Non-aneurysmal subarachnoid hemorrhage in 173 patients: a prospective study of long-term outcome

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1 ORIGINAL ARTICLE Non-aneurysmal subarachnoid hemorrhage in 173 patients: a prospective study of long-term outcome J. Konczalla, J. Schmitz, S. Kashefiolasl, C. Senft, V. Seifert and J. Platz Department of Neurosurgery, Goethe-University Hospital, Frankfurt am Main, Germany Keywords: aneurysm, long-term outcome, nonaneurysmal, nonperimesencephalic, perimesencephalic, prepontine, SAH, SF-36, short-term, subarachnoid hemorrhage Received 19 January 2015 Accepted 27 April 2015 European Journal of Neurology 2015, 0: 1 8 doi: /ene Background and purpose: In some patients with subarachnoid hemorrhage (SAH) a bleeding source cannot be identified. Perimesencephalic (PM) SAH is assumed to have an excellent outcome. Our objective was to analyze the longterm physical and psychological outcome of patients after non-aneurysmal SAH. Methods: One hundred and seventy-three patients met the inclusion criteria. Short-term follow-up 6 months after SAH was assessed according to the modified Rankin Scale (0 2 favorable). A short-form health survey with 36 questions (SF-36) and eight scales was used as questionnaire for long-term followup. Results: Thirty-seven answers were received from the two groups, PM and non-perimesencephalic (NPM) SAH, on average 76 months after ictus (range years). PM- and NPM-SAH without Fisher grade 3 blood pattern have excellent short-term outcomes. The quality of life (QoL) is significantly reduced after non-aneurysmal SAH, especially in NPM-SAH. In particular, patients with a Fisher 3 blood pattern had significantly higher risks for cerebral vasospasm, delayed cerebral ischaemia, unfavorable outcome, reduced QoL and mortality in short- and long-term follow-up. Conclusions: Excluding rolph, only patients with a PM-SAH have a similar QoL at long-term follow-up compared to the standard population. Patients with NPM-SAH have a significantly decreased QoL in long-term follow-up. Furthermore, the Fisher 3 blood pattern group in particular had a significantly worse outcome at short-term and long-term follow-up. Therefore the NPM- SAH group was stratified into patients with Fisher 3 blood pattern and patients without Fisher 3 in further investigations. Background Spontaneous subarachnoid hemorrhage (SAH) is usually caused by rupture of an intracranial aneurysm, but in up to 15% of patients with spontaneous SAH no discernible bleeding source can be identified despite repeated radiological imaging [1,2]. The majority of patients with non-aneurysmal SAH (NASAH) are in good clinical condition at admission [3 9]. The blood Correspondence: J. Konczalla, Department of Neurosurgery, Johann Wolfgang Goethe-University Frankfurt am Main, Schleusenweg 2-16, Frankfurt am Main, Germany (tel.: ; fax: ; J.Konczalla@med.uni-frankfurt.de). Clinical Trial Registration: URL: Unique identifier: NCT distribution can be described as perimesencephalic/ prepontine or non-perimesencephalic (NPM) [4,6,9]. Depending on the pattern of SAH the clinical course of the patients can be similar to aneurysmal SAH [6,9]. NASAH and especially perimesencephalic (PM) SAH are therefore often associated with favorable short-term outcome compared to aneurysmal SAH [1,2,6,10,11]. However, data on patients with spontaneous NASAH are commonly based on case series and are therefore rare [3,4,12 15]. But even more, data assessing the long-term outcome are scarce [5,16] and lacking for physiological and psychological outcome in a series with more than 50 patients. Therefore, the aim of the present study was to investigate the long-term physical and psychological outcome in 1

2 2 J. KONCZALLA ET AL. Figure 1 Flow diagram with detailed information about enrollment and short- and long-term follow-up. From over 1400 patients 173 patients were eligible to receive the questionnaire. Short- and long-term follow-up results and mortality rates are presented. Overall in every group a good response rate was achieved of over 50%, especially against the background of patients suffering from NASAH starting 15 years ago. patients suffering from non-aneurysmal spontaneous SAH prospectively. Material and methods Between 1999 and 2012 information on all patients with SAH, including patient characteristics, treatment, radiological features and outcome, was prospectively entered into a computerized database. SAH was confirmed on computed tomography (CT) or lumbar puncture. Only patients with a non-traumatic SAH were included. All patients had a regular follow-up after 6 months following our hospital algorithm. Patients with an SAH more than 18 months ago received additionally a questionnaire; see also the flow chart (Fig. 1). In all, 173 patients (12% of all SAH patients) with a spontaneous NASAH after diagnostic work-up were identified. In our hospital algorithm all patients with SAH underwent angiography including three-dimensional digital subtraction angiography (DSA) since 2002 to rule out intracranial sources for SAH. In the case of a negative initial angiography, DSA was repeated after 14 days. Additionally, magnetic resonance imaging (MRI) of head/spine was performed to rule out any spinal bleeding sources. In patients with blood distribution exceeding the typical perimesencephalic pattern, a third DSA was performed 3 months after SAH. Our treatment protocol includes the application of nimodipine in all patients with SAH from the day of admission and has been described in detail previously [17]. NASAH was stratified into PM- and NPM-SAH. Recently published data showed differences between Fisher grade 3 blood pattern and NPM-SAH without Fisher 3 blood pattern [9]; therefore the NPM-SAH group was further stratified into Fisher 3 blood pattern and NPM-SAH without Fisher 3 blood pattern. NASAH was defined as perimesencephalic hemorrhage according to Van Gijn et al. [1] and Rinkel et al. [10] hemorrhages located around

3 LONG-TERM OUTCOME AFTER NON-ANEURYSMAL SAH 3 (a) (b) (c) Figure 2 Long-term outcome compared to standard population, measured by SF-36. The eight items of the SF-36 are shown on the x-axis. On the left side the ordinate is scaled metrically. The line graph shows the standard population, whereas the bar chart represents the different groups. *P < (a) Long-term outcome of NASAH patients. Pfi/rolph/ghp/rolem and mhi were significantly reduced after SAH compared to the standard population. (b) The two bars represent the long-term outcome of the two subgroups (white for PM-SAH, grey for NPM-SAH). In the PM-SAH group only rolph is significantly reduced compared to the standard population, whereas in the NPM-SAH group all physical items (pfi/rolph/pain/ghp) are significantly reduced. (c) The NPM subgroups Fisher 3 blood pattern (light grey) and NPM without Fisher 3 blood pattern (dark grey) were compared to the standard population. In this subgroup analysis in both groups all items are reduced compared to the standard population, but for the NPM without Fisher 3 blood pattern no significant decrease was calculated. In the Fisher 3 blood pattern group one physical item (rolph) and all psychological items (vital/social/rolem/mhi) are significantly reduced. the brain stem, most often located in the interpeduncular cistern. For NPM-SAH blood was not located mainly in the interpeduncular cistern but in the Sylvian cistern, interhemispheric cistern, convexity or a CT-negative and lumbar puncture positive bleeding (Fig. S1). The first (short-term) follow-up was performed 6 months after ictus. Outcome was measured according to the modified Rankin Scale (mrs) and stratified into favorable (mrs 0 2) and unfavorable (mrs 3 6) after 6 months. Trial registration This prospective non-interventional study was approved by the local ethics committee of Goethe-University Hospital Frankfurt and registered on (identifier no. NCT ). Assessment and statistical analysis From November 2013 to February 2014 patients at least 18 months after ictus of NASAH received a regular mail. This mail included a letter explaining the study purpose, statement of consent and the postal questionnaire consisting of a short-form health survey with 36 simple questions (SF-36) [18,19], which was used for the long-term (second) follow-up. These 36 questions were converted to an eight-item scale, which was divided into two categories (physical and psychological health) (Table 1). Furthermore the data can be compared with a standard population from the US health survey (n = 2474) to make our results comparable with future data. Table 1 The items of SF-36 are listed with their appropriate abbreviations Items Physical Physical functioning pfi Role limitations because of physical rolph health problems Bodily pain pain General health perceptions ghp Psychological Vitality vital Social functioning social Role limitations because of rolem emotional problems General mental health mhi If answers were not received after 3 months telephone interviews were carried out with the patients, their family members or their general practitioner. An unpaired t test with Welch correction was used for parametric statistics. For categorical variables Fisher s exact test was used. Results with a P value <0.05 were considered statistically significant. All calculations were made with standard commercial software (IBM SPSS Inc., Armonk, NY, USA). Patient characteristics Results Abbreviation A cohort of 173 patients met the inclusion criteria (at least 18 months after non-aneurysmal non-traumatic SAH), including patients with ictus from 1999 to patients (9%) had died by the short-term outcome (Table 2). Another 16 patients died by the long-term outcome questionnaire (9%) (Table 3); most of them

4 4 J. KONCZALLA ET AL. Table 2 Patients characteristics, complications and short-term follow-up after 6 months P (NPM Fisher 3 vs. NPM w/o Fisher 3) Odds ratio (95% CI) NPM w/o Fisher 3 NPM Fisher 3 Odds ratio (95% CI) P (PM- vs. NPM-SAH)* NPM-SAH PM-SAH Characteristics NASAH No. of patients Mean age SD NS NS WFNS I III at 151 (87) 79 (91) 72 (84) NS 19 (59) 53 (98) < ( ) for w/o Fisher 3 admission Early hydrocephalus 46 (27) 20 (23 26 (30) NS 19 (59 7 (13 < ( ) for Fisher 3 Shunt dependence 15 (9) 5 (6) 10 (12) NS 4 (13) 6 (11) NS Cerebral vasospasm 37 (17) 13 (15) 24 (28) < ( ) 19 (59) 5 (9) < ( ) for Fisher 3 28 (13) 8 (9) 20 (23) < ( ) 14 (44) 6 (11) < ( ) for Fisher 3 Delayed cerebral ischaemia Favorable outcome 147 (85) 76 (87) 71 (83) NS 20 (63) 51 (88) < ( ) for w/o Fisher 3 Death 16 (9) 7 (8) 9 (10) NS 8 (25) 1 (2) < ( ) for Fisher 3 NASAH, non-aneurysmal subarachnoid hemorrhage; PM, perimesencephalic; NPM, non-perimesencephalic; 95% CI, 95% confidence interval; NS, not significant (P > 0.05); NPM Fisher 3, NPM- SAH with Fisher 3 blood pattern; NPM w/o Fisher 3, NPM-SAH without Fisher 3 blood pattern; WFNS, World Federation of Neurological Societies; favorable outcome, modified Rankin Scale (mrs) 0 2. *Unpaired t test for parametric statistics and Fisher exact test for categorical variables. (75%) were 70 years or older. In the majority (56%) the definitive cause of death is known (Table 4). In seven patients with a mean age of 74.4 years a definitive diagnosis was not available. In a 65-year-old male and an 86-year-old female intracranial bleeding was assumed. Unfortunately, scans were not available, and therefore it was not possible to differentiate between potential causes (like SAH, intracranial hemorrhage for example). Overall, one rebleeding occurred without detection of a bleeding source also after the second round of diagnostic work-up. Of the remaining 141 patients five patients (4%) did not answer (Table 3). Finally, answers were received from 74 patients (52%). 62 patients (44%) were lost to follow-up, resulting in an acceptable to good response rate of 56% for a questionnaire up to 15 years after ictus [20]. Answers were received on average more than 6 years after ictus (76.1 months, range months). The mean age at ictus was years. Thirty-seven answers were received from the two groups, PM- and NPM-SAH. The mean age and time interval from ictus did not differ significantly between them (Table 2). Concomitant diseases and complications Whereas the admission status between the PM- and NPM-SAH groups was similar, patients with a Fisher 3 blood pattern had a significantly worse admission status compared to patients with NPM-SAH without Fisher 3 [59% vs. 98%; P < ; odds ratio (OR) 36.3]. Similarly the rate of early hydrocephalus did not differ between the PM- and NPM-SAH groups but was significantly increased in the Fisher 3 blood pattern. However, the rate of shunt dependence was similar in all groups (Table 2). Cerebral vasospasm and delayed cerebral ischaemia In this cohort the NPM-SAH group compared to the PM-SAH group had cerebral vasospasm (CVS) (28% vs. 15%; P < 0.05) and delayed cerebral ischaemia (DCI) (23% vs. 9%; P < 0.05) significantly more often. However, for Fisher 3 blood pattern the data demonstrate more clearly a higher rate of CVS (59% vs. 9%; P < 0.01) and DCI (44% vs. 11%; P < 0.01) compared to NPM-SAH without Fisher 3 blood pattern. Therefore, the outcome of the Fisher 3 group was significantly reduced (Table 2) and a further stratification into these two subgroups seems reasonable for long-term follow-up. Neurological complications after NASAH At long-term follow-up nine patients (12%) had a newly diagnosed neurological or psychiatric disease

5 LONG-TERM OUTCOME AFTER NON-ANEURYSMAL SAH 5 Table 3 Mortality and response rate Characteristics Number of patients at ictus Deaths at short-term + long-term follow-up P value* Number of patients sent questionnaire Response rate No answer NASAH = 32 (18) (56) 5 (4) PM-SAH 87 (50) = 12 (14) NS vs. NPM-SAH (51) 1 (1) NPM-SAH 86 (50) = 20 (23) (62) 4 (6) NPM-SAH with 32 (18) = 13 (41) <0.01; OR (53) 1 (5) Fisher 3 pattern NPM-SAH without Fisher 3 54 (31) = 7 (13) 95% CI for Fisher 3 vs. w/o Fisher (66) 3 (6) NASAH, non-aneurysmal subarachnoid hemorrhage; PM, perimesencephalic; NPM, non-pm; OR, odds ratio; 95% CI, confidence interval; NS, not significant (P > 0.05). *Fisher exact test for categorical variables. Table 4 Outcome of NASAH, stratified to PM-, NPM-SAH, Fisher 3 blood pattern and without Fisher 3 blood pattern Characteristics NASAH PM-SAH NPM-SAH P value* (PM vs. NPM) NPM-SAH with Fisher 3 NPM-SAH without Fisher 3 P value* (with Fisher 3 vs. without Fisher 3) No. of. patients Rebleeding 1 (1) 0 1 (3) NS 1 (11) 0 NS Newly diagnosed after NASAH Psychiatric disease 5 (7) 2 (5) 3 (8) NS 2 (22) 1 (4) NS Seizure 5 (7) 1 (3) 4 (11) NS 2 (22) 2 (7) NS Chronic headache 3 (4) 0 3 (8) NS 2 (22) 1 (4) NS No. of patients with 9 (12) 3 (8) 6 (16) NS 4 (44) 2 (7) NS new diagnosis Death between short-term 16 of 157 (10) 5 of 80 (6) 11 of 77 (14) NS 5 of 24 (21) 6 of 53 (11) NS and long-term follow-up Deaths due to Intracranial bleeding 2 of 16 (13) 0 of 5 2 of 11 (18) NS 0 of 5 2 of 6 (17) NS malignant tumors 3 (19) 1 (20) 2 (18) NS 1 (20) 1 (17) NS Other causes 4 (25) 2 (40) 2 (18) NS 0 2 (33) NS Without definitive diagnosis 7 (44) 2 (40) 5 (45) NS 4 (80) 1 (17) NS NASAH, non-aneurysmal subarachnoid hemorrhage; PM, perimesencephalic; NPM, non-perimesencephalic; NS, not significant (P > 0.05). *Unpaired t test for parametric statistics and Fisher exact test for categorical variables. after NASAH: three had chronic headache, five had psychiatric diseases (including four with additional depression) and five had seizures (Table 4). The subgroup of PM-SAH seems to be less often affected, even though this was not statistically significant. Of these nine patients, only three had a PM-SAH, whereas six had a NPM-SAH. Once again, the Fisher 3 group (44%) had complications significantly more often compared to the NPM-SAH group without Fisher 3 blood pattern (7%; Table 4). Long-term outcome of NASAH and comparison with standard population Three of the four physical items (Table 1) were reduced compared to the general population: pfi (P < 0.01), rolph (P < 0.001) and ghp (P < 0.01). For the psychological items two of four were reduced: rolem (P < 0.05) and mhi (P < 0.05). The items pain, vital and social were also reduced, but this was not statistically significant (Fig. 2a). A comparison to the general population was performed, using the US health survey. This made our results comparable with future data. Results of the SF-36 are shown in Fig. 2a. Compared to the general population, patients after NASAH experienced a reduction in all eight classes of the SF-36 (Fig. 2a). Therefore, patients after NASAH had physical and psychological disturbances. Long-term outcome and comparison of PM- and NPM- SAH Whereas PM-SAH is generally considered a benign entity, patients after NPM-SAH, especially with a

6 6 J. KONCZALLA ET AL. Fisher 3 bleeding pattern, are known to have a worse outcome after 6 months. This was demonstrated especially in recent years due to more complex cases (e.g. anticoagulation) [6,7,9,21]. Also in our cohort a high mortality rate was identified for this group: 25% up to short-term follow-up and 41% up to long-term follow-up (Tables 2 and 3). The patient characteristics at short-term outcome (Table 2) and long-term outcome (Table 4) of the PM- and NPM-SAH groups are very similar. But at long-term follow-up in all items except the rolem the NPM-SAH group has reduced values compared to PM-SAH. For PM-SAH only the physical item rolph was decreased significantly, whereas for the NPM- SAH group all physical items (pfi, rolph, pain and ghp) were reduced significantly compared to the standard population. Therefore, the NPM-SAH group seems to have a worse long-term outcome and higher mortality rates (Table 2 and Fig. 3b). Long-term outcome and comparison of NPM-SAH with Fisher 3 pattern versus NPM-SAH without Fisher 3 pattern A closer look at the NPM-SAH revealed that it is necessary to stratify this group into Fisher 3 blood pattern and NPM-SAH without the subgroup Fisher 3. Patients with a Fisher 3 blood pattern had a significantly worse World Federation of Neurological Societies status and higher hydrocephalus rate on admission. Also the rate of CVS, DCI, unfavorable outcome and death was significantly higher (Table 2). The highest rate of deaths at short-term outcome was in the Fisher 3 group too (Table 4). Unfortunately only nine patients with a Fisher 3 blood pattern answered the questionnaire (with an acceptable to good response rate of 53% [20]), so that statistical analysis is limited. Also 44% had neurological or psychiatric diseases after NASAH (Table 4), which may influence the data. Nonetheless, except for pfi (P ~ 0.5), pain (P = 0.07) and ghp (P = 0.05), all other items were significantly lower compared to the standard population, whereas for the NPM-SAH without Fisher 3 group no significant differences were calculated (Fig. 3c). Discussion In up to 15% of patients suffering from SAH, no source of bleeding can be found [3 5,7,8,14]. The majority of patients with NASAH are in good clinical condition at admission [3 9]. Non-aneurysmal and especially PM-SAH are therefore often associated with favorable short-term outcome compared to aneurysmal SAH [1,2,6,10,11]. However, data on patients with spontaneous NASAH are commonly based on case series and are therefore rare [3,4,6,8,9,12 15]. But even more, data assessing the long-term outcome are scarce [5,16] and lacking for physiological and psychological outcome in a series with more than 50 patients. Our neurovascular database was therefore analyzed concerning patients suffering from NASAH. In our study, 85% achieved a favorable outcome at short-term follow-up (Table 2). As for aneurysmal SAH [22] patients after NASAH had a reduced quality of life (QoL) in all eight classes of the SF-36 compared to the reference population (Fig. 2). Therefore, after NASAH, apart from the patients with newly diagnosed neurological or psychiatric diseases (18%), most patients had physical and psychological disturbances at long-term follow-up. Three of four physical items were statistically significantly reduced compared to the general population: pfi, rolph and ghp. For the psychological items two of four items were reduced significantly: rolem and mhi (Fig. 2a). This was even more significant in the group of NPM- SAH, which had significant reductions in all physical items (Fig. 2b). As in the study by Beseoglu et al. [5] the QoL is reduced in the NPM-SAH group compared to PM-SAH. Kapapa et al. [23] and Tjahjadi et al. [24] presented already a reduced QoL after SAH, but data for PM-SAH are still lacking. Except for pain and social all scales are decreased in PM-SAH but only significantly for rolph (Fig. 2b), suggesting a similar QoL after PM-SAH excluding the rolph. The highest risk for unfavorable outcome and/or death was found for the Fisher 3 blood pattern group (Table 2). Therefore the NPM-SAH data were stratified into subgroups with Fisher 3 blood pattern and without Fisher 3. The NPM-SAH without Fisher 3 group had a very similar excellent outcome like PM-SAH (Table 2). The Fisher 3 group had a very high risk for unfavorable outcome (OR 10.2) and mortality after 6 months (25%; OR 17.7, Table 2) and at long-term follow-up (41%; OR 4.6, Table 3). For the Fisher 3 group the QoL is reduced in all eight scales, but significantly in any psychological scales (vital, social, rolem, mhi) and also in rolph (Fig. 2c). 44% had neurological or psychiatric diseases after NASAH (Table 4), which may influence the outcome of these nine patients. Some reports also identified different functional outcomes of NASAH according to the blood distribution [7,9,21]. The reason for the worse short- and long-term outcomes seems to be the higher incidence of CVS, DCI and death (Table 2) [6,7,9,13,21,25] and the higher incidence of newly

7 LONG-TERM OUTCOME AFTER NON-ANEURYSMAL SAH 7 diagnosed neurological and psychiatric diseases (Table 4). Limitations The study has several limitations. Statistical analysis was retrospectively performed for the short-term outcome and conducted from a single center. Due to the retrospective design there are the typical restrictions such as the lack of data not documented initially in the medical records. The long-term follow-up was performed prospectively, but based on the data of our computerized database. Also 62 patients (44%) were lost to follow-up, limiting the data, but resulting in an acceptable to good response rate of 56% for a questionnaire up to 15 years after ictus. Patients with Fisher 3 blood pattern had a significantly higher rate of neurological and psychiatric diseases, which may influence the outcome. But the number of absolute patients for Fisher 3 blood pattern was only nine. Conclusion Excluding rolph, only patients with a PM-SAH have a similar QoL at long-term follow-up compared to the reference population. Patients with NPM-SAH had a significantly decreased QoL at the long-term followup. In this large study a significantly worse clinical outcome was identified for the Fisher 3 blood pattern group at short-term and long-term follow-up. Therefore our advice is to stratify the NPM-SAH into patients with Fisher 3 blood pattern and without Fisher 3 in further investigations. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest. Funding statement The author JK receive foundation grants for earmarked funding of research projects of the medicalmdepartment of Goethe-University. Acknowledgements We thank Marina Heibel and Anne Sicking for excellent technical support. This study was partly funded by Frankfurt University Hospital s Foundation grants. Author contributions: JK, DS, SK, JP acquired and analyzed the data. JK performed the statistical analysis and drafted the manuscript. JK, CS, VS interpreted the data and contributed to critical revision of the manuscript for important intellectual content. JP performed critical supervision of the manuscript. All authors read and approved the final manuscript. Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Perimesencephalic and non-perimesencephalic SAH. References 1. Van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985; 35: Van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001; 124: Gupta SK, Gupta R, Khosla VK, et al. Nonaneurysmal nonperimesencephalic subarachnoid hemorrhage: is it a benign entity? Surg Neurol 2009; 71: ; discussion Ildan F, Tuna M, Erman T, G ocer AI, Cetinalp E. Prognosis and prognostic factors in nonaneurysmal perimesencephalic hemorrhage: a follow-up study in 29 patients. Surg Neurol 2002; 57: ; discussion Beseoglu K, Pannes S, Steiger HJ, H anggi D. Long-term outcome and quality of life after nonaneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien) 2010; 152: Konczalla J, Platz J, Schuss P, Vatter H, Seifert V, G uresir E. Non-aneurysmal non-traumatic subarachnoid hemorrhage: patient characteristics, clinical outcome and prognostic factors based on a single-center experience in 125 patients. BMC Neurol 2014; 14: Nayak S, Kunz AB, Kieslinger K, Ladurner G, Killer M. Classification of non-aneurysmal subarachnoid haemorrhage: CT correlation to the clinical outcome. Clin Radiol 2010; 65: Pyysalo LM, Niskakangas TT, Keski-Nisula LH, K ah ar a VJ, Ohman JE. Long term outcome after subarachnoid haemorrhage of unknown aetiology. J Neurol Neurosurg Psychiatry 2011; 82: Konczalla J, Schuss P, Platz J, Vatter H, Seifert V, G uresir E. Clinical outcome and prognostic factors of patients with angiogram-negative and non-perimesencephalic subarachnoid hemorrhage: benign prognosis like perimesencephalic SAH or same risk as aneurysmal SAH? Neurosurg Rev 2015; 38: Rinkel GJ, Wijdicks EF, Hasan D, et al. Outcome in patients with subarachnoid haemorrhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet 1991; 338: Rinkel GJ, Wijdicks EF, Vermeulen M, Hasan D, Brouwers PJ, van Gijn J. The clinical course of perime-

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