Inflammatory markers for brain edema after aneurysmal subarachnoid hemorrhage

Inflammatory markers for brain edema after aneurysmal subarachnoid hemorrhage

The onset of aneurysmal subarachnoid hemorrhage (aSAH) elicits activation of the inflammatory cascade, and ongoing neuroinflammation is suspected to contribute to secondary complications, such as vasospasm and delayed cerebral ischemia.

To date, the monitoring of the inflammatory response to detect secondary complications such as DCI has not become part of the clinical routine diagnostic.

Höllig et al. estimated that the wide range of the measured values hampers their interpretation and usage as a biomarker. However, understanding the inflammatory response after aSAH and generating a multicenter database may facilitate further studies: realistic sample size calculations on the basis of a multicenter database will increase the quality and clinical relevance of the acquired results 1).

In a review, of Watson et al. analyze the extent literature regarding the relationship between neuroinflammation and cognitive dysfunction after aSAH. Pro-inflammatory cytokines appear to play a role in maintaining normal cognitive function in adults unaffected by aSAH. However, in the setting of aSAH, elevated cytokine levels may correlate with worse neuropsychological outcomes. This seemingly dichotomous relationship between neuroinflammation and cognition suggests that the action of cytokines varies, depending on their physiologic environment. Experimental therapies which suppress the immune response to aSAH appear to have a beneficial effect on cognitive outcomes. However, further studies are necessary to determine the utility of inflammatory mediators as biomarkers of neurocognitive outcomes, as well as their role in the management of aSAH 2).

Ahn et al. investigated inflammatory markers in subjects with early brain edema which does not resolve, i.e., persistent brain edema after SAH.

Computed tomography scans of SAH patients were graded at admission and at 7 days after SAH for Brain edema using the 0-4 ‘subarachnoid hemorrhage early brain edema score‘ (SEBES). SEBES ≤ 2 and SEBES ≥ 3 were considered good and poor grade, respectively. Serum samples from the same subject cohort were collected at 4 time periods (at < 24 h [T1], at 24 to 48 h [T2]. 3-5 days [T3] and 6-8 days [T4] post-admission) and concentration levels of 17 cytokines (implicated in peripheral inflammatory processes) were measured by multiplex immunoassay. Multivariable logistic regression analyses were step-wisely performed to identify cytokines independently associated with persistent CE adjusting for covariables including age, sex and past medical history (model 1), and additional inclusion of clinical and radiographic severity of SAH and treatment modality (model 2).

Of the 135 patients enrolled in the study, 21 of 135 subjects (15.6%) showed a persistently poor SEBES grade. In multivariate model 1, higher Eotaxin (at T1 and T4), sCD40L (at T4), IL-6 (at T1 and T3) and TNF-α (at T4) were independently associated with persistent CE. In multivariate model 2, Eotaxin (at T4: odds ratio [OR] = 1.019, 95% confidence interval [CI] = 1.002-1.035) and possibly PDGF-AA (at T4), sCD40L (at T4), and TNF-α (at T4) was associated with persistent CE.

They identified serum cytokines at different time points that were independently associated with persistent Brain edema. Specifically, persistent elevations of Eotaxin is associated with persistent Brain edema after SAH 3).

Leucocytosis and change in IL-6 prior to DCI reflect impending cerebral ischemia. The time-independent association of ESR with DCI after SAH may identify this as a risk factor. These data suggest that systemic inflammatory mechanisms may increase the susceptibility to the development of DCI after SAH 4)

Platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, soluble CD40 ligand, and tumor necrosis factor-α (TNF-α) increased over time. Colony-stimulating factor (CSF) 3, interleukin (IL)-13, and FMS-like tyrosine kinase 3 ligand decreased over time. IL-6, IL-5, and IL-15 peaked and decreased. Some cytokines with insignificant trends show high correlations with other cytokines and vice versa. Many correlated cytokine clusters, including a platelet-derived factor cluster and an endothelial growth factor cluster, were observed at all times. Participants with higher clinical severity at admission had elevated levels of several proinflammatory and anti-inflammatory cytokines, including IL-6, CCL2, CCL11, CSF3, IL-8, IL-10, CX3CL1, and TNF-α, compared to those with lower clinical severity 5).


Höllig A, Stoffel-Wagner B, Clusmann H, Veldeman M, Schubert GA, Coburn M. Time Courses of Inflammatory Markers after Aneurysmal Subarachnoid Hemorrhage and Their Possible Relevance for Future Studies. Front Neurol. 2017 Dec 22;8:694. doi: 10.3389/fneur.2017.00694. PMID: 29312122; PMCID: PMC5744005.

Watson E, Ding D, Khattar NK, Everhart DE, James RF. Neurocognitive outcomes after aneurysmal subarachnoid hemorrhage: Identifying inflammatory biomarkers. J Neurol Sci. 2018 Jun 25;394:84-93. doi: 10.1016/j.jns.2018.06.021. [Epub ahead of print] Review. PubMed PMID: 30240942.

Ahn SH, Burkett A, Paz A, Savarraj JP, Hinds S, Hergenroeder G, Gusdon AM, Ren X, Hong JH, Choi HA. Systemic inflammatory markers of persistent cerebral edema after aneurysmal subarachnoid hemorrhage. J Neuroinflammation. 2022 Aug 4;19(1):199. doi: 10.1186/s12974-022-02564-1. PMID: 35927663.

McMahon CJ, Hopkins S, Vail A, King AT, Smith D, Illingworth KJ, Clark S, Rothwell NJ, Tyrrell PJ. Inflammation as a predictor for delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage. J Neurointerv Surg. 2013 Nov;5(6):512-7. doi: 10.1136/neurintsurg-2012-010386. Epub 2012 Sep 5. PMID: 22952245; PMCID: PMC3812893.

Savarraj JPJ, Parsha K, Hergenroeder GW, Zhu L, Bajgur SS, Ahn S, Lee K, Chang T, Kim DH, Liu Y, Choi HA. Systematic model of peripheral inflammation after subarachnoid hemorrhage. Neurology. 2017 Apr 18;88(16):1535-1545. doi: 10.1212/WNL.0000000000003842. Epub 2017 Mar 17. PMID: 28314864; PMCID: PMC5395070.

Brain edema after cranioplasty

Brain edema after cranioplasty

Some authors have reported a rare unexplained complication of sudden death in association with massive brain edema immediately after cranioplasty.

Causes of cerebral edema and hemorrhage immediately after cranioplasty include reperfusion, reduction of automatic adjustment function, sinking skin flap syndrome, negative pressure due to s.c. drain, venous stasis, vascular damage following restoration of midline shift, and allergic reaction1).

Once the computed tomography scan shows malignant cerebral swelling, the patient is expected to have a poor prognosis 2) 3).

It is hypothesized that intracranial hypotension (IH) caused stagnation of venous flow. Neurosurgeons should be aware that fatal venous congestion induced by IH may occur after cranioplasty. To avoid this, tight dural closure should be obtained, and avoidance of the use of subcutaneous drains should be considered 4).

Zhang et al., reported one fatal case and analyze the possible mechanism of this complication.

The patient was a 40-year-old man who had a severe right basal ganglia hemorrhage and underwent DC ∼ 2 months before. One day before scheduled cranioplasty, a External lumbar cerebrospinal fluid drainage was placed. The cranioplasty itself was uneventful. However, he gradually fell into a coma, and his right pupil was moderately dilated 20 hours after the surgery. A brain computed tomography (CT) scan indicated massive right cerebral edema with compressed right midbrain. The patient did not regain consciousness, and he remained quadriplegic.

It is necessary to increase awareness of complications of cranioplasty in high-risk patients. The lessons learned from this case include avoiding excessive drainage of cerebrospinal fluid. Patients with low-density lesions in the brain need to be treated with caution. Once the CT scan shows massive cerebral swelling, the patient has a poor prognosis 5).

A 51-year-old man who was a victim of traumatic brain injury underwent emergency clot removal and decompression craniectomy. His neurologic condition improved with subsequent rehabilitation therapy, and he had left sinking skin flap syndrome where the skull was defective. Six months after the initial surgery, he underwent a cranioplasty; however, he did not recover from the uneventful anesthesia. A vacuum suction drain showed 300 mL of flow outflow had drained when his pupils dilated and fixed. An immediate computed tomography scan showed ipsilateral diffuse cerebral swelling with diffuse cerebral hemorrhage. Despite all approaches that were considered, the cerebral swelling continued to worsen until death 6).

Two cases of critical brain swelling after otherwise uneventful cranioplasty. Both cases had subarachnoid hemorrhage and extremely similar clinical courses. They underwent decompressive craniotomy and clipping in the acute phase and had cranioplasty in the chronic phase, resulting in serious cerebral swelling and death. Deep venous sinus thrombosis was revealed in the autopsy for one case. Although no venous occlusion was identified in the other case, radiological findings suggested venous congestion. In both cases, intraoperative cerebrospinal fluid leakage was massive and was prolonged by a drain 7).

A 64-year-old man was admitted with the diagnosis of cerebral hemorrhage, and emergency surgery for hemorrhage removal and decompressive craniotomy were performed. One month after surgery, cranioplasty was performed using a titanium mesh plate. Sixteen hours after the surgery, the patient became comatose with bilateral dilated pupils followed by blood pressure lowering. Computed tomography of the brain showed bilateral massive cerebral edema. The titanium mesh plate was immediately removed, however, the patient’s neurological condition did not recover and he died 7 days after the surgery. We speculated that the negative pressure difference and increase in cerebral blood flow after cranioplasty may have attributed to the fatal cerebral swelling 8).

A 84-year-old man with subarachnoid hemorrhage underwent craniotomy and clipping with external decompression. Perfusion magnetic resonance imaging showed subclinical sinking skin flap syndrome, and he underwent cranioplasty on postoperative day 58. No problems occurred during the operation, but cerebral edema and hemorrhage were recognized on immediate postoperative computed tomography. Edema continued to progress, but edema and bleeding eventually improved without additional surgery.

Neurological symptoms improved to presurgical baseline and stabilized 9).

A 50-year-old female was admitted with sudden onset of stuporous consciousness. A brain computed tomography (CT) revealed a subarachnoid hemorrhage with intracranial hemorrhage and subdural hematoma. Emergency decompressive craniectomy and aneurysmal neck clipping were performed. Following recovery, the decision was made to proceed with an autologous cranioplasty. The cranioplasty procedure was free of complications. An epidural drain was placed and connected to a suction system during skin closure to avoid epidural blood accumulation. However, following the procedure, the patient had a seizure in the recovery room. An emergency brain CT scan revealed widespread cerebral edema, and the catheter drain was clamped. The increased intracranial pressure and cerebral edema were controlled with osmotic diuretics, corticosteroids, and antiepileptic drugs. The edema slowly subsided, but new low-density areas were noted in the brain on follow-up CT 1 week later. They speculated that placing the epidural drain on active suction may have caused an acute decrease in intracranial pressure and subsequent rapid expansion of the brain, which impaired autoregulation and led to reperfusion injury 10).

Sviri reported on 4 patients who underwent cranioplasty after DC between January 2005 and August 2010 and died because of massive cerebral edema immediately after uneventful surgery and anesthesia. All 4 of the new cases reported involved young male patients who underwent decompressive hemicraniectomy after traumatic brain injury. They developed massive cerebral swelling immediately after uneventful cranioplasty (3 patients) or after removal of an epidural hematoma several hours after surgery (1 patient). All 4 patients had a large skull defect and significantly sunken craniotomy site, and all were treated with a closed vacuum suction system that was placed under the scalp and kept open at the end of the cranioplasty procedure. After surgery, the patients’ pupils became fixed and dilated, and brain CT scans showed massive brain edema. Despite emergency DC, the patients did not recover, and all 4 died. A MEDLINE search showed 8 similar cases that were reported previously. Fatal cerebral swelling after uneventful cranioplasty is a distinct clinical entity, although it is unpredictable. It is postulated that a negative pressure difference from the elimination of atmospheric pressure that had been chronically applied on the injured sinking brain in combination with the negative pressure applied by the closed subgaleal suction drain may lead to a massive brain shift toward the cranioplasty site and initiate a fatal vasomotor reaction 11).


1) , 9)

Kato A, Morishima H, Nagashima G. Unexpected complications immediately after cranioplasty. Acute Med Surg. 2017 Feb 22;4(3):316-321. doi: 10.1002/ams2.260. eCollection 2017 Jul. PubMed PMID: 29123881; PubMed Central PMCID: PMC5674471.
2) , 6)

Shen L, Zhou Y, Xu J, Su Z. Malignant Cerebral Swelling After Cranioplasty: Case Report and Literature Review. World Neurosurg. 2018 Feb;110:4-10. doi: 10.1016/j.wneu.2017.10.102. Epub 2017 Oct 28. Review. PubMed PMID: 29101073.
3) , 5)

Zhang X, Pan B, Ye Z, Li Z, Mo F, Wang X. Massive Brain Swelling after Cranioplasty: A Case Report. J Neurol Surg A Cent Eur Neurosurg. 2019 May 10. doi: 10.1055/s-0039-1688726. [Epub ahead of print] PubMed PMID: 31075809.

Nomura M, Ota T, Ishizawa M, Yoshida S, Hara T. Intracranial Hypotension-associated Cerebral Swelling following Cranioplasty: Report of Two Cases. Asian J Neurosurg. 2017 Oct-Dec;12(4):794-796. doi: 10.4103/1793-5482.185070. PubMed PMID: 29114315; PubMed Central PMCID: PMC5652127.

Nomura M, Ota T, Ishizawa M, Yoshida S, Hara T. Intracranial Hypotension-associated Cerebral Swelling following Cranioplasty: Report of Two Cases. Asian J Neurosurg. 2017 Oct-Dec;12(4):794-796. doi: 10.4103/1793-5482.185070. PubMed PMID: 29114315; PubMed Central PMCID: PMC5652127.

Kaneshiro Y, Murata K, Yamauchi S, Urano Y. Fatal cerebral swelling immediately after cranioplasty: A case report. Surg Neurol Int. 2017 Jul 25;8:156. doi: 10.4103/sni.sni_137_17. eCollection 2017. PubMed PMID: 28808605; PubMed Central PMCID: PMC5535512.

Lee GS, Park SQ, Kim R, Cho SJ. Unexpected Severe Cerebral Edema after Cranioplasty : Case Report and Literature Review. J Korean Neurosurg Soc. 2015 Jul;58(1):76-8. doi: 10.3340/jkns.2015.58.1.76. Epub 2015 Jul 31. PubMed PMID: 26279818; PubMed Central PMCID: PMC4534744.

Sviri GE. Massive cerebral swelling immediately after cranioplasty, a fatal and unpredictable complication: report of 4 cases. J Neurosurg. 2015 Jun 19:1-6. [Epub ahead of print] PubMed PMID: 26090828.
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