**Conflict of interest**

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

increase the risk of secondary brain injury following SAH.

FAs interventions during the acute stage of the disease.

therapy in their treatment protocols for SAH patients [92].

**11. Final remarks**

inflammatory diseases, it is not yet known whether enzymatic deficiencies contribute to IA growth and rupture, and this novel hypothesis requires further investigation [85, 86].

The vital roles of EPA and DHA in the human body emphasize the evolutionary importance of maintaining efficient functional couplings between chemical and biological systems as well as between the vasculature and the brain [87]. Resolution of inflammation and endogenous neuroprotective signaling are interrelated processes that largely depend on EPA and DHA derivatives. This novel concept may open new avenues for public health interventions and innovative research in IAs and SAH.

Although nutrition has been traditionally viewed as a supportive measure, increasing evidence strongly suggests that a more balanced dietary intake of omega-6 and omega-3 FAs may represent the most efficient means of improving the status of inflammation resolution at the population level [48, 82, 83]. This specific dietary recommendation could contribute to decrease the risk of IAs growth and rupture and the devastating consequences of SAH, along with other important health benefits. The pathological significance of the loss of brain DHA after SAH has been widely ignored, even though strong preclinical evidence supports the hypothesis that the integrity of the neurovascular unit largely depends on high DHA enrichment. This previously unrecognized pathophysiological process may significantly

The robust demonstration of the clinical efficacy of EPA in patients with chronic CV disease supports the encouraging results obtained in preliminary clinical studies of omega-3 FAs in SAH and warrants a large-scale RCT. It needs to be emphasized that DHA should always be included in neuroprotective interventions, as DHA plays an essential role in neural tissue and is the cornerstone for docosanoid generation. Parenteral pharmaconutrition with FO offers major clinical advantages for the treatment of SAH patients and should also be an integral component of omega-3

The design of future RCTs of omega-3 FAs in SAH should bear in mind a potentially important factor. Clinical approaches that mainly focus on large-artery vasospasm may actually counteract the beneficial effects of omega-3 FAs and other neuroprotective interventions. The main rationale behind this seemingly paradoxical notion is based on both theoretical models and clinical perspectives [3, 31]. An unpublished subgroup analysis of our pilot pharmaconutrition trial of omega-3 FAs showed unexpected differences in the occurrence of cerebral infarction due to DCI between study centers, each of which had different clinical approaches to large-artery vasospasm [13]. In addition, a recently published observational study performed in the UK showed centers that screened for large-artery vasospasm using transcranial Doppler ultrasound (TCD) had poorer inhospital outcomes and similar rates of DCI diagnosis compared to centers that did not [88]. These results support the dissociation between large-artery vasospasm and clinical outcome that has been observed in major phase 3 RCTs in SAH [8]. Therefore, reliance on a surrogate clinical endpoint such as large-artery vasospasm may lead to the adoption of useless or even harmful clinical approaches [88–91]. Indeed, some research centers in Europe do not include TCD ultrasound or endovascular rescue

Moreover, it would be clinically meaningful to determine if correlations exist between the omega-3 index and the concentrations of EPA and DHA as well as the status of inflammation resolution in the wall of ruptured and non-ruptured IAs. There may be a real opportunity for a readily implementable and low-cost therapy if

the walls of IAs are as responsive to omega-3 FAs as atherosclerotic plaques.

**248**

The authors have no conflicts of interest to declare.
