Introduction
Spontaneous subarachnoid hemorrhage (SAH) is a devastating clinical problem and is most commonly caused by a rupture of an intracranial aneurysm. In approximately 15% of patients with spontaneous SAH, the origin of the hemorrhage cannot be detected, despite extensive diagnostic imaging studies, and this is called non-aneurysmal subarachnoid hemorrhage (NSAH) [
1,
2]. NSAH can be subdivided into two different subgroups: perimesencephalic non-aneurysmal subarachnoid hemorrhage (P-NSAH) and non-perimesencephalic non-aneurysmal subarachnoid hemorrhage (nP-NSAH). P-NSAH is characterized by accumulation of subarachnoid blood, predominantly around the midbrain, and a lack of blood in the brain parenchyma or ventricular system [
1,
2]. In contrast, computed tomography (CT) scans of patients with nP-NSAH reveal bleeding patterns similar to those seen in aneurysmal SAH.
P-NSAH has generally been considered a distinct entity after the identification of different prognoses from the other NSAH by van Gijn
et al.[
2]. Patients with P-NSAH not only have a much lower risk of morbidity and mortality than the patients with aneurysmal SAH, but also have better outcomes than patients with nP-NSAH [
1‐
3].
It has repeatedly been shown that genetic factors play an important role in the pathogenesis of SAH [
4,
5]. An apparent relationship between genetic factors and P-NSAH has not been defined; however, accumulating reports of familial cases of P-NSAH and nP-NSAH raise the question of whether there are genetic factors that play an important role in the development of SAH [
6,
7].
We report the cases of two siblings with P-NSAH, which suggest first-degree relatives of individuals with this entity may have a higher risk for SAH.
Discussion
P-NSAH was first described by van Gijn
et al.[
2] and characterized by subarachnoid blood predominantly around the mesencephalon without any vascular pathology or any other source of bleeding [
2,
3]. The typical CT pattern of P-NSAH has been described by Rinkel
et al. as follows: 1) subarachnoid blood around the mesencephalon, with possible extension to the posterior part of the interhemispheric fissure without complete filling of the fissure; 2) extension of the subarachnoid blood to the basal part of the sylvian cistern; 3) minimal sedimentation of intraventricular blood; 4) absence of intraventricular blood [
8]. While both arterial and venous origins have been postulated as the source of hemorrhage, the precise etiology of P-NSAH remains enigmatic despite extensive diagnostic investigation [
1,
3]. A non-arterial origin has been proposed in the literature due to infrequent loss of consciousness, lack of blood in the brain parenchyma or ventricular system, and low incidence of vasospasm and hydrocephalus. Furthermore, accumulation of subarachnoid blood around the brainstem has drawn the attention of investigators to variations of the perimesencephalic and deep cerebral veins [
8]. Typically, blood is found in the interpeduncular, crural and ambient cisterns, all of which have a close relationship with the BVR.
A growing body of evidence has supported the role of anatomic variations of this vein as a critical contributor to P-NSAH pathogenesis [
9‐
12]. Watanabe
et al. studied the relationship between P-NSAH and variations of deep cerebral veins in particular BVR and classified the venous drainage of BVR into three types [
12]. Type A is the normal continuous pattern, in which the BVR is continuous with the deep middle cerebral vein and drains mainly to the vein of Galen (VG). Type B is a normal discontinuous pattern with drainage anterior to uncal veins and posterior to VG. Type C is a primitive variant with drainage to other veins but not to the VG. In a study by Watanabe
et al., Type C variants of the BVR on one or both sides were identified in all patients with P-NSAH . Moreover, the Type C pattern was found much more frequently in patients with P-NSAH than in patients with aneurysmal SAH [
12]. Similar findings have been later reported by different groups [
9‐
11]. In these studies, in addition to Type C, Type B also was found to be associated with P-NSAH more frequently than SAH [
9,
10]. All venograms of our two patients have been retrospectively reviewed by two separate neuroradiologists who confirmed the presence of a Type C variant on the left side in patient 1 and a Type B variant on the right side in patient 2. Both patients had Type A on the contralateral side (Figures
2D,
2E and
4C,
4D).
A series of reports have highlighted the critical role of genetic factors in the pathogenesis of aneurysmal SAH [
4‐
7,
13]. A large population-based study by Bor
et al. revealed that people with two first-degree relatives affected with SAH have a higher risk of SAH in comparison with individuals with just one affected first-degree relative [
4]. Furthermore, Bromberg
et al. have shown that the SAH occurrence in first-degree relatives is up to seven times greater than in second-degree relatives [
13]. It is suggested that the first-degree relatives of patients with aneurysmal SAH are at a higher risk of bleeding than the general population, similar results for NSAH have not been reported however [
4,
5,
13].
Although the etiology of NSAH has not been determined, some risk factors for NSAH have been defined, such as: female sex, arterial hypertension, smoking, and excessive use of alcohol [
14,
15]. There are only two case reports describing an association between the familial predisposition of venous system variants and NSAH in the literature [
6,
7]. Type C variant of the BVR has been reported in two first-degree relatives with P-NSAH [
7] (Table
1); however, three siblings with NSAH (one with nP-NSAH, two of them with P-NSAH) have been described with no report of BVR variant [
6].
Table 1
Spontaneous perimesencephalic subarachnoid hemorrhage in siblings
| Patient 1 | 51 years | Man | Headache, vomiting, left gaze diplopia | No | No recurrent subarachnoid hemorrhage and no neurological deficits | Type C/Type C |
| Patient 2 | 50 years | Woman | Headache, loss of consciousness, vomiting | No | No recurrent subarachnoid hemorrhage and no neurological deficits | Type C/Type C |
Cikla
et al
.
(this article)
| Patient 1 | 39 years | Man | Headache, diplopia, nuchal rigidity | No | No recurrent subarachnoid hemorrhage and no neurological deficits | Type A/Type C |
| Patient 2 | 44 years | man | Headache, slight nuchal rigidity | No | no recurrent subarachnoid hemorrhage and no neurological deficits | Type B/Type A |
Our report is the second familial occurrence of P-NSAH in two siblings with Type B and Type C BVR variants.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
UC, MKB, DBN and GM designed the study, drafted and revised the manuscript. BAK and PAT were responsible for radiological assessment. All authors read and approved the final manuscript.