Next Article in Journal
Reliability of a Novel Preoperative Protocol for Determining Graft Sizes for Superior Capsular Reconstruction Using Plain Film Radiography
Next Article in Special Issue
Computational and Experimental Analyses for Pathogenicity Prediction of ACVRL1 Missense Variants in Hereditary Hemorrhagic Telangiectasia
Previous Article in Journal
Skull-Base Surgery—A Narrative Review on Current Approaches and Future Developments in Surgical Navigation
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 12
Issue 7
10.3390/jcm12072704
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
Comment published on 20 November 2023, see J. Clin. Med. 2023, 12(22), 7179.
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT

by
Alexandra Kilian
1,2,
Giuseppe A. Latino
2,3,
Andrew J. White
4,
Felix Ratjen
5,
Jamie McDonald
6,
Kevin J. Whitehead
7,8,
James R. Gossage
9,
Timo Krings
10,
Michael T. Lawton
11,
Helen Kim
12,13,14,
Marie E. Faughnan
2,15,* and
The Brain Vascular Malformation Consortium HHT Investigator Group
†
1
Department of Paediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
2
Toronto HHT Centre, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, Toronto, ON M5B 1W8, Canada
3
Department of Pediatrics, North York General Hospital, University of Toronto, Toronto, ON M2K 1E1, Canada
4
Department of Pediatrics, St Louis University, St. Louis, MO 63103, USA
5
Division of Respiratory Medicine and Translational Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
6
Department of Pathology, University of Utah, Salt Lake City, UT 84132, USA
7
Department of Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT 84132, USA
8
Department of Pediatrics, Division of Pediatric Cardiology, University of Utah, Salt Lake City, UT 84132, USA
9
Department of Medicine, Augusta University, Augusta, GA 30912, USA
10
Division of Neuroradiology, Toronto Western Hospital, University Health Network, Toronto, ON M5T 2S8, Canada
11
Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ 85013, USA
12
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94110, USA
13
Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA
14
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 94158, USA
15
Division of Respirology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada
 
add Show full affiliation list
 
remove Hide full affiliation list
*
Author to whom correspondence should be addressed.
†
For the Collaborator Tab: Mary E. Atherton, Murali M. Chakinala, Marianne S. Clancy, Marie E. Faughnan, James R. Gossage, Adrienne M. Hammill, Katharine Henderson, Steven Hetts, Peter Hountras, Vivek Iyer, Raj S. Kasthuri, Helen Kim, Timo Krings, Michael T. Lawton, Doris Lin, Johannes Jurgen Mager, Douglas A. Marchuk, Justin P. McWilliams, Jamie McDonald, Ludmila Pawlikowska, Jeffrey Pollak, Felix Ratjen, Karen Swanson, Dilini Vethanayagam, Shantel Weinsheimer, Andrew J. White, Pearce Wilcox.
J. Clin. Med. 2023, 12(7), 2704; https://doi.org/10.3390/jcm12072704
Submission received: 17 February 2023 / Revised: 24 March 2023 / Accepted: 27 March 2023 / Published: 4 April 2023
(This article belongs to the Special Issue Hereditary Hemorrhagic Telangiectasia: Diagnosis and Management—Part II)
Versions Notes

Abstract

:
Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease characterized by the development of vascular malformations (VMs) in organs such as the brain and lungs, as well as telangiectases on mucosal surfaces. Prophylactic treatment of organ VMs may prevent potential complications, such as hemorrhage. However, brain VM treatment—surgical resection, embolization, and/or radiosurgery—is not recommended for all patients due to the associated risks. Given the scarcity of data regarding HHT-related brain VM presentation and treatment trends in pediatric patients, we aim to describe the clinical presentations and the patterns of treatment of HHT-related brain VMs in a pediatric cohort, and compare pediatric trends to those of adults. Demographic and clinical data were analyzed in 114 pediatric patients with HHT-related brain VMs and compared with a cohort of 253 adult patients enrolled in the multicenter Brain Vascular Malformation Consortium HHT Project. Our data demonstrated that a higher proportion of pediatric patients with HHT-related brain VMs were symptomatic at presentation (p = 0.004). Moreover, a higher proportion of pediatric patients presented with intracranial hemorrhage (p < 0.001) and seizure (p = 0.002) compared to adult patients. Surgical resection was the most common brain VM treatment modality in both children and adults. We conclude that pediatric patients may be more likely to present with symptoms and complications from brain VMs, supporting the case for screening for brain VMs in children with HHT.

1. Introduction

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease with an estimated prevalence of 1 in 5000 [1,2,3]. It is mainly caused by mutations in three known genes; Endoglin (ENG), Activin A Receptor Like Type 1 (ACVRL1) and SMAD family member 4 (SMAD4), as well as in rare families, with mutations in Growth Differentiation Factor 2 (GDF2) or RAS P21 Protein Activator 1(RASA1). In addition to telangiectases in the nasal mucosa and gastrointestinal (GI) tract, resulting in epistaxis and GI bleeding, patients can present with pulmonary arteriovenous malformations (AVMs) and brain, spine and liver vascular malformations (VMs) [4].
HHT-related brain VMs occur in approximately 10% of patients with HHT, based on a 2017 meta-analysis and systematic review [5]. Brain VMs are known to be more common in patients with an ENG mutation. Patients with HHT often have multiple brain VMs [6,7] and multiplicity has been found to be predictive of HHT diagnosis [5,8,9]. The complications of brain VMs, including rupture with intracranial hemorrhage (ICH), are associated with significant morbidity and a high risk of mortality. In patients with non-HHT related brain VMs, there is evidence that children may be more likely to present with ICH than in adults [10], despite a lower frequency of angio-architectural features typically associated with elevated risk of hemorrhage, such as aneurysms and venous outflow stenoses [11]. There is no published direct comparison of hemorrhage rates between adults and children in the HHT population.
The risks of hemorrhage, neurological deficits, and infection accompany all treatment options for brain VMs, namely surgery, stereotactic radiosurgery, and embolization [12,13,14,15]. As such, the decision to treat, and with which modality, is individualized for each patient [14]. The risk of treatment complications is weighed against the risks of spontaneous rupture and ICH of an untreated lesion. Given that identification of a brain VM via screening may not always result in preventative treatment, brain VM screening has been a subject of international controversy. There was insufficient expert agreement to recommend routine screening for brain VMs at the development of the 2009 International Guidelines [14], though brain VM screening for children with HHT was recommended in the 2020 HHT Guidelines [16]. Current practice trends suggest that screening for brain VMs is the North American standard of practice [17], while screening is uncommon in Europe [18], and remains controversial internationally.
There is a relative scarcity of evidence describing the clinical manifestations and treatment trends for HHT-related brain VMs, particularly in children. In response to this, and the international controversy surrounding the role of brain VM screening, we report and compare data on the clinical manifestations and treatment trends for HHT-related brain VMs from a large pediatric and adult cohort of patients.

2. Materials and Methods

2.1. Cohort

HHT patients with a brain VM from the Brain Vascular Malformation Consortium (BVMC) HHT Project were included in the study cohort. Demographic and clinical data were collected from 114 pediatric patients (age at brain VM diagnosis < 18 years) and 253 adult patients (age at brain VM diagnosis ≥ 18 years) enrolled in the BVMC HHT Project. All patients had a diagnosis of HHT and all patients had one or more brain VMs. The BVMC HHT cohort aims to recruit a cohort in which 25% of patients have a brain VM. Other clinical characteristics of the cohort are similar to other cohorts of HHT patients [19,20]. For the purpose of our study, arteriovenous fistulae (AVF), nidus type AVM, and capillary VM qualified as HHT related brain VMs [21].
The BVMC HHT Project includes 1679 HHT patients with a definite clinical or genetic diagnosis of HHT, enrolled at multiple recruiting centers in the US, Canada, and the Netherlands between 2010 and 2019. Cohort recruitment has been previously described [22,23]. Informed written consent was obtained from all patients (or guardians) in order to be included in all BVMC related projects. The study protocol was approved by the institutional review board at each recruiting center. Patients were screened for organ VMs and other clinical features according to standard clinical practice and International HHT Guidelines [14]. This typically included: comprehensive history, physical exam, and routine investigations; pulmonary AVM screening with contrast echocardiography or positional oximetry (protocols vary by center); brain VM screening by magnetic resonance imaging (MRI); clinical screening for liver VMs (chronic right upper quadrant pain, portal hypertension, high-output heart failure, liver bruit on examination); clinical screening for recurrent spontaneous epistaxis (>1 episode per month for >1 year); and screening for HHT-related GI-bleeding (history of anemia, iron deficiency, known GI telangiectases on endoscopy, melena, rectal bleeding). If screening was positive for pulmonary AVM or brain VM, patients underwent confirmatory diagnostic imaging and treatment where appropriate. If clinical assessment was suggestive of symptomatic liver VM, diagnostic imaging was recommended, along with therapy where appropriate. If initial clinical assessment was suggestive of GI bleeding, diagnostic endoscopy was recommended and endoscopic, medical, and supportive therapies were undertaken on a case-by-case basis. Decisions regarding brain VM treatment were made on a case-by-case basis by the clinical multidisciplinary team of the HHT treatment center. Data was collected both retrospectively at the time of enrolment and prospectively, during the period of data collection.

2.2. Analysis

We calculated the proportions of pediatric and adult patients with HHT-related brain VMs who presented with each clinical characteristic (asymptomatic, ICH, stroke, focal deficits, seizure, headache) and the proportion of patients in each group who underwent treatment, and by which modality. The two-sample z-test was used to compare proportions of various variables (clinical characteristics, treatment modalities) between the two cohorts (pediatric and adult patients). All p-values calculated were two-sided and significance was defined at p < 0.05.

3. Results

3.1. Demographics

54.4% of pediatric patients were female, compared with 63.6% of adult patients. This difference was not statistically significant. In the pediatric cohort, the average age at diagnosis of brain VM was 9.2 years (range: birth-17 years). In the adult cohort, the average age at diagnosis was 41.1 years (range: 18–77 years).

3.2. Clinical Presentation of HHT-Related Brain VMs

A significantly smaller proportion of pediatric patients with HHT and brain VMs were diagnosed by screening (p = 0.034); concordantly, a significantly higher proportion of pediatric patients were symptomatic at presentation (p = 0.004). The most common symptom at presentation was headaches for both pediatric and adult patients. Almost one-quarter of our pediatric cohort (23.7%) had ICH at presentation. A higher proportion of pediatric patients presented with intracranial hemorrhage (p < 0.001), compared to their adult counterparts (9.9%). Pediatric patients also experienced seizures at presentation in a higher proportion (18.3%) than adults (7.5%) (p = 0.002). Of note, patients may present with multiple symptoms, and in our data focal neurologic deficits refer to those unrelated to stroke or hemorrhage.
Demographic and clinical characteristics of pediatric and adult patients with HHT-related brain VMs in our cohort are summarized in Table 1.

3.3. Treatment of HHT Related Brain VMs

Table 2 describes treatment modalities and complications in both patient groups.
Sixty percent (60%) of pediatric patients with brain VMs underwent treatment compared to 51% of adults. This difference was not statistically significant. Surgical resection was the most common brain VM treatment modality in pediatric and adult patients with HHT.
Ten children and 31 adults underwent treatment using multiple modalities. Seven children and 18 adults underwent surgery and embolization. Two pediatric patients underwent gamma knife radiosurgery and embolization, compared to seven adult patients. Five adult patients underwent gamma knife radiosurgery and surgery, compared to one pediatric patient. One adult patient was treated with all three modalities; no pediatric patients were treated with the same.
There was no difference in the cumulative incidence of post-treatment hemorrhage (Table 2), nor when the incidence of post-treatment hemorrhage was analysed by intervention type (Table 3). The timing of post-treatment hemorrhage by intervention is captured in Table 4. Of note, for Table 3 and Table 4, hemorrhage is related to the treatment modality preceding ICH for patients who underwent multiple modalities, hence representing cumulative proportions.

3.4. Treatment for Brain VMs Complicated by ICH

Table 5 describes and compares treatment modalities in pediatric and adult patients with brain VMs complicated by pre-intervention ICH.
A significantly greater proportion of adult (23/27, 85%, p < 0.001) and pediatric patients (22/25, 88%, p = 0.002) with brain VMs complicated by ICH at initial presentation underwent treatment. Comparatively, brain VMs were treated in 46/87 (52.9%) of pediatric patients without initial ICH and 107/228 (46.9%) of adults without initial ICH. Surgery was the most common treatment modality in both pediatric (17/27, 63%) and adult patients (15/25, 60%) with ICH at initial presentation. Radiosurgery and multiple modalities were uncommon in both adult and pediatric patients with initial ICH. Overall, there was no statistically significant difference in the treatment trends of pediatric and adult patients presenting with ICH.

4. Discussion

Our data illustrates key differences between adult and pediatric patients with HHT-related brain VMs.
In our cohort, the majority of pediatric patients were symptomatic, compared to a minority of adult patients. A systematic review and meta-analysis found that 50% of HHT patients with brain VMs have symptoms related to brain VM, including headache, seizure, and/or focal neurological deficits [5]. Previous studies suggest that between 40% to 79% of patients with HHT and brain VMs are asymptomatic from the perspective of their brain VMs [8,24,25]. This range aligns with the percentage of patients that were asymptomatic within our adult and pediatric cohorts. As in previous cohorts, the most common symptom was headache [7,24,26]. The age-dependent nature of many HHT-related symptoms might explain, in part, why significantly higher proportion adults were asymptomatic at time of brain VM diagnosis and were diagnosed by screening. Mucocutaneous telangiectases and spontaneous recurrent epistaxis—two of the four Curacao criteria—are more prevalent with older age [27,28,29]. The absence or mild nature of these features in children can result in delayed diagnosis [4,14,30,31]. Moreover, the additional considerations associated with neuroimaging in children, including the need for sedation, may delay pediatric screening at the time of diagnosis [14,32]. Thus, a greater portion of adult patients may have been diagnosed with HHT following presentation with other features of HHT, and were subsequently screened for brain VMs. In contrast, for pediatric patients, the symptoms of brain VMs—headache, seizures, neurological deficits, among others—may have brought them to medical attention, ultimately prompting neuroimaging and the subsequent diagnosis of HHT, as suggested previously [25]. It is also important to acknowledge here that neurological symptoms are not all likely to be related to brain VMs, as pulmonary AVMs can result in paradoxical emboli, brain abscess and ischemic stroke and, more broadly, headaches in children have multifactorial etiologies.
Our data demonstrate an increased prevalence of ICH at presentation in children compared to adults. Similarly, the data from pediatric patients with non-HHT-related brain VMs also show that pediatric patients are more likely to present with ICH, compared to adults [10,33,34]. This has been explained by the finding that brain VMs are less likely to be diagnosed incidentally in pediatric patients, and that the initial bleed brings these patients to medical attention [34]. This is reflected in our data, which demonstrate that pediatric patients are more likely to be symptomatic at presentation, rather than be diagnosed by screening. Fullerton et al., demonstrated that, while pediatric patients with non-HHT related brain VMs were more likely to initially present with intracranial bleeding, the risk of subsequent hemorrhage was not increased compared to adults [33]. Given the current guideline support screening for adults, partially based on risk of hemorrhage, this finding further supports screening at diagnosis in the pediatric population. Finally, in the non-HHT population, an age-dependent trend in the risk of hemorrhage has also been described [35,36].
For HHT-related brain VMs, the rate of rupture and ICH has been difficult to quantify. The first study of bleeding related to brain VMs in HHT by Willemse et al. suggested that the bleeding rate in HHT may be lower than in sporadic brain VMs [37]. Similarly, Maher et al., suggested that ICH risk in patients with HHT-related brain VMs is low, after reporting that only 7 of 321 patients presented with ICH over 20-year period [38]. The evidence regarding a lower rate of rupture for HHT-related brain VMs compared to sporadic VMs, as well as the results of the ARUBA trial—a prospective, randomized controlled trial, which showed superior outcomes with medical management compared to intervention for patients with unruptured AVMs [13]—have fueled the international controversy around screening. However, the ARUBA trial specifically excluded pediatric patients. This and other identified methodological limitations call into question the applicability of its conclusions with regards to HHT-related brain VM management in pediatric patients [39,40].
There is a body of literature that suggests that the hemorrhage rate of HHT-related brain VMs approximates that of the non-HHT population [41,42]. In 2015, in a cohort of 153 patients, Kim et al. suggested that the rupture rate of HHT-related brain VMs approximates that of sporadic AVMs, particularly for previously ruptured AVMs. In this cohort, the rupture rate was 0.4% per year for unruptured VMs, and rose to 10% per year for previously ruptured lesions [41]. In another study of 44 patients, 10% of patients presented with ICH [6]. Finally, a systematic review concluded that approximately 20% of HHT patients with brain VMs will suffer ICH [5].
While the evidence regarding the hemorrhage risk for pediatric patients with HHT-related brain VMs arises from smaller cohorts, these cohorts do report a higher rate of ICH, compared to those reported in adult patients. ICH was the most common presentation of an HHT-related brain VM in a pediatric cohort of 61 patients [43]. In another pediatric cohort of 11 patients with HHT-related brain VMs, 55% patients (6/11) had ICH secondary to brain VMs [44]. Importantly, in this cohort, in 4/11 cases, ICH was a presenting feature of HHT [44]. In a cohort of 44 pediatric patients with HHT, seven had brain VM (15.9%). Two of these seven children had brain VM related complications; with one presenting with ICH and the other with seizures [45]. In a cohort of 171 pediatric and adult patients, 27% patients had a history of ICH, which approximates the rate in our pediatric cohort [19]. Morgan et al. reported a case series of nine pediatric patients with HHT-related brain VMs who suffered catastrophic consequences; five patients passed away and four patients were left with significant motor and cognitive impairment. The authors argue that screening may prevent such catastrophic sequelae [46]. Furthermore, a 2006 literature review concluded that ICH related to brain VMs was the leading cause of death in the pediatric HHT population, as reflected in the literature [47]. The higher rate of ICH in childhood may be related to the increased prevalence of (AVF), which are more commonly present in pediatric patients and carry a higher rate of hemorrhage than other VM subtypes [15,18,25,27]. Given that our pediatric cohort demonstrated increased prevalence of ICH at presentation, and a higher symptom burden, compared to adults, we emphasize that children may particularly benefit from screening to prevent the potential sequelae of brain VMs.
There are very few pediatric specific studies to guide treatment for pediatric patients with HHT-related brain VMs. Surgery was the most common modality in pediatric and adult patients in our cohort. It was also the most common modality in patients presenting with ICH in pediatric and adult patients; this is likely attributable to the fact that surgery allows for decompression and shunt placement when required [48]. The largest surgical cohort of patients with HHT-related brain VMs showed that surgical treatment was both safe and had favorable outcomes when compared to a cohort that did not undergo surgical treatment [26]. In the untreated cohort, functional status worsened at a rate of almost 1.5 times that of the surgically treated group [26]. Given that embolization is frequently used as an adjunct to surgery and radiosurgery (in order to decrease flow to the brain VM, reduce the size of the brain VM or decrease the risk of blood loss prior to surgery or radiosurgery [48]), it follows that embolization was commonly a component of multi-modal treatment plans in our series, but a rare standalone treatment. The evidence for embolization in pediatric patients with HHT remains limited. In a series of 31 pediatric patients with HHT-related brain VMs who underwent embolization, 60% of patients had symptomatic improvement or achieved occlusion, two patients (6.5%) had a persistent new neurological deficit, and two patients (6.5%) died as a result of the embolization [15]. In 19/31 of these patients, there was incomplete embolization. There was no subsequent rebleed or complications over the follow-up period, leading the authors to hypothesize that embolization could still be therapeutic [15]. Radiosurgery has been shown to be effective and safe in small cohorts of adult [49] and pediatric [50] patients with HHT, especially as brain VMs in HHT are often smaller than sporadic AVMs [9,25,49]. In a pediatric series of patients with non-HHT-related brain VMs, stereotactic radiosurgery was effective for smaller AVMs [51]. Given that radiosurgery is more likely chosen as the treatment modality in smaller brain VMs for which surgery or embolization is not feasible [52,53], future analyses comparing treatment trends would benefit from reporting VM size.
Our conclusions must be interpreted in the context of the limitations of our study. The targeted recruitment of patients with brain VMs may predispose to the recruitment of symptomatic patients or patients with more severe disease, which may have impacted the treatment trends we present. Patients with more severe or symptomatic disease may be more likely to be selected for therapeutic interventions, may be more likely to undergo multiple interventions, and/or experience treatment complications. However, given that this recruitment bias is assumed to affect the two populations being compared, it would follow that it should not significantly affect our ability to compare treatment trends between pediatric and adult patients with HHT. Additionally, the data collected in the BVMC HHT project is limited by its retrospective nature. Finally, our analysis did not include brain VM size, location, multiplicity, or subtype, which may impact choice of treatment intervention and thus treatment trends.
Despite these limitations, the large sample size and multi-center nature of our data supports the generalizability and validity of our results. Moreover, the characteristics described in our sample are similar to previously published pediatric and adult HHT populations [5]. The similarities between our sample and previously described clinical characteristics of pediatric and adult patients with non-HHT brain VMs suggest that our results may be generalizable to this population also, with appropriate caveats.

5. Conclusions

Our data, from a large cohort of pediatric and adult patients with HHT, suggests that pediatric patients with HHT present with symptoms and complications of undiagnosed brain VM at higher rates compared to adults with HHT; brain AVM rupture may be the first symptom of HHT in children and can be devastating. Surgical resection was the most common brain VM treatment modality in pediatric and adult patients with HHT. Our large data cohort supports the current recommendation for screening for brain VMs in pediatric patients and supports the case for systematic brain VM screening for adult patients with HHT.

Author Contributions

Conceptualization,, A.K., G.A.L., A.J.W., F.R. and M.E.F.; Data curation, The Brain Vascular Malformation Consortium HHT Investigator Group; Formal analysis, A.K., G.A.L. and M.E.F.; Investigation, A.K., G.A.L., A.J.W., F.R., J.M., K.J.W., J.R.G., T.K., M.T.L., H.K. and M.E.F.; Methodology, A.K., G.A.L. and M.E.F.; Project administration, H.K., M.T.L. and M.E.F.; Supervision, M.E.F.; Writing—original draft, A.K., G.A.L., A.J.W. and M.E.F.; Writing—review and editing, A.K., G.A.L. and M.E.F. All authors have read and agreed to the published version of the manuscript.

Funding

The Brain Vascular Malformation Consortium (BVMC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Office of Rare Diseases Research (ORDR). BVMC is funded under grant number U54NS065705 as a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). All RDCRN consortia are supported by the network’s Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and NINDS.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of St. Michael’s Hospital (Protocol #: BVMC3 6203; Last approval date: 26 July 2022).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions.

Acknowledgments

T.K. acknowledges the generous support from the Patricia Holt-Hornsby and Dan Andreae Vascular Research Unit and UMIT (University Medical Imaging Toronto).

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

References

  1. Kjeldsen, A.D.; Vase, P.; Green, A. Hereditary haemorrhagic telangiectasia: A population-based study of prevalence and mortality in Danish patients. J. Intern. Med. 1999, 245, 31–39. [Google Scholar] [CrossRef] [PubMed]
  2. Donaldson, J.; McKeever, T.M.; Hall, I.P.; Hubbard, R.; Fogarty, A.W. The UK prevalence of hereditary haemorrhagic telangiectasia and its association with sex, socioeconomic status and region of residence: A population-based study. Thorax 2014, 69, 161–167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Sabba, C.; Pasculli, G.; Cirulli, A.; Gallitelli, M.; Virgilio, G.; Resta, F.; Guastamacchia, E.; Palasciano, G. Hereditary hemorrhagic teleangiectasia (Rendu-Osler-Weber disease). Minerva Cardioangiol. 2002, 50, 221–238. [Google Scholar] [PubMed]
  4. Shovlin, C.L.; Guttmacher, A.E.; Buscarini, E.; Faughnan, M.E.; Hyland, R.H.; Westermann, C.J.; Kjeldsen, A.D.; Plauchu, H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am. J. Med. Genet. 2000, 91, 66–67. [Google Scholar] [CrossRef]
  5. Brinjikji, W.; Iyer, V.N.; Wood, C.P.; Lanzino, G. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: A systematic review and meta-analysis. J. Neurosurg. 2017, 127, 302–310. [Google Scholar] [CrossRef] [Green Version]
  6. Brinjikji, W.; Iyer, V.; Yamaki, V.; Lanzino, G.; Cloft, H.; Thielen, K.; Swanson, K.; Wood, C. Neurovascular manifestations of hereditary hemorrhagic telangiectasia: A consecutive series of 376 patients during 15 years. Am. J. Neuroradiol. 2016, 37, 1479–1486. [Google Scholar] [CrossRef] [Green Version]
  7. Woodall, M.N.; McGettigan, M.; Figueroa, R.; Gossage, J.R.; Alleyne, C.H. Cerebral vascular malformations in hereditary hemorrhagic telangiectasia. J. Neurosurg. 2014, 120, 87–92. [Google Scholar] [CrossRef] [Green Version]
  8. Bharatha, A.; Faughnan, M.E.; Kim, H.; Pourmohamad, T.; Krings, T.; Bayrak-Toydemir, P.; Pawlikowska, L.; McCulloch, C.E.; Lawton, M.T.; Dowd, C.F. Brain arteriovenous malformation multiplicity predicts the diagnosis of hereditary hemorrhagic telangiectasia: Quantitative assessment. Stroke 2012, 43, 72–78. [Google Scholar] [CrossRef] [Green Version]
  9. Putman, C.M.; Chaloupka, J.C.; Fulbright, R.K.; Awad, I.A.; White, R.I.; Fayad, P.B. Exceptional multiplicity of cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Am. J. Neuroradiol. 1996, 17, 1733–1742. [Google Scholar]
  10. Ding, D.; Starke, R.M.; Kano, H.; Mathieu, D.; Huang, P.P.; Feliciano, C.; Rodriguez-Mercado, R.; Almodovar, L.; Grills, I.S.; Silva, D. International multicenter cohort study of pediatric brain arteriovenous malformations. Part 1: Predictors of hemorrhagic presentation. J. Neurosurg. Pediatr. 2017, 19, 127–135. [Google Scholar] [CrossRef] [Green Version]
  11. Hetts, S.W.; Cooke, D.L.; Nelson, J.; Gupta, N.; Fullerton, H.; Amans, M.R.; Narvid, J.A.; Moftakhar, P.; McSwain, H.; Dowd, C.F. Influence of patient age on angioarchitecture of brain arteriovenous malformations. Am. J. Neuroradiol. 2014, 35, 1376–1380. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Ding, D.; Xu, Z.; Yen, C.-P.; Starke, R.M.; Sheehan, J.P. Radiosurgery for unruptured cerebral arteriovenous malformations in pediatric patients. Acta Neurochir. 2015, 157, 281–291. [Google Scholar] [CrossRef] [PubMed]
  13. Mohr, J.; Parides, M.K.; Stapf, C.; Moquete, E.; Moy, C.S.; Overbey, J.R.; Salman, R.A.-S.; Vicaut, E.; Young, W.L.; Houdart, E. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): A multicentre, non-blinded, randomised trial. Lancet 2014, 383, 614–621. [Google Scholar] [CrossRef] [Green Version]
  14. Faughnan, M.; Palda, V.; Garcia-Tsao, G.; Geisthoff, U.; McDonald, J.; Proctor, D.; Spears, J.; Brown, D.; Buscarini, E.; Chesnutt, M. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J. Med. Genet. 2011, 48, 73–87. [Google Scholar] [CrossRef] [PubMed]
  15. Krings, T.; Chng, S.M.; Ozanne, A.; Alvarez, H.; Rodesch, G.; Lasjaunias, P.L. Hereditary haemorrhagic telangiectasia in children. Endovascular treatment of neurovascular malformations. Results in 31 patients. Interv. Neuroradiol. 2005, 11, 13–23. [Google Scholar] [CrossRef] [PubMed]
  16. Faughnan, M.E.; Mager, J.J.; Hetts, S.W.; Palda, V.A.; Lang-Robertson, K.; Buscarini, E.; Deslandres, E.; Kasthuri, R.S.; Lausman, A.; Poetker, D. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann. Intern. Med. 2020, 173, 989–1001. [Google Scholar] [CrossRef]
  17. Kilian, A.; Clancy, M.S.; Olitsky, S.; Gossage, J.R.; Faughnan, M.E. Screening for pulmonary and brain vascular malformations is the North American standard of care for patients with hereditary hemorrhagic telangiectasia (HHT): A survey of HHT Centers of Excellence. Vasc. Med. 2021, 26, 53–55. [Google Scholar] [CrossRef]
  18. Eker, O.F.; Boccardi, E.; Sure, U.; Patel, M.C.; Alicante, S.; Alsafi, A.; Coote, N.; Droege, F.; Dupuis, O.; Fialla, A.D.; et al. European Reference Network for Rare Vascular Diseases (VASCERN) position statement on cerebral screening in adults and children with hereditary haemorrhagic telangiectasia (HHT). Orphanet J. Rare Dis. 2020, 15, 165. [Google Scholar] [CrossRef]
  19. Nishida, T.; Faughnan, M.E.; Krings, T.; Chakinala, M.; Gossage, J.R.; Young, W.L.; Kim, H.; Pourmohamad, T.; Henderson, K.J.; Schrum, S.D. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene–phenotype correlations. Am. J. Med. Genet. Part A 2012, 158, 2829–2834. [Google Scholar] [CrossRef] [Green Version]
  20. Letteboer, T.G.; Mager, J.; Snijder, R.J.; Koeleman, B.P.; Lindhout, D.; Van Amstel, J.P.; Westermann, C. Genotype-phenotype relationship in hereditary haemorrhagic telangiectasia. J. Med. Genet. 2006, 43, 371–377. [Google Scholar] [CrossRef] [Green Version]
  21. Krings, T.; Kim, H.; Power, S.; Nelson, J.; Faughnan, M.; Young, W.L.; Brain Vascular Malformation Consortium HHT Investigator Group. Neurovascular manifestations in hereditary hemorrhagic telangiectasia: Imaging features and genotype-phenotype correlations. Am. J. Neuroradiol. 2015, 36, 863–870. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Pawlikowska, L.; Nelson, J.; Guo, D.E.; McCulloch, C.E.; Lawton, M.T.; Young, W.L.; Kim, H.; Faughnan, M.E.; Brain Vascular Malformation Consortium HHT Investigator Group; Chakinala, M.; et al. The ACVRL1 c. 314—35A> G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations. Am. J. Med. Genet. Part A 2015, 167, 1262–1267. [Google Scholar] [CrossRef] [Green Version]
  23. Akers, A.L.; Ball, K.L.; Clancy, M.; Comi, A.M.; Faughnan, M.E.; Gopal-Srivastava, R.; Jacobs, T.P.; Kim, H.; Krischer, J.; Marchuk, D.A. Brain vascular malformation consortium: Overview, progress and future directions. J. Rare Disord. 2013, 1, 5. [Google Scholar] [PubMed]
  24. Yang, W.; Liu, A.; Hung, A.L.; Braileanu, M.; Wang, J.Y.; Caplan, J.M.; Colby, G.P.; Coon, A.L.; Tamargo, R.J.; Ahn, E.S. Lower risk of intracranial arteriovenous malformation hemorrhage in patients with hereditary hemorrhagic telangiectasia. Neurosurgery 2016, 78, 684–693. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Matsubara, S.; Manzia, J.L.; ter Brugge, K.; Willinsky, R.A.; Montanera, W.; Faughnan, M.E. Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. Am. J. Neuroradiol. 2000, 21, 1016–1020. [Google Scholar] [PubMed]
  26. Meybodi, A.T.; Kim, H.; Nelson, J.; Hetts, S.W.; Krings, T.; terBrugge, K.G.; Faughnan, M.E.; Lawton, M.T.; Brain Vascular Malformation Consortium HHT Investigator Group. Surgical treatment vs nonsurgical treatment for brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: A retrospective multicenter consortium study. Neurosurgery 2018, 82, 35–47. [Google Scholar] [CrossRef]
  27. Krings, T.; Ozanne, A.; Chng, S.; Alvarez, H.; Rodesch, G.; Lasjaunias, P. Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age. Neuroradiology 2005, 47, 711–720. [Google Scholar] [CrossRef]
  28. Pasculli, G.; Resta, F.; Guastamacchia, E.; Suppressa, P.; Sabbà, C. Health-related quality of life in a rare disease: Hereditary hemorrhagic telangiectasia (HHT) or Rendu–Osler–Weber Disease. Qual. Life Res. 2004, 13, 1715–1723. [Google Scholar] [CrossRef]
  29. Plauchu, H.; De Chadarévian, J.P.; Bideau, A.; Robert, J.M. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am. J. Med. Genet. 1989, 32, 291–297. [Google Scholar] [CrossRef]
  30. Pierucci, P.; Lenato, G.M.; Suppressa, P.; Lastella, P.; Triggiani, V.; Valerio, R.; Comelli, M.; Salvante, D.; Stella, A.; Resta, N. A long diagnostic delay in patients with Hereditary Haemorrhagic Telangiectasia: A questionnaire-based retrospective study. Orphanet J. Rare Dis. 2012, 7, 33. [Google Scholar] [CrossRef] [Green Version]
  31. Pahl, K.S.; Choudhury, A.; Wusik, K.; Hammill, A.; White, A.; Henderson, K.; Pollak, J.; Kasthuri, R.S. Applicability of the Curaçao criteria for the diagnosis of hereditary hemorrhagic telangiectasia in the pediatric population. J. Pediatr. 2018, 197, 207–213. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Schulte-Uentrop, L.; Goepfert, M.S. Anaesthesia or sedation for MRI in children. Curr. Opin. Anesthesiol. 2010, 23, 513–517. [Google Scholar] [CrossRef] [PubMed]
  33. Fullerton, H.J.; Achrol, A.S.; Johnston, S.C.; McCulloch, C.E.; Higashida, R.T.; Lawton, M.T.; Sidney, S.; Young, W.L. Long-term hemorrhage risk in children versus adults with brain arteriovenous malformations. Stroke 2005, 36, 2099–2104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Oulasvirta, E.; Koroknay-Pál, P.; Hafez, A.; Elseoud, A.A.; Lehto, H.; Laakso, A. Characteristics and long-term outcome of 127 children with cerebral arteriovenous malformations. Neurosurgery 2019, 84, 151–159. [Google Scholar] [CrossRef]
  35. ApSimon, H.; Reef, H.; Phadke, R.; Popovic, E. A population-based study of brain arteriovenous malformation: Long-term treatment outcomes. Stroke 2002, 33, 2794–2800. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Kim, H.; Salman, R.A.-S.; McCulloch, C.E.; Stapf, C.; Young, W.L.; Coinvestigators, M. Untreated brain arteriovenous malformation: Patient-level meta-analysis of hemorrhage predictors. Neurology 2014, 83, 590–597. [Google Scholar] [CrossRef] [Green Version]
  37. Willemse, R.B.; Mager, J.J.; Westermann, C.J.; Overtoom, T.T.; Mauser, H.; Wolbers, J.G. Bleeding risk of cerebral vascular malformations in hereditary hemorrhagic telangiectasia. J. Neurosurg. 2000, 92, 779–784. [Google Scholar] [CrossRef] [Green Version]
  38. Maher, C.O.; Piepgras, D.G.; Brown, R.D., Jr.; Friedman, J.A.; Pollock, B.E. Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke 2001, 32, 877–882. [Google Scholar] [CrossRef] [Green Version]
  39. Amin-Hanjani, S. ARUBA results are not applicable to all patients with arteriovenous malformation. Stroke 2014, 45, 1539–1540. [Google Scholar] [CrossRef] [Green Version]
  40. Cockroft, K.M.; Jayaraman, M.V.; Amin-Hanjani, S.; Derdeyn, C.P.; McDougall, C.G.; Wilson, J.A. A perfect storm: How a randomized trial of unruptured brain arteriovenous malformations’ (ARUBA’s) trial design challenges notions of external validity. Stroke 2012, 43, 1979–1981. [Google Scholar] [CrossRef] [Green Version]
  41. Kim, H.; Nelson, J.; Krings, T.; Terbrugge, K.G.; McCulloch, C.E.; Lawton, M.T.; Young, W.L.; Faughnan, M.E.; Brain Vascular Malformation Consortium HHT Investigator Group; Chakinala, M.; et al. Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke 2015, 46, 1362–1364. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Easey, A.J.; Wallace, G.M.; Hughes, J.M.; Jackson, J.E.; Taylor, W.J.; Shovlin, C.L. Should asymptomatic patients with hereditary haemorrhagic telangiectasia (HHT) be screened for cerebral vascular malformations? Data from 22,061 years of HHT patient life. J. Neurol. Neurosurg. Psychiatry 2003, 74, 743–748. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Al-Saleh, S.; Mei-Zahav, M.; Faughnan, M.; MacLusky, I.; Carpenter, S.; Letarte, M.; Ratjen, F. Screening for pulmonary and cerebral arteriovenous malformations in children with hereditary haemorrhagic telangiectasia. Eur. Respir. J. 2009, 34, 875–881. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Saleh, M.; Carter, M.T.; Latino, G.A.; Dirks, P.; Ratjen, F. Brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: Clinical presentation and anatomical distribution. Pediatr. Neurol. 2013, 49, 445–450. [Google Scholar] [CrossRef]
  45. Giordano, P.; Lenato, G.M.; Suppressa, P.; Lastella, P.; Dicuonzo, F.; Chiumarulo, L.; Sangerardi, M.; Piccarreta, P.; Valerio, R.; Scardapane, A. Hereditary hemorrhagic telangiectasia: Arteriovenous malformations in children. J. Pediatr. 2013, 163, 179–186.e3. [Google Scholar] [CrossRef]
  46. Morgan, T.; McDonald, J.; Anderson, C.; Ismail, M.; Miller, F.; Mao, R.; Madan, A.; Barnes, P.; Hudgins, L.; Manning, M. Intracranial hemorrhage in infants and children with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Pediatrics 2002, 109, e12. [Google Scholar] [CrossRef] [Green Version]
  47. Folz, B.J.; Zoll, B.; Alfke, H.; Toussaint, A.; Maier, R.F.; Werner, J.A. Manifestations of hereditary hemorrhagic telangiectasia in children and adolescents. Eur. Arch. Oto-Rhino-Laryngol. Head Neck 2006, 263, 53–61. [Google Scholar] [CrossRef]
  48. Ashley, W.W., Jr.; Charbel, F.T.; Amin-Hanjani, S. Surgical management of acute intracranial hemorrhage, surgical aneurysmal and arteriovenous malformation ablation, and other surgical principles. Neurol. Clin. 2008, 26, 987–1005. [Google Scholar] [CrossRef]
  49. Maarouf, M.; Runge, M.; Kocher, M.; Zähringer, M.; Treuer, H.; Sturm, V. Radiosurgery for cerebral arteriovenous malformations in hereditary hemorrhagic telangiectasia. Neurology 2004, 63, 367–369. [Google Scholar] [CrossRef]
  50. Kuo, Y.-H.; Santoreneos, S.; Roos, D.; Brophy, B.P. Treatment of multiple arteriovenous malformations in pediatric patients with hereditary hemorrhagic telangiectasia and spontaneous hemorrhage: Report of two cases. J. Neurosurg. Pediatr. 2007, 107, 489–494. [Google Scholar] [CrossRef]
  51. Pan, D.H.-C.; Kuo, Y.-H.; Guo, W.-Y.; Chung, W.-Y.; Wu, H.-M.; Liu, K.-D.; Chang, Y.-C.; Wang, L.-W.; Wong, T.-T. Gamma Knife surgery for cerebral arteriovenous malformations in children: A 13-year experience. J. Neurosurg. Pediatr. 2008, 1, 296–304. [Google Scholar] [CrossRef] [PubMed]
  52. Blauwblomme, T.; Bourgeois, M.; Meyer, P.; Puget, S.; Di Rocco, F.; Boddaert, N.; Zerah, M.; Brunelle, F.; Rose, C.S.; Naggara, O. Long-term outcome of 106 consecutive pediatric ruptured brain arteriovenous malformations after combined treatment. Stroke 2014, 45, 1664–1671. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Kano, H.; Kondziolka, D.; Flickinger, J.C.; Yang, H.-c.; Flannery, T.J.; Awan, N.R.; Niranjan, A.; Novotny, J.; Lunsford, L.D. Stereotactic radiosurgery for arteriovenous malformations, part 2: Management of pediatric patients. J. Neurosurg. Pediatr. 2012, 9, 1–10. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Demographic and clinical characteristics of pediatric and adult HHlT patients with Brain VMs.
Table 1. Demographic and clinical characteristics of pediatric and adult HHlT patients with Brain VMs.
Characteristic
(n, %)		Pediatric Patients
n = 114		Adult Patients
n = 253		p-Value
Female62 (54.4%)161 (63.6%)0.076
Age at diagnosis (years) -
Mean9.241.1
Standard deviation ±5.5±14.6
Median1040
RangeBirth-1718–77
Interquartile Range5–1428–54
Number of brain VMs (range)1–41–10-
>1 brain VM15 (13.1%)38 (15.0%)0.638
Diagnosed by screening63 (56.1%)168 (66.4%)0.034
Asymptomatic at presentation54 (47.4%)160 (63.2%)0.004
ICH at presentation27 (23.7%)25 (9.9%)<0.001
Ischemic stroke at presentation14 (12.3%)24 (9.5%)0.417
Focal neurological deficit10 (8.8%)30 (11.9%)0.379
Seizure21 (18.4%)19 (7.5%)0.002
Headache34 (29.8%)53 (20.9%)0.064
Hereditary Hemorrhagic Telangiectasia (HHT); Vascular Malformation (VM); Intracranial Hemorrhage (ICH).
Table
Table 2. Treatment Modalities for Pediatric and Adult patients with HHT related brain VMs.
Table 2. Treatment Modalities for Pediatric and Adult patients with HHT related brain VMs.
Treatment Modality (n, %)Pediatric Patients
n = 114		Adult Patients
n = 253		p-Value
Treatment for brain VM69 (60.5%)128 (50.6%) 0.076
n = 69n = 128
Surgery only34 (49.3%)43 (33.5%)0.032
Embolization only19 (27.5%)16 (12.5%)0.008
Radiosurgery only6 (8.7%)38 (29.7%)<0.001
Multiple modalities10 (14.58%)31 (24.2%)0.110
Surgery + Embolization7 (10.1%)18 (14.1%)0.429
Surgery + Radiosurgery1 (1.5%)5 (3.9%)0.246
Embolization + Radiosurgery2 (3.0%)7 (5.4%)0.337
Embolization + Radiosurgery + Surgery0 (0.0%)1 (0.01%)0.459
Post-treatment hemorrhage3 (4.3%)9 (6.9%)0.453
Hereditary Hemorrhagic Telangiectasia (HHT); Vascular Malformation (VM). Of note, this table includes all patients who underwent treatment, including those treated prophylactically.
Table
Table 3. Incidence of Post-treatment Hemorrhage by Intervention.
Table 3. Incidence of Post-treatment Hemorrhage by Intervention.
Incidence of Post-Treatment Hemorrhage
InterventionPediatric PatientsAdult Patientsp-Value
Surgery0/42 (0.0%)1/67 (1.4%)0.423
Embolization2/28 (7.1%)4/42 (9.5%)0.726
Radiosurgery1/9 (11.1%)4/51 (7.8%)0.741
Table
Table 4. Timing of Post-treatment Hemorrhage by Intervention.
Table 4. Timing of Post-treatment Hemorrhage by Intervention.
Timing of Post-Treatment Hemorrhage
InterventionAcute (<30 Days)Remote (>30 Days)RangeMissing Data
PediatricAdultsPediatricAdults
Surgery0/42
(0.0%)		0/67
(0.0%)		0/42
(0.0%)		1/67
(1.4%)		15 years0
Embolization 0/28
(0.0%)		2/42
(4.8%)		1/28
(3.5%)		1/42
(2.3%)		1–118 days2
Radiosurgery0/9
(0.0%)		0/51
(0.0%)		1/9
(11.1%)		1/51
(1.9%)		1–2 years 3
Table
Table 5. Treatment for brain VMs complicated by ICH at initial presentation.
Table 5. Treatment for brain VMs complicated by ICH at initial presentation.
Initial ICHp-Value
Pediatric
(27/114, 23.7%)		Adult Patients
(25/253, 9.9%)
n = 27n = 25
Underwent treatment for brain VM23 (85.1%)22 (88.0%)0.764
Surgery17 (63.0%)15 (60.0%)0.825
Embolization6 (22.2%)5 20.0%)0.888
Radiosurgery0 (0%)5 (20.0%)0.423
Multiple modalities0 (0%)3 (12.0%)0.118
Hereditary Hemorrhagic Telangiectasia (HHT); Vascular Malformation (VM); Intracranial Hemorrhage (ICH).
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kilian, A.; Latino, G.A.; White, A.J.; Ratjen, F.; McDonald, J.; Whitehead, K.J.; Gossage, J.R.; Krings, T.; Lawton, M.T.; Kim, H.; et al. Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT. J. Clin. Med. 2023, 12, 2704. https://doi.org/10.3390/jcm12072704

AMA Style

Kilian A, Latino GA, White AJ, Ratjen F, McDonald J, Whitehead KJ, Gossage JR, Krings T, Lawton MT, Kim H, et al. Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT. Journal of Clinical Medicine. 2023; 12(7):2704. https://doi.org/10.3390/jcm12072704

Chicago/Turabian Style

Kilian, Alexandra, Giuseppe A. Latino, Andrew J. White, Felix Ratjen, Jamie McDonald, Kevin J. Whitehead, James R. Gossage, Timo Krings, Michael T. Lawton, Helen Kim, and et al. 2023. "Comparing Characteristics and Treatment of Brain Vascular Malformations in Children and Adults with HHT" Journal of Clinical Medicine 12, no. 7: 2704. https://doi.org/10.3390/jcm12072704

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop