Nonaneurysmal Perimesencephalic Subarachnoid Hemorrhage: Diagnosis, Pathophysiology, Clinical Characteristics, and Long-Term Outcome

Accepted Manuscript Nonaneurysmal perimesencephalic subarachnoid hemorrhage: diagnosis, pathophysiology, clinical characteristics and long-term outcome Anish Kapadia, Tom A. Schweizer, Ph.D. Julian Spears, M.D. Michael Cusimano, M.D., Ph.D., R. Loch Macdonald, M.D., Ph.D. PII:

S1878-8750(14)00664-0

DOI:

10.1016/j.wneu.2014.07.006

Reference:

WNEU 2453

To appear in:

World Neurosurgery

Received Date: 11 July 2013 Revised Date:

24 June 2014

Accepted Date: 3 July 2014

Please cite this article as: Kapadia A, Schweizer TA, Spears J, Cusimano M, Macdonald RL, Nonaneurysmal perimesencephalic subarachnoid hemorrhage: diagnosis, pathophysiology, clinical characteristics and long-term outcome, World Neurosurgery (2014), doi: 10.1016/j.wneu.2014.07.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Nonaneurysmal perimesencephalic subarachnoid hemorrhage: diagnosis, pathophysiology, clinical characteristics and long-term outcome Anish Kapadia1, Tom A. Schweizer, Ph.D., 1-4, Julian Spears, M.D. 1-3, Michael Cusimano M.D., Ph.D.,1-3, R. Loch Macdonald, M.D., Ph.D. 1-3 1

Division of Neurosurgery, St. Michael’s Hospital, Toronto, ON, Canada Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada 3 Keenan Research Centre of the Li Ka Shing Knowledge Institute at St. Michael’s Hospital, Toronto, ON, Canada 4 Heart and Stroke Foundation of Ontario Centre for Stroke Recovery, Toronto, Canada

RI PT

2

SC

Keywords: Perimesencephalic, Subarachnoid Hemorrhage, SAH, Pretruncal, Nonaneurysmal, Angiogramnegative, review

M AN U

Address correspondence to:

AC C

EP

TE D

R. Loch Macdonald, M.D., Ph.D. Keenan Endowed Chair in Surgery Head, Division of Neurosurgery St. Michael's Hospital Professor of Surgery, University of Toronto 30 Bond Street, Toronto, Ontario, Canada M5B 1W8 P: 416-864-5393 F: 416-864-5634 [email protected]

ACCEPTED MANUSCRIPT ABSTRACT Patients with nonaneurysmal perimesencephalic subarachnoid hemorrhage (NAPSAH) have no discernible source for the bleeding and are generally considered to have a benign condition. Correctly diagnosing these patients is essential as a missed aneurysm can have catastrophic consequences. Those

RI PT

presenting with NAPSAH have a low risk of complications, and better outcome than aneurysmal SAH (aSAH). However, a limited body of literature suggests that not all of these patients are able to return to their premorbid functional status. Clinical screens of cognitive status, such as the mini-mental status exam (MMSE)

SC

suggest good recovery of these patients although these tests may lack sensitivity for identifying deficits in this patient population. More comprehensive neuropsychological testing in some studies has identified deficits in a

M AN U

wide range of cognitive domains at long-term follow-up in patients with NAPSAH. Since these patients often do not lose consciousness (and thus do not have substantial transient global ischemia) and they do not undergo an aneurysm repair procedure, the cognitive sequelae can be explained by the presence of blood in the subarachnoid space. NAPSAH presents an opportunity to understand the effects of subarachnoid blood in a

TE D

clinical setting. INTRODUCTION

Subarachnoid hemorrhage (SAH) is a pathologic condition characterized by the presence of blood in the

EP

subarachnoid space. Eighty-five percent of patients with non-traumatic SAH have an underlying cerebral aneurysm as the cause, and the remaining 15% are idiopathic 82. Patients with aneurysmal SAH have a mortality

AC C

of 35% and poor neuropsychological outcome is common in survivors 3,67. For patients that present with SAH in whom the source of the bleeding cannot be found, the clinical course and outcome depends on the pattern of the SAH 29. Patients with non-aneurysmal, non-perimesencephalic SAH tend to have a clinical course similar to aneurysmal SAH (aSAH), and have some risk of having an underlying cause for the hemorrhage. In contrast, no cause for the hemorrhage can be found in non-aneurysmal perimesencephalic subarachnoid hemorrhage (NAPSAH), which is typically considered to have a benign clinical course. NAPSAH was described by van Gijn et al 83

, who defined it as focal SAH in the midbrain cisterns with no more than minimal blood in the Sylvian and

interhemispheric fissures and without frank intraventricular blood. Patients presenting with NAPSAH usually

ACCEPTED MANUSCRIPT have a relatively uncomplicated clinical course. However, some studies suggest NAPSAH is not as benign as previously thought. Cognitive deficits have been reported in patients with NAPSAH, and may include deficits in memory, attention and executive function. These persisting deficits may prevent these patients from regaining their pre-morbid function. This review summarizes the clinical characteristics, diagnostic approaches, potential

RI PT

pathophysiology, and cognitive and functional outcomes of patients with NAPSAH. METHODS

Peer-reviewed articles reporting diagnostic approaches, pathophysiology, clinical characteristics,

SC

cognitive outcomes or functional outcomes of patients with perimesencephalic SAH were identified. The search terms “perimesencephalic” OR “perimesencephalic subarachnoid hemorrhage” OR “pretruncal” OR “pre-

M AN U

mesencephalic” were used to search MEDLINE. English language articles from January 2000 to June 2012 were considered. Of 164 references returned, 65 studies were included. Case reports were excluded unless they illustrated a specific novel point; all other papers were reviewed. Reference lists of suitable studies were scrutinized for additional articles.

TE D

RESULTS Diagnostic Approach

EP

The diagnosis of NAPSAH is a diagnosis of exclusion. The perimesencephalic bleeding pattern on unenhanced CT is commonly defined using the guidelines set out by Rinkel, et al: (1) center of the hemorrhage

AC C

located immediately anterior to the midbrain, with or without extension of blood to the anterior part of the ambient cistern or to the basal part of the Sylvian fissures; (2) no complete filling of the anterior interhemispheric fissure and no extension to the lateral Sylvian fissures, except for minute amounts of blood; and (3) absence of frank intraventricular hemorrhage 68. If an angiographic study does not disclose a source of bleeding, NAPSAH is diagnosed. The first question is what kind of angiographic study to conduct in a patient with NAPSAH (Figures 1 and 2). According to criteria put forward by Rinkel and colleagues, up to 27% of patients classified to have a perimesencephalic hemorrhage pattern on unenhanced CT will have an aneurysm 82 . Correct identification of

ACCEPTED MANUSCRIPT the perimesencephalic bleeding pattern on unenhanced CT is important for making decisions about patient management. Patients with a perimesencephalic pattern of bleeding are less likely to have an identifiable source of hemorrhage compared to those with a non-perimesencephalic pattern. The initial CT must be acquired in a timely manner, as subarachnoid blood clearance can result in false-positives 68. It was estimated that 7 to 17% of

RI PT

patients with ruptured posterior circulation aneurysms have a perimesencephalic pattern 4,39 and 5 to 7% of patients with this pattern of bleeding will be found to have an aneurysm 4,66. Consequently, there is a tendency for patients with the perimesencephalic pattern of bleeding to undergo fewer or even no catheter angiograms.

SC

Hence, a greater possibility exists for missing the source of hemorrhage if the pattern is incorrectly identified. Alen, et al., found 8.9 % of patients with a perimesencephalic SAH pattern on CT had a posterior circulation

M AN U

aneurysm detected on initial angiographic study 4.

Nayak, et al., proposed a system for classifying non-aneurysmal SAH 61. Pattern type 1a (blood in basal cisterns only) provides a more strict criterion for the diagnosis of NAPSAH than that put forth by Rinkel, et al 68. Naidech and colleagues studied a series of patients with non-aneurysmal SAH. They elected to ignore the exact

TE D

CT bleeding pattern entirely, citing the poor inter-rater reliability. Instead, they were able to demonstrate a significant association between hemorrhage volume, and poor outcome at 14 days, as measured by the modified Rankin scale (mRS), as well as in the incidence of hydrocephalus 60.

EP

Rinkel, et al., suggested that it was possible to distinguish NAPSAH from aneurysmal SAH with high positive predictive value (0.95 and 0.94, two respective observers), and high interobserver reliability (Cohen’s k

AC C

= 0.87), based on the pattern on noncontrast CT scans in 52 non-aneurysmal patients 68. A subsequent study of 40 patients with posterior fossa SAH supported these findings with 95% interobserver agreement (Cohen’s k = 0.89 [95% CI: 0.75, 1.00]) on noncontrast CT and 100% agreement on CT angiography (CTA), and no errors in identifying NAPSAH 85. Brinjikji, et al., assessed inter- and intraobserver variability in the diagnosis of NAPSAH and included 4 neuroradiologists who assessed noncontrast CT scans obtained on 4- and 16-slice scanners, taken within 24 hours of ictus in 37 patients with normal catheter digital subtraction angiography. Interobserver (Cohen’s k = 0.79) and intraobserver (Cohen’s k = 0.80) agreement was good in identifying NAPSAH 10. However, there was disagreement in 22% of cases even among these expert reviewers. Van Dijk and coworkers compared

ACCEPTED MANUSCRIPT the findings of two observers for 303 patients with noncontrast CT scans taken within 72 hours of ictus, and demonstrated a 93% agreement (Cohen’s k = 0.65) for identifying NAPSAH from CT in all SAH patients. Aneurysms were found in 23% and 27% (observer 1 and observer 2, respectively) of patients who were identified as having NAPSAH, with 19% demonstrating vertebrobasilar aneurysms (both observers)82. In that

RI PT

study, observers were expected to identify NAPSAH while blinded to angiography results which is not representative of the clinical setting 10,82. Another study using 16-, 40- and 64-slice CT scanners demonstrated excellent agreement between 2 neuroradiologists who (Cohen’s k = 0.91; 95% CI: 0.89, 0.93) categorized

SC

noncontrast CT scans of 77 patients with angiogram negative SAH into NAPSAH, nonperimesencephalic SAH, and CSF xanthochromia 18. In summary, five of five studies suggest NAPSAH can be correctly identified on

M AN U

noncontrast CT, with excellent positive predictive value, when neuroradiologists have access to angiography results 18,68,85. Thus, there is emerging data that CTA may be adequate to exclude vascular pathology in patients with NAPSAH.

On the other hand, exclusion of aneurysms is critical to diagnosing NAPSAH, as aSAH is associated with a

TE D

high risk of rebleeding, and mortality. For this reason some authors continue to advocate for catheter angiographic studies. Catheter angiography with 3 dimensional reconstruction is the gold standard technique in patients with SAH 15. However, in some studies, catheter angiography is associated with up to a 2.6% risk of

EP

permanent neurological complications in NAPSAH 69. As a result, the omission of catheter angiography from the investigation of patients with NAPSAH has been suggested, being replaced by CT angiography (CTA). The

AC C

sensitivity of CTA for detecting aneurysms is high and several studies have investigated its use as the primary and/or only angiographic modality for investigation of patients with NAPSAH. Catheter angiography-related complications have been reported in 6 of 295 patients with NAPSAH, with 1 patient developing a permanent stroke 1,16. The literature estimates of complications related to catheter angiography range from 0.9%-2.3%16. Ruigrok, et al., recommended CTA as the sole angiographic modality in NAPSAH based on a decision analysis which demonstrated that CTA should be preferred over catheter angiography if the rate of complications with catheter angiography is greater than 0.2% 69. This strategy assumes correct diagnosis of NAPSAH on CT.

ACCEPTED MANUSCRIPT In studies where CTA was the primary investigation modality, follow-up catheter angiography found only one (0.3%) aneurysm among 290 patients across seven studies (Table 2) 50. In contrast, studies using catheter angiography as one of the initial modalities reported 6 missed sources that were found on repeat catheter angiography and 1 source discovered on subsequent magnetic resonance imaging (MRI) in 435 patients among

RI PT

13 studies (Table 2) 6,37,54. CTA performed within 72 hours of SAH demonstrates excellent results when detecting aneurysms, which differentiates NAPSAH from aSAH, with a sensitivity of 99.9% (95% confidence interval [CI]: 99.5%, 100.0%), specificity of 99.4% (95% CI: 96.1%, 99.7%), a positive predictive value of 99.9% (NPV; 95% CI:

SC

99.5%, 100.0%) and a negative predictive value of 99.4% (PPV; 95% CI: 96.1%, 100.0%) However, one of the studies included patients undergoing CTA up to two weeks post-ictus; this may lead to incorrect identification of

M AN U

the bleeding pattern and explain the one aneurysm identified on subsequent angiographic studies. Of the seven studies that used CTA for initial investigation, three studies were excluded from this pooled analysis because false-positives were not reported or the population was repeated in another study. For comparison, in the angiogram-negative patients, as a whole, CTA demonstrated sensitivity of 97.5% (95% CI: 96.5%, 98.2%), specificity of 98.9% (95% CI: 97.2%, 99.6%), PPV of 99.6% (95% CI: 99.1%, 99.9%) and NPV of 92.3% (95% CI:

TE D

89.4%, 94.5%) in the same studies. One of the five studies used a 64-slice CT scanner and found 12 falsenegatives (no NAPSAH) in 912 patients, while the other three studies used 16- or 64-slice scanners, and found 24 false-negatives (1 in NAPSAH) in 905 patients. None of the ten studies which used catheter angiography as one

EP

of the initial diagnostic modalities reported false positives, thus restricting pooled analysis 1,43,50,87. The use of catheter angiography as an initial study demonstrated a sensitivity of 99.9% (95% CI: 99.8%, 100.0%) for

AC C

NAPSAH, and a sensitivity of 99.2% (95% CI: 99.0%, 99.4%) for all angiographically-negative cases across ten studies. These results support previous suggestions for the use of CTA as a primary diagnostic test 1,16,43,88. A recent meta-analysis addressing the use of CTA for intracerebral hemorrhage demonstrated sensitivity, specificity, PPV and NPV of 97.0% (95% CI: 93.2, 99.1%), 98.9% (95% CI: 97.0, 99.7%), 97.8% (95% CI: 94.2, 99.5%) and 98.5% (95% CI: 96.6, 99.5%), respectively, suggesting CTA as a viable replacement for catheter angiography, at least for intracerebral hemorrhage. Thus, results of recent studies support the omission of catheter angiography from the diagnostic protocol for patients with NAPSAH in favor of CTA 1,2,16,87. This is

ACCEPTED MANUSCRIPT consistent with our practice, but performing catheter angiography in these patients continues to be a reasonable option. While there is some debate about the initial type of angiography to use in patients with NAPSAH, it is agreed that a second catheter angiogram in such patients is generally unnecessary. MRI of the brain and spine,

RI PT

and MR angiography have only very rarely demonstrated lesions in NAPSAH patients 6,50,54,80. Lin, et al., reported a single patient with NAPSAH who was found to have a venous infarct diagnosed on MRI as the source of the hemorrhage 49. Although MRI is a low-yield test, it may help identify uncommon lesions such as spinal

SC

arteriovenous fistulae, which can present as a NAPSAH. Thus, we do not perform MRI in a delayed fashion in these patients.

M AN U

There are some caveats to the recommendations for investigating patients with suspected NAPSAH. The main one is the subjective variability in interpreting the pattern of hemorrhage. If only CA is conducted, it must be a technically adequate study visualizing the appropriate areas of the cerebral circulation, particularly given that, as mentioned above, up to 10% of SAH from posterior circulation aneurysms has a NAPSAH pattern (Figure

TE D

2). Complicating matters further, a more diffuse SAH can potentially mimic a perimesencephalic pattern if imaged after partial clot resorption. Many of the studies have applied a cut-off at 72 hours post-ictus for interpreting the bleeding pattern, however, clinical evidence for this time-frame is lacking and maybe an area

EP

that can be addressed in future studies. We did not find any studies examining the clot clearance rates and patterns after aneurysmal SAH compared to NAPSAH. There also is some concern that extrapolating results

AC C

obtained from prospective imaging studies (i.e. where the investigators may pay special attention to the radiology investigations) may not reflect day-to-day practice. Finally, strict guidelines don’t take into account the endless minor variations in cases that do not conform exactly to accepted definitions. Etiology and Pathophysiology

The etiology of the bleeding in patients with NAPSAH is unknown. Theories include variations in deep venous drainage of the brain, rupture of perforating arteries or veins, basilar artery dissection and hemorrhage from the artery of Davidoff and Schecter. The theory that NAPSAH is of venous origin, due to variations in the basal vein of Rosenthal or one of its tributaries, was proposed in the first description of NAPSAH, although no

ACCEPTED MANUSCRIPT abnormalities could be identified 81,83,86. Watanabe, et al., examined the venous drainage and basal vein of Rosenthal in 6 patients with NAPSAH 86. They found that 58% of the basal veins had primitive configurations in patients with NAPSAH compared to only 22% of 102 patients with aneurysmal SAH. Furthermore, the primitive venous configuration was localized to the side of hemorrhage 86. Subsequent studies supported these findings; 3

RI PT

studies of 275 patients reported 40-66% of patients with NAPSAH had a primitive configuration of the basal vein of Rosenthal compared to 10-19% in patients with aneurysmal SAH 41,81,89. However, Daenekindt and colleagues compared the venous phases of catheter angiography in 59 patients with NAPSAH and 59 with aSAH and did not

SC

find a difference in venous configuration between the groups 17. Furthermore, the primitive configuration of the basal vein of Rosenthal failed to explain the hemorrhage in all NAPSAH patients, with many patients

M AN U

demonstrating normal venous drainage. Although a primitive configuration of the basal vein of Rosenthal is most commonly studied, other venous abnormalities such as stenosis of vein of Galen, jugular vein, cavernous sinus and straight sinus have also been implicated in various case reports as potential sources of the bleeding 47,55,72,77

. Other authors have proposed the anterior longitudinal pontine or interpeduncular and posterior

communicating veins as the source 68, and wide spread venous thrombosis and venulitis (associated with

TE D

Behcet’s disease) has also been reported to present with NAPSAH 48. Thus, venous abnormalities may account for cases of NAPSAH, however, studies are not uniformly suggestive of this, and a variety of other pathologies

EP

have been theorized to give rise to NAPSAH.

One study found that 3 of 13 patients with NAPSAH had small aneurysms of mesencephalic perforating

AC C

arteries that were visualized on three dimensional CTA reconstructions. These spontaneously resolved. Other studies supporting these findings have not been reported 64. Other vascular pathologies such as rupture of thalamoperforating arteries 5 and cryptic brain stem arteriovenous malformations have also been suggested to cause NAPSAH 14. Schievink and Wijdicks postulated that NAPSAH was due to primary intramural hematoma (spontaneous bleeding into the artery wall) of the basilar artery 74. Case reports have provided evidence for these and other pathologies; including spinal arteriovenous fistula, small dissections of the basilar artery and spinal arachnoid cyst presenting as NAPSAH 28,63,79. Therefore, these pathologies should be considered, in

ACCEPTED MANUSCRIPT addition to an aneurysm, when assessing a NAPSAH patient, although they don’t account for the majority of cases, for which the etiology remains elusive. The current literature suggests that the etiology may be a diverse group of pathologies which happen to present with the NAPSAH picture. In current clinical practice there is no routine search for many of the

searching for these lesions, as chances of a second event are very small. Demographics and Clinical Factors

RI PT

uncommon non-aneurysmal etiologies suggested in the literature. However, there may be no benefit in

SC

Approximately 15% of patients with SAH have no identifiable cause for the hemorrhage on initial diagnostic work-up. Thirty-eight percent of these patients (range 21%-77%) have NAPSAH based on the bleeding

M AN U

patter on their admission CT scan 1,6,9,11,12,16,18-20,26,27,31,34,37,40,41,43,49,50,53,57,59,62,73,80. Patients with NAPSAH have a mean age of 53 (range 22 to 86 years) and demonstrate a unique gender demographic, with the majority of studies demonstrating a predominantly male, comprising of 54% (24%-75% male), patient population compared to the predominantly female population in aneurysmal SAH 1,4,6,8,12,16-19,21,24,32,34,40,41,44-46,50-53,56-58,60,70,80,86,89.

TE D

The prevalence of pre-existing hypertension in patients with NAPSAH is 35% (14% to 39%), which is only slightly higher than the global prevalence of hypertension in adults (26%) 4,8,19,24,34,42,45,46,73,89. Twenty seven percent (17%-31%) of patients with NAPSAH are smokers 8,19,24,27,45,73. This is lower than the

EP

incidence of smoking among patients with aneurysmal SAH, which is approximately 2/3 of patients 7. Gupta, et al., reported a significantly higher prevalence of diabetes (17%) in NAPSAH patients compared to aSAH, with an

AC C

overall prevalence of 12% in six studies 19,27,46,53,60,73. Three studies found the prevalence of alcohol abuse in NAPSAH to be 11%, 17% and 34% respectively 27,46,57. In contrast, Caerio and Ildan found no patients with NAPSAH who had a history of alcohol abuse 11,34. However, no consistent definition is provided across studies for what is considered alcohol abuse. NAPSAH is suggested to be more commonly associated with straining at the time of ictus than aSAH. Yamakawa, et al., found that 69% of patients with NAPSAH were performing activities which involved the Valsalva maneuver at the time of ictus, which was significantly higher than the number of aSAH occurring during exertion (14%)89. Other studies reported that 16%-50% of patients with NAPSAH were

ACCEPTED MANUSCRIPT straining at the time of ictus, with a mean of 36% across all studies 4,41,86. The types of physical activities included swimming, lifting, defecation and sexual intercourse. Patients with NAPSAH generally present with milder symptoms than aSAH. There are infrequent mentions of loss of consciousness at ictus in the literature 4,56,89. However, Ildan and colleagues reported loss of

RI PT

consciousness at presentation in 31% of NAPSAH patients, accounting for 9 of 10 cases reported from a total of 110 NAPSAH patients 34. The Hunt and Hess grade, World Federation of Neurological Surgeons (WFNS) grade and Glasgow Coma Scale (GCS) have been used to report the neurological condition of patients presenting with

SC

NAPSAH. Most studies report that greater than 90% of patients are Hunt and Hess or WFNS grade 1 or 2 (Table 3)1,8,11,13,16,20,21,25,32-34,37,40,41,43,44,46,50-52,56,58,73,80,81,86,89. Only 0.6% of NAPSAH patients had a Hunt and Hess score of

M AN U

4, 1.3% had a WFNS score of 4 or higher, and 2.2% had a GCS of 12 or less 8,32,37,41,73. Only 2 of 281 (0.7%) patients with NAPSAH died in hospital 6,19,34,53,60,73. In contrast, aSAH patients often present with poorer neurological condition and the in-hospital mortality is 15% to 20% 30,35.

Patients with congenital or acquired coagulation or platelet-vessel defects may be more likely to

TE D

present with larger volumes of SAH and to have poorer outcome. Most studies do not comment on this factor, and in those that do, the vast majority of the abnormalities are secondary to anticoagulant or antiplatelet drugs. Five studies identified NAPSAH patients with antithrombotic states, with 12 of 162 patients (7.4%) identified as

EP

having an antithrombotic state. However, it should be noted that Naidech, et al., did not follow the strict

AC C

definition of NAPSAH, and they accounted for 8 of the 12 cases identified 60. The incidence of complications such as rebleeding, angiographic vasospasm, delayed cerebral ischemia (DCI) and hydrocephalus are lower after NAPSAH than after aSAH. Only 5 cases of early rebleeding were reported among patients with NAPSAH across 16 studies and 576 patients (0.9%) 6,9,12,20,21,24,34,37,40,46,49,51,52,56,62,86. One patient died of rebleeding 6,34,52. Boswell and colleagues calculated that the odds ratio for not rebleeding was 2.78 for NAPSAH in comparison to diffuse non-aneurysmal SAH 9. The incidence of hydrocephalus within days of the hemorrhage was 9.3% (range of 0 to 17%) of patients with NAPSAH 4,6,8,11,20,21,25,32,34,37,40,41,51,52,56,89, which is significantly less than after diffuse non-aneurysmal SAH 40 and aSAH (20%-30%) 22. DCI is reported in 2.3% (0 to 9.6% study ranges) of patients with NAPSAH in 10 studies that included 313 patients 21,33,37,40,52,80.

ACCEPTED MANUSCRIPT Gross, et al., reviewed literature on angiographic vasospasm and DCI in patients with NAPSAH and reported that the odds ratio for development of DCI in patients with diffuse, nonaneurysmal SAH was 3.79 when compared to patients with NAPSAH 26. Only two patients with NAPSAH out of 206 have been reported to have had infarctions due to angiographic vasospasm 6,21.

RI PT

Hospitalization after NAPSAH is on average shorter than for aSAH 6,8,9,33,43,44,50,80,90. The mean duration of stay in hospital was 10.5 days (4.3 to 19.6 days study means) among 195 patients with NAPSAH 6,8,9,33,43,44,50,80. This is also shorter than patients with a non-perimesencephalic pattern of angiographically negative SAH 6,8,80.

SC

Outcome at discharge after a SAH is often categorized on the mRS or the Glasgow Outcome Scale (GOS)36,84. The GOS was used to assess condition at discharge for 136 patients with NAPSAH in six studies (Table

M AN U

5). One hundred thirty three (97.8%) of these patients had good recovery or moderate disability on the GOS at discharge (Table 5) 20,21,46,56,89. The mRS was used to assess outcome at discharge in five studies that included 108 patients 6,11,31,41,50. Only 5 (4.6%) patients demonstrated moderate to severe disability, with a small number demonstrating mild deficits and the majority being symptom free. Hence, overall 97% of patients with NAPSAH

TE D

are expected to be able to live independently at the time of discharge. Matsuyama and colleagues reported outcome at discharge qualitatively, rating all NAPSAH patients as having an “excellent” outcome, indicating their ability to return to daily activity. Thus, on these relatively simple outcome scales, the evidence supports the

EP

notion that NAPSAH is a relatively mild condition with good outcomes, as early as at the time of discharge.

AC C

The demographic and risk profiles of patients with NAPSAH suggests that this condition afflicts middle aged individuals without particularly high incidence for vascular disease. Patients presenting with NAPSAH typically have fewer risk factors and present with smaller localized clots, compared to aSAH. Consequently, they are generally in good clinical condition at the time of presentation, develop relatively few complications and require fewer days in hospital. Although measures of gross outcome demonstrate excellent outcome at discharge, certainly superior to patients with aSAH and non-perimesencephalic pattern of angiographically negative SAH, more subtle cognitive changes may occur.

ACCEPTED MANUSCRIPT Management of patients with NAPSAH has seldom been discussed. Our practice, which is not based on high-level medical evidence, is to admit these patients to the intensive care unit. They are given oral nimodipine for up to 14 days but they are generally transferred to an intermediate care or ward setting within several days of the hemorrhage, and are not monitored with transcranial Doppler.

RI PT

Long-term Functional and Cognitive Outcome

The pathogenesis of cognitive dysfunction after NAPSAH is not worked out but is of interest because these patients do not have other confounding procedures such as aneurysm repair procedures. They do not

SC

usually lose consciousness at ictus so there is no initial transient global ischemia. Thus, any observed deficits may be due to the effects of the SAH. Although, NAPSAH is generally considered a benign entity, many patients

M AN U

complain of functional decline on long-term follow-up. While a number of factors bear on whether patients return to work after illness, it is of note that 16 of 49 patients across three studies did not return to work in their original occupations, though the type of occupations were not usually reported

8,51,52

. Furthermore, if they do

return to their original occupation it is unclear if they are able to return to their previous level of responsibility.

TE D

Many patients do not return to work after NAPSAH; none of the 12 patients studied in one paper were working full-time after their hemorrhage 58. Patients with NAPSAH often have ongoing complaints, with 62% reporting symptoms such as headache, dizziness, irritability and forgetfulness at an average of 23 months (range: 5 - 41

EP

months) post-ictus, and 29% reporting symptoms on average 7.5 years (range: 1-23 years) post ictus 24,52. Greebe, et al., also reported persistent anosmia (self reported) in 7 of 148 patients at an average follow up of 9

AC C

years, with 2 experiencing transient anosmia post-ictus 25. Subjectively, patients rated their vitality and general health poorly and at a level comparable to patients with aSAH 8. However, life expectancy for NAPSAH is comparable to the general population 24. More detailed tests of functional outcome have occasionally been reported in patients with NAPSAH. Measures of functional outcome provide an indication of how well a patient is able to re-integrate into the community after NAPSAH and SAH. Activities of daily living (ADLs; Juul 1986), GOS, and mRS are often used to gauge function 38. The ADL grading scale is almost identical to the GOS 38. Ildan, et al., reported that 90% of patients with NAPSAH were well and fully capable of working according to the ADLs grading scale 34. Eighty-nine

ACCEPTED MANUSCRIPT percent to 100% of patients were described to have good recovery to moderate disability according to the GOS at an average follow up time of 3 months to 1.8 years, and 100% at average follow up of 10.6 years 8,13,20,27,31,32. These outcomes are consistent with outcome as measured by the mRS; Hui and colleagues found 91% (mean 62 month follow-up) and Canovas, et al., found 100% of patients to have no symptoms, while Kang and coworkers

RI PT

found 95.6% (typically at 6 months) and Naidech, et al., showed 96.8% of patients had only mild deficits and were able to live independently 12,32,40,60. Boswell, et al., conducted a meta-analysis and reported an odds ratio of 6.23 (95% CI: 2.65, 14.65) for good outcome, based on mRS at greater than 6 months, in NAPSAH compared to

SC

diffuse non-aneurysmal SAH. The Barthel and Karnofsky scores typically fail to demonstrate any functional deficits in patients with NAPSAH 8,46. Along with the GOS, mRS and the ADL grading scale, these measures fail to

M AN U

account for subtle cognitive impairments which can impact post-hemorrhage functioning. A recent review assessing outcome after aSAH concluded that the GOS and mRS were sub-optimal predictors of cognitive and real world functional outcome3, raising the question whether patients with NAPSAH may have deficits in finer aspects of cognitive and functional outcome.

Two studies have examined long-term cognitive outcome in patients with NAPSAH 51,58. Madureira, et

TE D

al., conducted neuropsychological assessment on 18 NAPSAH patients. Twelve neuropsychological tests were used to assess cognition at an average of 54 months after the hemorrhage. Patients who scored below the 10th percentile compared to age and education matched normative values were considered impaired. Thirteen

EP

patients (72%) were impaired on at least one cognitive domain, and nine (50%) were impaired on two or more cognitive domains. Patients were most often impaired on abstraction (33%), verbal fluency (28%), immediate

AC C

memory (33%) and visual memory (39%) 51. Deficits in attention, orientation, remote memory, learning and motor initiation were also observed. The mini-mental state examination (MMSE) demonstrated poor sensitivity with only three patients scoring below 26; two of these patients had scores below the 10th percentile in several cognitive domains. It should be noted that patient in this study had on average 4.6 years of education. Mukerji and coworkers subjected 12 patients with NAPSAH, 65 patients with aSAH and 30 healthy controls to 2.5 hours of neuropsychological assessment 58. The assessment was performed at least 12 months post-ictus. Three patients with NAPSAH (25%) demonstrated deficits in attention switching and mental

ACCEPTED MANUSCRIPT flexibility, and three patients demonstrated deficits in selective attention, visual search capacity, and speed of visual processing. However, it is unclear if these were the same three patients. Memory outcome was defined as “poor” in 8 patients and “impaired” in 2 patients; the exact definition of these labels is not clear. In addition, four patients scored lower than average on the behavioral assessment of the dysexecutive syndrome (BADS)

RI PT

with one patient being “impaired”. However, patients with NAPSAH did not have statistically significant differences from the controls on any of the cognitive domains. None of the patients with NAPSAH were found to be impaired on the MMSE, however, a cutoff of <24 may not be the sensitive enough to assess impairment in

SC

non-dementia populations 23. As suggested by the two studies above, patients who are classified as having a good recovery according to the GOS or mRS often have underlying cognitive and functional deficits.

M AN U

One case report suggests the cognitive deficits seen in patients with NAPSAH may be attributable to white matter damage. A patient with deficits in memory and planning demonstrated reduced fractional anisotropy on diffusion tensor imaging in the white matter of the hippocampus and the dorsolateral prefrontal cortex in the absence of infarction or atrophy 75. This is further supported by evidence in animal models. Long-

TE D

term potentiation in the hippocampus was disrupted by blood in the subarachnoid space even in the absence of cellular damage, and it may be suggestive of issues with white matter integrity 78. Although the mechanism of SAH induced white matter damage is not known, microthromboemboli resulting as a complication of SAH may

outcome after NAPSAH.

AC C

CONCLUSIONS

EP

underlie these changes 71. More research is needed that assess the contribution of these processes to poor

The diagnosis of NAPSAH can be made by perimesencephalic pattern of hemorrhage on initial noncontrast CT and absence of a bleeding source on CTA. Current literature supports not obtaining catheter angiography when neuroradiologic opinion supports a CT diagnosis of NAPSAH on CT soon after the ictus, initial CTA is high quality and clearly normal and the clinical scenario is consistent 1,43,50,87.The evidence suggests the likelihood of rebleeding is less than one percent in NAPSAH and that follow-up catheter angiography is unnecessary, which is our practice 69. Patients with NAPSAH usually have an uneventful clinical course, and are discharged with excellent outcomes, according to the mRS and GOS, and are expected to return to their daily

ACCEPTED MANUSCRIPT activities. They continue to demonstrate excellent outcome years post-ictus, according to mRS and GOS. However, these figures may not reflect the difficulties faced by NAPSAH patients in the community 8,51,52,75. There is some evidence that NAPSAH patients may have difficulty returning to work. Limited data suggest clinical assessment of cognition with the MMSE may be insufficient to demonstrate deficits in NAPSAH patients 65,76.

RI PT

Neuropsychological assessments in a small number of studies of NAPSAH have demonstrated deficits in a wide range of cognitive domains, many which are poorly assessed by the MMSE, including: memory, attention, verbal fluency, executive function and abstraction. In addition, the cognitive domains affected have been found to be

SC

frequently affected in patients with aSAH as well, suggesting a common underlying mechanism. Future studies need to characterize the cognitive and functional deficits experienced by NAPSAH patients. This will aid in

M AN U

designing targeted rehabilitation efforts for patients with NAPSAH who, at present, frequently receive no support after discharge. In addition, a basic understanding of the effects of blood in the subarachnoid space might aid in developing therapeutic approaches to reduce or rehabilitate cognitive changes. REFERENCES

4.

5. 6.

7.

8. 9. 10.

TE D

3.

EP

2.

Agid R, Andersson T, Almqvist H, Willinsky RA, Lee SK, terBrugge KG, Farb RI, Soderman M: Negative CT angiography findings in patients with spontaneous subarachnoid hemorrhage: When is digital subtraction angiography still needed? AJNR Am J Neuroradiol 31:696-705, 2010 Agid R, Lee SK, Willinsky RA, Farb RI, terBrugge KG: Acute subarachnoid hemorrhage: using 64-slice multidetector CT angiography to "triage" patients' treatment. Neuroradiology 48:787-794, 2006 Al-Khindi T, Macdonald RL, Schweizer TA: Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke 41:e519-536, 2010 Alen JF, Lagares A, Lobato RD, Gomez PA, Rivas JJ, Ramos A: Comparison between perimesencephalic nonaneurysmal subarachnoid hemorrhage and subarachnoid hemorrhage caused by posterior circulation aneurysms. J Neurosurg 98:529-535, 2003 Alexander MS, Dias PS, Uttley D: Spontaneous subarachnoid hemorrhage and negative cerebral panangiography. Review of 140 cases. J Neurosurg 64:537-542, 1986 Andaluz N, Zuccarello M: Yield of further diagnostic work-up of cryptogenic subarachnoid hemorrhage based on bleeding patterns on computed tomographic scans. Neurosurgery 62:1040-1046; discussion 1047, 2008 Anderson CS, Feigin V, Bennett D, Lin RB, Hankey G, Jamrozik K: Active and passive smoking and the risk of subarachnoid hemorrhage: an international population-based case-control study. Stroke 35:633-637, 2004 Beseoglu K, Pannes S, Steiger HJ, Hanggi D: Long-term outcome and quality of life after nonaneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien) 152:409-416, 2010 Boswell S, Thorell W, Gogela S, Lyden E, Surdell D: Angiogram-Negative Subarachnoid Hemorrhage: Outcomes Data and Review of the Literature. J Stroke Cerebrovasc Dis, 2012 Brinjikji W, Kallmes DF, White JB, Lanzino G, Morris JM, Cloft HJ: Inter- and intraobserver agreement in CT characterization of nonaneurysmal perimesencephalic subarachnoid hemorrhage. AJNR Am J Neuroradiol 31:1103-1105, 2010

AC C

1.

ACCEPTED MANUSCRIPT

17. 18.

19.

20.

21.

22. 23.

24. 25. 26. 27.

28. 29. 30. 31.

RI PT

16.

SC

15.

M AN U

14.

TE D

13.

EP

12.

Caeiro L, Santos CO, Ferro JM, Figueira ML: Neuropsychiatric disturbances in acute subarachnoid haemorrhage. Eur J Neurol 18:857-864, 2011 Canovas D, Gil A, Jato M, de Miquel M, Rubio F: Clinical outcome of spontaneous non-aneurysmal subarachnoid hemorrhage in 108 patients. Eur J Neurol 19:457-461, 2012 Carvi y Nievas MN, Archavlis E: Atypical causes of nontraumatic intracranial subarachnoid hemorrhage. Clin Neurol Neurosurg 111:354-358, 2009 Cioffi F, Pasqualin A, Cavazzani P, Da Pian R: Subarachnoid haemorrhage of unknown origin: clinical and tomographical aspects. Acta Neurochir (Wien) 97:31-39, 1989 Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P: Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 43:1711-1737, 2012 Cruz JP, Sarma D, Noel de Tilly L: Perimesencephalic subarachnoid hemorrhage: when to stop imaging? Emerg Radiol 18:197-202, 2011 Daenekindt T, Wilms G, Thijs V, Demaerel P, Van Calenbergh F: Variants of the basal vein of Rosenthal and perimesencephalic nonaneurysmal hemorrhage. Surg Neurol 69:526-529; discussion 529, 2008 Delgado Almandoz JE, Jagadeesan BD, Refai D, Moran CJ, Cross DT, 3rd, Chicoine MR, Rich KM, Diringer MN, Dacey RG, Jr., Derdeyn CP, Zipfel GJ: Diagnostic yield of repeat catheter angiography in patients with catheter and computed tomography angiography negative subarachnoid hemorrhage. Neurosurgery 70:1135-1142, 2012 Flaherty ML, Haverbusch M, Kissela B, Kleindorfer D, Schneider A, Sekar P, Moomaw CJ, Sauerbeck L, Broderick JP, Woo D: Perimesencephalic subarachnoid hemorrhage: incidence, risk factors, and outcome. J Stroke Cerebrovasc Dis 14:267-271, 2005 Fontanella M, Rainero I, Panciani PP, Schatlo B, Benevello C, Garbossa D, Carlino C, Valfre W, Griva F, Bradac GB, Ducati A: Subarachnoid hemorrhage and negative angiography: clinical course and long-term follow-up. Neurosurg Rev 34:477-484, 2011 Franz G, Brenneis C, Kampfl A, Pfausler B, Poewe W, Schmutzhard E: Prognostic value of intraventricular blood in perimesencephalic nonaneurysmal subarachnoid hemorrhage. J Comput Assist Tomogr 25:742746, 2001 Germanwala AV, Huang J, Tamargo RJ: Hydrocephalus after aneurysmal subarachnoid hemorrhage. Neurosurg Clin N Am 21:263-270, 2010 Godefroy O, Fickl A, Roussel M, Auribault C, Bugnicourt JM, Lamy C, Canaple S, Petitnicolas G: Is the Montreal Cognitive Assessment superior to the Mini-Mental State Examination to detect poststroke cognitive impairment? A study with neuropsychological evaluation. Stroke 42:1712-1716, 2011 Greebe P, Rinkel GJ: Life expectancy after perimesencephalic subarachnoid hemorrhage. Stroke 38:1222-1224, 2007 Greebe P, Rinkel GJ, Algra A: Anosmia after perimesencephalic nonaneurysmal hemorrhage. Stroke 40:2885-2886, 2009 Gross BA, Lin N, Frerichs KU, Du R: Vasospasm after spontaneous angiographically negative subarachnoid hemorrhage. Acta Neurochir (Wien) 154:1127-1133, 2012 Gupta SK, Gupta R, Khosla VK, Mohindra S, Chhabra R, Khandelwal N, Gupta V, Mukherjee KK, Tewari MK, Pathak A, Mathuriya SN: Nonaneurysmal nonperimesencephalic subarachnoid hemorrhage: is it a benign entity? Surg Neurol 71:566-571; discussion 571,571-562,572, 2009 Hashimoto H, Iida J, Shin Y, Hironaka Y, Sakaki T: Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage. J Clin Neurosci 7:64-66, 2000 Herrmann LL, Zabramski JM: Nonaneurysmal subarachnoid hemorrhage: a review of clinical course and outcome in two hemorrhage patterns. J Neurosci Nurs 39:135-142, 2007 Hop JW, Rinkel GJ, Algra A, van Gijn J: Changes in functional outcome and quality of life in patients and caregivers after aneurysmal subarachnoid hemorrhage. J Neurosurg 95:957-963, 2001 Hui FK, Schuette AJ, Moskowitz SI, Gupta R, Spiotta AM, Obuchowski NA, Cawley CM: Antithrombotic states and outcomes in patients with angiographically negative subarachnoid hemorrhage. Neurosurgery 68:125-130; discussion 130-121, 2011

AC C

11.

ACCEPTED MANUSCRIPT

39.

40. 41. 42. 43. 44.

45. 46. 47.

48. 49.

50.

51. 52. 53.

RI PT

38.

SC

36. 37.

M AN U

35.

TE D

34.

EP

33.

Hui FK, Tumialan LM, Tanaka T, Cawley CM, Zhang YJ: Clinical differences between angiographically negative, diffuse subarachnoid hemorrhage and perimesencephalic subarachnoid hemorrhage. Neurocrit Care 11:64-70, 2009 Huttner HB, Hartmann M, Kohrmann M, Neher M, Stippich C, Hahnel S, Kress B: Repeated digital substraction angiography after perimesencephalic subarachnoid hemorrhage? J Neuroradiol 33:87-89, 2006 Ildan F, Tuna M, Erman T, Gocer AI, Cetinalp E: Prognosis and prognostic factors in nonaneurysmal perimesencephalic hemorrhage: a follow-up study in 29 patients. Surg Neurol 57:160-165; discussion 165-166, 2002 Ingall T, Asplund K, Mahonen M, Bonita R: A multinational comparison of subarachnoid hemorrhage epidemiology in the WHO MONICA stroke study. Stroke 31:1054-1061, 2000 Jennett B, Bond M: Assessment of outcome after severe brain damage. Lancet 1:480-484, 1975 Jung JY, Kim YB, Lee JW, Huh SK, Lee KC: Spontaneous subarachnoid haemorrhage with negative initial angiography: a review of 143 cases. J Clin Neurosci 13:1011-1017, 2006 Juul R, Fredriksen TA, Ringkjob R: Prognosis in subarachnoid hemorrhage of unknown etiology. J Neurosurg 64:359-362, 1986 Kallmes DF, Clark HP, Dix JE, Cloft HJ, Evans AJ, Dion JE, Kassell NF: Ruptured vertebrobasilar aneurysms: frequency of the nonaneurysmal perimesencephalic pattern of hemorrhage on CT scans. Radiology 201:657-660, 1996 Kang DH, Park J, Lee SH, Park SH, Kim YS, Hamm IS: Does non-perimesencephalic type non-aneurysmal subarachnoid hemorrhage have a benign prognosis? J Clin Neurosci 16:904-908, 2009 Kawamura Y, Narumi O, Chin M, Yamagata S: Variant deep cerebral venous drainage in idiopathic subarachnoid hemorrhage. Neurol Med Chir (Tokyo) 51:97-100, 2011 Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J: Global burden of hypertension: analysis of worldwide data. Lancet 365:217-223, 2005 Kelliny M, Maeder P, Binaghi S, Levivier M, Regli L, Meuli R: Cerebral aneurysm exclusion by CT angiography based on subarachnoid hemorrhage pattern: a retrospective study. BMC Neurol 11:8, 2011 Kershenovich A, Rappaport ZH, Maimon S: Brain computed tomography angiographic scans as the sole diagnostic examination for excluding aneurysms in patients with perimesencephalic subarachnoid hemorrhage. Neurosurgery 59:798-801; discussion 801-792, 2006 Kleinpeter G, Lehr S: Characterization of risk factor differences in perimesencephalic subarachnoid hemorrhage. Minim Invasive Neurosurg 46:142-148, 2003 Kong Y, Zhang JH, Qin X: Perimesencephalic subarachnoid hemorrhage: risk factors, clinical presentations, and outcome. Acta Neurochir Suppl 110:197-201, 2011 Kurosu A, Suzukawa K, Amo M, Horinaka N, Arai H: Perimesencephalic non-aneurysmal subarachnoid hemorrhage caused by cavernous sinus thrombosis: case report. Neurol Med Chir (Tokyo) 47:258-260, 2007 Lee J, Koh EM, Chung CS, Hong SC, Kim YB, Chung PW, Suh BC, Moon HS: Underlying venous pathology causing perimesencephalic subarachnoid hemorrhage. Can J Neurol Sci 36:638-642, 2009 Lin N, Zenonos G, Kim AH, Nalbach SV, Du R, Frerichs KU, Friedlander RM, Gormley WB: Angiogramnegative subarachnoid hemorrhage: relationship between bleeding pattern and clinical outcome. Neurocrit Care 16:389-398, 2012 Little AS, Garrett M, Germain R, Farhataziz N, Albuquerque FC, McDougall CG, Zabramski JM, Nakaji P, Spetzler RF: Evaluation of patients with spontaneous subarachnoid hemorrhage and negative angiography. Neurosurgery 61:1139-1150; discussion 1150-1131, 2007 Madureira S, Canhao P, Guerreiro M, Ferro JM: Cognitive and emotional consequences of perimesencephalic subarachnoid hemorrhage. J Neurol 247:862-867, 2000 Marquardt G, Niebauer T, Schick U, Lorenz R: Long term follow up after perimesencephalic subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 69:127-130, 2000 Maslehaty H, Barth H, Petridis AK, Doukas A, Maximilian Mehdorn H: Special features of subarachnoid hemorrhage of unknown origin: a review of a series of 179 cases. Neurol Res 34:91-97, 2012

AC C

32.

ACCEPTED MANUSCRIPT

60. 61. 62. 63.

64. 65.

66. 67. 68.

69. 70.

71.

72.

73.

RI PT

59.

SC

58.

M AN U

57.

TE D

56.

EP

55.

Maslehaty H, Petridis AK, Barth H, Mehdorn HM: Diagnostic value of magnetic resonance imaging in perimesencephalic and nonperimesencephalic subarachnoid hemorrhage of unknown origin. J Neurosurg 114:1003-1007, 2011 Mathews MS, Brown D, Brant-Zawadzki M: Perimesencephalic nonaneurysmal hemorrhage associated with vein of Galen stenosis. Neurology 70:2410-2411, 2008 Matsuyama T, Okuchi K, Seki T, Higuchi T, Murao Y: Perimesencephalic nonaneurysmal subarachnoid hemorrhage caused by physical exertion. Neurol Med Chir (Tokyo) 46:277-281; discussion 281-272, 2006 Miranpuri AS, Akture E, Baggott CD, Miranpuri A, Uluc K, Gunes VE, Lin Y, Niemann DB, Baskaya MK: Demographic, circadian, and climatic factors in non-aneurysmal versus aneursymal subarachnoid hemorrhage. Clin Neurol Neurosurg, 2012 Mukerji N, Holliman D, Baisch S, Noble A, Schenk T, Nath F: Neuropsychologic impact of treatment modalities in subarachnoid hemorrhage: clipping is no different from coiling. World Neurosurg 74:129138, 2010 Muroi C, Bellut D, Coluccia D, Mink S, Fujioka M, Keller E: Systemic interleukin-6 concentrations in patients with perimesencephalic non-aneurysmal subarachnoid hemorrhage. J Clin Neurosci 18:16261629, 2011 Naidech AM, Rosenberg NF, Maas MB, Bendok BR, Batjer HH, Nemeth AJ: Predictors of hemorrhage volume and disability after perimesencephalic subarachnoid hemorrhage. Neurology 78:811-815, 2012 Nayak S, Kunz AB, Kieslinger K, Ladurner G, Killer M: Classification of non-aneurysmal subarachnoid haemorrhage: CT correlation to the clinical outcome. Clin Radiol 65:623-628, 2010 Oda S, Shimoda M, Hoshikawa K, Osada T, Yoshiyama M, Matsumae M: Cortical subarachnoid hemorrhage caused by cerebral venous thrombosis. Neurol Med Chir (Tokyo) 51:30-36, 2011 Ogiichi T, Endo S, Onizuka K, Takaba M, Takaku A, Yasuda M: Non-aneurysmal subarachnoid hemorrhage associated with basilar artery dissection--autopsy case report. Neurol Med Chir (Tokyo) 37:612-615, 1997 Park SQ, Kwon OK, Kim SH, Oh CW, Han MH: Pre-mesencephalic subarachnoid hemorrhage: rupture of tiny aneurysms of the basilar artery perforator. Acta Neurochir (Wien) 151:1639-1646, 2009 Pendlebury ST, Mariz J, Bull L, Mehta Z, Rothwell PM: MoCA, ACE-R, and MMSE versus the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards Neuropsychological Battery after TIA and stroke. Stroke 43:464-469, 2012 Pinto AN, Ferro JM, Canhao P, Campos J: How often is a perimesencephalic subarachnoid haemorrhage CT pattern caused by ruptured aneurysms? Acta Neurochir (Wien) 124:79-81, 1993 Rinkel GJ, Algra A: Long-term outcomes of patients with aneurysmal subarachnoid haemorrhage. Lancet Neurol 10:349-356, 2011 Rinkel GJ, Wijdicks EF, Vermeulen M, Ramos LM, Tanghe HL, Hasan D, Meiners LC, van Gijn J: Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture. AJNR Am J Neuroradiol 12:829-834, 1991 Ruigrok YM, Rinkel GJ, Buskens E, Velthuis BK, van Gijn J: Perimesencephalic hemorrhage and CT angiography: A decision analysis. Stroke 31:2976-2983, 2000 Ruigrok YM, Rinkel GJ, Van Gijn J: CT patterns and long-term outcome in patients with an aneurysmal type of subarachnoid hemorrhage and repeatedly negative angiograms. Cerebrovasc Dis 14:221-227, 2002 Sabri M, Ai J, Knight B, Tariq A, Jeon H, Shang X, Marsden PA, Loch Macdonald R: Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 31:190-199, 2011 Sangra MS, Teasdale E, Siddiqui MA, Lindsay KW: Perimesencephalic nonaneurysmal subarachnoid hemorrhage caused by jugular venous occlusion: case report. Neurosurgery 63:E1202-1203; discussion E1203, 2008 Sarabia R, Lagares A, Fernandez-Alen JA, Arikan F, Vilalta J, Ibanez J, Maillo A, Gabarros A, Dominguez J, Horcajadas A, Ballenilla F, Rodriguez-Boto G, Llacer JL, Arrese I, de la Lama A, Santamarta D, Delgado P, Munoz MF: Idiopathic subarachnoid hemorrhage: a multicentre series of 220 patients. Neurocirugia (Astur) 21:441-451, 2010

AC C

54.

ACCEPTED MANUSCRIPT

79. 80.

81. 82.

83. 84. 85. 86.

87.

88. 89.

AC C

90.

RI PT

78.

SC

77.

M AN U

76.

TE D

75.

Schievink WI, Wijdicks EF: Origin of pretruncal nonaneurysmal subarachnoid hemorrhage: ruptured vein, perforating artery, or intramural hematoma? Mayo Clin Proc 75:1169-1173, 2000 Schweizer TA, Al-Khindi T, Loch Macdonald R: Diffusion tensor imaging as a surrogate marker for outcome after perimesencephalic subarachnoid hemorrhage. Clin Neurol Neurosurg 114:798-800, 2012 Schweizer TA, Al-Khindi T, Macdonald RL: Mini-Mental State Examination versus Montreal Cognitive Assessment: rapid assessment tools for cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. J Neurol Sci 316:137-140, 2012 Shad A, Rourke TJ, Hamidian Jahromi A, Green AL: Straight sinus stenosis as a proposed cause of perimesencephalic non-aneurysmal haemorrhage. J Clin Neurosci 15:839-841, 2008 Tariq A, Ai J, Chen G, Sabri M, Jeon H, Shang X, Macdonald RL: Loss of long-term potentiation in the hippocampus after experimental subarachnoid hemorrhage in rats. Neuroscience 165:418-426, 2010 Thines L, Khalil C, Fichten A, Lejeune JP: Spinal arachnoid cyst related to a nonaneurysmal perimesencephalic subarachnoid hemorrhage: case report. Neurosurgery 57:E817, 2005 Topcuoglu MA, Ogilvy CS, Carter BS, Buonanno FS, Koroshetz WJ, Singhal AB: Subarachnoid hemorrhage without evident cause on initial angiography studies: diagnostic yield of subsequent angiography and other neuroimaging tests. J Neurosurg 98:1235-1240, 2003 van der Schaaf IC, Velthuis BK, Gouw A, Rinkel GJ: Venous drainage in perimesencephalic hemorrhage. Stroke 35:1614-1618, 2004 van Dijk EJ, Hupperts RM, van der Jagt M, Bijvoet HW, Hasan D: Diagnosis of perimesencephalic nonaneurysmal subarachnoid hemorrhage with computed tomography. J Stroke Cerebrovasc Dis 10:247-251, 2001 van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A: Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 35:493-497, 1985 van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J: Interobserver agreement for the assessment of handicap in stroke patients. Stroke 19:604-607, 1988 Velthuis BK, Rinkel GJ, Ramos LM, Witkamp TD, van Leeuwen MS: Perimesencephalic hemorrhage. Exclusion of vertebrobasilar aneurysms with CT angiography. Stroke 30:1103-1109, 1999 Watanabe A, Hirano K, Kamada M, Imamura K, Ishii N, Sekihara Y, Suzuki Y, Ishii R: Perimesencephalic nonaneurysmal subarachnoid haemorrhage and variations in the veins. Neuroradiology 44:319-325, 2002 Westerlaan HE, Gravendeel J, Fiore D, Metzemaekers JD, Groen RJ, Mooij JJ, Oudkerk M: Multislice CT angiography in the selection of patients with ruptured intracranial aneurysms suitable for clipping or coiling. Neuroradiology 49:997-1007, 2007 Wong GK, Siu DY, Abrigo JM, Ahuja AT, Poon WS: Computed tomographic angiography for patients with acute spontaneous intracerebral hemorrhage. J Clin Neurosci 19:498-500, 2012 Yamakawa H, Ohe N, Yano H, Yoshimura S, Iwama T: Venous drainage patterns in perimesencephalic nonaneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg 110:587-591, 2008 Zhu HF, Newcommon NN, Cooper ME, Green TL, Seal B, Klein G, Weir NU, Coutts SB, Watson T, Barber PA, Demchuk AM, Hill MD: Impact of a stroke unit on length of hospital stay and in-hospital case fatality. Stroke 40:18-23, 2009

EP

74.

FIGURE LEGENDS

Figure 1: One possible imaging algorithm for investigation of patients with SAH. Figure 2: Computed tomography in 5 patients with aneurysmal SAH from aneurysms of the right middle cerebral artery (A), right internal carotid artery (B), anterior communicating artery (C), left middle cerebral artery (D) and right superior cerebellar artery (E). Computed tomography of patients with NAPSAH (F-H, J) are similar to aneurysmal SAH from a basilar bifurcation aneurysm (I), exemplifying the need to perform CT and/or catheter angiography in all patients with NAPSAH. Nonaneurysmal SAH patterns from cerebral venous thrombosis are also shown (K,L).

ACCEPTED MANUSCRIPT

Table 1. Summary of demographics, risk factors and complications in patients with NAPH. *** Total NAPH population of 9 but discusses 7

Kleinpeter

2003

23

Beseoglu

2010

12

Mukerji

2010

12

Caeiro

2010

10

Greebe

2007

165

Franz

2001

24

Mean Age

% female

Hypertention

Smoking

48.0%

30.0%

30.0%

25.0%

33.3%

53.8

Alcohol Abuse

Vasospasm

.

.

.

.

.

.

41.7%

.

.

60.0%

.

.

54.8

40.6%

.

.

.

50.3

37.0%

.

.

.

.

Gupta

2009

18

Idan

2001

29

49.5

75.9%

14.0%

28.7%

Kong

2011

12

49.1

25.0%

16.7%

Ruigrok

2002

73

53.0

Kang

2009

23

54.2

.

54.0

34.8%

.

38.9%

.

Topcuoglu

2003

36

Jung

2006

94

Marquardt

2000

21

55.8

47.6%

Alen

2003

44

51.9

36.6%

Sarabia

2010

94

.

.

Huttner

2006

69

.

.

Mejdoubi

2006

73

.

.

Ildan

2002

29

.

.

Flaherty

2005

24

Whiting

2009

24

.

Nievas

2009

8

.

Hui

2011

79

.

Hui

2009

31

.

Cruz

2011

41

Kershenovich

2006

Little

.

49.0

. . 25.0%

.

.

.

.

.

.

.

0.0%

Death

.

.

.

0.0%

.

. 20.0%

.

.

.

.

0.0%

3.4%

3.4%

.

3.4%

0.0%

0.0%

.

0.0%

.

.

0.0%

.

0.0%

0.0%

8.3%

.

.

Fixed Ischemic Deficits

20.0%

0.0%

17.2%

16.7%

0.0%

.

12.5%

.

.

.

.

11.0%

Hydrocephalus

.

20.0%

.

25.0%

0.0%

.

8.7%

0.0%

.

.

25.0%

.

.

13.8%

.

.

0.0%

.

.

.

.

.

.

.

.

.

.

.

.

.

.

30.5%

30.9%

.

.

.

.

.

.

.

.

.

.

.

50.0%

17.0%

25.0%

2.9%

0.0%

.

4.8%

7.2%

. 11.7%

.

0.0%

.

9.1%

. 1.1%

.

7.4%

.

.

.

.

3.6% 0.0%

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

38.7%

.

.

.

9.6%

.

49.9

41.5%

.

.

.

2.4%

.

.

.

.

30

53.0

61.5%

.

.

.

.

.

.

.

.

2007

16

50.0

43.8%

.

.

.

.

.

.

.

.

Agid

2010

93

.

Madureira

2000

18

Greebe

2009

Matsuyama

2006

Oda

2011

8

Watanabe

2002

6

van der schaaf Yamakawa

2004

55

2008

18

AC C

EP

.

16.7% .

TE D

.

0.0%

Rebleed

RI PT

NAPH

SC

Year

M AN U

Author

.

37.6%

.

.

.

54.0

50.0%

.

.

.

.

54.0

41.0%

27.0%

9 ***

50.0

42.9%

28.6%

.

. 56.8

.

50.0%

. 58.4

61.1%

26.0%

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

38.9%

. 5.6%

.

9.6%

. 0.0%

. 22.2%

0.0% . 0.0%

. 0.0%

.

.

.

.

16.7%

.

.

13.0%

.

.

11.1%

28.6%

.

.

.

.

.

.

.

.

.

.

0.0%

.

0.0%

ACCEPTED MANUSCRIPT 10

61.5

40.0%

.

.

.

.

.

Kelliny

2011

19

Daenekindt

2008

59

.

.

.

.

.

.

.

.

.

.

.

.

Park

2009

13

.

.

.

.

.

.

.

.

Agid

2006

10

.

.

.

.

.

.

.

.

Caeiro

2004

9

.

.

.

.

.

.

.

.

Andaluz

2008

45

48.0

66.7%

.

.

.

11.0%

2.2%

4.4%

Fontenella

2011

23

53.6

30.4%

.

.

8.6%

0.0%

0.0%

Ruigrok

2001

73

53.0

42.0%

DelgadoAlmandoz Maslehaty

2012

29

.

58.6%

.

44.8%

2012

47

.

36.1%

36.2%

.

.

12.8%

Naidech

2012

31

53.9

48.4%

48.4%

.

.

3.2%

Miranpuri

2012

32

55.8

40.6%

37.9%

Boswell

2012

14

Canovas

2012

60

Gross

2012

31

.

.

.

Lin

2012

27

.

.

.

Muroi

2011

11

.

.

.

52.0

.

50.4

26.1%

.

34.5%

.

52.0%

20.0%

24.1%

34.5%

.

.

.

.

.

.

.

.

.

.

.

.

.

10.6%

.

35.5%

.

0.0%

0.0%

50.0%

0.0%

0.0%

1.7%

16.1%

.

3.7%

.

.

.

M AN U

.

47.5%

10.0%

RI PT

2011

SC

Kawamura

NAPH

First

Subsequent Yield

Study Type

CT type

0

Retrospective

N/A

1

Retrospective

N/A

1

Retrospective

N/A

0

Prospective

N/A

0

Retrospective

N/A

0

Retrospective

N/A

3

Retrospective

N/A

TE D

Year

Investigation

Topcuoglu

2003

36

catheter

Jung

2006

94

EP

angiography catheter

Maslehaty

AC C

angiography

2010

47

catheter

angiography

Hashimoto

2000

6

catheter

angiography

Kershenovich

2006

11

catheter angiography

Franz

2001

24

catheter angiography

Andaluz

2008

45

catheter angiography

.

.

.

.

.

.

2.2%

0.0%

.

0.0%

. 0.0%

0.0%

.

0.0%

.

. 0.0%

.

.

. 3.2%

3.7%

Table 2. Diagnostic yield of a second angiographic investigation following DSA or CTA. Authors

.

. 0.0%

.

.

.

.

.

.

.

ACCEPTED MANUSCRIPT 2011

Fontenella

23

catheter

0

Retrospective

N/A

1

Prospective

N/A

0

Retrospective

N/A

0

Retrospective

N/A

1

Retrospective

N/A

64- slice

angiography 2012

Delgado

29

catheter

angiography 2012

Gross

31

catheter

2009

Nieva

8

catheter

RI PT

angiography

angiography 2012

Lin

27

catheter

2011

49

CTA

1 (not source)

Retrospective

Little

2007

16

CTA

1

Retrospective

Huttner

2006

69

CTA

0

Retrospective

Westerlaan

2007

30

CTA

0

Agid

2010

97

CTA

0

Kelliny

2011

19

CTA

0

16- or 64- slice N/A

M AN U

Cruz

SC

angiography

Prospective

16- or 64- slice

Retrospective

64- slice

Retrospective

16- or 64- slice

Table 3. Hunt and Hess grade and World Federation of Neurological Society grade for neurological

Author

Year

NAPH

H&H

II

Caeiro

2010

10

90%

Franz

2001

24

Idan

2001

29

Kong

2011

12

EP

I

TE D

condition on presentation. ***Total NAPH population of 9 but discusses 7.

Kang

2009

23

Topcuoglu

2003

Jung

III

WFNS IV

10%

I

II

III

IV

V

.

.

.

.

.

21%

0%

0

.

.

.

.

.

72%

21%

7%

.

.

.

.

.

.

50%

50%

0

0

.

.

.

.

.

13%

78%

9%

0

.

.

.

.

.

36

83%

14%

3%

.

.

.

.

.

.

2006

94

7.50%

82%

7.50%

3%

.

.

.

.

.

Marquardt

2000

21

100%

0

0

.

.

.

.

.

Huttner

2006

69

99%

1%

0

.

.

.

.

.

Nievas

2009

8

0

.

.

.

.

.

Hui

2009

31

7%

3%

.

.

.

.

.

Cruz

2011

41

7%

93%

0

0

98%

2%

0

0

0

Kershenovich

2006

30

67%

23%

10%

0

.

.

.

.

.

Little

2007

16

31.25

68.75

0

0

.

.

.

.

.

Madureira

2000

18

22%

72%

6%

0

.

.

.

.

.

AC C

79%

100% 90%

ACCEPTED MANUSCRIPT Watanabe

2002

6

83.30%

16.70%

0

0

.

.

.

.

.

Yamakawa

2008

18

16.70%

83.30%

0

0

.

.

.

.

.

Fontenella

2011

23

13%

0

.

.

.

.

.

Delgado

2012

29

38%

59%

0

3%

.

.

.

.

.

Maslehaty

2012

47

26%

59%

15%

0

.

.

.

.

.

Canovas

2012

60

0

2%

.

.

.

.

.

Beseoglu

2010

12

84%

8%

0

8%

0

Mukerji

2010

0

0

0

Alen

2003

Sarabia

98% .

.

.

.

.

.

.

.

44

.

.

.

.

86%

12%

2010

94

.

.

.

.

94%

4%

Matsuyama

2006

.

.

.

.

29%

71%

van der schaaf

2004

7 (of 9)*** 55

.

.

.

.

100%

0

Kawamura

2011

10

.

.

.

.

70%

Kelliny

2011

19

.

.

.

.

100%

Naidech

2012

31

.

.

.

.

84%

100%

RI PT

87%

0

0

0

1%

1%

0

0

0

0

0

0

10%

10%

10%

0

0

0

0

0

16%

0

0

0

M AN U

SC

2%

Table 4. The modified Rankin Scale for outcome at discharge. *These authors did not indicate that outcomes

hemorrhage pattern. Author

Year

NAPH

mRS

79

Little

2007

16

Caeiro

2010

10

Kawamura* Andaluz

Nayak**

AC C

2011

1

2

3

4

5

6

91.1%

8.9%

0

0

0

0

0

31.3%

50%

6.3%

6.3%

6.3%

0

0

0

0

0

0

EP

0 Hui

TE D

were at discharge, however, the studies were not assessing long-term follow-ups. .** Used own classification for

100.0%

10

70.0%

20.0%

10.0%

0

0

0

0

2008

45

77.8%

17.8%

2.2%

0

0

0

2.2%

2011

122

100.0%

0

0

0

0

0

0

Table 5. The Glasgow Outcome Scale for outcome at discharge. *These authors did not indicate that outcomes were at discharge; however, the studies were not assessing long-term follow-ups. Author

Year

NAPH

GOS at Discharge

ACCEPTED MANUSCRIPT 1

2

3

4

5

Beseoglu

2010

12

0

0

16.7%

25.0%

58.3%

Franz

2001

24

0

0

0

0

100.0%

Kong

2011

12

0

0

0

0

100.0%

Matsuyama*

2006

7

Yamakawa*

2008

18

0

0

0

0

100.0%

Fontenella

2011

23

0

0

0

8.7%

91.3%

AC C

EP

TE D

M AN U

SC

RI PT

All Excellent

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

NAPH - nonaneurysmal perimesencephalic subarachnoid hemorrhage MMSE- mini-mental status exam SAH- subarachnoid hemorrhage

RI PT

aSAH- aneurysmal subarachnoid hemorrhage mRS- modified Rankin scale CTA- Computed tomography angiography

SC

MRI- magnetic resonance imaging GOS- Glasgow Outcome Scale

M AN U

ADLs- Activities of daily living

AC C

EP

TE D

BADS- behavioral assessment of the dysexecutive syndrome

ACCEPTED MANUSCRIPT

Conflict-of-Interest and Financial Disclosure I certify that there is no actual or potential conflict of interest in relation to this article. None of the authors have any financial disclosures to make.

AC C

EP

TE D

M AN U

SC

RI PT

Anish Kapadia