with DCI, in many centers medical therapy has for decades been employment of hypervolemia, hypertension, and hemodilution – the so-called triple H therapy – without, however, good evidence of effectiveness of this strategy [77]. Apart from lack of evidence for beneficial effects, this therapy can have downsides. In a retrospective study from the Mayo Clinics, hypervolemia was independently associated with poor functional outcome [78]. This negative effect is probably explained by the fact that patients with a “positive fluid balance” have extravasation of intravascular fluids, and are therefore in fact in a hypovolemic state [79]. Similar results were found in a prematurely stopped randomized trial on the effects of induced hypertension. Despite a higher overall mean arterial blood pressure in the intervention arm, cerebral perfusion and clinical outcome were similar in both groups, but the intervention did lead to serious adverse events [80]. For endovascular procedures to overcome vasospasm in patients with DCI there are only uncontrolled series, and therefore lack of evidence of effectiveness.

Our strategy is to start nimodipine immediately and to aim for normovolemia. In patients with DCI we do not induce hypertension or employ vasodilatation.

Related posts:

Chapter 4 – Imaging for Prediction of Functional Outcome and for Assessment of Recovery Chapter 8 – Cardiac Diseases Relevant to Stroke Chapter 12 – Intracerebral Hemorrhage Chapter 19 – Acute Therapies for Stroke Chapter 22 – Management of Acute Ischemic Stroke and its Late Complications Chapter 21 – Intensive Care of Stroke

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