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Year : 2015  |  Volume : 63  |  Issue : 4  |  Page : 483--485

Vasospasm: The enigma of subarachnoid hemorrhage

Bhawani Shanker Sharma, Dattaraj Paramanand Sawarkar 
 Department of Neurosurgery and Gamma knife, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Bhawani Shanker Sharma
Department of Neurosurgery and Gamma knife, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi

How to cite this article:
Sharma BS, Sawarkar DP. Vasospasm: The enigma of subarachnoid hemorrhage.Neurol India 2015;63:483-485

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Sharma BS, Sawarkar DP. Vasospasm: The enigma of subarachnoid hemorrhage. Neurol India [serial online] 2015 [cited 2022 May 18 ];63:483-485
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The most common cause of subarachnoid hemorrhage (SAH) is trauma; and, rupture of a cerebral aneurysm is the most common cause of nontraumatic SAH. The treatment of a cerebral aneurysm is either surgical clipping or endovascular obliteration. [1] Despite the advancements in diagnostic modalities and treatment measures, the condition is still associated with a high morbidity and mortality. [2],[3] Besides rebleeding from an aneurysm, cerebral vasospasm is the major cause of morbidity and mortality in patients who survive the initial ictus. [3]

The risk factors for the presence of vasospasm are the presence of a greater quantity of blood in the basal cisterns; a poor neurological status; the female gender; a history of smoking; and, the presence of hydrocephalus or increased intracranial pressure. [4] Cerebrovascular vasospasm most commonly occurs between 3 and 14 days post-SAH (highest around 7-10 days) and the severity of the condition may vary, ranging from vasospasm that is apparent only on angiogram (radiographic vasospasm) without any clinical impairment in up to 67% cases, to clinically symptomatic vasospasm leading to cerebral infarction in 20-30% cases. [5] An early detection of vasospasm and assessment of its severity may help in identifying the subset of individuals in whom treatment measures may be initiated before the condition results in ischemic neurological deficits and infarction.

Although the exact pathophysiology of vasospasm remains unclear, many studies point toward blood degradation products, that is, oxyhemoglobin and other vasoactive substances in the subarachnoid spaces as an inciting agent. They produce pronounced immune responses mediated by pro-inflammatory cytokines. [3],[4] Reduction in the production of nitric oxide; increase in the levels of endothelin-1; production of free radicals; lipid peroxidation; modification of calcium and potassium channels; neuronal apoptosis; and, differential upregulation of genes, thrombin, and oxidation products of bilirubin have been implicated. [4] These responses produce direct oxidative stress affecting the reactivity and relaxation of smooth muscles cells of cerebral vessels leading to vasospasm. [4]

Recently Yoneda et al. [6] has shown that activation of sphingosylphosphorylcholine (SPC)-Rho kinase pathway through the interaction of spasmogens such as SPC, thromboxane A 2 , and arachidonic acid has a role in the pathogenesis of vasospasm. Eicosapentaenoic acid may prevent vasospasm by inhibition of the SPC-Rho kinase pathway. [6]

However, a more complex relationship occurs between radiographic vasospasm and the clinical outcome, and vasospasm is not the only factor related to a poor outcome. Various mechanisms including microthrombosis, microcirculatory failure, cortical depolarization, and autoregulatory dysfunction are implicated in the causation of delayed cerebral ischemia (DCI). [7]

Several genes like endothelial nitric oxide synthase (eNOS), haptoglobin (Hp), PAI-1, ApoE, RyR1, and CBS are under evaluation to assess their association with vasospasm. Lai and Du [7] in their recent meta-analysis confirmed a strong association between genetic mutation and polymorphisms (eNOS VNTR and Hp allele) with the causation of vasospasm and DCI.

A variety of methods such as digital substraction angiography, transcranial Doppler sonography, computed tomographic angiography, computed tomographic perfusion, magnetic resonance angiography, and serial neurological examination are used for the assessment of vasospasm. Nimodipine, double or triple H therapy, and vasodilatation either by intrathecal, intraventricular, intracisternal, intravenous or intra-arterial administered medications or angioplasty are the currently accepted methods of treatment. [3],[5]

Acute brain injury following aneurysmal rupture causes a marked sympathetic nervous system activation and systemic inflammatory response, leading to the elevation of circulating catecholamines, which persist for at least 10 days. The catecholamines directly and indirectly cause stress-induced hyperglycemia through hypothalamic involvement causing a direct and independent deleterious effect on the outcome, and hence, there is need for a tight glycemic control in these patients. [8]

The components of the metabolic syndrome like obesity (high body mass index [BMI]), hypertension, hypertriglyceridemia, insulin resistance, a low level of high-density lipoprotein cholesterol, and increased coagulation activity increase the risk of ischemic cardiac and cerebrovascular events through several mechanisms like vasculopathy, endothelial dysfunction, and inflammation. Chronic hypertension causes a shift in the cerebral autoregulation curve to the right by inducing arteriolar smooth muscle cell changes rendering them more vulnerable to cerebral ischemia after the occurrence of SAH. [8]

Obesity (or a high BMI) is a risk factor for cardiovascular diseases and stroke and is an important predictor of death in the general population. Respiratory complications, infections, or a prolonged hospital stay are more common in these patients compared with patients who have a normal weight. [9] Juvela et al. [8] reported that the presence of hypertension preceding the onset of SAH, the patient's age, an elevated BMI, and excessive alcohol consumption may lead to an increased risk of death or poor outcome. However, recently, a phenomenon called the "obesity paradox" was introduced, as better outcomes for obese patients after an ischemic heart disease or stroke were shown in various studies. This led to the hypothesis that obese patients have a greater energy reservoir than normal weight or underweight patients and, therefore, might better tolerate catastrophic events. [9] Platz et al. [9] in their retrospective study, did not observe the obesity paradox after SAH. They emphasize that obese patients should be treated with the same dedication as any other patients after SAH. However, malnutrition, which is related to underfeeding and inflammation mediated protein catabolism, is prevalent after SAH and is associated with a short-term secondary injury and a long-term poor outcome. Hence, protein-energy malnutrition may be another target for intervention with the implementation of amino acid supplementation. [10]

Currently, research is underway to identify the biochemical markers of cell damage and inflammation for diagnosis and monitoring of vasospasm in body fluids, such as serum/plasma and cerebrospinal fluid (CSF). Development of genomics and proteomics may help in identifying biomarkers like the 25-kDa protein, HMGB 1 , MMP-9, etc., that help to predict vasospasm. Various neurodegeneration biomarkers and molecules of inflammatory processes like interleukin-2 (IL-2), IL-6, IL-8, E-selectins, vascular cell adhesion molecule, intercellular adhesion molecule, and tumor necrosis factor-alpha (TNF-α) have been investigated in relation to SAH and its complications. [11] Recently, Wu et al. [12] provided strong evidence that IL-6 and TNF-α CSF levels are elevated in SAH. They, therefore, suggested that these two cytokines could be helpful in the early diagnosis and monitoring in patients with a SAH.

The development of cerebral vasospasm after an aneurysmal SAH is multifactorial and may involve several distinct but interconnected pathological processes. Based on these processes, multiple biomarkers have been proposed to be used as predictors of cerebral vasospasm. [11] Przybycien and Ashley [11] in their review highlighted the complexities involved in the development of cerebral vasospasm and supported the idea that it is very unlikely that a single protein biomarker will be clinically effective and reliable in predicting vasospasm.

Dhandapani et al., [10] in their study of 56 cases used the simple and inexpensive anthropometric indices like mid-arm circumference, skinfold thickness using triceps skinfold (TSF), and mid-arm muscle circumference (MAMC) to correlate the influence of vasospasm in determining outcome in SAH. The authors are the first to use the correlation of TSF with vasospasm in SAH, which is a better marker of excess adiposity than the BMI. They found that a higher TSF, a marker of excessive adipose tissue, is significantly associated with clinical vasospasm. They pointed out that the effect of TSF on clinical vasospasm may have been due to the release of pro-inflammatory adipokines, free fatty acid-induced lipid peroxidation, neurotoxicity due to leptin resistance, a pro-coagulant and pro-thrombotic state, vasculopathy, endothelial dysfunction, or a combination of these factors. [10] However, admission TSF values and fall in TSF values in the first week were not significantly related to the mortality. They also confirmed the fact that a fall in MAMC (indicating negative nitrogen balance) had some impact on mortality. This again shows the scope for early and adequate correction of nutrition by supplementing amino acids and instituting of immunomodulatory therapy. Overall, this information opens the arena for further research aimed at consolidating this relationship between excess adiposity and vasospasm and ultimately taking one more step toward the goal of improved outcome following a SAH.


1Sharma BS, Gupta A, Ahmad FU, Suri A, Mehta VS. Surgical management of giant intracranial aneurysms. Clin Neurol Neurosurg 2008;110:674-81.
2Sharma BS, Sinha S, Mehta VS, Suri A, Gupta A, Mahapatra AK. Pediatric intracranial aneurysms-clinical characteristics and outcome of surgical treatment. Childs Nerv Syst 2007;23:327-33.
3Gupta D, Sharma BS, Gupta SK, Bapuraj R, Khosla VK. Postoperative hypertensive-hypervolaemic-haemodilution (Triple H) therapy in the treatment of vasospasm following aneurysmal subarachnoid haemorrhage. Neurol India 2000;48:126-31.
4Balanzar GG, Guinto-Nishimura Y. Vasospasm in subarachnoid hemorrhage. World Neurosurg 2014;82:e677-8.
5Hollingworth M, Chen PR, Goddard AJ, Coulthard A, Söderman M, Bulsara KR. Results of an international survey on the investigation and endovascular management of cerebral vasospasm and delayed cerebral ischemia. World Neurosurg 2015;83:1120-6.e1.
6Yoneda H, Shirao S, Nakagawara J, Ogasawara K, Tominaga T, Suzuki M. A prospective, multicenter, randomized study of the efficacy of eicosapentaenoic acid for cerebral vasospasm: The EVAS study. World Neurosurg 2014;81:309-15.
7Lai PM, Du R. Role of genetic polymorphisms in predicting delayed cerebral ischemia and radiographic vasospasm after aneurysmal subarachnoid hemorrhage: A meta-analysis. World Neurosurg 2015. DOI: 10.1016/j.wneu.2015.05.070.
8Juvela S, Siironen J, Kuhmonen J. Hyperglycemia, excess weight, and history of hypertension as risk factors for poor outcome and cerebral infarction after aneurysmal subarachnoid hemorrhage. J Neurosurg 2005;102:998-1003.
9Platz J, Güresir E, Schuss P, Konczalla J, Seifert V, Vatter H. The impact of the body mass index on outcome after subarachnoid hemorrhage: Is there an obesity paradox in SAH? A retrospective analysis. Neurosurgery 2013;73:201-8.
10Dhandapani S, Kapoor A, Gaudihalli S, Dhandapani M, Mukherjee KK, Gupta SK. A prospective study of trends in anthropometric nutritional indices and the impact of adiposity among patients of subarachnoid hemorrhage. Neurol India 2015;63:532-7.
11Przybycien-Szymanska MM, Ashley WW Jr. Biomarker discovery in cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 2015;24:1453-64.
12Wu W, Guan Y, Zhao G, Fu XJ, Guo TZ, Liu YT, et al. Elevated IL-6 and TNF-α levels in cerebrospinal fluid of subarachnoid hemorrhage patients. Mol Neurobiol 2015. PMID: 26063595.