Subarachnoid hemorrhage and negative angiography: clinical course and long-term follow-up

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1 DOI /s ORIGINAL ARTICLE Subarachnoid hemorrhage and negative angiography: clinical course and long-term follow-up Marco Fontanella & Innocenzo Rainero & Pier Paolo Panciani & Bawarjan Schatlo & Chiara Benevello & Diego Garbossa & Christian Carlino & Walter Valfrè & Federico Griva & Gianni Boris Bradac & Alessandro Ducati Received: 18 November 2010 /Revised: 1 March 2011 /Accepted: 6 March 2011 # Springer-Verlag 2011 Abstract The aim of this study was to investigate the longterm natural history of nontraumatic angiogram-negative subarachnoid hemorrhage with typical pretruncal (P-SAH) and diffuse (D-SAH) pattern of hemorrhage. A retrospective review of 102 patients who experienced angiographically negative SAH at our institution was undertaken (11.6% of 882 spontaneous SAH). Follow-ups were obtained at 7.9 to 16 years. In the D-SAH group, 11 patients (13.9%) out of 79 had an aneurysm, and four (5.1%) had rebleeding episodes. In the P-SAH group, the second angiography was negative in all of the 23 cases, and no rebleeding episodes were recorded. The long-term follow-up confirms that P-SAH is a benign disease. A second angiography could not be necessary. D-SAH is probably due to an aneurysm that thrombose early after the bleeding. At short-term follow-up, the sack could frequently recanalize and rebleed, whereas a late follow-up shows that rebleeding is very rare. M. Fontanella (*) : P. P. Panciani : C. Benevello : D. Garbossa : C. Carlino : F. Griva : A. Ducati Division of Neurosurgery, Department of Neuroscience, University of Torino, Via Cherasco 15, Torino, Italy marco.fontanella@tin.it I. Rainero : W. Valfrè Division of Neurology, Department of Neuroscience, University of Torino, Torino, Italy B. Schatlo Department of Neurosurgery, University Hospital Geneva, Geneva, Switzerland G. B. Bradac Division of Neuroradiology, Department of Neuroscience, University of Torino, Torino, Italy Keywords Negative angiography. Pretruncal subarachnoid hemorrhage. Intracranial aneurysms. Subarachnoid hemorrhage of unknown cause. Angiogram-negative subarachnoid hemorrhage Introduction A considerable improvement in neurodiagnostic techniques has increased our ability to detect intracranial aneurysms with angiography and Angio-CT. However, angiogramnegative subarachnoid hemorrhage (SAH) still accounts for 2 24% of the cases of SAH [3, 18]. Jung et al. analyzed over 3,000 patients with SAH. In their series, 4.4% (143) showed no evidence and found that 18 patients showed an aneurysm on a repeat angiography exam. Of these 18 patients, all but one had a blood distribution on CT which was sylvian, interhemispheric, diffuse, or tentorial suggesting an aneurysm [18]. The pattern of blood distribution in the subarachnoid cisterns on the computed tomography scan (CT) at SAH onset is thus very important for predicting the possible negative result of cerebral angiographic examination [17, 31]. In particular, subarachnoid blood which is limited to the prepontine, pretruncal region, as reported in the literature [27, 28, 30, 31], is associated with good outcome and a lower risk of rebleeding. On the other hand, a diffuse SAH may be due to the presence of an intracranial aneurysm. The long-term follow-up and in particular the long-term risk of rebleeding in perimesencephalic and diffuse subarachnoid hemorrhage are not clear and require further study. In the present study, we considered initial angiogramnegative SAH patients with diffuse SAH and pretruncal SAH. Our aim was to study (1) the clinical course and the outcome at discharge, (2) the percentage of intracranial

2 aneurysms diagnosed after a first negative angiogram, (3) the early rebleeding rate, and (4) the long-term followup, in particular in terms of rebleeding and vascular events. Methods A series of 882 (332 males and 550 females) patients admitted within 72 h after a nontraumatic SAH to the neurosurgery section of the University of Torino from November 1991 to December 1999 was investigated. A total of 780 (88.4%) patients showed an aneurysmal SAH (A-SAH). One hundred two cases (11.6%) did not show any vascular malformation at their first cerebral six-vessel angiography. The percentage of negative angiographies for spontaneous SAH did not change significantly from year to year in the studied period. All the initial CT were evaluated by two senior neurosurgeons (MF and DG) and a senior neuroradiologist (GBB) for Fisher s scoring and to distinguish the cases of diffuse SAH (D-SAH) and perimesencephalic SAH (P-SAH). Groups A-SAH All patients in whom the initial angiogram showed the presence of an aneurysm, which was compatible with the SAH on CT, were attributed to the A-SAH group. The initial angiogram-negative cases were divided in two groups: D-SAH The diffuse subarachnoid hemorrhage subtype was assigned to scans demonstrating subarachnoid blood throughout multiple cisterns, typically involving Sylvian, suprasellar, interhemispheric, and perimesencephalic cisterns [13] (Fig. 1a). P-SAH The criteria for a perimesencephalic pattern of hemorrhage were: (1) center of the hemorrhage located immediately Fig. 1 a D-SAH: subarachnoid blood throughout multiple cisterns, typically involving sylvian, suprasellar, interhemispheric, and perimesencephalic cisterns. b P-SAH: perimesencephalic- SAH with center of the hemorrhage located immediately anterior to the midbrain without extension of blood to the ambient cistern or to the basal part of the sylvian fissure. c P-SAH plus: perimesencephalic-sah with hemorrhage located immediately anterior to the midbrain, with extension of blood to the ambient cistern and to the basal part of the sylvian fissure, but with no complete filling of the anterior interhemispheric fissure

3 anterior to the midbrain, with or without extension of blood to the ambient cistern or to the basal part of the sylvian fissure; (2) no complete filling of the anterior interhemispheric fissure and no extension to the lateral sylvian fissure, except for minute amount of blood; (3) absence of frank intraventricular hemorrhage [4] (Fig.1b, c). We found n=79 patients with D-SAH and 23 patients with pretruncal hemorrhage. For inclusion in the study, CT scanning had to be performed within 72 h of the first symptoms and had to show subarachnoid blood at the base of the brain. Patients with a negative CT and where SAH was suspected only on the basis of a positive lumbar puncture were excluded from this study. All the patients were classified on admission according to the Hunt Hess grade [14]. We graded the CT scans using the Fisher scale [7]. We reviewed the clinical course including neurological and other medical complications. Cerebral blood flow velocities were measured in the basal cerebral arteries every 24 h using transcranial Doppler (TCD) to assess large vessel vasospasm [9]. No antifibrinolytic therapy and no seizure medication were administered during hospitalization. Bed rest was maintained until the second angiography. Follow-ups were obtained at 7.9 to 16 years after SAH, with a mean follow-up period of 10.6 years. For the follow-up, patients were contacted by phone to obtain their consent to participate in the data collection. The patients were invited to have a neurological examination at the hospital or at their home, if necessary. The examination was followed by a questionnaire about new stroke events or cardiovascular disease. If a patient had died, the cause of death was retrieved by contacting the physicians in question. Statistical analyses between the A-SAH, D-SAH, and P-SAH groups were performed using the chi-squared test. Clinical characteristic of D-SAH patients In 79 patients, the CT scan showed a diffuse distribution of blood (D-SAH); 44 cases were males (55.7%) and 35 females (44.3%) with an overall mean age of 55.3% years (Table 1). A significantly younger age and a male prevalence was present in this group in comparison with the aneurysmal group (χ 2 =23.506; p=0.000). Hypertension frequency before SAH is reported in Table 1. There was no significant difference in the prevalence of hypertension between the groups. Sixty-eight of the D-SAH patients (86.1%) were in good clinical condition at admission (Hunt Hess grade I II), six cases (7.6%) were grade III, five cases (6.3%) were grade IV, and none grade V. The frequency of patients with Hunt Hess grades I and II was significantly higher in the D-SAH and P-SAH groups compared to the A-SAH group (χ 2 =23.361; p=0.000) (Table 1). The amount of blood on the CT scans according to the Fisher scale is reported in Table 1. The higher percentage of Fisher grade 4 in A-SAH patients is due to the presence of intracranial hematomas in this group. There were no parenchymal hematomas in the D-SAH and P-SAH groups. Nine D-SAH patients (11.4%) showed intraventricular hemorrhage. Seventy-two cases underwent a second angiography between day 11 and day 20 after SAH. In all the cases, the second angiographic study was a digital subtraction conventional (catheter) six-vessel angiography (DSA). In 61 patients, magnetic resonance imaging with the study of the brain and craniocervical junction and a magnetic resonance angiography (Angio-MR) were performed days after SAH. A third angiography was performed only in six cases. In one case described elsewhere [5], a surgical exploration was performed after three negative angiographies, and a thrombosed calloso-marginal artery aneurysm was found. The mean hospitalization time was 22.4 days. TCD was performed daily since admission and until discharge. Clinical characteristic of P-SAH patients The absence of hyperdensity in the anterior interhemispheric or sylvian fissure (pure perimesencephalic hemorrhage; Fig. 1b) was observed in 14 cases (60.9%), the presence of blood in one or both these two fissures ( perimesencephalic plus hemorrhage ; Fig. 1c) was present in nine cases (39.1%). Table 1 Clinical characteristic of the patients on admission A-SAH D-SAH P-SAH Number Age (years±sd) 58.7± ± ±13.0 Males 272 (34%) 44 (55.7%) 16 (69.6%) Females 508 (65.1%) 35 (44.3%) 7 (30.4%) Fischer grade (mean±sd) 3.15± ± ±0.45 Hunt Hess (mean±sd) 2.26± ± ±0.52 Number of hypertensive patients 274 (35.1%) 26 (32.9%) 6 (26.1)

4 Males were predominant in P-SAH patients (16 males and seven females), and the mean overall age was 53.6 years (Table 1). Hypertension is reported in Table 1. On admission, 20 cases (87%) were in good neurological condition (Hunt Hess grade I II), three cases (13%) presented a grade III scale and none grade IV or V patient was present (Table 1). All the 23 patients underwent a second DSA between 11 and 20 days after SAH. In only five patients, a magnetic resonance imaging study of the brain and craniocervical junction and an Angio-MR were performed days after SAH. No third angiography and no surgical exploration were performed. The mean hospitalization time was 19.6 days. TCD was performed daily since admission and until discharge. Results D-SAH group: in hospital course and short-term outcome of 79 patients Four patients out of 79 died prior to the second angiography. Two of them died due to systemic complications: pulmonary embolism occurred in one, and a 75-year-old subject succumbed to pneumonia early on. The other two patients died due to a rebleed before a second angiography. An autopsy was performed in only one of the rebleed cases and showed a 2-mm aneurysm of the anterior communicating artery. A second angiography was not performed in three more cases because of the patient s refusal. At 13, 11.2, and 8 years follow-up, these three patients were in good neurological condition and no rebleeding has occurred. Seventy-two cases out of 79 (91.1%) underwent a second DS angiography. Aneurysms: N=9 out of the 72 (12.5%) patients undergoing a second angiography revealed an intracranial aneurysm. The aneurysm was located in the anterior communicating artery (five cases), the M1 segment of the middle cerebral artery (two cases), the posterior inferior cerebellar artery (one case), and the carotid ophthalmic segment (one case). These cases are described elsewhere [3]. One case was surgically explored after three negative angiographies, and a calloso-marginal artery aneurysm was found [5]. Therefore, 11 patients out of 79 (13.9%) had an intracranial aneurysm in the D-SAH group. In nine cases, the aneurysm was discovered at the second angiography, in one case it was explored and identified surgically, and in one case it was revealed by autopsy. Rebleeding Four out of 79 (5.1%) patients examined with a first pan-angiography had rebleeding episodes: two died before the second angiography as described before and two had an intracranial aneurysm at second angiography. The day of rebleeding was: day 3 and day 8 (died without second angiography) and day 11 and 17. In the last two cases, the second angiography was performed immediately after the rebleeding, and the aneurysm was clipped: the outcome was poor in one case and good in the other one. In 63 out of the 72 patients (87.5%) undergoing the second angiography, a diagnosis of nonaneurysmal diffuse subarachnoid hemorrhage (NAD-SAH) was established (7.1% out of 882 SAH). MR and MR angiography No vascular malformations were found in the 61 patients studied with MR out of 63 with a negative second DSA. Vasospasm TCD monitoring performed daily during hospitalization showed: mean MCA velocities between 120 and 200 cm/s in five cases out of 63 (7.9%) and velocities higher than 200 cm/s in two cases (3.2%) (Table 2). Ischemia Clinical symptoms due to vasospasm occurred in two cases out of 63 (3.2%). In these cases, vasospasm was reversible with good outcome and absence of infarct on CT (Table 2). Hydrocephalus There was an increase of the ventricular size in six patients (9.5%) out of 63; only two patients (3.2%) were shunted with a moderate outcome. Therefore, the frequency of hydrocephalus was significantly lower in comparison with the patients with aneurysmal SAH (χ 2 =16,108; p=0.000) (Table 2). Outcome at discharge Fifty-eight patients out of 63 NAD-SAH were discharged neurologically intact (GOS 5). In four cases, the patients had a minimal neurological deficit Table 2 Complications of SAH: vasospasm, ischemia, and hydrocephalus TCD vasospasm Clinical vasospasm Ischemia Increase of ventricular size Hydrocephalus treated surgically Total A-SAH 211 (27%) 141 (18%) 56 (7.1%) 152 (19.5%) 86 (11.0%) 780 NAD-SAH 7 (11.1%) 2 (3.2%) 0 6 (9.5%) 2 (3.2%) 63 P-SAH 1 (4.3%) 1 (4.3%)

5 (slight hemiparesis in two cases and gait and memory disturbances in two cases) and were classified as GOS 4. One patient was in poor neurological condition and left our department with impaired consciousness (GOS 3). Long-term follow-up of NAD-SAH group In all 63 cases, we obtained information about the medical status for follow-up. Three of them died for malignant tumor (lung in two cases and bowel in one case), 6, 6, 5, and 9 years after SAH. No autopsy was performed with intracranial vessel exploration. No signs of rebleeding were recorded until they died. Vascular events Two patients out of 63 NAD-SAH had a vascular event during follow-up. The first was a 68-year-old man. Five years after SAH, he suddenly lost consciousness. An electrocardiographic assessment performed at the ambulance, on the way to the hospital, showed an ST segment depression; the diagnosis was myocardial infarction, and the patient died before reaching the hospital. An assessment of myocardial enzymes and a cerebral CT scan were not performed, and myocardial infarction was recorded as the cause of death. Postmortem examination was not performed. In this case, a new episode of SAH cannot be excluded because the electrocardiographic anomalies could be a consequence of SAH [11]. The second patient was a 54-year-old man with a history of tobacco use. Sixteen months after SAH, he had a thromboembolic stroke with left-sided hemiplegia. A CT scan had proven an infarct in the territory of the right middle cerebral artery. There was a little improvement in the following months, but he remained disabled. The GOS of the NAD-SAH patients at time of follow-up is reported in Table 3. P-SAH group: in hospital course and short-term outcome of 23 patients Aneurysms and rebleeding The second angiographical study was negative in all of the 23 cases, no rebleeding episodes were recorded during hospitalization. MR and MR angiography No vascular malformations were founded in the five patients studied with MR out of 23 with a negative second DSA. Vasospasm TCD monitoring during hospitalization showed, on MCA, velocities between 120 and 200 cm/s in one case out of 23. This case was a perimesencephalic plus hemorrhage and showed only slight clinical symptoms. No velocities higher than 200 cm/s were found. Hydrocephalus No increase of ventricular size was recorded during hospitalization. Outcome at discharge Twenty-one patients out of 23 P- SAH were discharged neurologically intact (GOS 5). Two patients had a minimal neurological deficit: bilateral VI nerve palsy in one case and memory disturbances in the other case (GOS 4). Long-term follow-up of P-SAH group In all 23 cases, we could achieve information about the medical status at the time of follow-up. All patients were alive. No signs of rebleeding or vascular events were recorded during the follow-up period. Twenty-two patients out of 23 were in good neurological condition. One patient had a persistent bilateral VI nerve palsy 6 years after hemorrhage. The GOS of the P-SAH patients at the time of follow-up is reported in Table 3. Discussion The percentage of patients with SAH and a first negative angiogram ranges between 2% and 24% of the total number of patients with nontraumatic SAH, in various reports [3, 18]. The amount of bleeding shown by CT, associated or not with intraventricular hemorrhage, is instrumental in defining outcome, the risk of rebleeding, and eventually a prediction of a negative cerebral angiography [17, 31]. P-SAH and D-SAH seem to have different prognoses and risk of rebleeding. Table 3 Outcome at discharge and follow-up Outcome GOS 5 GOS 4 GOS 3 and 2 Deaths Total Outcome at discharge Long-term follow-up A-SAH 457 (58.6%) 157 (20.1%) 33 (4.2%) 133 (17.1%) 780 NAD-SAH 58 (92.1%) 4 (6.3%) 1 (1.6%) 0 63 P-SAH 21 (91.3%) 2 (8.7%) NAD-SAH 55 (87.3%) 2 (3.2%) 2 (3.2%) 4 (6.3%) 63 P-SAH 22 (95.7%) 1 (4.3%)

6 The incidence of P-SAH ranges from 20% to 65% of all angiogram-negative SAH. The region where bleeding occurs is mostly immediately anterior to the midbrain, in the interpeduncular and prepontine cisterns and, in some cases, with an anterior expansion towards the ambient cisterns [30]. Blood is rarely located posteriorly towards the quadrigeminal cisterns, anteriorly towards the basal portion of the sylvian fissure or towards the posterior portion of the interhemispheric fissure [4, 24, 29]. However, by definition, a complete filling of the anterior interhemispheric or sylvian cistern is excluded [4, 24]. In our series, a pure pretruncal hemorrhage was more frequent than an extension of the hemorrhage to other cisterns (14 cases out of 23). Some studies support that there is no completely sensitive and specific CT pattern for a nonaneurysmal SAH [1], and a first angiographic study must be performed. We agree with this idea, and we continue to perform a six-vessel angiography even in patients who have the characteristic perimesencephalic SAH pattern on admission CT scans. The predominance of young age and male sex is reported in literature [12, 26, 30]. Our series confirms these data with 69.6% of P-SAH males and an overall mean age of 53.6 years, good prognosis, and with return to a normal life in almost all cases. Some authors believe that the source of the bleeding could be the ventriculostriate or thalamoperforating or interpeduncular veins in the prepontine or interpeduncular cisterns [6, 22, 23, 26], and this can explain the behavioral disturbances, the irritability, and the lack of concentration in affected patients [2, 6, 8]. Most of the authors do not report any association between P-SAH and microaneurysms, concluding therefore that such patients have no indication for a second angiography [31]. In the literature, some authors report 2 16% of posterior circulation aneurysms identified with explorative surgery, where almost all cases had diffuse subarachnoid hemorrhage (microaneurysms or thrombotic aneurysms which could subsequently recanalize) [16, 20, 31]. Patients having aneurysms located on the basilar artery are also described in the literature, but these cases had diffuse hemorrhage in suprasellar and ambient cisterns [4, 21, 28]. In our cases, we found only one aneurysm of the posterior inferior cerebellar artery, diagnosed at a second cerebral angiography, in a patient with a diffuse hemorrhage (0.98% of 102 cases). However, some authors reported that the index of suspicion for a posterior circulation aneurysm should remain high in patients with P-SAH [28]. For this reason, if it is clear that a first cerebral angiography must be performed even in cases of P-SAH, it is not clear if in these cases a second angiographical study is necessary. Our series of patients confirms the data reported in the literature and, according to some authors, the P-SAH can be identified as a clinical entity alone, mostly benign, with a very good outcome and a low rate of complications [15, 20, 24, 30, 34]. Only a case of recurrent P-SAH was observed following the administration of anticoagulant therapy in the early phase after hemorrhage [33]. In our series and as other reports showed, no rebleeding occurred while waiting for cerebral angiography, and no intracranial aneurysm was found [15, 22]. For this reason, we think that a second angiography in P-SAH is not necessary. The role of MRI, Angio-MRI, or Angio-CT to determine the cause of SAH was discussed [5]. In our experience, these techniques provided little diagnostic yield when performed in addition to DSA and did not offer any further information. We think that Angio-MRI is not necessary. The occurrence of hydrocephalus, which generally is transitory or treatable with lumbar punctures alone [31], varies from 1% to 15% among all nonaneurysmal subarachnoid hemorrhage, in 1% of P-SAH and in 4% of D-SAH [31]. The difference is due to the absence of intraventricular hemorrhage and to the small amount of blood in the cisterns that allows the absorption [30]. In our report, as in many others, there were no cases of surgical hydrocephalus for P-SAH [4]. A minimal increase of the ventricular size was observed in six patients (9.5%) with NAD-SAH, and only two cases (3.2%) needed a shunt. Vasospasm, which is asymptomatic and transitory in P-SAH, is described in 5 10% of the diffuse hemorrhage cases [4, 19, 30]. In our series, and in some other reports [19], no ischemia occurred in P-SAH patients, and only one patient had slight symptomatic vasospasm. In patients with diffuse hemorrhage, rebleeding was reported in 2 5% of cases [4, 25, 30]. In our series, the percentage of rebleeding is high (four cases out of %), but all the episodes occurred within 17 days after first SAH. Late rebleeding was suspected in only one case. Therefore, in our opinion a second angiography is mandatory during hospitalization, but further studies are usually not indicated. Only in cases of poor clinical grade at admission, where the blood is predominantly in the sylvian fissure and in the interhemispheric fissure, a second or even a third angiography is indicated [24]. The second angiography should be performed early after the bleeding between the third and the tenth day after SAH. Considering all this, the suggestion not to perform a cerebral angiography after a CT showing a pretruncal pattern [10, 16, 20] seems reasonable, even though almost all the authors still indicate it [2, 25, 31, 32]. The outcome is good, even in some cases, after rebleeding [4]. Complications are rare, and patients with a nonaneurysmal subarachnoid

7 hemorrhage have a good outcome in 84 93% of the cases [2, 4, 25]. The surgical exploration after P-SAH is not indicated even if some authors described it [17]. In our series, we performed a surgical exploration finding a thrombosed aneurysm. Therefore, it is possible that many cases of diffuse nonaneurysmal subarachnoid hemorrhage are due to an intracranial aneurysm thrombosed after the bleeding. The recanalization of the sac seems to be possibly early after the bleeding. In fact, the second DSA performed within 21 days shows intracranial aneurysms in a high percentage of patients (nine of %); a late recanalization of the aneurysm with rebleeding seems to be rare, as the follow-up shows. Moreover, DSA may miss a first aneurysm because of a mistake by the examiner due to thrombosis, technical difficulties, surrounding hematoma, its size, and because of focal arterial spasm which may lead to a temporary obliteration of the aneurysm neck [18]. Although most authors agree that this disease is benign in the short run, very few series analyze the long-term follow-up. Our series demonstrated that several complications may occur shortly after bleeding, but a late rebleeding is very rare, therefore the life expectancy of these patients should be considered as the general population. Conclusions Short- and long-term follow-up show that P-SAH is a benign disease. A first angiographical study is mandatory in all cases, but a second angiography could not be necessary. D-SAH is probably due to an intracranial aneurysm that thromboses early after the bleeding. In these cases, at shortterm follow-up, the sack could frequently recanalize and rebleed, whereas a late follow-up shows that rebleeding is very rare. References 1. Alén JF, Lagares A, Lobato RD, Gómez PA, Rivas JJ, Ramos A (2003) Comparison between perimesencephalic nonaneurysmal subarachnoid hemorrhage and subarachnoid hemorrhage caused by posterior circulation aneurysms. 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8 26. Rogg JM, Smeaton S, Doberstein C, Goldstein JH, Tung GA, Haas RA (1999) Assesment of the value of MR imaging for examining patients with angiographically negative subarachnoid hemorrhage. Am J Roentgenol 172: Schievnik WI, Wijdicks EF (1997) Pretruncal subarachnoid hemorrhage: an anatomically correct description of the perimesencephalic subarachnoid hemorrhage. Stroke 28: Schievnik WI, Wijdicks EF, Piepgras DG, Nichols DA, Ebersold MJ (1994) Perimesencephalic subarachnoid hemorrhage. Additional perspectives from four cases. Stroke 25: Schwartz TH, Mayer SA (2000) Quadrigeminal variant of perimesencephalic nonaneurysmal subarachnoid hemorrhage. Neurosurgery 46: Schwartz TH, Solomon RA (1996) Perimesencephalic nonaneurysmal subarachnoid hemorrhage: review of the literature. Neurosurgery 39: Tatter SB, Crowell RM, Ogilvy CS (1995) Aneurysmal and microaneurysmal angiogram-negative subarachnoid hemorrhage. Neurosurgery 37: Topcuoglu MA, Ogilvy CS, Carter BS, Buonanno FS, Koroshetz WJ, Singhal AB (2003) Subarachnoid hemorrhage without evident cause on initial angiography studies: diagnostic yield of subsequent angiography and other neuroimaging tests. J Neurosurg 98: van der Worp HB, Fonville S, Ramos LM, Rinkel GJ (2009) Recurrent perimesencephalic subarachnoid hemorrhage during antitrombotic therapy. Neurocrit Care 10: Velthuis BK, Rinkel GJ, Ramos LM, Witkamp TD, van Leeuwen MS (1999) Perimesencephalic hemorrhage. Exclusion of vertebrobasilar aneurysms with CT angiography. Stroke 30: Comments Deanna Sasaki-Adams, Saint Louis, USA The manuscript entitled, Subarachnoid Hemorrhage and Negative Angiography: Clinical Course and Long-term Follow-up submitted by Dr. Fontanella et al. seeks to evaluate radiographic and clinical characteristics that differentiate between diffuse and perimesencephalic angiographically negative subarachnoid hemorrhage. It has been customary in many institutions to perform two to three angiograms in these patients to confirm no aneurysmal origin of the subarachnoid hemorrhage. Fontanella et al. have demonstrated that a second angiogram may not be necessary in those patients whose initial CT scan shows blood limited to the area just anterior to the midbrain without significant extension into the interhemispheric fissures or ambient cisterns. In a retrospective review of 79 patients with angiogram negative for underlying aneurysm, 23 patients were defined as having a characteristic pattern in the perimesencephalic region as opposed to a more diffuse pattern of hemorrhage. None of those patients labeled with perimesencephalic hemorrhage alone were found to have a lesion upon repeat angiography, and all demonstrated a benign clinical course. The data suggest that a repeat arteriogram in a select group of patients may not be necessary. The present study supports what many neurosurgeons have found to be true anecdotally and will add to our armamentarium when dealing with these often challenging scenarios in an evidence-driven and cost-effective manner. Giuseppe Lanzino, Emanuela Crobeddu, Rochester, MN, USA Fontanella and coworkers retrospectively analyzed a consecutive series of patients with subarachnoid hemorrhage (SAH) and no evidence of aneurysm on first catheter angiography. Patients were followed for a mean of 10.6 years. Two groups are considered: patients with classic pretruncal SAH (23 patients) and those with a diffuse pattern suggestive of aneurysm rupture (72 patients). Patients underwent a second look angiography between day 11 and day 20 after SAH. In patients with diffuse SAH, the second angiogram revealed an aneurysm in nine out of 72 (12.5%), and four patients in this group suffered a rebleeding before a definitive diagnosis of the aneurysm. Angiography-negative SAH continues to be not an uncommon diagnosis among patients with nontraumatic SAH despite sophisticated and ever improving diagnostic imaging. Patients with a classic pattern of pretruncal hemorrhage share other clinical characteristics, namely good clinical appearance on presentation, a relatively benign course (even though they can occasionally suffer from vasospasm and hydrocephalus), and a uniformly good outcome. We agree with the authors that in patients with a classic pattern a high-quality sixvessel angiogram suffices and no repeat imaging studies are necessary. Patients with a diffuse, true aneurysmal pattern continue to represent a challenge. It has been our experience that with modern 3D angiography capabilities, these patients are less common than a few decades ago. In these patients, careful search of an offending underlying vascular cause is imperative given the risk of rebleeding. We routinely perform a second look catheter angiography in this group. The timing of the repeat angiogram in this situation is controversial. However, this study suggests that another catheter angiography should probably be performed 1 week after presentation since the four rebleedings observed occurred between days 3 and 17. We have noticed that more and more patients with angiographynegative SAH fall within a third category: the pretruncal plus pattern. In this category, the epicenter of the bleeding is still in the area of the interpeduncular cistern, but the subarachnoid blood extends beyond the confines considered classic for the pretruncal type such as the distal sylvian fissure and the distal two thirds of the interhemispheric fissure. We have noted (a finding corroborated by others) that often these patients are on antiplatelet or anticoagulation therapy. Therefore, it is conceiveable that in some of these cases, the bleeding originates from the same source which gives rise to the classic pretruncal pattern, but the blood burden may be increased by the pharmacological effects of the antiplatelet/anticoagulant treatment allowing for extension beyond the boundaries of the pretruncal type. In these patients, we perform a second look catheter angiography only selectively and often consider a noninvasive method instead. Future research will likely further characterize this specific subgroup. One final word about the use of axial imaging studies such as MRI of the brain and cervical spine. These have been traditionally recommended to rule out possible, less common causes of SAH such as cavernous malformations or the sporadic tumor (usually ependymoma or schwannoma). For the past 9 years, we have been doing axial imaging of the brain and the cervical spine routinely in patients with angiography-negative SAH, but in accordance with Fontanella and coworkers findings, we have not found these studies useful. We now consider MRI of the brain and cervical spine only selectively in those patients with atypical features or when symptom onset clearly suggests a possible upper spinal origin of the bleed (i.e., sudden, severe pain starting in the spine, and then migrating upward).