**3.2 Demographic characteristics**

*Advancement and New Understanding in Brain Injury*

IA and suggested their congenital origin.

the risk of overlooking small aneurysms.

**3. Characteristics of cerebral aneurysms in TSC**

**2. Epidemiology**

**3.1 Case illustration**

the region of the carotid siphon were diagnosed [10].

Cerebral aneurysms, also known as intracranial aneurysms (IA), are usually pouch-like (saccular) or spindle-shaped (fusiform) focal dilations in the wall of major arteries in the circle of Willis [7] that grow and present a certain risk of rupture. To date, arterial wall anomalies in TSC, particularly in aneurysms, were only described in the extracranial vasculature, such as aortic aneurysms or kidney aneurysms that were considered as the result of a congenital defect [8]. The distinct features of IA in these patients have not previously been addressed in the literature. Indeed, there are sporadic cases or small case series that reported the coexistence of

First cases of TSC and IA were reported in 1974. The first patient was a 24-year

Heritable connective tissue disorders such as Marfan syndrome, Ehlers-Danlos Syndrome, Loeys-Dietz syndrome and autosomal dominant polycystic kidney disease (ADPKD) are commonly associated with small saccular aneurysms [10]. Our recent systematic review of the English literature [11] is the first to describe the characteristics of IA in TSC in comparison to the features of IA in healthy adults. Despite the eventuality of a congenital origin in TSC, there are some distinct features that characterize IA in TSC and differentiate them from common nonsyndromal IA. The purpose of this book chapter is to give an overview on the particular demographic, clinical, and radiologic features through a case illustration and discuss the possible natural history of IA in TSC patients. Patient informed consent was obtained.

TSC is a rare condition. It has a birth incidence of 1 per 5800 and an incidence of 1 per 30,000 in the general population [6]. From all cases between 1900 and 2018 that were published in the English literature, only 33 patients with 42 IA were found [11]. But the incidence of IA in TSC might be higher as reported, as no screening trial has been performed yet. Furthermore, according to the recommendations of the 2012 TSC Consensus Conference [12], the MRI at diagnosis and every 1–3 years until the age of 25 years does not involve a special sequence for the vascular system, so-called time-of-flight MR angiography (TOF-MRA). This circumstance increases

A 2.5-year-old child presented with new-onset focal seizures characterized by rightward head deviation and rhythmic movements of the right arm. Seizures were treated with Vigabatrin and were controlled. The child was born at term of 37 weeks gestation to a healthy mother who had an uncomplicated pregnancy. Further evaluation revealed multiple rhabdomyomas on echocardiography, subependymal tubers on cranial MRI leading to the diagnosis of TSC. Additionally, a left cavernous lesion was detected on MRI. A TOF-MRA showed an 8-mm-diameter left cavernous ICA aneurysm. A year later, a control MRI revealed a rapid growth of the aneurysm whose diameter reached 15.5 mm (**Figure 1**). At the age of 14 months, the child

old man who died after a subarachnoid hemorrhage (SAH), and the ruptured aneurysm of the right middle cerebral artery was diagnosed at autopsy [9]. The second patient was a 12-year old girl that presented in 1965 with a sudden blurry vision, and bilateral aneurysms of both internal carotid arteries (ICAs) involving

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The collected series [11] showed a specific demographic pattern. In particular, the male/female ratio was 1.9:1 and 66.7% of the patients were under the age of 18, among them 36.4% were 2 years of age or younger.

### **3.3 Clinical characteristics**

Most IA in patients with TSC were diagnosed incidentally (36.4%) or due to a new onset of a neurological deficit (21.2%). IA were ruptured in only 7.1% of the cases [11].

### **3.4 Radiological characteristics**

The most frequent location of IA was the anterior circulation (85.7%) in favor of the ICA (61.9%), where aneurysms originated remote from branching zones. Of the 42 IA, 57.1% were large (size: 10–24 mm) or giant (size: ≥25 mm) and 45.2% had a fusiform configuration. Multiple aneurysms were seen only in 21.2% of the cases and a rapid growth was described and documented only in 2 patients (6%) [11, 13].

#### **3.5 Summary and comparison with other series**

Cerebral aneurysms in TSC have distinct demographic, clinical and radiological features. Indeed, comparing TSC patients with those of the unruptured cerebral aneurysm Study of Japan (UCAS Japan) [14], significant differences are found between both series in the location on the ICA (61.9 vs. 34.1%, respectively), large/giant size (57.1 vs. 10.4%, respectively) and proportion of multiple

#### **Figure 1.**

*TOF-MRA showing an incidental fusiform left cavernous ICA aneurysm (8 mm) of a 2.5-year-old child (a) with a rapid aneurysmal growth (+7.5 mm diameter within 12 months of period). (b) ICA: internal carotid artery, TOF-MRA: time-of-flight-magnetic resonance angiography.*

#### **Figure 2.**

*DSA showing a lateral view of the fusiform left cavernous ICA aneurysm, obtained when the child was 14 months old. DSA: digital subtraction angiography, ICA: internal carotid artery, OA: ophthalmic artery, PCoA: posterior communicating artery.*

IA (21.2 vs. 13.9%, respectively). Comparing TSC patients with individuals suffering from giant aneurysms, [15] a difference in the location of the IA (anterior vs. posterior circulation, respectively) and in patients' demographics are noticed, as giant IAs frequently manifest in women and during the fifth and sixth decades. Comparing TSC patients with pediatric series [16], several similarities are noticed, including the male predominance and high frequency of large/giant and fusiform aneurysms. However, the location on the ICA remote from branching zones remains the distinct characteristic of TSC.

A further comparison of IA in TSC patients with those with ADPKD [7] shows notable differences in the location on the ICA (61.9 vs. 16.8%, respectively), rupture status (7.1 vs. 37.9%, respectively), large/giant size (57.1 vs. 11.6%, respectively), fusiform configuration (57.1 vs. 2.1%, respectively), proportion of multiple IA (21.2 vs. 45.3%, respectively) and patient's median age (10.5 vs. 48.5 years, respectively).

The prevalence of IA in patients with TSC was retrospectively estimated to be 0.74% during a 10-year period in a cohort of 404 patients [17]. This is definitely lower than the prevalence of IA in the general population (3.2%) [18], but slightly higher than that of the incidental findings of IA on brain MRI after screening of "asymptomatic individuals" in the general population (0.35%) [19]. In a large series of patients with heritable connective disorders, the prevalence of IA during a 10-year period was estimated to be 14% by Marfan syndrome, 12% by Ehlers-Danlos syndrome and 28% by Loeys-Dietz syndrome [20]. Patients were adult individuals (mean age: 49.4 vs. 41.7 vs. 36.5, respectively) with a male/female equidistribution or female predominance (49 vs. 82 vs. 52%). IA were small (mean size: 4.4 vs. 6.9 vs. 4.8 mm), mostly saccular (75 vs. 64.3 vs. 87.5%), located on the ICA (75 vs. 85.7 vs. 62.5%) and unruptured (0 vs. 14.3 vs. 12.5%) [20].

In contrast, TSC patients are mostly young male individuals that present with asymptomatic, unruptured, large/giant, fusiform aneurysms that are located on the ICA, remote from the branching zones, with an eventual rapid growth. These

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*Demographic, Clinical, and Radiographic Characteristics of Cerebral Aneurysms in Tuberous…*

characteristics may support the idea that IA in patients with TSC are characteristically

In our systematic review [11], digital subtraction angiography (DSA) was the most common diagnostic modality (57.6%)for the identification of IA followed by MRI (30.3%). DSA remains the gold-standard in the diagnosis of IA. However, because of the crucial technological advances, MR angiography at 3 Tesla was found to have a high positive predictive value (mean: 93.4%) and high sensitivity for the detection of unruptured IA (74.1% for aneurysms <3 mm and 100% for aneurysms ≥3 mm) [21]. Furthermore, contrast-free 3D-TOF-MRA at 3 Tesla accurately identifies the presence of IA and may replace DSA as a contrast-free, noninvasive, and nonradiation-based modality for the diagnosis and screening of IA [22].

Several treatment strategies were performed including aneurysm clipping and endovascular coiling. However, because of the complex morphology of IA with oftentimes fusiform and/or giant aneurysm sac, many other techniques as surgical ICA occlusion after superficial temporal artery-MCA bypass or stent-assisted coiling or endovascular ICA occlusion were also performed [11]. In the last two decades, an increase in endovascular treatment of IA was noticed. Nevertheless, the proportion of microsurgical vs. endovascular treatment was almost the same in the pooled TSC cohort. This circumstance might be related to high prevalence of above-mentioned complex IA, which are less eligible for conventional endovascular treatment. However, recent improvements in neuro-interventional radiology such as flow-

Among 16 patients that were operated, neurological outcome was reported in only 12 patients. Six patients had postoperatively no neurological deficits, three patients met an improvement of their focal neurological deficits (Oculomotor paresis/palsy, visual loss) and four patients experienced focal deficits (Oculomotor

The natural history of saccular aneurysms is to date well established, as higher hemodynamic shear stress and consequently stronger flow acceleration frequently promote aneurysm formation in cerebral vessel bifurcations [23]. In contrast, natural history of cerebral aneurysms remote from the branching zones as fusiform aneurysms still remains unclear. Some authors found a correlation between fusiform aneurysms and larger aortic root dimension, suggesting a shared pathophysiological mechanism with aortopathy [24, 25]. However, the lack of histological findings of IA in TSC patients represents a considerable drawback in understanding aneurysm pathogenesis in this disease. The sole histological analysis was performed in 1980 at autopsy on the cerebral aneurysm wall of a 26-year-old woman.

diverters might enhance the indications to endovascular treatment.

paresis, facial palsy and hemiparesis) [11].

different from other syndromal and nonsyndromal aneurysms.

**4. Diagnostic modalities, treatment strategies, and outcome**

*DOI: http://dx.doi.org/10.5772/intechopen.93802*

**4.1 Diagnostic modalities**

**4.2 Treatment strategies**

**4.3 Outcome**

**5. Pathogenesis**

*Demographic, Clinical, and Radiographic Characteristics of Cerebral Aneurysms in Tuberous… DOI: http://dx.doi.org/10.5772/intechopen.93802*

characteristics may support the idea that IA in patients with TSC are characteristically different from other syndromal and nonsyndromal aneurysms.
