Perimesencephalic nonaneurysmal subarachnoid hemorrhage

INTRODUCTION AND DEFINITION — 

Subarachnoid hemorrhage (SAH) refers to bleeding within the subarachnoid space, which lies between the arachnoid and pia mater overlying the brain. Most spontaneous (nontraumatic) cases of SAH are caused by rupture of an intracranial aneurysm, but approximately 20 percent of patients do not have an established vascular lesion on initial four-vessel cerebral angiography. The causes of nonaneurysmal SAH (NASAH) are potentially diverse, and often the mechanism of bleeding in these cases is not identified.

In 1985, a subtype of NASAH, so-called perimesencephalic NASAH (P-NASAH), was identified in a case series of 13 patients who had a specific pattern of bleeding on computed tomography (CT) and normal cerebral angiography [1]. This observation has subsequently been confirmed by other reports [2-6]. It is important to recognize P-NASAH because it is typically associated with a more benign course than many patients with both aneurysmal SAH and many other types of NASAH.

This topic will review the pathogenesis, clinical features, diagnosis, and management of P-NASAH. Other causes of NASAH are reviewed separately. (See "Nonaneurysmal subarachnoid hemorrhage".)

Aneurysmal SAH is reviewed elsewhere.

●(See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".)

●(See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

●(See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".)

EPIDEMIOLOGY — 

P-NASAH represents up to 10 percent of all SAH cases [7]. The reported proportion of cases of P-NASAH among NASAH varies between 21 and 68 percent [2,5,8-12]. In a 2018 systematic review, the annual rate of P-NASAH was estimated to be 0.5 per 100,000 persons over 18 years of age [13].

The mean age at diagnosis is approximately 53 years old, with reported cases ranging in age from 3 to 90 years. In contrast with aneurysmal SAH, there is no clear female predisposition for P-NASAH, with females accounting for 42 percent of P-NASAH cases in one systematic review [13].

Risk factors for P-NASAH include hypertension and cigarette smoking, but these appear to be somewhat less prevalent among patients with P-NASAH compared with those with aneurysmal SAH [9,14-16]. A 2018 systematic review reported a trend toward an association with hypertension and smoking that did not reach statistical significance, but substantial heterogeneity among the studies limits the certainty in these data [13].

P-NASAH is not known to have a genetic predisposition; however, rare cases in first-degree relatives have been described [17].

PATHOGENESIS — 

In most cases, the etiology of P-NASAH is not defined, even after extensive evaluation. Theories regarding its origin in some or all cases include [18]:

●Venous origin – Rupture of deep veins around the brainstem may be the cause of many cases of P-NASAH [19,20]. In multiple case series, variant forms of venous drainage were found more frequently in patients with P-NASAH than those with aneurysmal SAH [21-23]. In such patients, the basal vein of Rosenthal and/or the perimesencephalic veins may drain directly into the dural sinuses rather than the vein of Galen, potentially making them more susceptible to venous congestion. Other reported venous anomalies in patients with P-NASAH include vein of Galen stenosis, evidence of venous infarction, and cerebral venous thrombosis [19,24-27].

The low volume of initial bleeding and modest rate of subsequent rebleeding suggest a low-pressure source, supporting a venous etiology for P-NASAH. P-NASAH often occurs in the setting of physical exertion, which in this paradigm sequentially produces increased intrathoracic pressure, impaired internal jugular venous return, elevated intracranial venous pressure, and leakage of venous blood from susceptible blood vessels [28].

●Rupture of a perforating artery – P-NASAH may also be due to rupture with or without occlusion of a perimesencephalic perforating artery arising from the posterior circulation [29]. In one case, this pathogenesis has been substantiated pathologically [30]. In addition, hypertension, a known risk factor for perforating artery disease, is also a risk factor for P-NASAH. (See 'Epidemiology' above.)

In one case series of 25 patients with P-NASAH, an acute lacunar infarction (typically attributed to occlusive disease of the perforating arteries) was found in four patients [31]. However, the acute lacunar infarctions in this and some other reports have been in the distribution of the anterior circulation, and their relationship to the P-NASAH is not clear [8,32].

●Basilar artery wall hematoma – Subarachnoid extension of an intraluminal hematoma has been posited as the cause for some cases of P-NASAH. Rupture of the vasa vasorum within the arterial wall and subsequent leakage into the subarachnoid space may account for the relatively limited bleeding that occurs in these cases. In some instances of P-NASAH, an abnormal contour of the basilar artery has been observed, either as a small bulge or luminal narrowing [18,33].

However, the role of a putative basilar artery wall hematoma in P-NASAH remains unproven. In one case series, systematic examination of basilar artery contours in 27 patients with P-NASAH found no variations that suggested this origin of bleeding [10]. This hypothesis awaits further study with high-resolution neuroimaging studies.

●Occult causes – Other potential causes of apparently spontaneous bleeding in P-NASAH include rupture and obliteration of a cryptic vascular malformation, cavernous angioma, or capillary telangiectasia [34-36].

Some patients with a perimesencephalic pattern of bleeding are found to have a specific underlying cause of the SAH such as an occult aneurysm or high cervical spinal dural arteriovenous fistula. Comprehensive testing is warranted to identify such cases for patients with atypical symptoms or clinical course. However, the low incidence of rebleeding in patients with P-NASAH suggests that these instances are rare. (See 'Differential diagnosis' below.)

CLINICAL PRESENTATION

Neurologic symptoms — The clinical manifestations of P-NASAH are generally similar to the features of other forms of SAH, most commonly presenting with a sudden onset of headache, nausea, and vomiting [13].

The clinical manifestations of P-NASAH are generally less severe than those of aneurysmal SAH. On initial evaluation in the hospital, over 90 percent of patients with P-NASAH are categorized in lower Hunt and Hess grades (table 1), a measure of the clinical severity of the SAH [5,6,8,37-39]. By contrast, patients with aneurysmal SAH present are likelier to present with more severe symptoms [5,38]. However, individual patients with P-NASAH cannot be distinguished from others with aneurysmal SAH based on clinical symptoms alone [40].

●Headache – Headache onset is abrupt in approximately 85 percent of cases and more gradual (beginning in minutes rather than seconds) in the remainder [13]. Meningismus and photophobia are also frequently reported [6,8].

Headache onset in P-NASAH may be rapid but typically not instantaneous (thunderclap) like in aneurysmal SAH. By contrast, sentinel headache, a prodromal feature of up to 40 percent of patients with aneurysmal SAH, is generally not reported in P-NASAH [8]. However, patients with P-NASAH may report severe neck pain prior to acute headache.

●Associated neurologic deficits – Transient focal deficits, including sensory symptoms, weakness, gait impairment, and speech arrest, are reported by approximately 10 percent of patients. Amnesia at the onset of bleeding has been reported in up to one-third of patients, possibly due to transient hydrocephalus or a seizure [41]. Loss of consciousness at the onset of SAH is reported in approximately 4 percent of patients with P-NASAH, less frequent than those with aneurysmal SAH [13]. Likewise, most patients with P-NASAH have no impairment on Glasgow Coma Scale (table 2) testing at presentation, unlike the majority of patients with aneurysmal SAH [42].

●Triggers and time of onset – Physical exertion appears to be a common trigger in P-NASAH [1,6,18,28]. The onset of both P-NASAH and aneurysmal SAH are more common during daytime and evening hours compared with nighttime [43]. One analysis of the circadian fluctuation found an increased risk of P-NASAH during the day and late evening hours compared with the overnight hours [44].

The clinical course is also typically less severe in P-NASAH, and complications are milder than with aneurysmal SAH. (See 'Management of complications' below and 'Long-term prognosis' below.)

Initial brain imaging findings — The characteristic pattern of acute blood on head CT (image 1 and image 2 and figure 1) helps to identify P-NASAH and indicates a low likelihood of an aneurysm [4,8,45-47]. Acute blood in P-NASAH is typically restricted to the prepontine, interpeduncular, suprasellar, crural, ambient, and/or quadrigeminal cistern and/or cisterna magna. A mild amount of intraventricular blood may also be seen. In some patients, the visualized blood is limited to the quadrigeminal or pretruncal cisterns [45,46,48]. (See 'Radiologic criteria for perimesencephalic bleeding' below.)

However, patients with SAH cannot be diagnosed with P-NASAH based on initial brain imaging findings alone. A ruptured aneurysm may be found in up to 17 percent of patients with a perimesencephalic pattern of bleeding in some series [40,49]. Vascular imaging is required to confirm the diagnosis of P-NASAH. A small percentage of patients with aneurysmal SAH or other conditions such as a ruptured brainstem arteriovenous malformation may present with a perimesencephalic pattern of subarachnoid bleeding. (See 'Differential diagnosis' below.)

DIAGNOSIS — 

SAH should be considered in any patient complaining of severe headache of sudden onset. Urgent CT of the head should immediately follow consideration of the diagnosis. If the suspicion is high and the CT scan is negative, a lumbar puncture is typically performed to identify blood in the subarachnoid space. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)

The diagnosis of P-NASAH is made when a patient with acute SAH has a perimesencephalic pattern of bleeding and at least one angiographic study has failed to demonstrate an aneurysm. (See 'Radiologic criteria for perimesencephalic bleeding' below and 'Initial cerebral angiography' below.)

Radiologic criteria for perimesencephalic bleeding — Specific radiographic criteria to support the diagnosis of P-NASAH include all of the following [13,47]:

●The center of the hemorrhage is located immediately anterior to and in contact with the brainstem in the prepontine, interpeduncular, or suprasellar cistern.

●Blood is limited to the prepontine, interpeduncular, suprasellar, crural, ambient, and/or quadrigeminal cistern and/or cisterna magna.

●Interventricular blood is limited to incomplete filling of the fourth ventricle and occipital horns of the lateral ventricle.

●Blood does not extend into the Sylvian or interhemispheric fissures.

●No intraparenchymal blood is present.

●The diagnostic head CT scan without contrast scan is done within 72 hours after the ictus.

There is high interobserver agreement among radiologists in the identification of P-NASAH on head CT (kappa 0.87 to 0.96) [4,47]. However, the ability to assess these features on head CT can sometimes be challenging with very large or very small hemorrhages. Of note, the timing of the CT scan is critical. Initial head CT cannot reliably support the diagnosis of P-NASAH when imaging is performed more than 48 to 72 hours after the clinical ictus because intervening blood resorption may obscure the initial pattern and extent of hemorrhage, such as in cases of aneurysmal SAH [6,8,50].

Evaluation — Cerebrovascular imaging evaluation is required for all patients with suspected P-NASAH to exclude an aneurysmal source of bleeding (algorithm 1). Additional imaging is reserved for selected patients with clinical or initial imaging features suspicious for an underlying cause of bleeding despite nondiagnostic initial cerebral angiography.

Initial cerebral angiography — All patients with a perimesencephalic pattern of bleeding must undergo angiographic evaluation because of the very high and immediate morbidity and mortality associated with aneurysmal SAH. We suggest conventional digital subtraction angiography (DSA) over other angiographic techniques such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA). However, the best modality for evaluation of cerebral vasculature in P-NASAH is somewhat controversial, and some authors support using noninvasive studies such as CTA alone [51,52].

Digital subtraction angiography — DSA has the highest resolution for the detection of intracranial aneurysms and remains the gold-standard vascular imaging test to diagnose P-NASAH. DSA is able to identify small aneurysms and lesions adjacent to bony structures that may be harder to visualize with noninvasive modalities. Causative lesions have been identified in multiple series of patients with SAH who underwent DSA following a nondiagnostic CTA [53-55]. Three-dimensional rotational techniques can further improve the diagnostic yield of DSA by identifying very small aneurysms that may be difficult to visualize with standard two-dimensional angiography [56]. In addition, DSA also has excellent resolution for identifying alternative causes of subarachnoid bleeding, such as an arteriovenous malformation or cerebral venous thrombosis.

While invasive, DSA has a relatively low morbidity in this setting. The estimated risk of procedural complications is 0.5 to 1 percent and includes puncture site hematoma, dissection, or infection as well as less common neurologic complications such as transient ischemic attack or stroke [57,58].

Multidetector CTA if digital subtraction angiography is unavailable — CTA may be used as an initial angiographic test to identify an aneurysm for patients with a perimesencephalic pattern of SAH when DSA is not immediately available, such as for patients with acute SAH awaiting transfer to a facility that can perform DSA if initial CTA was negative. In addition, some centers with a high volume of cases of SAH and documented experience with multidetector CTA may choose CTA over DSA for the diagnostic evaluation of patients with a perimesencephalic pattern of SAH.

CTA has a high sensitivity for detecting an aneurysm and has been the best-studied noninvasive angiographic test for acute SAH. The sensitivities and specificities of CTA for aneurysm detection range in different meta-analyses from 83 to 97 and 88 to 97 percent, respectively [59-63]. There is likely to be appreciable interinstitutional variability related to expertise in interpretation and also in the specific technology used. Use of multidetector CTA may improve diagnostic yield in P-NASAH. A 2011 meta-analysis of CTA diagnosis of intracranial aneurysms found that compared with single-detector CTA, the use of multidetector CTA was associated with an overall improved sensitivity and specificity for aneurysm detection (both >97 percent) as well as improved detection of smaller aneurysms ≤4 mm in diameter [61]. Another systematic review and meta-analysis restricted to patients with SAH found similar results [62]. Multidetector CTA also allows for a superior depiction of aneurysm morphology [64].

One decision analysis study reported that CTA alone had higher utility in the setting of P-NASAH compared with other diagnostic strategies including no investigation, DSA alone, and CTA plus DSA [51]. However, these results may be disputed as certain assumptions in the analysis favored this outcome, including a low prevalence of aneurysm (4 percent), a high complication rate of angiography (2.7 percent morbidity and mortality), and a high sensitivity and specificity of CTA (both 97 percent).

The role of repeat angiography — We repeat angiographic testing for selected patients with P-NASAH when initial negative angiography is felt to be inadequate, including cases that were [1-3,8,65-71]:

●Technically difficult and/or with insufficient vascular opacification

●Performed without three-dimensional (rotational) imaging reconstruction

●Complicated by cerebral arterial vasospasm

●Associated with severe clinical grade at presentation (eg, Hunt and Hess grades 4 and 5 (table 1))

●Accompanied by atypical imaging features (eg, blood in Sylvian fissure)

In addition, for patients with rebleeding, we repeat angiographic testing with DSA. Rebleeding suggests the presence of an occult aneurysm and is an indication for repeat DSA. For patients without rebleeding who undergo repeat angiography, we typically perform testing one to two weeks following initial testing.

For other patients with P-NASAH and negative initial angiography, it is reasonable to avoid repeat testing.

When DSA is repeated after an initial negative study, an aneurysm may be revealed in 2 to 24 percent of patients, depending on the specific pattern of subarachnoid bleeding [5,8,11,72]. Reasons for an initial false-negative angiogram include technical or reading errors, small aneurysm size, and obscuration of the aneurysm because of associated vasospasm, hematoma, or thrombosis within the aneurysm [5,73]. A technically adequate, false-negative angiogram in the setting of P-NASAH is a rare but reported event [5,11,37,72-75].

Other experts advocate repeating DSA in all patients [50,63]. Yet others advocate for a conservative, middle-road approach with follow-up imaging using noninvasive CTA [5,75].

Other imaging

●Brain MRA – Brain MRA may be performed as an alternative to CTA based on local protocol and availability, but experience with this modality for P-NASAH is limited. Limited data suggest CTA may be more sensitive than MRA in this setting [76].

●Magnetic resonance vessel wall imaging – High-resolution magnetic resonance vessel wall imaging is an advanced imaging technique that can assess the arterial vessel wall. Vessel wall imaging has been used to identify luminal abnormalities or focal enhancement in some patients with P-NASAH and others with angiographically negative diffuse SAH [77-79]. However, the causal roles of these abnormal findings are uncertain. High-resolution vessel wall imaging is not widely available, and additional data are warranted to help identify its role in the evaluation of P-NASAH.

●CT- or magnetic resonance venography – CT-venography (CTV) or MR-venography (MRV) may be performed when a cerebral venous thrombosis is suspected but not identified on initial angiographic testing. As examples, CTV or MRV may be warranted for patients with a history of prior venous thrombosis or a clinical susceptibility for hypercoagulability whose initial angiographic testing with CTA provided suboptimal contrast opacification of venous structures. (See 'Cerebral venous thrombosis' below.)

●Brain MRI – Brain magnetic resonance imaging (MRI) has no proven additional benefit for the detection of a bleeding source compared with CT, CTA, or DSA and is not cost-effective in the evaluation of most patients with P-NASAH [13,72,80-82]. However, brain MRI with and without contrast may be helpful for selected patients with an atypical pattern of bleeding who have a suspected intracerebral cause of bleeding such as a cavernous malformation. (See 'Vascular malformations' below.)

●Spinal MRI – Spinal MRI with and without contrast is typically reserved for patients with subarachnoid bleeding in the caudal brainstem and those with a clinically suspected spinal source to bleeding such as patients with arm pain or weakness. (See 'Vascular malformations' below.)

DIFFERENTIAL DIAGNOSIS — 

A pattern of acute bleeding consistent with P-NASAH on initial brain imaging may be due to other conditions, such as aneurysmal SAH, traumatic SAH, cerebral venous thrombosis (CVT), or arteriovenous malformation (AVM). It is important to exclude these P-NASAH mimics as their treatments and prognoses differ from those of P-NASAH. These alternative conditions are typically identified by clinical circumstances and vascular imaging.

Aneurysmal SAH — A ruptured saccular aneurysm is the cause of SAH in patients with a perimesencephalic pattern of bleeding in 2 to 9 percent of patients [1,4,8,40,51,83,84]. The clinical features of aneurysmal SAH are often similar to those of P-NASAH, but a more abrupt onset or severe presentation is more common with aneurysmal SAH. A ruptured aneurysm is also more likely when brain imaging features are atypical such as when one or more of the criteria are not met. (See 'Radiologic criteria for perimesencephalic bleeding' above.)

The aneurysm in these cases arises from the posterior circulation: the basilar tip, the vertebrobasilar junction, or the posterior inferior cerebellar, superior cerebellar, or posterior cerebral artery [4,49,73,85]. When posterior circulation aneurysms rupture, a focal or regionally extensive pattern of bleeding is often seen, but a perimesencephalic pattern of SAH may be present in up to 17 percent of cases [40,49,84]. An aneurysm is identified by angiographic evaluation. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

Traumatic SAH — Nonaneurysmal SAH is frequently due to trauma and may present with acute bleeding in a perimesencephalic pattern [86,87]. However, a careful review of neuroimaging may identify other imaging features suggestive of trauma such as focal cerebral contusions, subdural hematomas, or skull fractures. In addition, a history of preceding trauma and evidence of noncerebral traumatic injuries can help identify trauma as the etiology of SAH in this setting. (See "Nonaneurysmal subarachnoid hemorrhage", section on 'Traumatic SAH'.)

Of note, P-NASAH may also lead to trauma (eg, fall). Evaluation for both P-NASAH and traumatic SAH may be warranted when the inciting event is uncertain.

Cerebral venous thrombosis — CVT can rarely present with P-NASAH as its primary manifestation [24-27]. Such patients may present with a more indolent course of subacute, progressive headache along with neurologic symptoms such as ataxia or cranial nerve deficits. Initial imaging may show venous infarction along with SAH.

CVT may be identified on the venous phase of digital subtraction angiography (DSA) and/or with a dedicated MRV or CTV. Identifying CVT as the cause of SAH is important as treatment differs significantly from the typical management of P-NASAH, and includes anticoagulation, even in the setting of acute hemorrhage. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis" and "Cerebral venous thrombosis: Treatment and prognosis".)

Vascular malformations — Rare cases of ruptured cerebral cavernous malformations or cerebral AVMs may present with acute SAH [13,36,88,89]. Such patients may have an intracerebral component of bleeding on imaging, depending on the location of the lesion. Cerebral cavernous malformations and AVMs are typically diagnosed with angiography. Some symptomatic cavernous malformations may be amenable to interventional treatment; ruptured AVMs typically require interventional or surgical treatment. (See "Brain arteriovenous malformations" and "Vascular malformations of the central nervous system".)

In addition, ruptured vascular malformation in the upper cervical region may cause bleeding to extend cephalad into the brainstem resulting in a perimesencephalic pattern of bleeding seen on brain imaging [90]. Such patients may have prominent neck pain and/or cervical radicular symptoms. Cervical spine imaging and/or angiography are used to identify these lesions.

MANAGEMENT

Initial treatment while aneurysm is being excluded — Patients with initial brain imaging findings suggestive of P-NASAH should be treated as though there is an underlying aneurysm until this has been satisfactorily excluded with angiographic testing. (See 'Evaluation' above.)

Initial treatment of patients with SAH includes:

●Admission to an intensive care setting for close neurologic, hemodynamic, and cardiac monitoring. This also includes patients with mild symptoms and those with head CT performed in the outpatient setting that shows acute perimesencephalic bleeding.

●Antithrombotic medications should be discontinued, and reversal agents should be given for patients on anticoagulants.

●Blood pressure should be monitored, and elevated blood pressure should be gradually treated. For most patients with acute SAH, we use a target systolic blood pressure (SBP) <160 mmHg or mean arterial pressure (MAP) <110 mmHg.

●Euvolemia should be maintained and nimodipine should be given to help prevent vasospasm and cerebral ischemia and improve outcomes.

●Measures to reduce hemodynamic fluctuations and risk of rebleeding should be administered including bedrest, stool softeners, and pain relief (eg, acetaminophen or short-acting opiates such as morphine sulfate).

●Pneumatic compression stockings should be used to limit the risk of deep vein thrombosis while patients are immobile.

The initial treatment of SAH is discussed in greater detail separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".)

Subsequent treatment — After ruptured aneurysm and other mimics have been excluded with angiographic testing, patients with P-NASAH should receive continued supportive care to monitor for and prevent the development of complications as well as treatment for any complications that arise.

Neurologic monitoring — Serial neurologic examinations are typically performed every two to four hours during the first couple days after negative initial angiography, more frequently for patients with severe or progressive symptoms or hydrocephalus on imaging. Thereafter, examinations may be performed less frequently for stable patients with improving headache and/or neurologic symptoms and subsequently discontinued for those who do not develop complications within the first two to four days [13,91]. (See 'Management of complications' below.)

We do not administer prophylactic antiseizure medications because the risk of seizures in patients with P-NASAH is low, and the benefit of this strategy has not been established [6].

Deterioration in neurologic examination typically warrants repeat brain and vascular imaging to assess for rebleeding or vasospasm. Other diagnostic tests, such as laboratory testing or electroencephalography, may also be warranted. (See 'Management of complications' below.)

Management of blood pressure and volume status — Patients with P-NASAH should receive intravenous fluids to maintain euvolemia while targeting electrolyte balance. Elevated blood pressure should be treated to a target of SBP <160 mmHg or MAP <110 mmHg, unless higher targets are required to provide adequate cerebral perfusion or prevent kidney impairment. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Euvolemia maintenance' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.)

Nimodipine duration — Nimodipine is typically started acutely following SAH diagnosis. For most patients with P-NASAH who have mild clinical symptoms, we discontinue nimodipine after initial cerebral angiography has excluded aneurysm as the cause of bleeding.

We continue nimodipine 60 mg every four hours for other patients with P-NASAH who have clinical features or initial cerebral angiographic findings that warrant repeat angiography including any of the following:

●Severe clinical grade at presentation (eg, Hunt and Hess grades 4 and 5 (table 1))

●Neurologic deterioration after presentation or evidence of rebleeding

●Technically difficult and/or inadequate initial angiographic study

●Evidence of arterial vasospasm

For these patients, we discontinue nimodipine once clinical features improve and/or repeat imaging excludes aneurysm and vasospasm.

The calcium channel blocker nimodipine may provide neuroprotection against vasospasm-induced cerebral ischemia and has been shown to improve outcomes in patients with aneurysmal SAH [92]. However, it is uncertain whether nimodipine provides benefit for patients with P-NASAH, who as a group incur little serious neurologic mortality and morbidity. At the same time, nimodipine is generally well tolerated and unlikely to be associated with significant adverse effects in this group. One single-center retrospective review of 93 patients with P-NASAH treated with nimodipine found functional outcomes were similar whether patients received nimodipine for 21 days or shorter regimens [93].

Managing discontinued antithrombotic therapy — Antithrombotic therapy is typically discontinued, and anticoagulation is reversed acutely, for patients with SAH. For patients with P-NASAH managed with antiplatelet therapy or anticoagulation with negative angiography, we individualize decisions regarding the optimal time of resumption, based on the strength of the indication and severity of the bleed. We typically avoid antiplatelet therapy or anticoagulation within the first three to five days following the onset of P-NASAH when possible. Early rebleeding has rarely been reported with restarting anticoagulation in the immediate posthemorrhagic period [94]. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Resumption of anticoagulation'.)

Management of complications — Neurologic and medical complications may occasionally occur early in the course of the initial management of patients with P-NASAH. They are identified by clinical deterioration or through diagnostic testing. Most clinical case series report that patients with P-NASAH have a lower incidence and severity of complications compared with patients with aneurysmal SAH and patients with non-P-NASAH [2,12,38,95-97].

●Rebleeding — Rebleeding is identified on repeat brain imaging, typically performed in patients with new or worsened neurologic exam findings. Rebleeding represents an indication for repeat angiography with digital subtraction angiography (DSA) to assess for occult aneurysm or other vascular lesions.

Such patients should be treated with measures used for other patients for whom an aneurysm has not been excluded. (See 'Initial treatment while aneurysm is being excluded' above.)

Rebleeding is very rare among patients with P-NASAH after initial negative angiography [98]. In a 2018 systematic review, in-hospital rebleeding was reported in only 3 of over 1220 patients with P-NASAH [13]. When rebleeding occurs in a patient with P-NASAH, the pattern of recurrent hemorrhage is often not perimesencephalic, suggesting aneurysmal or other vascular causes of bleeding may be more likely [5,99].

●Vasospasm and delayed cerebral ischemia — Arterial vasospasm may be asymptomatic, identified on initial angiography, or symptomatic, identified on repeat angiography prompted by neurologic deterioration. Vasospasm management includes:

•Prevention by maintaining euvolemia and administering nimodipine

•Surveillance by neurologic monitoring or diagnostic testing via DSA, CT-angiography (CTA), or transcranial Doppler (TCD) sonography

•Treatment with hemodynamic augmentation and intra-arterial vasodilation for severe cases

Vasospasm management is discussed in greater detail separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Vasospasm and delayed cerebral ischemia'.)

Vasospasm with cerebral ischemia is a leading cause of death and disability after aneurysm rupture, occurring in 20 to 30 percent of patients with aneurysmal SAH [100]. In P-NASAH, vasospasm is less common and is typically associated with milder clinical symptoms [101]. In a 2018 systematic review of patients with P-NASAH, angiographic vasospasm was detected in 9 percent (95% CI 6-14) [13]. However, there are reported cases of symptomatic, diffuse, and severe vasospasm affecting the anterior and posterior circulations in some patients with P-NASAH [2,102-107]. Symptomatic vasospasm has also been precipitated by DSA in some cases [6,8,95]. The lower incidence of vasospasm in P-NASAH compared with aneurysmal SAH may be due to the lower volume or less oxyhemoglobin from venous source of bleeding in these patients, although this specific association has not been demonstrated.

●Hydrocephalus — Hydrocephalus occurs in patients with P-NASAH due to obstruction of the flow of cerebrospinal fluid (CSF), often at the intraventricular foramen or the Sylvian aqueduct. Hydrocephalus is identified on brain imaging that is typically prompted by new neurologic deterioration (eg, reduced level of consciousness) or an unexplained elevation in intracranial pressure on monitoring. Symptomatic hydrocephalus is managed with CSF diversion or osmotic therapy. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Elevated intracranial pressure'.)

A 2018 systematic review of P-NASAH found that hydrocephalus occurred in 14 percent (95% CI 10-18) [13], a rate similar to aneurysmal SAH. However, symptomatic hydrocephalus, defined as radiographic hydrocephalus with a diminished level of consciousness leading to drainage, was less frequent, occurring in 3 percent (95% CI 2-6). One case series found that among patients with P-NASAH, filling of all perimesencephalic cisterns was a prerequisite for developing hydrocephalus [108]. In more than half of the cases, hydrocephalus resolved spontaneously without intervention (ventriculostomy and/or shunting), perhaps because of the rapid washout of the low volume of blood limited to the cisterns.

●Hyponatremia — Hyponatremia following SAH is due to increased secretion of antidiuretic hormone. Treatment typically consists of administration of hypertonic saline. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Hyponatremia'.)

In one series, 10 of 35 patients with P-NASAH developed hyponatremia, only five of whom had sodium levels less than 130 mmol/L [95].

●Seizures — Acute seizures have been described in P-NASAH, but are uncommon [13]. The management of seizures in patients with SAH is discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Seizures'.)

LONG-TERM PROGNOSIS — 

Patients with P-NASAH generally have a good outcome, typically more favorable than patients with aneurysmal SAH and patients with other types of nonaneurysmal SAH [2,5,95].

With rare exceptions, patients do not have significant neurologic deficits after P-NASAH. Some uncontrolled studies suggest that many patients report residual headaches, depression, minor cognitive deficits, and fatigue several years after the P-NASAH, in some cases affecting employment status [3,109-111]. Persistent anosmia is an infrequent (5 percent) complication of P-NASAH [112]. However, one study found that quality of life two years after P-NASAH was not significantly different from controls [113].

Long-term follow-up studies suggest that rebleeding is rare and life expectancy is not altered [38,109,110,114].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)

SUMMARY AND RECOMMENDATIONS

●Definition – P-NASAH refers to a subset of patients with NASAH who have a characteristic pattern of localized blood on brain imaging, normal cerebral angiography, and a typically benign course. P-NASAH represents up to 10 percent of SAH cases, and the incidence is estimated to be 0.5 per 100,000 adults. (See 'Introduction and definition' above and 'Epidemiology' above.)

●Presentation

•Clinical features — The clinical manifestations of P-NASAH are similar to those of other forms of SAH and include a sudden onset of headache, nausea, and vomiting. Some patients also have meningismus and associated neurologic deficits such as weakness, numbness, or impairment in consciousness. Patients with P-NASAH generally have milder clinical features than those with aneurysmal SAH. (See 'Neurologic symptoms' above.)

•Findings on initial head CT – The characteristic findings of P-NASAH on head CT consist of acute blood restricted to the prepontine, interpeduncular, suprasellar, crural, ambient, and/or quadrigeminal cistern and/or cisterna magna (image 1 and image 2 and figure 1). A mild amount of intraventricular blood may also be seen. (See 'Initial brain imaging findings' above.)

●Diagnosis – The diagnosis of P-NASAH is made when a patient with acute SAH has a perimesencephalic pattern of bleeding and at least one angiographic study has failed to demonstrate an aneurysm. (See 'Diagnosis' above.)

●Evaluation – Cerebrovascular imaging evaluation is required for all patients with suspected P-NASAH to exclude an aneurysmal source of bleeding (algorithm 1). We suggest conventional digital subtraction angiography (DSA) over other angiographic techniques due to superior resolution for excluding small aneurysms and other vascular pathologies. Multidetector CT-angiography (CTA) may be performed as an alternative imaging modality. (See 'Initial cerebral angiography' above.)

Repeat angiographic testing (one to two weeks after the initial study) is reserved for selected patients with P-NASAH when initial negative angiography is felt to be technically inadequate, complicated by cerebral arterial vasospasm, or associated with a severe clinical grade at presentation. We also repeat angiographic testing with DSA for patients who have rebleeding, due to the risk of occult aneurysm. (See 'The role of repeat angiography' above.)

●Differential diagnosis – A pattern of acute bleeding consistent with P-NASAH on initial brain imaging may be due to other conditions, such as aneurysmal SAH, traumatic SAH, cerebral venous thrombosis (CVT), or arteriovenous malformation (AVM). These alternative conditions are typically identified by clinical circumstances and vascular imaging. (See 'Differential diagnosis' above.)

●Management

•Patients with initial brain imaging findings suggestive of P-NASAH should be treated as though there is an underlying aneurysm until this has been satisfactorily excluded with angiographic testing. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".)

•After ruptured aneurysm and other mimics have been excluded with angiographic testing, patients with P-NASAH should receive continued supportive care to monitor for and prevent the development of complications as well as treatment for any complications that arise. Supportive treatment includes (see 'Subsequent treatment' above):

-Clinical monitoring – Serial neurologic examinations are typically performed every two to four hours during the first few days after negative initial angiography until symptoms improve. Deterioration in neurologic examination typically warrants repeat brain and vascular imaging or other diagnostics such as electroencephalography. (See 'Neurologic monitoring' above.)

-Euvolemia and blood pressure management – Intravenous fluids should be given to maintain euvolemia while targeting electrolyte balance. Elevated blood pressure should be treated to a target of systolic blood pressure <160 mmHg or mean arterial blood pressure <110 mmHg, unless higher targets are required to provide adequate cerebral perfusion or prevent kidney impairment. (See 'Management of blood pressure and volume status' above.)

-Nimodipine – For most patients with P-NASAH with mild clinical symptoms, we discontinue nimodipine after initial cerebral angiography has excluded aneurysm. For other patients with P-NASAH who have more severe clinical features or initial cerebral angiographic findings, we continue nimodipine until aneurysm and vasospasm have been excluded with repeat angiography. (See 'Nimodipine duration' above.)

•Neurologic and medical complications are identified by clinical deterioration or through diagnostic testing and include rebleeding, vasospasm and delayed cerebral ischemia, hydrocephalus, hyponatremia, and seizures. Complications in P-NASAH are managed the same as complications for aneurysmal SAH. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Managing early complications'.)

●Prognosis – Patients with P-NASAH generally have a good outcome, and long-term follow-up studies suggest that rebleeding is rare and life expectancy is not altered. (See 'Long-term prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges David Brock, MD, CIP, who contributed to earlier versions of this topic review.