What is subarachnoid hemorrhage, including its introduction, risk factors, etiology, pathophysiology, clinical presentation, severity grading, diagnostic evaluation, differential diagnosis, complications, management, prognosis, and recent or ongoing trials?

Subarachnoid Hemorrhage: Comprehensive Review

Introduction

Subarachnoid hemorrhage (SAH) is a devastating neurologic emergency characterized by bleeding into the cerebrospinal fluid-filled space beneath the arachnoid membrane, with population-based mortality rates reaching 45% and approximately 12% of patients dying before receiving medical attention. 1, 2 The condition accounts for 5% of all strokes and affects approximately 30,000 Americans annually. 1 Approximately 80% of nontraumatic SAH cases result from ruptured intracranial aneurysms, with the remainder from idiopathic peri-mesencephalic hemorrhage or other less common causes. 3, 4

Risk Factors

Modifiable Risk Factors

• Hypertension is a major modifiable risk factor that influences both aneurysm formation and rupture risk. 2
• Smoking significantly increases the risk of aneurysm formation and rupture. 4
• Medical comorbidities including atrial fibrillation, heart failure, coronary artery disease, and renal disease all increase mortality risk. 2

Non-Modifiable Risk Factors

• Age and sex are important demographic factors, with older age associated with worse outcomes. 2
• Family history is critical—screening should be reserved for patients with at least one first-degree family member with a history of intracranial aneurysm or SAH. 4
• The prevalence of intracranial aneurysms in the global population is 2% to 6%, many found incidentally. 4

Emerging Risk Factors

• Body mass index, hyperglycemia, elevated troponin levels, hyperthermia, peak white blood cell count, C-reactive protein, and high neutrophil counts have been associated with clinical outcomes, though additional investigation is required for their prognostic value. 1

Etiology

The most common cause of spontaneous SAH is rupture of a saccular intracranial aneurysm arising from the larger conducting arteries at the base of the brain. 5 These aneurysms are small bag-shaped or pouch-shaped outpouchings that develop at arterial branch points. 5 As these are high-pressure, higher-volume arterial hemorrhages, they are associated with high early mortality and substantial long-term morbidity. 5

Pathophysiology

Initial Injury Mechanisms

• The initial hemorrhage causes direct devastating impact on brain tissue, accounting for 19-23% of deaths. 2
• SAH induces decreased microvascular perfusion and increased permeability, leading to widespread brain injury. 1
• The severity of the initial bleed is the most useful indicator of outcome and should be determined rapidly. 1

Secondary Injury Mechanisms

• Cerebral vasospasm develops in the days following SAH and contributes significantly to delayed ischemic deficits. 6
• Acute hydrocephalus occurs more frequently in patients with poor neurological status, high Hunt-Hess grade, larger aneurysm diameter, and intraventricular blood. 1
• Patients who have no grossly evident neurological deficits frequently have subtle cognitive or neurobehavioral difficulties that impair social adjustment and ability to return to previous occupations, likely due to diffuse effects of SAH rather than focal tissue loss. 1

Clinical Presentation

Classic Presentation

• The hallmark symptom is sudden-onset severe headache reaching maximal intensity within 1 hour, described as "the worst headache of my life" by 80% of patients who can provide history. 1, 7, 8 This headache is present in 74% of confirmed SAH cases. 7, 8
• The headache reaches peak intensity immediately or within seconds to minutes, distinguishing it from other headache types. 8

Associated Symptoms

• Nausea and/or vomiting occur in 77% of cases. 8
• Nuchal rigidity/neck stiffness is present in 35% of cases. 8
• Brief loss of consciousness occurs in 53% of cases. 8
• Photophobia is a common associated symptom. 8
• Focal neurological deficits including cranial nerve palsies may be present. 8

Sentinel Hemorrhage

• A warning or sentinel headache precedes the major SAH-associated presentation in 10% to 43% of cases. 1
• Diagnosis of a sentinel bleed before catastrophic rupture can be lifesaving. 1

Critical Pitfall

• Misdiagnosis or delayed diagnosis can have grave consequences, including death and severe disability. 1 Physicians must maintain a high level of awareness and pursue appropriate workup when necessary. 1

Severity Grading

Hunt and Hess Grading Scale

• This is the most commonly used clinical grading system, ranging from Grade I (minimal symptoms) to Grade V (deep coma, moribund). 1, 6
• Clinical grade on admission strongly predicts outcome, with worse neurological status associated with higher mortality. 2
• Higher Hunt-Hess grades are independent predictors of acute hydrocephalus. 1

Glasgow Coma Scale

• Recent reports have tended to use the Glasgow Coma Scale, though it was originally designed to predict outcome after head injury and has not been fully assessed for SAH outcomes. 1
• The admission Glasgow Coma Scale score should be documented as a minimum in all studies reporting on SAH. 1

Modified Rankin Scale

• Used to assess functional outcomes, particularly in clinical trials such as the International Subarachnoid Aneurysm Trial (ISAT). 1

Key Recommendation

• The severity of the initial bleed should be determined rapidly because it is the most useful indicator of outcome after aneurysmal SAH, and grading scales that rely heavily on this factor are helpful in planning future care. 1

Diagnostic Evaluation

Initial Imaging: Non-Contrast Head CT

For patients presenting within 6 hours of headache onset with no new neurological deficits, a negative high-quality non-contrast head CT performed on a high-quality scanner and interpreted by a board-certified neuroradiologist is sufficient to exclude SAH (sensitivity 98.7%, missing <1.5 in 1000 cases). 1, 8

• The sensitivity of CT remains very high (close to 100%) in the first 3 days after SAH. 8
• Sensitivity declines to 93% at 24 hours and 57-85% at 6 days. 8
• Noncontrast head CT remains the mainstay of SAH diagnosis. 1, 3

Ottawa SAH Rule

In patients with acute onset of severe headache without a new neurological deficit, application of the Ottawa SAH Rule may be reasonable to identify those at high risk for aSAH. 1

The Ottawa SAH Rule applies to alert patients >15 years of age with new severe nontraumatic headache reaching maximum intensity within 1 hour. Patients require additional investigation for SAH if they meet any of the following criteria: 1

• Age ≥40 years
• Neck pain or stiffness
• Witnessed loss of consciousness
• Onset during exertion
• Thunderclap headache (instantly peaking pain)
• Limited neck flexion on examination

Lumbar Puncture

After 5-7 days, or when CT is performed >6-12 hours after symptom onset and is negative or inconclusive, lumbar puncture is required to demonstrate xanthochromia. 1, 8

• Spectrophotometric analysis for xanthochromia has a sensitivity of 100% and specificity of 95.2% when performed >6-12 hours after symptom onset. 1, 8
• LP is often performed >6 to 12 hours after symptom onset to allow time for xanthochromia development. 1

Vascular Imaging

In patients with spontaneous SAH with high level of concern for aneurysmal source and a negative or inconclusive CT, digital subtraction angiography (DSA) is indicated to diagnose/exclude cerebral aneurysm(s). 1

• In patients with SAH from confirmed cerebral aneurysm(s), DSA can be useful to determine the optimal strategy for aneurysm intervention. 1
• CT angiography (CTA) has a sensitivity of approximately 97.2% for detecting aneurysms, but sensitivity for ruptured aneurysms <3 mm is only 61%. 1
• CTA does not directly evaluate for SAH, only cerebrovascular pathology. 1

Critical Pitfall

• Given the severe morbidity and potential mortality associated with a missed aSAH, when CT is inconclusive and clinical suspicion remains high, proceed with LP for xanthochromia evaluation rather than relying solely on CTA. 1

Differential Diagnosis

When evaluating sudden severe headache, consider:

• Primary thunderclap headache (diagnosis of exclusion after SAH ruled out). 1
• Reversible cerebral vasoconstriction syndrome (may present with thunderclap headache). 1
• Cervical artery dissection (may present with neck pain and headache). 1
• Meningitis (fever, nuchal rigidity, but typically more gradual onset). 8
• Migraine (typically does not reach maximal intensity within seconds to minutes). 8
• Intracranial hypotension (positional headache, not thunderclap). 1

Complications

Rebleeding

Rebleeding remains the most serious and currently most treatable cause of poor outcomes, with a case fatality rate of 70% for patients who rebleed. 1, 2

• The risk of ultra-early rebleeding (within 24 hours) may be as high as 15%, considerably higher than previously recognized. 1, 2
• 70% of ultra-early rebleeds occur within 2 hours of the initial SAH. 1, 2
• Rebleeding is maximal (4%) on the first day after SAH, then constant at 1% to 2% per day over the subsequent 4 weeks. 1, 2
• Long-term risk stabilizes at 3% per year after 3 months. 1
• Rebleeding accounts for 22-23% of all SAH deaths. 2

Risk Factors for Rebleeding

• Longer interval from hemorrhage to admission and treatment. 1
• Higher initial blood pressure. 1
• Worse neurological status on admission. 1
• Poor neurological status and high Hunt-Hess grade. 1
• Larger aneurysm diameter. 1

Delayed Cerebral Ischemia/Vasospasm

• Cerebral vasospasm develops in the days following SAH and contributes to delayed ischemic deficits. 6
• Nimodipine reduces the incidence and severity of ischemic deficits related to vasospasm. 6

Hydrocephalus

• Acute hydrocephalus occurs more frequently in patients with poor neurological status, high Hunt-Hess grade, larger aneurysm diameter, and intraventricular blood. 1
• Recent data suggest that when preoperative ventriculostomy is followed by early treatment of the ruptured aneurysm, the risk of rebleeding is not increased by the ventriculostomy. 1

Seizures

• Seizures occur in up to 20% of patients, most commonly in the first 24 hours. 8
• Antiseizure medications may provide dual benefits for seizure prophylaxis and headache management in select patients. 7

Cardiac Complications

• Elevated troponin levels are associated with worse outcomes. 1
• Cardiac arrest and cardiovascular collapse can occur, particularly with inappropriate administration of nimodipine. 6

Cognitive and Neurobehavioral Deficits

• Patients who have no grossly evident neurological deficits frequently have subtle cognitive or neurobehavioral difficulties that impair social adjustment and ability to return to previous occupations. 1
• These deficits are not correlated with tissue loss on MRI and are likely due to diffuse effects of SAH. 1

Management

Initial Stabilization and Blood Pressure Control

Urgent evaluation and treatment of patients with suspected SAH are recommended given the 3% to 4% risk of rebleeding in the first 24 hours—and possibly significantly higher—with a high percentage occurring immediately (within 2 to 12 hours) after the initial ictus. 1

• Systolic blood pressure should be maintained below 160 mmHg using titratable agents (nicardipine, labetalol, or clevidipine) to prevent rebleeding. 7, 8
• Blood pressure control is essential not only for preventing rebleeding but also for managing headache. 7
• Avoid hypervolemia when managing blood pressure, as this can increase complications without improving outcomes; maintain euvolemia instead. 7, 8
• Blood pressure should be carefully monitored during treatment with nimodipine based on its known pharmacology. 6

Definitive Aneurysm Treatment

Early neurosurgical or endovascular intervention is critical to prevent rebleeding, which carries the highest risk in the first 24 hours. 8

• Digital subtraction angiography can be useful to determine the optimal strategy for aneurysm intervention. 1
• Treatment options include surgical clipping or endovascular coiling, with choice depending on aneurysm characteristics and patient factors. 1

Nimodipine for Vasospasm Prevention

Nimodipine 60 mg every 4 hours for 21 days should be administered to all SAH patients for improved neurological outcomes, with potential secondary benefits for headache management. 7, 8, 6

• Nimodipine is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with SAH from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (Hunt and Hess Grades I-V). 6
• Four randomized, double-blind, placebo-controlled trials demonstrated that nimodipine reduces the severity of neurological deficits resulting from vasospasm. 6
• Nimodipine is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations as high as 12.5 ng/mL have been detected in CSF of treated SAH patients. 6
• The terminal elimination half-life is approximately 8 to 9 hours, necessitating dosing every 4 hours. 6

Critical Nimodipine Warnings

• Intravenous administration of the contents of nimodipine capsules has resulted in serious adverse consequences including death, cardiac arrest, cardiovascular collapse, hypotension, and bradycardia. 6
• About 5% of patients were reported to have lowering of blood pressure and about 1% left studies because of this. 6
• Blood pressure should be carefully monitored during treatment with nimodipine. 6

Nimodipine Drug Interactions

Strong CYP3A4 inducers (rifampin, carbamazepine, phenobarbital, phenytoin, St. John's Wort) should generally not be administered concomitantly with nimodipine as they may significantly reduce nimodipine plasma concentration and efficacy. 6

• Strong CYP3A4 inhibitors (clarithromycin, telithromycin, HIV protease inhibitors, azole antimycotics, nefazodone) should not be coadministered with nimodipine as they can significantly increase nimodipine plasma concentration and blood pressure lowering effect. 6
• Grapefruit juice ingestion is not recommended while taking nimodipine, as the blood pressure lowering effect may last for at least 4 days after the last ingestion. 6

Nimodipine in Hepatic Disease

• The metabolism of nimodipine is decreased in patients with impaired hepatic function. 6
• Such patients should have their blood pressure and pulse rate monitored closely and should be given a lower dose. 6
• Bioavailability is significantly increased in patients with hepatic cirrhosis, with Cmax approximately double that in normals. 6

Headache Management

Oral acetaminophen should be administered to all patients with SAH-associated headache as the foundation of pain management. 7, 8

• Avoid routine long-term opioid management, as the actual efficacy of opioids for SAH headache is disappointingly poor, with a median pain reduction after opioid administration of only -1 point on the numeric rating scale. 7
• Counsel patients early about the risks of medication overuse headache by avoiding simple analgesics on more than 15 days per month or opioids on greater than 10 days per month for more than 3 months. 7
• Consider headache specialist referral for patients with persistent post-SAH headache. 7

Hydrocephalus Management

• Ventriculostomy may be required for acute hydrocephalus. 1
• When preoperative ventriculostomy is followed by early treatment of the ruptured aneurysm, the risk of rebleeding is not increased. 1

Seizure Management

• Seizures should be managed accordingly when they occur, most commonly in the first 24 hours. 8
• Antiseizure medications may provide dual benefits for seizure prophylaxis and headache management in select patients. 7

Hospital Volume Considerations

• 30-day mortality is 39% at low-volume hospitals (<10 SAH patients annually) versus 27% at high-volume hospitals (>35 patients annually). 2
• The lowest-volume hospitals have mortality rates of 49% compared to 32% at highest-volume hospitals. 2
• Transfer to high-volume specialty centers should be strongly considered for optimal outcomes. 2

Prognosis

Overall Mortality

The 30-day mortality rate for all patients who suffer subarachnoid hemorrhage is 45%, based on population-based studies, with most deaths concentrated in the initial days following hemorrhage. 2

• Approximately 12% of patients die before receiving any medical attention. 2
• The in-hospital mortality rate for SAH patients admitted through emergency departments is approximately 33%. 2
• The case fatality rate is approximately 50% overall when including pre-hospital deaths. 2
• Mortality can reach 50% in various studies. 3

Causes of Death

• Initial hemorrhage effects account for approximately 19-23% of deaths. 2
• Rebleeding accounts for 22-23% of deaths, with a case fatality rate of 70% for patients who experience rebleeding. 2

Prognostic Factors

Clinical grade on admission strongly predicts outcome, with worse neurological status associated with higher mortality. 2

• Age, sex, time to treatment, and medical comorbidities (hypertension, atrial fibrillation, heart failure, coronary disease, renal disease) all influence mortality. 2
• Higher initial blood pressure and worse neurological status on admission are related to recurrent hemorrhage. 1
• Poor neurological status, high Hunt-Hess grade, and larger aneurysm diameter are independent predictors of acute hydrocephalus. 1

Functional Outcomes

Nimodipine tends to improve good recovery of SAH patients with poor neurological status post-ictus (Hunt and Hess Grades IV or V), while decreasing the numbers with severe disability and vegetative survival. 6

• When data were combined for Canadian and UK studies, the treatment difference on success rate (good recovery) on the Glasgow Outcome Scale was 25.3% (nimodipine) versus 10.9% (placebo) for Hunt and Hess Grades IV or V. 6
• Patients who have no grossly evident neurological deficits frequently have subtle cognitive or neurobehavioral difficulties that impair their social adjustment and ability to return to their previous occupations. 1
• Perhaps the most meaningful measure of the effect of these deficits is whether the patient is able to return to his or her previous occupation. 1

Recent and Ongoing Trials Supporting Management and Diagnosis

Completed Landmark Trials

The International Subarachnoid Aneurysm Trial (ISAT) used written questionnaires sent to patients to determine modified Rankin Scale outcomes and influenced current treatment protocols. 1

• Four randomized, double-blind, placebo-controlled trials established nimodipine's efficacy in reducing the severity of neurological deficits resulting from vasospasm. 6
• These trials used doses ranging from 20-30 mg to 90 mg every 4 hours, with drug given for 21 days in 3 studies and for at least 18 days in the other. 6
• Three of the four trials followed patients for 3 to 6 months. 6

Study Populations and Outcomes

• Two studies (one U.S., one French) showed significantly fewer severe deficits due to spasm in the nimodipine group. 6
• A large UK study showed a significant reduction in the overall rate of infarction and severely disabling neurological outcome at 3 months. 6
• A Canadian study of sicker patients (Hunt and Hess Grades III-V) showed significant reduction in spasm-related deficits. 6

Knowledge Gaps and Future Research Directions

Several medical parameters have been associated with clinical outcomes in aSAH, including body mass index, hypertension, hyperglycemia, troponin levels, hyperthermia, peak white blood cell, C-reactive protein, and high neutrophil counts, but additional investigation is required for determination of their prognostic value and influence on treatment outcomes. 1

• Novel biomarkers including imaging, serum, and cerebrospinal fluid (CSF) are an active area of research in aSAH. 1
• Further studies incorporating new methods of proteomics, genomics, and other biological markers with existing clinical, radiographic, and physiological monitoring data will be necessary. 1
• Despite recent advances in understanding the mechanisms of SAH-induced brain injury, few effective treatments exist, and further research is needed. 1