Impact of thyroid hormone replacement therapy on the course and functional outcome of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Thyroid hormones were reported to exert neuroprotective effects after ischemic stroke by reducing the burden of brain injury and promoting post-ischemic brain remodeling. OBJECTIVE: We aimed to analyze the value of thyroid hormone replacement therapy (THRT) due to pre-existing hypothyroidism on the clinical course and outcome of aneurysmal subarachnoid hemorrhage (SAH). METHODS: SAH individuals treated between January 2003 and June 2016 were included. Data on baseline characteristics of patients and SAH, adverse events and functional outcome of SAH were recorded. Study endpoints were cerebral infarction, in-hospital mortality and unfavorable outcome at 6 months. Associations were adjusted for outcome-relevant confounders. RESULTS: 109 (11%) of 995 individuals had THRT before SAH. Risk of intracranial pressure- or vasospasm-related cerebrovascular events was inversely associated with presence of THRT (p = 0.047). In multivariate analysis, THRT was independently associated with lower risk of cerebral infarction (adjusted odds ratio [aOR] = 0.64, 95% confidence interval [CI] = 0.41-0.99, p = 0.045) and unfavorable outcome (aOR = 0.50, 95% CI = 0.28-0.89, p = 0.018), but not with in-hospital mortality (aOR = 0.69, 95% CI = 0.38-1.26, p = 0.227). CONCLUSION: SAH patients with THRT show lower burden of ischemia-relevant cerebrovascular events and more favorable outcome. Further experimental and clinical studies are required to confirm our results and elaborate the mechanistic background of the effect of THRT on course and outcome of SAH.

Is there a difference in the clinical profile and outcome of women using levonorgestrel IUD for abnormal uterine bleeding and those using it for contraception?: A comparative cross-sectional study.

Objective: The most common indications for Levonorgestrel intrauterine device (LNG-IUD) are contraception and management of abnormal uterine bleeding (AUB). This study was conducted with the aim of exploring the differences in the clinical profile and outcome of women using LNG-IUD for contraception and AUB. Materials and Methods: This was a retrospective comparative cross-sectional study of women who underwent LNG-IUD (52 mg) between 2012 and 2017. Their electronic health records were reviewed until the last documented follow-up or until December 2021. Results: A total of 235 women had LNG-IUD with an age range of 21 to 62 years and a mean of (37.98 years±6.76). Of these women, 153/235 (65.1%) had it for contraception and 82/235 (34.89%) had it for AUB. The follow-up was 1-94 months with (mean ± SEM) follow-up for the AUB group of (21.48±2.31) months and for contraception group was (20.74±1.76) months (p-value of 0.80). There was a significant difference between the two groups in the age and body mass index (BMI), where women who had LNG-IUD for AUB were older (mean of 42.54±6.49 years, p-value <0.001) and had higher BMI (31.88±7.52 kg/m2, p-value =0.011). All LNG-IUDs that were indicated for contraception were inserted in an outpatient setting. However, 68.3% in the AUB, the insertion was in the operating theater in conjunction with hysteroscopy. After combining both expulsion and removal of LNG-IUD during the follow-up period, there was no significant difference between the 2 groups in the overall retention rate during the follow-up (p-value =0.998). Conclusion: this study shows that women using LNG-IUD for the management of AUB are older and have a higher BMI compared with those using it for contraception. AUB women experienced more expulsion compared with the contraception group, but there was no difference between the 2 groups in the overall survival/retention of LNG-IUD.

The value of ventricular measurements in the prediction of shunt dependency after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Chronic hydrocephalus requiring shunt placement is a common complication of aneurysmal subarachnoid hemorrhage (SAH). Different risk factors and prediction scores for post-SAH shunt dependency have been evaluated so far. We analyzed the value of ventricle measurements for prediction of the need for shunt placement in SAH patients. METHODS: Eligible SAH cases treated between 01/2003 and 06/2016 were included. Initial computed tomography scans were reviewed to measure ventricle indices (bifrontal, bicaudate, Evans', ventricular, Huckman's, and third ventricle ratio). Previously introduced CHESS and SDASH scores for shunt dependency were calculated. Receiver operating characteristic analyses were performed for diagnostic accuracy of the ventricle indices and to identify the clinically relevant cut-offs. RESULTS: Shunt placement followed in 221 (36.5%) of 606 patients. In univariate analyses, all ventricular indices were associated with shunting (all: p<0.0001). The area under the curve (AUC) ranged between 0.622 and 0.662. In multivariate analyses, only Huckman's index was associated with shunt dependency (cut-off at ≥6.0cm, p<0.0001) independent of the CHESS score as baseline prediction model. A combined score (0-10 points) containing the CHESS score components (0-8 points) and Huckman's index (+2 points) showed better diagnostic accuracy (AUC=0.751) than the CHESS (AUC=0.713) and SDASH (AUC=0.693) scores and the highest overall model quality (0.71 vs. 0.65 and 0.67), respectively. CONCLUSIONS: Ventricle measurements are feasible for early prediction of shunt placement after SAH. The combined prediction model containing the CHESS score and Huckman's index showed remarkable diagnostic accuracy regarding identification of SAH individuals requiring shunt placement. External validation of the presented combined CHESS-Huckman score is mandatory.

Morphometric Study of the Initial Ventricular Indices to Predict the Complications and Outcome of Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Acute hydrocephalus is a common complication in patients with aneurysmal subarachnoid hemorrhage (SAH). Several ventricular indices have been introduced to enable measurements of ventricular morphology. Previously, researchers have showed their diagnostic value for various neurological disorders. In this study, we evaluated the association between ventricular indices and the clinical course, occurrence of complications and outcome of SAH. METHODS: A total of 745 SAH patients with available early admission computed tomography scans were included in the analyses. Six ventricular indices (bifrontal, bicaudate, ventricular and third ventricle ratios and Evans' and Huckman's indices) were measured. Primary endpoints included the occurrence of cerebral infarctions, in-hospital mortality and a poor outcome at 6 months. Secondary endpoints included different adverse events in the course of SAH. Clinically relevant cut-offs for the indices were determined using receiver operating curves. Univariate analyses were performed. Multivariate analyses were conducted on significant findings in a stepwise backward regression model. RESULTS: The higher the values of the ventricular indices were and the older the patient was, the higher the WFNS and Fisher's scores were, and the lower the SEBES score was at admission. Patients with larger ventricles showed a shorter duration of intracranial pressure increase > 20 mmHg and required decompressive craniectomy less frequently. Ventricular indices were independently associated with the parameters of inflammatory response after SAH (C-reactive protein in serum and interleukin-6 in cerebrospinal fluid and fever). Finally, there were independent correlations between larger ventricles and all the primary endpoints. CONCLUSIONS: The lower risk of intracranial pressure increase and absence of an association with vasospasm or systemic infections during SAH, and the poorer outcome in individuals with larger ventricles might be related to a more pronounced neuroinflammatory response after aneurysmal bleeding. These observations might be helpful in the development of specific medical and surgical treatment strategies for SAH patients depending on the initial ventricle measurements.

Regular medication as a risk factor for intracranial aneurysms: A comparative case-control study.

Background: Previous medical history strongly contributes to the genesis of intracranial aneurysms (IA). A possible impact of regular medication on the occurrence of abdominal aortic aneurysms has been reported. Aim: To evaluate the value of regular medication on the risk of development and rupture of IA. Methods: Data on medication use and related comorbidities were obtained from the institutional IA registry. A 1:1 age- and sex-matched patient sample was collected from the population-based Heinz Nixdorf Recall Study with individuals from the same area. Results: In the analysis comparing IA cohort (n = 1960) with the matched normal population (n = 1960), the use of statins (adjusted odds ratio, 1.34 [95% confidence interval 1.02-1.78]), antidiabetics (1.46 [1.08-1.99]), and calcium channel blockers (1.49 [1.11-2.00]) was independently associated with higher risk of IA, whereas uricostatics (0.23 [0.14-0.38]), aspirin (0.23 [0.13-0.43]), beta-blockers (0.51 [0.40-0.66]), and angiotensin-converting enzyme inhibitors (0.38 [0.27-0.53]) were related to lower risk of IA. In the multivariable analysis within the IA cohort (n = 2446), SAH patients showed higher drug exposure with thiazide diuretics (2.11 [1.59-2.80]), but lower prevalence of remaining antihypertensive medication-beta-blockers (0.38 [0.30-0.48]), calcium channel blockers (0.63 [0.48-0.83]), angiotensin-converting enzyme inhibitors (0.56 [0.44-0.72]), and angiotensin-1 receptor blockers (0.33 [0.24-0.45]). Patients with ruptured IA were less likely to be treated with statins (0.62 [0.47-0.81]), thyroid hormones (0.62 [0.48-0.79]), and aspirin (0.55 [0.41-0.75]). Conclusions: Regular medication might impact the risks related to the development and rupture of IA. Further clinical trials are required to clarify the effect of regular medication on IA genesis.

Circadian rhythm and aneurysmal subarachnoid hemorrhage: Is there an alarm clock for the rupture timing?

BACKGROUND AND PURPOSE: Data on the temporal distribution of the bleeding time of intracranial aneurysms are limited to a few small studies. With this study, the aim was to analyze time patterns of the occurrence of aneurysmal subarachnoid hemorrhage (SAH), particularly focusing on the impact of patients' socio-demographic and clinical characteristics on the ictus timing. METHODS: The study is based on an institutional SAH cohort with 782 consecutive cases treated between January 2003 and June 2016. Data were collected on the ictus time, patients' socio-demographic and clinical characteristics, as well as the initial severity and outcome. Univariate and multivariate analyses were performed on the bleeding timeline. RESULTS: There were two peaks in the circadian rhythm of SAH, one in the morning (7-9 a.m.) and the other in the evening (7-9 p.m.). The strongest alterations in the bleeding time patterns were observed for weekdays, patients' age, sex and ethnicity. Individuals with chronic alcohol and painkiller consumption showed a higher bleeding peak between 1 and 3 p.m. Finally, the bleeding time showed no impact on the severity, clinically relevant complications and the outcome of SAH patients. CONCLUSIONS: This study is one of the very few detailed analyses of the impact of specific socio-demographic, ethnic, behavioral and clinical characteristics on the rupture timing of aneurysms. Our results point to the possible relevance of the circadian rhythm for the rupture event, and therefore might be useful in the elaboration of preventive measures against aneurysm rupture.

Reevaluation of risk factors for aneurysmal subarachnoid hemorrhage associated epilepsy.

BACKGROUND: Symptomatic epilepsy is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) associated with poor outcome. We sought to analyze the risk factors leading to post-SAH epilepsy. METHODS: All consecutive aSAH cases treated between 01/2003 and 06/2016 were retrospectively included. Post-aSAH period was followed up to 03/2020 for the occurrence of epilepsy. Demographic characteristics and previous medical history of the patients, parameters of initial severity, performed treatments, certain early and late complications of aSAH, as well as routine laboratory and vital parameter measurements were collected. Functional outcome was assessed at discharge and 6 months after aSAH using the modified Rankin scale (mRS). RESULTS: During the post-aSAH follow-up (median: 8.93 months/patient), 85 of 948 individuals (9%) in the final analysis developed symptomatic epilepsy (median: 3.43 months). In the majority of cases, epilepsy was diagnosed >3 weeks after aSAH (n = 67, 78.8%) and in survivors with poor outcome at discharge (mRS = 4-5, 15.8% vs. 5.3%, p < 0.0001). Of over 150 analyzed potential risk factors, the following parameters were independently associated with the risk of symptomatic epilepsy after aSAH: thyroid dysfunction (aHR = 1.81, p = 0.029), need for decompressive craniectomy (aHR = 2.32, p = 0.011) and shunt placement (aHR = 1.94, p = 0.022), prolonged tachycardia (≥4 days, aHR = 2.06, p = 0.025), as well as anemia signs (mean red blood cell count <3.6 × 1012 /L [aHR = 2.4, p = 0.015] and mean hematocrit <31% [aHR = 2.13, p = 0.044]) during first 2 weeks after aSAH. CONCLUSION: Symptomatic epilepsy occurs predominantly in individuals with poor outcome at discharge and after the acute phase of aSAH. Knowledge of risk factors associated with aSAH-related epilepsy might help in early identification and treatment of compromised individuals, and therefore, help to improve their outcome.

Comparing radiographic scores for prediction of complications and outcome of aneurysmal subarachnoid hemorrhage: Which performs best?

BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) is characterized by high morbidity and mortality proceeding from the initial severity and following complications of aSAH. Various scores have been developed to predict these risks. We aimed to analyze the clinical value of different radiographic scores for prognostication of aSAH outcome. METHODS: Initial computed tomography scans (≤48 h after ictus) of 745 aSAH cases treated between January 2003 and June 2016 were reviewed with regard to Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and Claassen, Barrow Neurological Institute (BNI), Hijdra, original Graeb and Fisher scale scores. The primary endpoints were development of delayed cerebral ischemia (DCI), in-hospital mortality and unfavorable outcome (modified Rankin Scale score >3) at 6 months after subarachnoid hemorrhage. Secondary endpoints included the different complications that can occur during aSAH. Clinically relevant cutoffs were defined using receiver-operating characteristic curves. The radiographic scores with the highest values for area under the curve (AUC) were included in the final multivariate analysis. RESULTS: The Hijdra sum score had the most accurate predictive value and independent associations with all primary endpoints: DCI (AUC 0.678, adjusted odds ratio [aOR] 2.83; p < 0.0001); in-hospital mortality (AUC 0.704, aOR 2.83; p < 0.0001) and unfavorable outcome (AUC 0.726, aOR 2.91; p < 0.0001). Multivariate analyses confirmed the independent predictive value of the radiographic scales for risk of decompressive craniectomy (SEBES and Fisher score), cerebral vasospasm (SEBES, BNI score and Fisher score) and shunt dependency (Hijdra ventricle score and Fisher score) after aSAH. CONCLUSIONS: Initial radiographic severity of aSAH was independently associated with occurrence of different complications during aSAH and the final outcome. The Hijdra sum score showed the highest diagnostic accuracy and robust predictive value for early detection of risk of DCI, in-hospital mortality and unfavorable outcome after aSAH.

Small intracranial aneurysms of the anterior circulation: A negligible risk?

BACKGROUND AND PURPOSE: According to the International Study of Unruptured Intracranial Aneurysms, small (<7 mm) unruptured intracranial aneurysms (IAs) of the anterior circulation (aC) carry a neglectable 5-year rupture risk. In contrast, some studies report frequencies of >20% of all ruptured IAs being small IAs of the aC. This contradiction was addressed in this study by analyzing the rates and risk factors for rupture of small IAs within the aC. METHODS: Of the institutional observational cohort, 1676 small IAs of the aC were included. Different demographic, clinical, laboratory, and radiographic characteristics were collected. A rupture risk score was established using all independent prognostic factors. The score performance was checked using receiver operating characteristic curve analysis. RESULTS: Of all registered small IAs of the aC, 20.1% were ruptured. The developed small IAs of the aC (SIAAC) score (range = -4 to +13 points) contained five major risk factors: IA location and size, arterial hypertension, alcohol abuse, and chronic renal failure. In addition, three putative protective factors were also included in the score: hypothyroidism, dyslipidemia, and peripheral arterial disease. Increasing rates of ruptured IA with increasing SIAAC scores were observed, from 0% (≤-1 points) through >50% (≥8 points) and up to 100% in patients scoring ≥12 points. The SIAAC score achieved excellent discrimination (area under the curveSIAAC  = 0.803) and performed better than the PHASES (Population,Hypertension, Age, Size of the aneurysm, Earlier SAH from another aneurysm, Site of aneurysm) score. CONCLUSIONS: Small IAs of the aC carry a considerable rupture risk. After external validation, the proposed rupture risk score might provide a basis for better decision-making regarding the treatment of small unruptured IAs of the aC.

Systematic review and meta-analysis of outcome-relevant anemia in patients with subarachnoid hemorrhage.

Anemia is a common, treatable condition in patients with aneurysmal subarachnoid hemorrhage (SAH) and has been associated with poor outcome. As there are still no guidelines for anemia management after aneurysm rupture, we aimed to identify outcome-relevant severity of anemia in SAH. We systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library for publications before Oct 23rd, 2022, reporting on anemia in SAH patients. The presence and severity of anemia were assessed according to the reported hemoglobin values and/or institutional thresholds for red blood cells transfusion (RBCT). Out of 1863 original records, 40 full-text articles with a total of 14,701 patients treated between 1996 and 2020 were included in the final analysis (mean 445.48 patients per study). A substantial portion of patients developed anemia during SAH (mean pooled prevalence 40.76%, range 28.3-82.6%). RBCT was administered in a third of the cases (mean 32.07%, range 7.8-88.6%), with institutional threshold varying from 7.00 to 10.00 g/dL (mean 8.5 g/dL). Anemia at the onset of SAH showed no impact on SAH outcome. In contrast, even slight anemia (nadir hemoglobin < 11.0-11.5 g/dL) occurring during SAH was associated with the risk of cerebral infarction and poor outcome at discharge and follow-up. The strongest association with SAH outcome was observed for nadir hemoglobin values ranging between 9.0 and 10.0 g/dL. The effect of anemia on SAH mortality was marginal. The development of anemia during SAH is associated with the risk of cerebral infarction and poor outcome at discharge and follow-up. Outcome-relevant severity of post-SAH anemia begins at hemoglobin levels clearly above the thresholds commonly set for RBCT. Our findings underline the need for further studies to define the optimal management of anemia in SAH patients.

Impact of Anemia Severity on the Outcome of an Aneurysmal Subarachnoid Hemorrhage.

Objective: Previous reports indicate a negative impact of anemia on the outcome of an aneurysmal subarachnoid hemorrhage (SAH). We aimed to identify the outcome-relevant severity of post-SAH anemia. Methods: SAH cases treated at our institution between 01/2005 and 06/2016 were included (n = 640). The onset, duration, and severity (nadir hemoglobin (nHB) level) of anemia during the initial hospital stay were recorded. Study endpoints were new cerebral infarctions, a poor outcome six months post-SAH (modified Rankin scale > 3), and in-hospital mortality. To assess independent associations with the study endpoints, different multivariable regression models were performed, adjusted for relevant patient and baseline SAH characteristics as well as anemia-associated clinical events during the SAH. Results: The rates of anemia were 83.3%, 67.7%, 40.0%, 15.9%, and 4.5% for an nHB < 11 g/dL, < 10 g/dL, < 9 g/dL, < 8 g/dL, and < 7 g/dL, respectively. The higher the anemia severity, the later was the onset (post-SAH days 2, 4, 5.4, 7.6 and 8, p < 0.0001) and the shorter the duration (8 days, 6 days, 4 days, 3 days, and 2 days, p < 0.0001) of anemia. In the final multivariable analysis, only an nHB < 9 g/dL was independently associated with all study endpoints: adjusted odds ratio 1.7/3.22/2.44 for cerebral infarctions/in-hospital mortality/poor outcome. The timing (post-SAH day 3.9 vs. 6, p = 0.001) and duration (3 vs. 5 days, p = 0.041) of anemia with an nHB < 9 g/dL showed inverse associations with the risk of in-hospital mortality, but not with other study endpoints. Conclusions: Anemia is very common in SAH patients affecting four of five individuals during their hospital stay. An nHB decline to < 9 g/dL was strongly associated with all study endpoints, independent of baseline characteristics and SAH-related clinical events. Our data encourage further prospective evaluations of the value of different transfusion strategies in the functional outcomes of SAH patients.

Development of multiple intracranial aneurysms: beyond the common risk factors.

OBJECTIVE: The prevalence of multiple intracranial aneurysms (MIAs) has increased over the last decades. Because MIAs have been identified as an independent risk factor for formation, growth, and rupture of intracranial aneurysms (IAs), a more profound understanding of the underlying pathophysiology of MIAs is needed. Therefore, the authors' extensive institutional aneurysm database was analyzed to elucidate differences between patients with a single IA (SIA) and those with MIAs. METHODS: A total of 2446 patients seen with or for IAs at the University Hospital of Essen, Essen, Germany, from January 2003 to June 2016 were included in this retrospective cohort study and were separated into MIA and SIA subgroups. Patient data were screened for sociodemographic and radiographic parameters, preexisting medical conditions, and results of blood examinations. These parameters were analyzed for their correlations with MIAs and absolute number of IAs. RESULTS: MIAs were identified in 853 (34.9%) patients. In multivariable analysis, MIAs were independently associated with female sex (p = 0.001), arterial hypertension (p = 0.023), tobacco abuse (p = 0.009), AB blood group (p = 0.010), and increased admission values for C-reactive protein (p = 0.006), mean corpuscular volume (p = 0.009), and total serum protein (p = 0.034), but not with diagnostic modality (3D vs 2D digital subtraction angiography, p = 0.912). Absolute number of IAs was independently associated with female sex (p < 0.001), arterial hypertension (p = 0.014), familial predisposition to IA (p = 0.015), tobacco consumption (p = 0.025), increased mean corpuscular volume (p = 0.002), and high platelet count (p = 0.007). CONCLUSIONS: In this sizable consecutive series of patients with IAs, the authors confirmed the impact of common IA risk factors on the genesis of MIAs. In addition, specific hemorheological and hemocytological features may also contribute to the development of MIAs.

Subarachnoid Hemorrhage Early Brain Edema Score (SEBES) as a radiographic marker of clinically relevant intracranial hypertension and unfavorable outcome after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: The severity of early brain edema (EBE) after aneurysm rupture was reported to be strongly associated with the risk of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Using the recently developed Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), we analyzed the predictors of EBE and its impact on complications related to intracranial pressure (ICP) increase after SAH and on poor outcome. METHODS: All consecutive SAH cases treated between January 2003 and June 2016 with assessable SEBES were included (n = 745). Data on demographic characteristics, medical history, initial severity of SAH, need for conservative ICP treatment and decompressive craniectomy, occurrence of cerebral infarctions and unfavorable outcome at 6 months (modified Rankin scale score > 2) were collected. Univariable and multivariable analyses were performed. RESULTS: Younger age (<55 years; adjusted odds ratio [aOR] 3.16, 95% confidence interval [CI] 2.28-4.38), female sex (aOR 1.64, 95% CI 1.16-2.31), poor initial clinical condition (World Federation of Neurosurgical Societies score 4-5; aOR 1.74, 95% CI 1.23-2.46), presence of intracerebral hemorrhage (aOR 1.63, 95% CI 1.12-2.36), hypothyroidism (aOR 0.60, 95% CI 0.37-0.98) and renal comorbidity (aOR 0.29, 95% CI 0.11-0.78) were independently associated with SEBES (scores 3-4). There was an independent association between SEBES 3-4 and the need for conservative ICP treatment (aOR 2.43, 95% CI 1.73-3.42), decompressive craniectomy (aOR 2.68, 95% CI 1.84-3.89), development of cerebral infarcts (aOR 2.24, 95% CI 1.53-3.29) and unfavorable outcome (aOR 1.48, 95% CI 1.0-2.17). CONCLUSIONS: SEBES is a reliable predictor of ICP-related complications and poor outcome of SAH. Our findings highlight the need for further research of the impact of patients' demographic characteristics and comorbidities on the severity of EBE after SAH.