An aneurysm is an abnormal dilatation or bulging in a blood vessel due to the intrinsic weakness of the vessel wall. Aneurysms can affect any blood vessel, but they are most commonly seen in arteries rather than veins. An aneurysm can be a true aneurysm or false aneurysm. A true aneurysm has all the three layers of the arterial wall (intima, media, and adventitia). A false aneurysm, also known as pseudoaneurysm, involves the outer layer of the artery (adventitia). Depending on their shape, they can be saccular or fusiform. Cerebral aneurysms are 90% saccular aneurysms (also known as berry aneurysms), unlike aortic aneurysms, which are about 94% fusiform. Aneurysms can be classified based on their location in the body. Depending on the etiology can be dissecting or mycotic aneurysms.
This review will focus on saccular cerebral and aortic aneurysms. Saccular cerebral aneurysms can also be classified by size (small: 5 mm or less, medium: 6 to 14 mm, large: 15 to 25 mm, giant: greater than 25 mm). Most cerebral aneurysms are asymptomatic and small, and they are found incidentally during brain imaging or during an autopsy. About 85% of cerebral aneurysms are located in the anterior circulation at the arterial bifurcations on the circle of Willis and the middle cerebral artery bifurcation. Most of the saccular aortic aneurysms are located in the descending thoracic aorta.
Although the formation of cerebral saccular aneurysms is not completely understood, it is thought to be primarily associated with hemodynamically induced degenerative vascular changes. Inflammatory changes also play a role in their formation. Most saccular aneurysms are acquired, but they can be inherited.
Family history is the strongest indicator of rupture among non-modifiable risk factors. Compared to the general population, first-degree relatives of persons with cerebral aneurysms or previous subarachnoid hemorrhage (SAH) have a risk of 3 to 7 times higher. Nicotine exposure promotes aneurysmal rupture through actions on vascular smooth muscle cells.
The etiology of saccular aortic aneurysms is almost similar to that of saccular cerebral aneurysms. The most common risk factor of saccular aortic aneurysms is atherosclerotic disease; other less common risk factors include aortic infections, trauma, chronic inflammatory/autoimmune conditions (Behcet disease, giant cell arteritis, rheumatoid arthritis, Takayasu arteritis, systemic lupus erythematosus, ankylosing spondylitis), presence of bicuspid aortic valve or previous aortic surgeries. In addition to the above genetic conditions listed under cerebral aneurysms, saccular aortic aneurysms can be associated with Turner syndrome.
The prevalence of cerebral aneurysms is estimated to be 3.2% to 4% in the general population without inherited risk factors. The most common age of presentation is between 30 and 60 (mean age of 50-years-old with 1:1 gender ratio). After the age of 50, the prevalence increases in women compared to male and may approach a 2:1 ratio. Approximately 20% to 30% of patients with cerebral aneurysms have multiple aneurysms. The incidence of cerebral aneurysm rupture causing SAH is estimated to be 6 to 16 per 100,000 population, and this accounts for 30,000 cases per year in the United States alone. The risk of rupture of an unruptured cerebral aneurysm is 1% to 2% per year. Approximately 10% to 30% of patients with aneurysm rupture die before reaching the hospital, and only 30% have a good outcome after appropriate treatment. Cerebral aneurysms rupture account for 0.4% to 0.6% of all deaths. Ruptured aneurysms have a 20% to 50% risk of rebleeding in the first two weeks if untreated. Cerebral aneurysms are uncommon in the pediatric population.
Approximately 85% of the cerebral aneurysms are located in the anterior circulation on the circle of Willis and the middle cerebral artery bifurcation. The most common sites of cerebral aneurysms are the junction of the anterior cerebral artery with the anterior communicating artery, the junction of the internal carotid artery with the posterior communicating artery and the bifurcation of the middle cerebral artery. In the posterior circulation, the most common sites often include the distal basilar bifurcation (basilar tip), the junction of the basilar artery and the superior or anterior inferior cerebellar arteries, and the junction of the vertebral artery with the posterior inferior cerebellar artery.
A study of 284 patients with 322 saccular aortic aneurysms showed that 68% were found in the thoracic aorta, 24.2% in the abdominal aorta, 7.1% in the arch of the aorta, and 0.6% in the ascending aorta. When aortic aneurysms are studied, aortic saccular aneurysms include 6% of them, while fusiform include 94% of them. As saccular aortic aneurysms are less common than fusiform aneurysms, most epidemiological studies report data that includes any type of aortic aneurysms; therefore, the true incidence and prevalence of saccular aortic aneurysm are unknown.
The pathophysiology for the formation and growth of cerebral and aortic saccular aneurysms is believed to be a multifactorial process that leads to degenerative changes in the blood vessel wall. These degenerative changes could be due to collagen deficiency or congenital weakness of the arterial wall layers. Alteration of the internal elastic lamina develops from hemodynamic shear stress, hypertension, turbulent blood flow, and atherosclerotic deposits, which is associated with focal defects, disorganization, or absence of the media layer. As it is well known that chronic inflammation and immunologic response are key pathogenic features of atherosclerosis, inflammatory mediators like T-cell and macrophages could be linked in causing histologic changes within the arterial wall resulting in formation, progression, and rupture of cerebral aneurysms. Endothelial dysfunction is considered the first step in the formation of cerebral aneurysms.
The majority of unruptured cerebral aneurysms are asymptomatic (85% to 90%), and they are incidentally found during brain imaging fo other reasons.
Signs and symptoms of unruptured cerebral aneurysm include:
Signs and symptoms of ruptured cerebral aneurysm include:
Headache described as the "worst headache of my life" is the most common symptom in a ruptured cerebral aneurysm. About 10 to 43% of patients with SAH experience mild-moderate headache approximately 2 months before aneurysm rupture and 30 to 50% of patients report sudden onset headache 6 to 20 days before rupture. This headache could be a warning sign of an impending rupture. Approximately 10 to 30% of patients with aneurysm rupture die before reaching the hospital, another 30% die in the hospital or are severely disabled when discharged, and only 30% have a good recovery after appropriate treatment.
The Hunt and Hess classification system is used to classify the severity of SAH based on clinical findings and to predict outcome and mortality. There are five different grades ranging in the severity of symptoms, which can correlate the overall mortality of SAH.
The modified Fisher classification describes the amount of blood seen on a head non-contrast computed tomography (CT) scan to predict the likelihood of developing vasospasm, ischemia, and stroke. It was adapted from the original Fisher classification.
Most of the people with aortic aneurysms are asymptotic. Symptoms develop as the aneurysm enlarges and creates pressure on surrounding structures.
Signs and symptoms of unruptured aortic aneurysms include:
Signs and symptoms of ruptured aortic aneurysms include:
The majority of unruptured cerebral aneurysms are found incidentally during brain imaging for some other reasons. High-risk individuals like those with a family history of cerebral aneurysms or those with medical conditions associated with cerebral aneurysms may be screened with magnetic reasoning angiography (MRA), computerized tomography angiography (CTA), or digital subtraction angiography (DSA). In view of the inflammatory changes and macrophage deposition occurring at the aneurysm wall, magnetic resonance imaging with contrast may be utilized to detect those aneurysms prone to rupture as their wall may enhance. Ferumoxytol is a nanoparticle cleared by macrophages and can be used as a contrast agent for the detection of inflammation. A head CT scan without contrast is the initial test for a suspected ruptured cerebral aneurysm causing SAH. It is 100% sensitive for SAH if it is done within 6 hours of symptoms onset, but sensitivity decreases over time to 95% in 12 hours, 92% in 24 hours, and 50% in one week. If clinical suspicion is very high, and the head CT scan is negative, a lumbar puncture should be performed to measure the cell count and to look for xanthochromia of the cerebrospinal fluid (CSF). CSF xanthochromia due to hemoglobin breakdown products may take 4 hours to develop, but it almost 100% sensitive between 12 hours and one week. Once the diagnosis of SAH is confirmed, the source of bleeding can be identified with either CTA, MRA, or digital subtraction angiography (DSA). DSA is considered the gold standard for the diagnosis of SAH due to cerebral aneurysm rupture.
Like cerebral aneurysms, they are usually found incidentally during imaging for other reasons. Chest (CXR) X-ray film is the study that most commonly identifies asymptomatic aortic aneurysms. CXR usually shows mediastinal widening, aortic knob enlargement, or tracheal deviation. It may also show the displacement of aortic calcifications, aortic kinking, and aortopulmonary window opacification. Aortic aneurysms may also be incidentally discovered with an echocardiogram, chest CT scan, or chest MRI performed for other reasons. In symptomatic patients, CTA or MRA is the imaging of choice for better characterization of aortic diameter, vessel anatomy, and to identify aortic dissection or aneurysm rupture. The choice of imaging technique depends on the clinical circumstances. In highly symptomatic patients, CTA is a better choice as it is readily available and requires much less time to perform. MRA is better than CTA in aneurysms involving aortic root sinus. It is also a more useful tool due to the lack of ionizing radiation for patients requiring repeated imaging. Transthoracic echocardiography should be performed in patients with a bicuspid aortic valve to assess the diameter of an aortic sinus. Transesophageal echocardiography is preferred over transthoracic echocardiography for the evaluation of the entire aorta.
Many factors should be considered when making decisions regarding the treatment of cerebral aneurysms. These factors include the patient's age and medical conditions, the size and location of the aneurysm, the presence or absence of symptoms, the presence or absence of other risk factors for aneurysm rupture, and if there has been a SAH. There are 3 main strategies for the management of cerebral aneurysms: observation, endovascular therapy, and surgical therapy. All ruptured aneurysms should receive endovascular or surgical therapy.
Patients with an unruptured cerebral aneurysm who are older than 64-years-old, aneurysm size less than 7 mm, asymptomatic, location is in the anterior circulation, no personal history of a SAH from another aneurysm or no family history of SAH can be observed with close clinically and radiological monitoring. Serial aneurysm monitoring can be achieved with CTA or MRA. Literature suggests that the annual risk of aneurysm rupture is approximately 1%. Recently, some studies are evaluating the use of nonsteroidal anti-inflammatory drugs and selective COX-2 inhibitors to inhibit key inflammatory mediators involved in the growth of unruptured aneurysms.
2. Endovascular Embolization
This is a minimally invasive technique in which a catheter is advanced from the femoral artery into the cerebral aneurysm, and with the use of a second microcatheter, platinum coils are inserted into the aneurysm. The coiled aneurysm forms a clot (embolization) and obliterates the aneurysm sac, thus preventing future rupture. The procedure can be performed either under local anesthesia or general anesthesia, although the latter is preferred. This procedure can be used to treat aneurysms that are difficult to approach surgically. Recently, flow diversion devices have been used to reduce the flow of blood inside the aneurysm, ultimately thrombosing the sac and creating a new endothelium at the neck. A new treatment with a flow disruption device is currently used in which the self-expanding mesh device is placed inside the aneurysm to prevent blood flow into the sac.
3. Surgical clipping
This procedure is performed in the operating room under general anesthesia and involves making an opening of the skull (craniotomy) and dissection through the brain cisterns and fissures to expose the aneurysm. Once the aneurysm is exposed, a metal clip is placed across the neck of the aneurysm to prevent blood flow into the aneurysm sac. One disadvantage of this procedure is that it is highly invasive. The annual risk of post-surgical rebleeding ranges from 0.0 to 0.9%, unlike endovascular coiling, which is 2.6%, but the morbidity and mortality associated with the surgery are higher.
Those patients with a ruptured cerebral aneurysm should be admitted to the intensive care unit for close monitoring. Endovascular coiling or surgical clipping of the ruptured aneurysm should be performed as early as possible in the majority of the cases to reduce the risk of rebleeding. Patients need to be monitored for the signs and symptoms of clinical deterioration due to vasospasm, rebleeding, seizures, cerebral edema, hydrocephalus, and hyponatremia. In the first 48 hours after a SAH, the major cause of morbidity or mortality is rebleeding. Blood pressure should be maintained near 120/80 mmHg before the definite procedure to occlude the aneurysm, but after the treatment, the mean arterial pressure should be maintained above 100 mmHg to reduce ischemic changes secondary to vasospasm. Cerebral vasospasm resulting in cerebral ischemic and neurologic deterioration starts around day 3 to 5 and peaks at day 7. Oral nimodipine at a dose of 60 mg every 4 hours is given for 21 days to improve outcomes. Daily transcranial doppler is recommended to monitor vasospasm. After aneurysm repair, cerebrovascular imaging is generally recommended to look for remnant or recurrence of the aneurysm that may require re-intervention. This can be performed intraoperative or a few days later.
Treatment modalities depend on size, symptoms, location, and other comorbidities. The most important determinant for rupture is the diameter of the aneurysm. The location of the aneurysm, presence of coronary artery disease, and aortic valve pathology dictate the type of repair to be performed.
1. Conservative management
Asymptomatic patients with aneurysm diameter <45 mm are managed with medical therapy and active surveillance. Saccular aortic aneurysm enlarges at a rate of 2.9 mm/year. This growth is similar to that of fusiform aneurysms. Conservative management includes an aggressive blood pressure control (goal <130/80 mmHg), screening for medical conditions associated with aortic aneurysms, avoidance of fluoroquinolones, cardiovascular risk reduction measures, serial imaging annually or biannually depending on the diameter of the aorta to evaluate changes in aortic diameter. Beta-blockers are the preferred blood pressure medications. Saccular aortic aneurysms become symptomatic/acute at smaller diameters than fusiform aneurysms, supporting the current idea that saccular aneurysms should be treated at smaller diameters than fusiform aneurysms.
2. Repair management
(Open repair vs. endovascular repair)
All symptomatic unruptured or ruptured saccular aortic aneurysm should undergo repair. The exact diameter threshold for elective treatment of asymptomatic aneurysms is difficult to determine, but a diameter of 45 mm seems to be an acceptable threshold. In asymptomatic patients with genetically mediated aneurysms, a smaller diameter is suggested as an indicator of repair. Asymptomatic aneurysm with expansion greater or equal to 5 mm per year should undergo repair. Patients undergoing coronary artery bypass or aortic valve surgery with ascending aorta aneurysms and diameter >45 mm should also have repair. Open repair is indicated for aneurysms that involve the aortic arch, ascending aorta, and aortic root. Endovascular aneurysm repair (EVAR) is preferred in patients with descending aortic aneurysms.
Small unruptured cerebral aneurysms (less than 7 mm) have a low risk of rupture. Morbidity and mortality are very high once a cerebral aneurysm ruptures. SAH due to aneurysm rupture is a catastrophic event with a mortality rate ranging from 25% to 50%. Nearly 50% of the survivors will have a permanent disability. Approximately one-third of patients have a good outcome after appropriate treatment. Cerebral aneurysms can also bleed into the brain parenchyma, causing intraparenchymal hemorrhage adding an extra insult to the brain. The outcome of a ruptured cerebral aneurysm depends on the extent of the bleed, the location of the bleed, the age of the patient, neurological status on presentation, the degree of vasospasm, and associated comorbidities.
The annual risk of rupture of an aortic aneurysm is low when the size is less than 45 mm. When an aneurysm ruptures, approximately 50% of patients die before they reach the emergency room. Those who survive have very high morbidity. When all locations are included, there is approximately perioperative mortality of 2% to 17%, with the arch of aorta location approaching a 25% mortality. The outcome depends on the timing of intervention, the location, the type of surgery, the experience of the surgeon, concomitant comorbidities, and if it has ruptured.
Patients should be educated about cerebral and aortic aneurysm and the risk associated with it.
A ruptured aneurysm is a serious and life-threatening emergency condition that needs to be treated promptly.
Approximately 10% to 30% of the patients with a cerebral aneurysm bleed die even before reaching the hospital and only about 30% recover after appropriate treatment.
Tobacco smoking and excessive alcohol consumption should be avoided as this can increase the risk of aneurysm progression or rupture.
Better blood pressure control is recommended as this is one of the risk factors for aneurysm formation, progression, and rupture.
Cardiovascular risk reduction measures should be implemented.
Early treatment of ruptured aneurysms reduces the rate of rebleeding and facilitates the treatment of vasospasm.
Noninvasive studies may be indicated in patients with conditions associated with cerebral aneurysms and those with a family history of SAH.
Cardiologist consultation may be used as these patients can develop stunt myocardium and pulmonary edema.
A nephrologist may be needed as these patients are at risk for electrolyte abnormalities.
An interprofessional approach is vital for better clinical outcomes. Early diagnosis and referral to a neurosurgeon, vascular surgeon, or interventional radiologist have better outcomes in patients with ruptured saccular aneurysms. An interprofessional team including but not limited to a neurosurgeon, an endovascular interventional neuroradiologist, intensivist, vascular surgeon, cardiothoracic surgeon, neurologist, cardiologist, physical therapist, speech therapist, occupational therapist, nurse, pharmacist, and a nephrologist is recommended for proper care and management for better clinical outcomes and early hospital discharge.
|||Salameh MJ,Black JH 3rd,Ratchford EV, Thoracic aortic aneurysm. Vascular medicine (London, England). 2018 Dec; [PubMed PMID: 30370834]|
|||Henkes H,Fischer S,Mariushi W,Weber W,Liebig T,Miloslavski E,Brew S,Kühne D, Angiographic and clinical results in 316 coil-treated basilar artery bifurcation aneurysms. Journal of neurosurgery. 2005 Dec; [PubMed PMID: 16381185]|
|||Jersey AM,Foster DM, Cerebral Aneurysm 2020 Jan; [PubMed PMID: 29939679]|
|||Nixon AM,Gunel M,Sumpio BE, The critical role of hemodynamics in the development of cerebral vascular disease. Journal of neurosurgery. 2010 Jun; [PubMed PMID: 19943737]|
|||Shang EK,Nathan DP,Boonn WW,Lys-Dobradin IA,Fairman RM,Woo EY,Wang GJ,Jackson BM, A modern experience with saccular aortic aneurysms. Journal of vascular surgery. 2013 Jan; [PubMed PMID: 23127980]|
|||Keedy A, An overview of intracranial aneurysms. McGill journal of medicine : MJM : an international forum for the advancement of medical sciences by students. 2006 Jul; [PubMed PMID: 18523626]|
|||Fennell VS,Kalani MY,Atwal G,Martirosyan NL,Spetzler RF, Biology of Saccular Cerebral Aneurysms: A Review of Current Understanding and Future Directions. Frontiers in surgery. 2016; [PubMed PMID: 27504449]|
|||Kamio Y,Miyamoto T,Kimura T,Mitsui K,Furukawa H,Zhang D,Yokosuka K,Korai M,Kudo D,Lukas RJ,Lawton MT,Hashimoto T, Roles of Nicotine in the Development of Intracranial Aneurysm Rupture. Stroke. 2018 Oct; [PubMed PMID: 30355112]|
|||Etminan N,Rinkel GJ, Unruptured intracranial aneurysms: development, rupture and preventive management. Nature reviews. Neurology. 2016 Dec; [PubMed PMID: 27808265]|
|||STEHBENS WE, ANEURYSMS AND ANATOMICAL VARIATION OF CEREBRAL ARTERIES. Archives of pathology. 1963 Jan; [PubMed PMID: 14087271]|
|||Sarti C,Tuomilehto J,Salomaa V,Sivenius J,Kaarsalo E,Narva EV,Salmi K,Torppa J, Epidemiology of subarachnoid hemorrhage in Finland from 1983 to 1985. Stroke. 1991 Jul; [PubMed PMID: 1853404]|
|||Schievink WI, Intracranial aneurysms. The New England journal of medicine. 1997 Jan 2; [PubMed PMID: 8970938]|
|||Karthaus EG,Tong TML,Vahl A,Hamming JF, Saccular Abdominal Aortic Aneurysms: Patient Characteristics, Clinical Presentation, Treatment, and Outcomes in the Netherlands. Annals of surgery. 2019 Nov; [PubMed PMID: 31498185]|
|||Gasparotti R,Liserre R, Intracranial aneurysms. European radiology. 2005 Mar; [PubMed PMID: 15678323]|
|||Tulamo R,Frösen J,Hernesniemi J,Niemelä M, Inflammatory changes in the aneurysm wall: a review. Journal of neurointerventional surgery. 2010 Jun; [PubMed PMID: 21990591]|
|||Texakalidis P,Sweid A,Mouchtouris N,Peterson EC,Sioka C,Rangel-Castilla L,Reavey-Cantwell J,Jabbour P, Aneurysm Formation, Growth, and Rupture: The Biology and Physics of Cerebral Aneurysms. World neurosurgery. 2019 Oct; [PubMed PMID: 31323409]|
|||Soldozy S,Norat P,Elsarrag M,Chatrath A,Costello JS,Sokolowski JD,Tvrdik P,Kalani MYS,Park MS, The biophysical role of hemodynamics in the pathogenesis of cerebral aneurysm formation and rupture. Neurosurgical focus. 2019 Jul 1; [PubMed PMID: 31261115]|
|||Staarmann B,Smith M,Prestigiacomo CJ, Shear stress and aneurysms: a review. Neurosurgical focus. 2019 Jul 1; [PubMed PMID: 31261124]|
|||Chalouhi N,Ali MS,Jabbour PM,Tjoumakaris SI,Gonzalez LF,Rosenwasser RH,Koch WJ,Dumont AS, Biology of intracranial aneurysms: role of inflammation. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2012 Sep; [PubMed PMID: 22781330]|
|||Packard RR,Libby P, Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction. Clinical chemistry. 2008 Jan; [PubMed PMID: 18160725]|
|||Lahoute C,Herbin O,Mallat Z,Tedgui A, Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nature reviews. Cardiology. 2011 Jun; [PubMed PMID: 21502963]|
|||Ait-Oufella H,Taleb S,Mallat Z,Tedgui A, Recent advances on the role of cytokines in atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. 2011 May; [PubMed PMID: 21508343]|
|||Frösen J,Tulamo R,Paetau A,Laaksamo E,Korja M,Laakso A,Niemelä M,Hernesniemi J, Saccular intracranial aneurysm: pathology and mechanisms. Acta neuropathologica. 2012 Jun; [PubMed PMID: 22249619]|
|||Frösen J,Cebral J,Robertson AM,Aoki T, Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms. Neurosurgical focus. 2019 Jul 1; [PubMed PMID: 31261126]|
|||Gorelick PB,Hier DB,Caplan LR,Langenberg P, Headache in acute cerebrovascular disease. Neurology. 1986 Nov; [PubMed PMID: 3762963]|
|||Hunt WE,Hess RM, Surgical risk as related to time of intervention in the repair of intracranial aneurysms. Journal of neurosurgery. 1968 Jan; [PubMed PMID: 5635959]|
|||Claassen J,Bernardini GL,Kreiter K,Bates J,Du YE,Copeland D,Connolly ES,Mayer SA, Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke. 2001 Sep; [PubMed PMID: 11546890]|
|||Fisher CM,Kistler JP,Davis JM, Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery. 1980 Jan; [PubMed PMID: 7354892]|
|||Fisher CL,Demel SL, Nonsteroidal Anti-Inflammatory Drugs: A Potential Pharmacological Treatment for Intracranial Aneurysm. Cerebrovascular diseases extra. 2019; [PubMed PMID: 31039577]|
|||Liu Z,Ajimu K,Yalikun N,Zheng Y,Xu F, Potential Therapeutic Strategies for Intracranial Aneurysms Targeting Aneurysm Pathogenesis. Frontiers in neuroscience. 2019; [PubMed PMID: 31849575]|
|||Shimizu K,Kushamae M,Mizutani T,Aoki T, Intracranial Aneurysm as a Macrophage-mediated Inflammatory Disease. Neurologia medico-chirurgica. 2019 Apr 15; [PubMed PMID: 30867357]|
|||Abi-Aad KR,Aoun RJN,Rahme RJ,Ward JD,Kniss J,Kwasny MJ,Sattur MG,Welz ME,Bendok BR, New generation Hydrogel Endovascular Aneurysm Treatment Trial (HEAT): a study protocol for a multicenter randomized controlled trial. Neuroradiology. 2018 Oct; [PubMed PMID: 30120516]|
|||Lindgren A,Vergouwen MD,van der Schaaf I,Algra A,Wermer M,Clarke MJ,Rinkel GJ, Endovascular coiling versus neurosurgical clipping for people with aneurysmal subarachnoid haemorrhage. The Cochrane database of systematic reviews. 2018 Aug 15; [PubMed PMID: 30110521]|
|||Pickard JD,Murray GD,Illingworth R,Shaw MD,Teasdale GM,Foy PM,Humphrey PR,Lang DA,Nelson R,Richards P, Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ (Clinical research ed.). 1989 Mar 11 [PubMed PMID: 2496789]|
|||Allen GS,Ahn HS,Preziosi TJ,Battye R,Boone SC,Boone SC,Chou SN,Kelly DL,Weir BK,Crabbe RA,Lavik PJ,Rosenbloom SB,Dorsey FC,Ingram CR,Mellits DE,Bertsch LA,Boisvert DP,Hundley MB,Johnson RK,Strom JA,Transou CR, Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage. The New England journal of medicine. 1983 Mar 17 [PubMed PMID: 6338383]|