Dispersal patterns and influence of air travel during the global expansion of SARS-CoV-2 variants of concern.

The Alpha, Beta, and Gamma SARS-CoV-2 variants of concern (VOCs) co-circulated globally during 2020 and 2021, fueling waves of infections. They were displaced by Delta during a third wave worldwide in 2021, which, in turn, was displaced by Omicron in late 2021. In this study, we use phylogenetic and phylogeographic methods to reconstruct the dispersal patterns of VOCs worldwide. We find that source-sink dynamics varied substantially by VOC and identify countries that acted as global and regional hubs of dissemination. We demonstrate the declining role of presumed origin countries of VOCs in their global dispersal, estimating that India contributed <15% of Delta exports and South Africa <1%-2% of Omicron dispersal. We estimate that >80 countries had received introductions of Omicron within 100 days of its emergence, associated with accelerated passenger air travel and higher transmissibility. Our study highlights the rapid dispersal of highly transmissible variants, with implications for genomic surveillance along the hierarchical airline network.

Early introductions and transmission of SARS-CoV-2 variant B.1.1.7 in the United States.

The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2,500 COVID-19 cases associated with this variant have been detected in the United States (US) since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight that the primary ports of entry for B.1.1.7 in the US were in New York, California, and Florida. Furthermore, we found evidence for many independent B.1.1.7 establishments starting in early December 2020, followed by interstate spread by the end of the month. Finally, we project that B.1.1.7 will be the dominant lineage in many states by mid- to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.

Coast-to-Coast Spread of SARS-CoV-2 during the Early Epidemic in the United States.

The novel coronavirus SARS-CoV-2 was first detected in the Pacific Northwest region of the United States in January 2020, with subsequent COVID-19 outbreaks detected in all 50 states by early March. To uncover the sources of SARS-CoV-2 introductions and patterns of spread within the United States, we sequenced nine viral genomes from early reported COVID-19 patients in Connecticut. Our phylogenetic analysis places the majority of these genomes with viruses sequenced from Washington state. By coupling our genomic data with domestic and international travel patterns, we show that early SARS-CoV-2 transmission in Connecticut was likely driven by domestic introductions. Moreover, the risk of domestic importation to Connecticut exceeded that of international importation by mid-March regardless of our estimated effects of federal travel restrictions. This study provides evidence of widespread sustained transmission of SARS-CoV-2 within the United States and highlights the critical need for local surveillance.

A new lineage nomenclature to aid genomic surveillance of dengue virus.

Dengue virus (DENV) is currently causing epidemics of unprecedented scope in endemic settings and expanding to new geographical areas. It is therefore critical to track this virus using genomic surveillance. However, the complex patterns of viral genomic diversity make it challenging to use the existing genotype classification system. Here, we propose adding 2 sub-genotypic levels of virus classification, named major and minor lineages. These lineages have high thresholds for phylogenetic distance and clade size, rendering them stable between phylogenetic studies. We present assignment tools to show that the proposed lineages are useful for regional, national, and subnational discussions of relevant DENV diversity. Moreover, the proposed lineages are robust to classification using partial genome sequences. We provide a standardized neutral descriptor of DENV diversity with which we can identify and track lineages of potential epidemiological and/or clinical importance. Information about our lineage system, including methods to assign lineages to sequence data and propose new lineages, can be found at: dengue-lineages.org.

Phylogeographic reconstruction of the emergence and spread of Powassan virus in the northeastern United States.

Powassan virus is an emerging tick-borne virus of concern for public health, but very little is known about its transmission patterns and ecology. Here, we expanded the genomic dataset by sequencing 279 Powassan viruses isolated from Ixodes scapularis ticks from the northeastern United States. Our phylogeographic reconstructions revealed that Powassan virus lineage II was likely introduced or emerged from a relict population in the Northeast between 1940 and 1975. Sequences strongly clustered by sampling location, suggesting a highly focal geographical distribution. Our analyses further indicated that Powassan virus lineage II emerged in the northeastern United States mostly following a south-to-north pattern, with a weighted lineage dispersal velocity of ~3 km/y. Since the emergence in the Northeast, we found an overall increase in the effective population size of Powassan virus lineage II, but with growth stagnating during recent years. The cascading effect of population expansion of white-tailed deer and I. scapularis populations likely facilitated the emergence of Powassan virus in the northeastern United States.

Hearing preservation and quality of life in small to medium sized vestibular schwannomas after a wait and scan approach or stereotactic radiosurgery: a systematic review and meta-analysis.

BACKGROUND: The management of vestibular schwannomas (VS) encompasses a choice between conservative "wait-and-scan" (WAS) approach, stereotactic radiosurgery (SRS) or open microsurgical resection. Currently, there is no consensus on the optimal management approach for small to medium sized VS. This study aims to compared outcomes related to hearing in patients with small and medium sized VS who underwent initial treatment with WAS versus SRS. METHODS: A systematic review of the available literature was conducted using PubMed/MEDLINE, Embase, and Cochrane up December 08, 2023. Meta-analysis was performed using a random-effect model to calculate mean difference (MD) and relative risk (RR). A leave-one-out analysis was conducted. The risk of bias was assessed via the Risk of Bias in Non-randomized Studies-Interventions (ROBINS-I) and Cochrane Risk of Bias assessment tool (RoB-2). Ultimately, the certainty of evidence was evaluated using the GRADE assessment. The primary outcomes were serviceable hearing, and pure-tone average (PTA). The secondary outcome was the Penn Acoustic Neuroma Quality of Life Scale (PANQOL) total score. RESULTS: Nine studies were eligible for inclusion, comprising a total of 1,275 patients. Among these, 674 (52.86%) underwent WAS, while 601 patients (47.14%) received SRS. Follow-up duration ranged from two to eight years. The meta-analysis indicated that WAS had a better outcome for serviceable hearing (0.47; 95% CI: 0.32 - 0.68; p < 0.001), as well as for postoperative functional measures including PTA score (MD 13.48; 95% CI 3.83 - 23.13; p < 0.01), and PANQOL total score (MD 3.83; 95% CI 0.42 - 7.25; p = 0.03). The overall certainty of evidence ranged from "very low" to "moderate". CONCLUSIONS: Treating small to medium sized VS with WAS increases the likelihood of preserving serviceable hearing and optimized PANQOL overall postoperative score compared to SRS. Nevertheless, the limited availability of literature and the methodological weakness observed in existing studies outline the need for higher-quality studies.

Real-time public health communication of local SARS-CoV-2 genomic epidemiology.

Genomic epidemiology can provide a unique, real-time understanding of SARS-CoV-2 transmission patterns. Yet the potential for genomic analyses to guide local policy and community-based behavioral decisions is limited because they are often oriented towards specially trained scientists and conducted on a national or global scale. Here, we propose a new paradigm: Phylogenetic analyses performed on a local level (municipal, county, or state), with results communicated in a clear, timely, and actionable manner to strengthen public health responses. We believe that presenting results rapidly, and tailored to a non-expert audience, can serve as a template for effective public health response to COVID-19 and other emerging viral diseases.

Longitudinal Immune Profiling of a Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection in a Solid Organ Transplant Recipient.

BACKGROUND: The underlying immunologic deficiencies enabling severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection are currently unknown. We describe deep longitudinal immune profiling of a transplant recipient hospitalized twice for coronavirus disease 2019 (COVID-19). METHODS: A 66-year-old male renal transplant recipient was hospitalized with COVID-19 March 2020 then readmitted to the hospital with COVID-19 233 days after initial diagnosis. Virologic and immunologic investigations were performed on samples from the primary and secondary infections. RESULTS: Whole viral genome sequencing and phylogenetic analysis revealed that viruses causing both infections were caused by distinct genetic lineages without evidence of immune escape mutations. Longitudinal comparison of cellular and humoral responses during primary SARS-CoV-2 infection revealed that this patient responded to the primary infection with low neutralization titer anti-SARS-CoV-2 antibodies that were likely present at the time of reinfection. CONCLUSIONS: The development of neutralizing antibodies and humoral memory responses in this patient failed to confer protection against reinfection, suggesting that they were below a neutralizing titer threshold or that additional factors may be required for efficient prevention of SARS-CoV-2 reinfection. Development of poorly neutralizing antibodies may have been due to profound and relatively specific reduction in naive CD4 T-cell pools. Seropositivity alone may not be a perfect correlate of protection in immunocompromised patients.

COVID-19 one year into the pandemic: from genetics and genomics to therapy, vaccination, and policy.

COVID-19 has engulfed the world and it will accompany us all for some time to come. Here, we review the current state at the milestone of 1 year into the pandemic, as declared by the WHO (World Health Organization). We review several aspects of the on-going pandemic, focusing first on two major topics: viral variants and the human genetic susceptibility to disease severity. We then consider recent and exciting new developments in therapeutics, such as monoclonal antibodies, and in prevention strategies, such as vaccines. We also briefly discuss how advances in basic science and in biotechnology, under the threat of a worldwide emergency, have accelerated to an unprecedented degree of the transition from the laboratory to clinical applications. While every day we acquire more and more tools to deal with the on-going pandemic, we are aware that the path will be arduous and it will require all of us being community-minded. In this respect, we lament past delays in timely full investigations, and we call for bypassing local politics in the interest of humankind on all continents.

Multiple Transmission Chains within COVID-19 Cluster, Connecticut, USA, 20201.

In fall 2020, a coronavirus disease cluster comprising 16 cases occurred in Connecticut, USA. Epidemiologic and genomic evidence supported transmission among persons at a school and fitness center but not a workplace. The multiple transmission chains identified within this cluster highlight the necessity of a combined investigatory approach.

Twenty years of West Nile virus spread and evolution in the Americas visualized by Nextstrain.

It has been 20 years since West Nile virus first emerged in the Americas, and since then, little progress has been made to control outbreaks caused by this virus. After its first detection in New York in 1999, West Nile virus quickly spread across the continent, causing an epidemic of human disease and massive bird die-offs. Now the virus has become endemic to the United States, where an estimated 7 million human infections have occurred, making it the leading mosquito-borne virus infection and the most common cause of viral encephalitis in the country. To bring new attention to one of the most important mosquito-borne viruses in the Americas, we provide an interactive review using Nextstrain: a visualization tool for real-time tracking of pathogen evolution (nextstrain.org/WNV/NA). Nextstrain utilizes a growing database of more than 2,000 West Nile virus genomes and harnesses the power of phylogenetics for students, educators, public health workers, and researchers to visualize key aspects of virus spread and evolution. Using Nextstrain, we use virus genomics to investigate the emergence of West Nile virus in the U S, followed by its rapid spread, evolution in a new environment, establishment of endemic transmission, and subsequent international spread. For each figure, we include a link to Nextstrain to allow the readers to directly interact with and explore the underlying data in new ways. We also provide a brief online narrative that parallels this review to further explain the data and highlight key epidemiological and evolutionary features (nextstrain.org/narratives/twenty-years-of-WNV). Mirroring the dynamic nature of outbreaks, the Nextstrain links provided within this paper are constantly updated as new West Nile virus genomes are shared publicly, helping to stay current with the research. Overall, our review showcases how genomics can track West Nile virus spread and evolution, as well as potentially uncover novel targeted control measures to help alleviate its public health burden.

Effect of Different Circuit Training on Cardiovascular Responses in Cirrhotic Patients.

The purpose of this study was to analyze and compare heart rate (HR), heart rate variability (HRV), and blood pressure (BP) responses during and after circuit resistance training with 1 min. (CIR1) vs. 2 min. (CIR2) rest intervals between exercises in liver cirrhosis patients. 10 patients (7 women, 3 men) participated in 2 experimental sessions (CIR1 and CIR2) in random order. Each experimental session consisted of 6 exercises performed for 3 sets of 10 repetitions with 70% of the 10-RM load. The only difference between experimental sessions was taking either 1 min. (CIR1) or 2 min. (CIR2) of rest between exercises. Prior and during each session, BP, HR and HRV (beat-to-beat intervals) were assessed. Training efficiency were significant higher for CIR1 when compared to CIR2, since same total training volume was performed in less time. Both protocols elicited significant changes in HR, SBP, and SampEn. Based on the ∆HR and ∆IRR between protocols, higher cardiovascular stress was observed for CIR1 vs. CIR2. However, the patients presented a similar recovery pattern between experimental sessions, and did not present significant alterations in the HRV at 60 min post-workout. In summary, the fast adjustment of autonomic modulation in HRV and BP suggests that circuit resistance training with 1-min or 2-min rest intervals between exercises elicits typical cardiovascular responses in liver cirrhosis patients.

Stereotactic radiosurgery for nonfunctioning pituitary tumor: A multicenter study of new pituitary hormone deficiency.

BACKGROUND: Stereotactic radiosurgery (SRS) is used to treat recurrent or residual nonfunctioning pituitary neuroendocrine tumors (NFPA). The objective of the study was to assess imaging and development of new pituitary hormone deficiency. METHODS: Patients treated with single-session SRS for a NFPA were included in this retrospective, multicenter study. Tumor control and new pituitary dysfunction were evaluated using Cox analysis and Kaplan-Meier curves. RESULTS: A total of 869 patients (male 476 [54.8%], median age at SRS 52.5 years [Interquartile range (IQR): 18.9]) were treated using a median margin dose of 14Gy (IQR: 4) for a median tumor volume of 3.4 cc (IQR: 4.3). With a median radiological follow-up of 3.7 years (IQR: 4.8), volumetric tumor reduction occurred in 451 patients (51.9%), stability in 364 (41.9%) and 54 patients (6.2%) showed tumor progression.The probability of tumor control was 95.5% (95% Confidence Interval [CI]: 93.8-97.3) and 88.8% (95%CI: 85.2-92.5) at 5 and 10 years, respectively. A margin dose >14 Gy was associated with tumor control (Hazard Ratio [HR]:0.33, 95% CI: 0.18-0.60, P < 0.001). The probability of new hypopituitarism was 9.9% (95% CI: 7.3-12.5) and 15.3% (95% CI: 11-19.4) at 5 and 10 years, respectively. A maximum point dose >10 Gy in the pituitary stalk was associated with new pituitary hormone deficiency (HR: 3.47, 95% CI: 1.95-6.19). The cumulative probability of new cortisol, thyroid, gonadotroph, and growth hormone deficiency was 8% (95% CI: 3.9-11.9), 8.3% (95% CI: 3.9-12.5), 3.5% (95% CI: 1.7-5.2), and 4.7% (95% CI: 1.9-7.4), respectively at 10 years. CONCLUSIONS: SRS provides long-term tumor control with a 15.3% risk of hypopituitarism at 10 years.

Long-term radiographic and endocrinological outcomes of stereotactic radiosurgery for recurrent or residual nonfunctioning pituitary adenomas.

OBJECTIVE: Stereotactic radiosurgery (SRS) is used for the treatment of residual/recurrent nonfunctional pituitary adenoma (NFPA). The aim of this study was to evaluate the factors related to long-term tumor control and delayed endocrinopathies following SRS. METHODS: This retrospective, multicenter study included patients with recurrent/residual NFPA treated with single-fraction SRS; they were then divided into two arms. The first arm included patients with at least 5 years of radiographic follow-up and all patients with local tumor progression. The second arm included patients with at least 5 years of endocrinological follow-up and all patients who developed endocrinopathy. Study endpoints were tumor control and new or worsening hypopituitarism after SRS and were analyzed using Cox regression and Kaplan-Meier methodology. RESULTS: There were 360 patients in the tumor control arm (median age 52.7 [IQR 42.9-61] years, 193 [53.6%] males) and 351 patients in the hypopituitarism arm (median age 52.5 [IQR 43-61] years, 186 [53.0%] males). The median follow-up in the tumor control evaluation group was 7.95 (IQR 5.7-10.5) years. Tumor control rates at 5, 8, 10, and 15 years were 93% (95% CI 90%-95%), 87% (95% CI 83%-91%), 86% (95% CI 82%-90%), and 69% (95% CI 59%-81%), respectively. The median follow-up in the endocrinopathy evaluation group was 8 (IQR 5.9-10.7) years. Pituitary function preservation rates at 5, 8, 10, and 15 years were 83% (95% CI 80%-87%), 81% (95% CI 77%-85%), 78% (95% CI 74%-83%), and 71% (95% CI 63%-79%), respectively. A margin dose > 15 Gy (HR 0.8, 95% CI 0.7-0.9; p < 0.001) and a delay from last resection to SRS > 1 year (HR 0.9, 95% CI 0.7-0.9; p = 0.04) were significant factors related to tumor control in multivariable analysis. A maximum dose to the pituitary stalk ≤ 10 Gy (HR 1.1, 95% CI 1.09-1.2; p < 0.001) was associated with pituitary function preservation. New visual deficits after SRS occurred in 7 (1.94%) patients in the tumor control group and 8 (2.3%) patients in the endocrinopathy group. Other new cranial nerve deficits post-SRS occurred in 4 of 160 patients with data in the tumor control group and 3 of 140 patients with data in the endocrinopathy group. CONCLUSIONS: SRS affords favorable and durable tumor control for the vast majority of NFPAs. Post-SRS hypopituitarism occurs in a minority of patients, but this risk increases with time and warrants long-term follow-up.

A new lineage nomenclature to aid genomic surveillance of dengue virus.

Dengue virus (DENV) is currently causing epidemics of unprecedented scope in endemic settings and expanding to new geographical areas. It is therefore critical to track this virus using genomic surveillance. However, the complex patterns of viral genomic diversity make it challenging to use the existing genotype classification system. Here we propose adding two sub-genotypic levels of virus classification, named major and minor lineages. These lineages have high thresholds for phylogenetic distance and clade size, rendering them stable between phylogenetic studies. We present an assignment tool to show that the proposed lineages are useful for regional, national and sub-national discussions of relevant DENV diversity. Moreover, the proposed lineages are robust to classification using partial genome sequences. We provide a standardized neutral descriptor of DENV diversity with which we can identify and track lineages of potential epidemiological and/or clinical importance. Information about our lineage system, including methods to assign lineages to sequence data and propose new lineages, can be found at: dengue-lineages.org.

Risk of new tumor, carotid stenosis, and stroke after Stereotactic Radiosurgery for Pituitary Tumor: A multicenter study of 2254 patients with imaging follow-up.

BACKGROUND: Higher risk of secondary brain tumor, carotid stenosis and stroke has been reported after conventional sella irradiation for pituitary neuroendocrine tumors (PitNET). Stereotactic radiosurgery (SRS), which is a more focused approach, is now increasingly used instead. The aim was to assess the risk of secondary brain tumor, carotid stenosis/occlusion and stroke after SRS. METHODS: In this multicentric retrospective study, 2,254 patients with PitNET were studied, 1,377 in the exposed group and 877 in the control group. RESULTS: There were 9,840.1 patient-years at risk for the SRS and 5,266.5 for the control group. The 15-year cumulative probability of secondary intracranial tumor was 2.3% (95%CI:0.5%, 4.1%) for SRS and 3.7% (95%CI:0%, 8.7%) for the control group (p=0.6), with an incidence rate of 1.32 per 1,000 and 0.95 per 1,000, respectively. SRS was not associated with increased risk of tumorigenesis when stratified by age (HR: 1.59 [95%CI: 0.57, 4.47], p=0.38). The 15-year probability of new carotid stenosis/occlusion was 0.9% (95%CI: 0.2, 1.6) in the SRS and 2% (95%CI: 0, 4.4) in the control group (p=0.8). The 15-year probability of stroke was 2.6% (95%CI: 0.6%, 4.6%) in the SRS and 11.1% (95%CI: 6%, 15.9%) in the control group (p<0.001). In cox multivariate analysis stratified by age, SRS (HR 1.85[95%CI:0.64, 5.35], p=0.26) was not associated with risk of new stroke. CONCLUSION: No increased risk of long-term secondary brain tumor, new stenosis or occlusion and stroke was demonstrated in SRS group compared to control in this study with imaging surveillance.

Nasal host response-based screening for undiagnosed respiratory viruses: a pathogen surveillance and detection study.

BACKGROUND: Symptomatic patients who test negative for common viruses are an important possible source of unrecognised or emerging pathogens, but metagenomic sequencing of all samples is inefficient because of the low likelihood of finding a pathogen in any given sample. We aimed to determine whether nasopharyngeal CXCL10 screening could be used as a strategy to enrich for samples containing undiagnosed viruses. METHODS: In this pathogen surveillance and detection study, we measured CXCL10 concentrations from nasopharyngeal swabs from patients in the Yale New Haven health-care system, which had been tested at the Yale New Haven Hospital Clinical Virology Laboratory (New Haven, CT, USA). Patients who tested negative for a panel of respiratory viruses using multiplex PCR during Jan 23-29, 2017, or March 3-14, 2020, were included. We performed host and pathogen RNA sequencing (RNA-Seq) and analysis for viral reads on samples with CXCL10 higher than 1 ng/mL or CXCL10 testing and quantitative RT-PCR (RT-qPCR) for SARS-CoV-2. We used RNA-Seq and cytokine profiling to compare the host response to infection in samples that were virus positive (rhinovirus, seasonal coronavirus CoV-NL63, or SARS-CoV-2) and virus negative (controls). FINDINGS: During Jan 23-29, 2017, 359 samples were tested for ten viruses on the multiplex PCR respiratory virus panel (RVP). 251 (70%) were RVP negative. 60 (24%) of 251 samples had CXCL10 higher than 150 pg/mL and were identified for further analysis. 28 (47%) of 60 CXCL10-high samples were positive for seasonal coronaviruses. 223 (89%) of 251 samples were PCR negative for 15 viruses and, of these, CXCL10-based screening identified 32 (13%) samples for further analysis. Of these 32 samples, eight (25%) with CXCL10 concentrations higher than 1 ng/mL and sufficient RNA were selected for RNA-Seq. Microbial RNA analysis showed the presence of influenza C virus in one sample and revealed RNA reads from bacterial pathobionts in four (50%) of eight samples. Between March 3 and March 14, 2020, 375 (59%) of 641 samples tested negative for 15 viruses on the RVP. 32 (9%) of 375 samples had CXCL10 concentrations ranging from 100 pg/mL to 1000 pg/mL and four of those were positive for SARS-CoV-2. CXCL10 elevation was statistically significant, and a distinguishing feature was found in 28 (8%) of 375 SARS-CoV-2-negative samples versus all four SARS-CoV-2-positive samples (p=4·4 × 10-5). Transcriptomic signatures showed an interferon response in virus-positive samples and an additional neutrophil-high hyperinflammatory signature in samples with high amounts of bacterial pathobionts. The CXCL10 cutoff for detecting a virus was 166·5 pg/mL for optimal sensitivity and 1091·0 pg/mL for specificity using a clinic-ready automated microfluidics-based immunoassay. INTERPRETATION: These results confirm CXCL10 as a robust nasopharyngeal biomarker of viral respiratory infection and support host response-based screening followed by metagenomic sequencing of CXCL10-high samples as a practical approach to incorporate clinical samples into pathogen discovery and surveillance efforts. FUNDING: National Institutes of Health, the Hartwell Foundation, the Gruber Foundation, Fast Grants for COVID-19 research from the Mercatus Center, and the Huffman Family Donor Advised Fund.

Thinking out of the box: revisiting health surveillance based on medical records.

Despite the considerable advances in the last years, the health information systems for health surveillance still need to overcome some critical issues so that epidemic detection can be performed in real time. For instance, despite the efforts of the Brazilian Ministry of Health (MoH) to make COVID-19 data available during the pandemic, delays due to data entry and data availability posed an additional threat to disease monitoring. Here, we propose a complementary approach by using electronic medical records (EMRs) data collected in real time to generate a system to enable insights from the local health surveillance system personnel. As a proof of concept, we assessed data from São Caetano do Sul City (SCS), São Paulo, Brazil. We used the "fever" term as a sentinel event. Regular expression techniques were applied to detect febrile diseases. Other specific terms such as "malaria," "dengue," "Zika," or any infectious disease were included in the dictionary and mapped to "fever." Additionally, after "tokenizing," we assessed the frequencies of most mentioned terms when fever was also mentioned in the patient complaint. The findings allowed us to detect the overlapping outbreaks of both COVID-19 Omicron BA.1 subvariant and Influenza A virus, which were confirmed by our team by analyzing data from private laboratories and another COVID-19 public monitoring system. Timely information generated from EMRs will be a very important tool to the decision-making process as well as research in epidemiology. Quality and security on the data produced is of paramount importance to allow the use by health surveillance systems.

Stereotactic radiosurgery for haemorrhagic cerebral cavernous malformation: a multi-institutional, retrospective study.

BACKGROUND: Cerebral cavernous malformations (CCMs) frequently manifest with haemorrhages. Stereotactic radiosurgery (SRS) has been employed for CCM not suitable for resection. Its effect on reducing haemorrhage risk is still controversial. The aim of this study was to expand on the safety and efficacy of SRS for haemorrhagic CCM. METHODS: This retrospective multicentric study included CCM with at least one haemorrhage treated with single-session SRS. The annual haemorrhagic rate (AHR) was calculated before and after SRS. Recurrent event analysis and Cox regression were used to evaluate factors associated with haemorrhage. Adverse radiation effects (AREs) and occurrence of new neurological deficits were recorded. RESULTS: The study included 381 patients (median age: 37.5 years (Q1-Q3: 25.8-51.9) with 414 CCMs. The AHR from diagnosis to SRS excluding the first haemorrhage was 11.08 per 100 CCM-years and was reduced to 2.7 per 100 CCM-years after treatment. In recurrent event analysis, SRS, HR 0.27 (95% CI 0.17 to 0.44), p<0.0001 was associated with a decreased risk of haemorrhage, and the presence of developmental venous anomaly (DVA) with an increased risk, HR 1.60 (95% CI 1.07 to 2.40), p=0.022. The cumulative risk of first haemorrhage after SRS was 9.4% (95% CI 6% to 12.6%) at 5 years and 15.6% (95% CI% 9 to 21.8%) at 10 years. Margin doses> 13 Gy, HR 2.27 (95% CI 1.20 to 4.32), p=0.012 and the presence of DVA, HR 2.08 (95% CI 1.00 to 4.31), p=0.049 were factors associated with higher probability of post-SRS haemorrhage. Post-SRS haemorrhage was symptomatic in 22 out of 381 (5.8%) patients, presenting with transient (15/381) or permanent (7/381) neurological deficit. ARE occurred in 11.1% (46/414) CCM and was responsible for transient neurological deficit in 3.9% (15/381) of the patients and permanent deficit in 1.1% (4/381) of the patients. Margin doses >13 Gy and CCM volume >0.7 cc were associated with increased risk of ARE. CONCLUSION: Single-session SRS for haemorrhagic CCM is associated with a decrease in haemorrhage rate. Margin doses ≤13 Gy seem advisable.

Clinical outcomes following stereotactic radiosurgery for cerebral cavernous malformations of the basal ganglia and thalamus.

OBJECTIVE: There are few reports of outcomes following stereotactic radiosurgery (SRS) for the management of cerebral cavernous malformations (CCMs) of the basal ganglia or thalamus. Therefore, the authors aimed to clarify these outcomes. METHODS: Centers participating in the International Radiosurgery Research Foundation were queried for CCM cases managed with SRS from October 2001 to February 2021. The primary outcome of interest was hemorrhage-free survival (HFS) with a secondary outcome of symptomatic adverse radiation events (AREs). Assessment of the association of prognostic factors with HFS was conducted via Kaplan-Meier analysis and log-rank test. Chi-square tests were conducted to assess potential factors associated with the incidence of AREs. RESULTS: Seventy-three patients were identified. The median patient age was 43.5 years (range 4.4-79.5 years). Fifty-nine (80.8%) patients had hemorrhage prior to SRS. The median treatment volume was 0.9 cm3 (range 0.07-10.1 cm3) with a median margin prescription dose (MPD) of 12 Gy (range 10-20 Gy). One-, 3-, 5-, and 10-year HFS were 93.0%, 89.9%, 89.9%, and 83.0%, respectively, with one hemorrhage-related death approximately 1 year after SRS and nearly 60% and 30% of patients having improvement or stability of symptoms, respectively. There was no correlation between lesion size or MPD and HFS. Seven (9.6%) patients experienced AREs (MPDs > 12 Gy in all cases). Lesion size > 1.0 cm3 was correlated with the incidence of an ARE (p = 0.019). Forty-two (93.3%) of 45 patients treated with an MPD ≤ 12 Gy experienced neither hemorrhage nor AREs following SRS versus 17 (60.7%) of 28 patients treated with an MPD > 12 Gy (p = 0.0006). CONCLUSIONS: SRS is a reasonable treatment strategy and confers clinical stability or improvement and hemorrhage avoidance in patients harboring CCMs of the basal ganglia or thalamus. An MPD of approximately 12 Gy is recommended for the management of CCM.