**8. Conclusions**

*Advancement and New Understanding in Brain Injury*

elastic fibers nor evidence of inflammation or necrosis [26].

of a coexistence of both diseases rather than a coincidence.

cranial aneurysms to better understand IA formation.

**6. Recommendations**

It revealed a "relatively hypocellular hyaline fibrous tissue." There were neither

The question of aneurysm formation always focused on their acquired vs. congenital nature. Many arguments plead in favor of a congenital defect of the arterial wall. First, the higher frequency of pediatric cases (66.7%) and the distinct location of IA unrelated to branching zones [11] might indicate the inferiority of extrinsic/environmental factors, which are considered to play a crucial role in the genesis of nonsyndromal IA in healthy adults [27]. Furthermore, the suspected rapid growth [11, 13] of these aneurysms could also support the presence of a genetic predisposition to IA development. Moreover, there is evidence of the

pathogenesis of extracranial aneurysms in TSC that are likely caused by disorders of the connective tissue [28–31]. In fact, the postoperative pathologic examination of a large thoracoabdominal aneurysm wall of a 3-year-old child with a TSC2 mutation revealed a subintimal proliferation of smooth muscle cells (SMC) [32]. Further, it was demonstrated that the de-differentiation of aortic SMC through the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling, characterized by increased proliferation of SMC and decreased expression of contractile proteins, contributed to the formation of the aneurysm [32]. Indeed, in vitro and in vivo evidence that the effect of TSC2 deficiency on vascular SMC is primarily driven by increased mTORC1 signaling was provided [32]. And these findings plead in favor

Therefore, genetic and histopathological studies must further investigate the anomalies of the vascular connective tissue in TSC, especially in the wall of intra-

Morbidity and quality of life during adulthood in patients with TSC are determined by the neurological manifestations [33]. Life expectancy can be reduced by uncontrolled seizures and tuber burden that significantly affect the cognitive impairment of patients [34]. Indeed, 13 cases of "unclear death circumstances" preceded by seizures were retrospectively reported among 639 patients with TSC in two different investigations at the Mayo Clinic [35] and the Bath TSC Clinic [36]. Status epilepticus was listed in 9 cases and sudden unexplained death in epilepsy in 4 cases. Because of advances in diagnostic procedures and medical management, life expectancy of patients with TSC has drastically improved during the last 2 decades and the number of patients who survive to middle age and beyond is increasing [37]. The relatively young age of the individuals with TSC, the disproportionally high number of large/giant IA and the well-described rapid aneurysm growth in two children are sufficient arguments to prompt aneurysm treatment. Additionally, three cases of SAH were described. As long as the real incidence of IA in TSC remains unknown, the risk of aneurysm rupture in this population cannot be estimated. Therefore, the enhancement of the 2012 International TSC Consensus Conference with a cranial TOF-MRA at diagnosis and at the control examinations every 1–3 years might be reasonable for young individuals [11]. Prospective IA screening studies on a national and even international scale are urgently needed.

The epidemiology and pathogenesis of intracranial aneurysm formation in patients with TSC remains unclear. IA in TSC seem to have distinct characteristics

**178**

**7. Conclusion**

Aneurysms were well described in the extracranial vasculature of patients with tuberous sclerosis complex (TSC) such as aortic and kidney aneurysms, where anomalies of the vascular connective tissue have been histopathologically and genetically investigated. In contrast, cerebral aneurysms remain uncommon and their incidence totally unknown. A recent systematic review of the literature found 33 patients with 42 intracranial aneurysms (IA) that seem to have distinct characteristics compared to other syndromal and nonsyndromal IA. Indeed, TSC patients with cerebral aneurysms were found to be young male individuals that present with large/giant, fusiform, mostly asymptomatic, and unruptured aneurysms, located on the internal carotid artery unrelated to branching zones, with an eventual rapid growth. Although the pathogenesis of IA in TSC is still unclear, several demographic, clinical, and radiological arguments plead in favor of the coexistence of both entities, due to a congenital defect of the cerebral arterial wall. As long as the real incidence of IA in TSC remains unknown, the risk of aneurysm rupture in this population cannot be estimated, especially that three cases of subarachnoid hemorrhage were reported. Therefore, prospective screening, genetic and histopathological studies are urgently needed to improve the understanding of the pathogenesis and epidemiology of IA formation in TSC. This cannot be achieved without enhancing the recommendations of the 2012 International TSC Consensus Conference with a cranial TOF-MRA at diagnosis and all regular screening consultations.
