Pediatric Cerebral Cavernous Malformations: A Systematic Review and Critical Evaluation of Clinical Features, Management Strategies and Outcomes

Review

Cesar A. Ramirez, BA1*; Umaru Barrie, PhD*2; Pooja Venkatesh, BS2; Emerson Lout, BS2; Momodou G. Bah, BS3; Sanjay V. Neerukonda, BS4; Usama AlDallal, BS5; Abigail Jenkins, BA2; Jonathan Tao, BS2; Donald Detchou, BA6; Soummitra Anand, BSA2; Faraaz Azam, BS2; Anant Naik, MD7; Brett A. Whittemore, MD2,8

*Co-first authors: contributed equally to this manuscript

Affiliations:
1Sam Houston State University College of Osteopathic Medicine, Conroe, TX, USA
2Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
3College of Human Medicine, Michigan State University East Lansing, MI, US
4McGovern Medical School, UT Health Science Center at Houston, Houston, TX, USA
5School of Medicine – Royal College of Surgeons in Ireland – Bahrain
6Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
7Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, IL, USA
8Center for Cerebrovascular Disease in Children, Children’s Health, Dallas, TX, USA

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ABSTRACT

Background: Pediatric studies investigating risk factors and treatment efficacy for cerebral cavernous malformations (CCM) are rare, characterized by small cohorts, heterogenous reporting, and limited postoperative follow-up. Consequently, pediatric and adolescent patients are frequently managed based on adult guidelines.

Objective: To examine the current literature to create an up to date, comprehensive summary of the management of CCM in pediatric patients, including risk factors, complications, and neurological morbidity following various treatment modalities.

Methods: A systematic review of the literature was conducted using PubMed, Google Scholar, and SCOPUS databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify retrospective studies detailing the use of conservative and/or surgical methods in the management of CCMs.

Results: 25 articles reported 1256 cases with studies ranging from 2 to 181 patients. Among the included patients, 719 were males and 537 females. The predominant symptoms were headache, predominantly attributed to hemorrhage, and sequelae of seizures. Patients were diagnosed based on CT or MRI. 532 lesions were supratentorial, and 432 were infratentorial, with average lesion size ranging from 2.1 cm to 22.5 cm with singular or multiple lesions. Patient management was based on an array of clinical and patient factors such as location, size, and nature of the CCM, with surgical treatment reported in 808 cases while the remainder were followed conservatively. Surgical resection proved to be the gold-standard therapy for patients with symptomatic CCM, particularly when lesions posed a substantial risk of morbidity. Conversely, lesions managed conservatively tended to be asymptomatic at diagnosis and smaller. The duration of follow-up varied across studies, ranging from 4 weeks to 29.7 years. Complications, including bleeding, infection, stroke, edema, and radiation-related morbidity, were reported in 67 cases. However, among the studies with available data, most patients demonstrated improvement in neurological outcomes, highlighting the overall positive response to both types of treatment interventions, regardless of surgical or conservative management.

Conclusions: CCMs in pediatric patients can present a diagnostic and treatment challenge due to their varying neurologic manifestations and clinical presentations. The primary treatment objective is to minimize complications and reduce rates of morbidity and mortality. The aggregate insights provided in this review serve as valuable guidance for tailoring individualized treatment plans in the context of pediatric CCM.

Keywords: Cavernous malformations; Cavernomas; Imaging; Management; Surgery; Conservative; Pediatrics

MANUSCRIPT

Introduction:
Cerebral cavernous malformations (CCM) are rare low-flow and low-pressure neurovascular lesions that commonly occur in the pediatric population, with a prevalence of 0.6%.1-5 These malformations can present as solitary or multiple lesions. CCMs, which may be discovered incidentally, can occur sporadically or secondary to familial cavernomatosis or radiation therapy.1 Pediatric CCMs have a higher risk of hemorrhage compared to adults2-4 and often present with headaches, epileptic seizures, and focal neurological deficits.5-11 Diagnosing these neurovascular lesions involves a comprehensive approach incorporating medical history, physical examination, neuroimaging through MRI/CT scans, electroencephalograms, blood testing, and genetic testing.

In its sporadic form, CCM presents as solitary or clustered lesions, often accompanied by developmental venous anomalies (DVA), though DVAs can occur independently of CCM.12 In its inherited form, CCM is characterized by an autosomal dominant inheritance pattern, manifesting as multifocal lesions within the brain and spinal cord. Inherited CCM is primarily a result of a heterozygous germline loss-of-function mutation in either the CCM1/KRIT1, CCM2/Malcavernin, or CCM3/PDCD10 genes.12-20 Notably, a founder mutation (Q455X, involving KRIT1) and an associated preserved haplotype have been found to cause clustering of familial CCM in Hispanic/Latino patients of Mexican descent.18 Clustering among patients of Ashkenazi Jew descendance is attributed to a deletion in CCM2/Malcavernin.22

Although intracerebral hemorrhage (ICH) is rare among young patients, CCMs carry an annual hemorrhage rate of up to 60%.21 It has also been observed that a prior history of hemorrhage significantly raises the overall risk of hemorrhagic events in the pediatric population (11.3% per year).3 Another factor associated with increased hemorrhage risk is the presence of familial forms of CCM.2,3,19,22,23 Understanding such factors is crucial as recurrent hemorrhage can be devastating given the longer life expectancy of children and adolescents compared to adults.23-25 The standard of care for young CCM patients involves neurosurgical resection or watchful waiting.26 Evidence-based management of pediatric CCMs is limited by the lack of prospective multicenter databases27,28 and the unique characteristics of the individual patient, including age, location of CCM, multiplicity of CCMs, and frequency of bleeding.29

Pediatric studies investigating risk factors and treatment efficacy for CCM are rare and are characterized by small cohorts, heterogenous reporting, and limited postoperative follow-up.1,8,26 Consequently, pediatric and adolescent patients are frequently managed based on adult guidelines. In this study, we assess the existing literature to examine critical factors that guide management (surgical versus conservative) considerations in CCM. In addition, we present one illustrative case of solitary CCM in a pediatric patient from our institution to provide clinical context for existing evidence regarding CCM management.

Methods:
Search Strategy
A literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Figure 1).24 The databases of PubMed, Web of Science, Google Scholar, Scopus, and Ovid Embase were queried on January 1st, 2023. The key search terms used included: “Pediatric cavernoma” OR “Pediatric Cavernous Hemangioma” OR “Pediatric Cavernous Angioma” OR “Pediatric Cerebral Cavernous Malformations.” Exclusion criteria were as follows: adult patient population (>18 years old), articles not written in English, literature reviews, correspondences, commentaries, book chapters, animal studies, incomplete reporting of primary outcomes, and studies with overlapping pediatric and adult populations.

The primary objective of the study was to discuss and examine all original articles exploring management, recommendations, and outcomes in pediatric patients with cerebral cavernous malformations. Patient characteristics, risk factors, complications, and perioperative factors were also evaluated.

Data Extraction and Critical Summary of Evidence
Five authors (S.N., P.V., C.R., U.B., M.B.) independently conducted data extraction based on the search strategy. Inconsistencies were resolved through author consensus. Articles were screened by title, abstracts, and full texts. Relevant data, including research aim, population demographics, clinical characteristics, management, outcomes, and recommendations, were extracted from retrospective reviews. Information on patient demographics, presentation, underlying conditions, imaging, hemorrhage risk, management (conservative or surgical), and postoperative outcomes were examined, including age, gender, presenting signs and symptoms, family history, malformation characteristics, intervention type, and postoperative outcomes (length of stay, follow-up period, complications, modified Rankin Scores (mRS), and mortality).

Results:

Electronic Search Yield

A total of 593 studies were identified through the primary database search, and an additional 124 studies were found through manual review. Initially, 528 studies were selected, but only 25 papers met the inclusion criteria.4,7,10,25-45 These included 23 retrospective studies, one cross-sectional study, and one prospective study. Of these, 16 studies did not compare surgical and conservative management4,25,26,30-32,34-42,45 (Table 1 and Table 2) while nine articles directly compared the two treatment strategies in their populations (Table 3 and Table 4).7,8,10,27-29,33,43,44

Study and Patient Characteristics 

In the included papers, a total of 1256 pediatric cases were discussed, with 719 male and 537 female patients. Demographics and patient characteristics of non-comparative studies are highlighted in Table 1. Bigi et al.10 found that CCMs more commonly presented as seizures in younger patients while headache and focal deficits were more common in older patients. In addition to seizures and headaches, other notable presenting characteristics included motor/sensory deficits, cranial nerve palsies, hydrocephalus, cerebellar symptoms, and increased intracranial pressure. Few cases were asymptomatic and found incidentally. The clinical course of brainstem cavernous malformations (BSCM) in children was highly variable, ranging from benign lesions to highly aggressive lesions with recurrent hemorrhages.43 CT and/or MRI were the most common diagnostic tools. Studies involving patients with preoperative seizures also used electroencephalography while six studies25,30,31,34,39,45 emphasized the use of cerebral angiography to rule out other diagnoses such as arteriovenous malformations (AVM) and to detect the existence of abnormal venous drainage associated with CCMs. One study required histological confirmation of the diagnosis for patients undergoing surgery whereas the presence of the near-pathognomonic “mulberry-like” lesions with signal susceptibility around the CCM (due to hemosiderin) on imaging was noted as a diagnostic feature critical to committing to conservative management.33 Most of the lesions (532, 55.2%) were supratentorial while the remainder (432, 44.8%) were infratentorial, with average lesion diameter ranging from 2.1 cm to 22.5 cm. Jaman et al. provided the largest range for CCM lesions from 0.004 cm3 to 38.44 cm3.35

Management: Surgical and Conservative Approaches

Management and neurological outcomes of non-comparative studies are presented in Table 2. The management of CCMs in pediatric patients is influenced by various factors, including lesion location, size, symptom burden, epilepsy workup, and clinical course. Individualized assessment of risks and benefits remains the mainstay of management for pediatric CCMs.7 When determining the appropriate treatment modality for CCM, it is essential to consider the individual needs of each patient and any clinical factors that could impact outcomes. A treatment algorithm proposed by Santos et al.4 takes these factors into account and recommends conservative management for asymptomatic CCMs in pediatric patients while management of patients with symptomatic lobar CCMs should aim for gross total resection. For deep CCMs, subtotal resection may be an option to prevent neurological compromise and sustainably improve neurological outcome.

Conservative versus Surgical Management 

Table 3 and Table 4 highlight the 9 studies that directly compared surgical and conservative management in CCMs. Demographics of these studies are presented in Table 3, and management and outcomes are presented in Table 4. Surgical resection is considered the gold standard for patients with symptomatic CCMs, especially if lesions do not pose excessive surgical risk.7,10,26,32,34,37,44 One study found that patients treated with surgical resection had significantly higher rates of ICH at presentation (OR: 6.30; 95% CI: 2.70–14.74; p<0.001) and were less likely to be asymptomatic at diagnosis compared to those managed conservatively (OR: 0.11; 95% CI: 0.04–0.35; p<0.001).4  Bhardwaj et al.28 recommended conservative management of BSCMs in asymptomatic patients with smaller lesions (mean size=10.6mm)  while patients with larger lesions (mean size=21.0 mm), pial presentation, and symptomatic presentation at a younger age were more likely to undergo surgical management. Complete microsurgical excision must be preceded by careful anatomical and functional evaluation, and risk reduction can be achieved with the help of neuronavigational and intraoperative ultrasonography.44 Surgical planning must be individualized for each patient to reduce the risk of morbidity, and complete resection should be attempted to reduce the rebleed risk.38

Samanci et al. reported that prior radiation treatment or CCM multiplicity did not influence the decision to perform surgery.42 Given the increased likelihood for functional recovery and longer life expectancy in children, surgical treatment in high-volume centers should be considered for young patients with surgically accessible lesions and an aggressive clinical course. Asymptomatic lesions or those in critical areas are monitored with serial MRI scans, and surgery is considered if there are clinical changes or lesion growth.7,32 It is crucial to note that the estimated annual hemorrhage risk from natural studies of CCM according to a review by Washington et al. ranges from 0.7% to 6% per patient-year.46 Given this risk, early management is strongly considered to monitor growth of the cavernoma and determine risk for hemmorhage.36

Functional and Neurological Outcomes

Although improvements in neurological outcomes, reduction in seizure incidence, and control of hemorrhage risk can be achieved with surgery for pediatric BSCMs, only a few patients may achieve full neurologic recovery.32,38,47,48 Acciari et al. reported improvement in neurological status with surgical treatment in 69% of cases (defined as complete resolution of presenting symptoms), unchanged deficits in 23.8% of cases, and surgical complications in 7.1%.25 Mortality was absent in this series, with data confirming surgical treatments as yielding favorable results at long-term follow-up. Following complete excision of lobar CCMs in pediatric patients, there appears to be both excellent symptom relief and durable radiographic cure rates.7 Two studies discussed clinical outcomes in children suffering from epileptic seizures before surgery,27,34 and two additional studies reported that seizure control improved in all patients who underwent cavernoma resection.26,31 Di Rocco et al. went on to describe that in these cases, lesionectomy alone may be sufficient to resolve epilepsy.31 Additionally, two papers investigated the natural history of CCMs, with emphasis on recurrent bleeding and hemorrhage.4,21 Much of early surgical morbidity tends to improve over time.28 Certain factors such as age, number of preoperative hemorrhages, and mRS have demonstrated utility in predicting postoperative outcomes and can be used to further guide treatment decisions. 

Illustrative Case

A 6-year-old female presented to the emergency department with left facial droop, left-sided weakness, numbness (most pronounced in the left upper extremity), ataxia, dizziness, anisocoria (left 3 mm, right 1 mm), and worsening headaches for 3 days. CT head revealed a hemorrhagic pontine lesion eccentric to the right with surrounding edema that nearly presented to the ependymal surface of the floor of the fourth ventricle. The lesion measured 2.5 x 2.4 x 2.5 cm, and MRI identified several other smaller lesions consistent with cavernomas (Figure 2A,B). Due to the location in the brainstem and potential morbidity of surgery, she was initially managed conservatively. On the evening of her 9th hospital day, she had several body spasms, an increase in left-sided weakness, with loss of coordination and balance. She was drowsy and did not respond to verbal commands. CT identified and MRI confirmed new hemorrhage within the lesion and worsening ventriculomegaly (Figure 2C,D) . She was admitted to the ICU, intubated, and an external ventricular drain (EVD) was placed. A pentobarbital coma was initiated for sedation and cerebral protection, and levetiracetam was started. She underwent surgery one week later (32 days after admission). A midline suboccipital craniotomy was performed after which the cavernoma was approached through a non-eloquent location in the floor of the fourth ventricle based on intraoperative neurophysiologic mapping. Cranial nerves (VI, VII, X, and XII) were monitored. The patient’s left facial nerve and lateral rectus were paretic but functional after surgery. The EVD was removed on postoperative day 2, and she was extubated on postoperative day 5.

During her hospitalization, the patient experienced several infections including a H. influenzae respiratory infection, possible CSF infection with Bacillus spp., and a urinary tract infection. Prior to surgery, she also suffered from severe constipation, which was resolved through sigmoidoscopy and disimpaction. After 68 days of admission, she was discharged. At neurosurgical follow-up 14 months later, MRI revealed further reduction in both the size of the resection cavity and the surrounding edema in the pons (Figure 2E,F). The other cavernous malformations remained stable. She was free from headaches and seizures, exhibited normal running and walking gaits, and had symmetric extremity motor function with mild dysmetria on finger-to-nose testing. Mild left facial weakness persisted. She excelled in school and was the top reader in her first-grade class. Genetic testing confirmed a de novo pathological mutation in the KRIT1 gene.

Discussion:

Cerebral cavernous malformations are rare in pediatric populations with an estimated prevalence of 0.6%, accounting for possibly one fourth of all CCM patients.4 However, the exact prevalence is not known because many are asymptomatic.6,36 CCM is characterized by dilated low-flow venous sinusoids without intervening brain tissue. They can be diagnosed at any age and present with a wide range of symptoms, from asymptomatic to hemorrhagic with seizures or focal neurological deficits. Younger age at diagnosis is associated with a higher risk of long-term neurologic injury due to recurrent hemorrhage or seizures.21,37,38 Patients can present with single or multiple lesions that can be sporadic or associated with genetic mutations.49 Lesions can produce symptoms due to hemorrhage or seizures, and neurologic deficits depend on anatomic location. Some lesions are found incidentally on workup of unrelated issues. 

CCMs are angiographically occult. Reports of hemorrhage rates in CCM have varied due to variability in the definition or recognition of hemorrhage and differences in study methodologies. Hemorrhage in CCM has been defined as any acute clinical symptom (headache, seizure, or focal neurologic deficit) that refers to the region of the CCM lesion and must be supported by imaging evidence.11 Recurrent hemorrhage risk is increased in CCMs that initially presented with a hemorrhagic event5,50,51 and less for lesions without such an event.52-54 However, reports often fail to make the distinction between incidentally found/asymptomatic patients and symptomatic patients, which can impact management and risk assesment.51 For solitary CCM lesions in all ages without initial hemorrhage, the estimated hemorrhage risk is 0.7-4.2% per patient-year.11 The annual risk of hemorrhage per year for BSCM significantly escalates, reaching a five-year hemorrhage risk of 8%, and approximately 30% if hemorrhage or a focal neurological deficit was identified at initial presentation.23,55

Primary assessment of a suspected symptomatic CCM often involves computed tomography (CT), although microcalcifications detected through CT can be a non-specific finding. CT imaging is not the first-line diagnostic tool for CCM, but it is commonly used in acute settings where MRI is unavailable. It is recommended to perform CT imaging within one week of symptom onset, followed by MRI within two weeks and a two-month follow-up to assess hemorrhage resolution.56 MRI is preferred over CT when possible due to its superior ability to visualize soft tissues and vascular structures with greater detail. It can also distinguish CCMs from other brain neoplasms due to their characteristic anatomic appearance and the presence of hemosiderin.56-58 The susceptibility-weighted sequence (a gradient-echo MRI technique) confers high sensitivity for blood breakdown products59 and has demonstrated high sensitivity in detecting multiple small CCM lesions in familial cases. The T1- and T2-weighted sequences also provide valuable information about the presence and age of the blood products associated with the lesion. Both sequences may exhibit the characteristic reticulated or “popcorn” appearance, surrounded by a hypointense hemosiderin rim.56,60 The Angioma Alliance recommends that MRI protocols for CCM should at the minimum include T2-weighted gradient sequences or SWI.56 The presence of DVA should also be assessed as these have been found to occur in about 30% of all CCM cases. However, presence of DVA has been shown to have no effect on hemorrhage risk and also does not affect surgical decision making.3

Lyne et al. found that biomarkers including sCD14, VEGF, IL-1β, and sROBO-4 have shown promise in predicting the risk of hemorrhage in the following year with high sensitivity (83%) and specificity (93%) (p=0.001).61 Thrombomodulin has also been proposed as a potential indicator of CCM presence and hemorrhage risk.62 Biomarkers could be useful in assessing hemorrhage morbidity during long-term CCM patient follow-up as vascular permeability within CCM lesions is hypothesized to play a significant role in hemorrhage. MRI techniques such as quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative permeability (DCEQP) have shown great diagnostic potential.63

The genetic basis of CCM is well established: familial CCM is due to loss of function mutations in genes CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10).64-67 These genes regulate junctional integrity between neighboring vascular endothelial cells,68,69 and 20% of cases are familial with autosomal dominant inheritance. Counseling families is difficult as risk estimation is complicated by incomplete penetrance and variability in presentation.70 Sporadic CCMs generally lack an association with genetic components in contrast to familial CCMs.

The Angioma Alliance (www.angioma.org) recommends the following approach to genetic testing and counseling: 1) obtain a 3-generation family history focused on symptoms of headache, stroke, abnormal MRI scan, or other neurological complication (Class I, Level C); 2) consider genetic testing of CCM1-3 genes by Sanger or NextGen sequencing followed by deletion/duplication analysis in cases of multiple CCM without associated DVA or in cases with known history of brain radiation or positive family history (Class I, Level B); and 3) if there is a positive mutation in a proband, counsel the patient and family about autosomal dominant inheritance and identifying at-risk individuals through pedigree. While genetic screening of asymptomatic family members is controversial due to the psychological effect it can have on these patients, genetic testing of at-risk adult family members should be offered with appropriate discussion and education about psychological consequences (Class I, Level C).56

Conservative versus Surgical Management

Conservative management can be considered for incidentally-discovered, non-progressive, or asymptomatic lesions, lesions that carry a high risk of surgical morbidity, and when seizures are adequately controlled with medications.71 While patients with supratentorial CCM in the frontal lobe carry the lowest annual risk of rebleeding,2 the risk of rebleed increases after the first hemorrhage, with reported rates of 7.0-8.9% per year.72,73 Other studies report patients 23.3-42.4% rate of recurrent bleed.5,52,56,74 Several factors are associated with a low hemorrhage risk such as location, absence of prior hemorrhages, moderate lesion size, no prior radiation or family history of CCM, no associated DVA, and seizure without hemorrhage,71 making conservative medical management potentially more attractive.

Positive aspects of surgical management include alleviation of mass effect, potential resolution of seizures, and a reduction (or elimination) of the hemorrhage risk. Early operative intervention may improve seizure outcome. Cons of surgical management include the invasiveness of cranial neurosurgery and perioperative morbidity.25,38,47,75 In a systemic pooled analysis, Gross et al. demonstrated that patients with CCM who present incidentally or with seizure have a 9.3% 5-year risk of developing epilepsy.3 Balancing the risks and benefits of surgery in CCM is challenging. Delaying intervention may result in long-term deficits or structural damage. However, surgical excision can lead to complete resolution of deficits and prevent future neurological complications. Watchful waiting may increase the risk of needing future surgery and can allow further significant neurological damage due to re-hemorrhage. In cases of BSCM, allowing the lesion to hemorrhage multiple times until it reaches the pial surface can decrease operative morbidity by reducing the length of the operative corridor through normal tissue, though neurologic damage accumulates due to recurrent hemorrhage. 

Gamma knife radiosurgery may also be considered as a therapeutic alternative for pediatric CCMs. In a study by Pollock et al., the annual hemorrhage rate during the 51 months preceding radiosurgery was 40.1%, compared with 8.8% in the first 2 years following radiosurgery and 2.9% thereafter.76 However, it does entail inherent risks, including radiation-induced toxicity to the adjacent normal tissue.42 Its efficacy is controversial, due to its safety profile, delayed therapeutic effects, side effects, and radiation exposure; therefore, radiation is not the recommended first-line treatment for CCM.42 Moreover, this treatment option may not be suitable for all patients, especially those with large or deep CCMs. In addition, there is a lack of consensus regarding the indications, contraindications, safe dosages, and long-term outcomes associated with this procedure. Laser Interstitial Thermal Therapy (LITT) offers a minimally invasive stereotactic approach for treating CCM by heating the lesion with a laser whose energy is transmitted through a stereotactically-placed fiberoptic catheter. Ogasawara et al. reviewed five studies with a total of 32 patients whose CCMs were treated with LITT.77 93% of patients had an improvement in symptoms with no new recurrence after a mean follow up of 21.4 months. LITT has also been shown to be effective and safe, particularly in cases involving deep, delicately located CCMs as well as lesions that are prone to hemorrhage or causing seizures.77,78 In conclusion, while gamma knife radiosurgery and LITT present promising therapeutic alternatives for pediatric CCMs, each modality comes with its own set of risks, limitations, and considerations, underscoring the importance of an individualized treatment approach.

Clinical trials, like the AT CASH EPOC trial, are exploring treatments for CCM hemorrhage, including atorvastatin (80 mg daily) to reduce re-bleeding79. Chen et al. found no effect of statins, beta-blockers, or other medications on hemorrhage risk in 1,116 CCM patients over five years74. Similarly, Wildi et al. reported no difference in hemorrhage risk for 428 CCM patients on statins compared to untreated patients, though antiplatelet or anticoagulant therapies appeared to reduce hemorrhage risk.80 The CARE pilot trial studied 72 patients with symptomatic CCMs, comparing medical management with and without surgery (resection or radiosurgery).81 Participants (median age 50.6) were mostly adults, with 78% having prior hemorrhage and 39% with seizures. Six-month follow-up showed 93% retention, with new or recurrent neurological deficits in 6% of both groups and no serious adverse events. While feasible, this study is not representative of pediatric patients and does not endorse a specific treatment based on symptoms or lesion characteristics.

While no treatment has been proven to be more effective in familial or sporadic cases of CCMs in pediatrics, it is crucial to identify symptoms and their progression early. Our study reviewed 14 articles noting family history, with five specifically addressing familial CCMs, finding no difference in symptoms. Limited genetic testing and follow-ups might explain this. Management is symptom-based, with conservative care for asymptomatic patients and symptomatic treatments like antiepileptics and beta-blockers as needed.72,82 Surgery or radiosurgery is considered only if symptoms progress and all other treatments fail, based on clinical presentation, lesion characteristics, and surgical risks.83-85. Lesion factors to consider include location, size, recent bleeds, and weighing the risks of surgery against the natural history of the lesion

Future Direction and Recommendations 

This review highlights several important future directions and recommendations for improving the understanding and management of CCMs in the pediatric population. First, establishment of prospective, multicenter registries and cohort studies with standardized data collection is critically needed to better characterize natural history, risk factors for hemorrhage/re-bleeding, and comparative outcomes between surgical and conservative management approaches. Additionally, long-term follow-up will be essential to further our understanding and outcomes. Development of evidence-based, pediatric-specific clinical guidelines tailored to the unique challenges and longer life expectancies of children and adolescents with CCMs is also warranted to provide clear strategies for screening, surveillance, genetic counseling, treatment selection, and follow-up. Additional research should focus on fully elucidating the genetic underpinnings, penetrance, and expressivity of familial CCM syndromes as well as further validation and longitudinal study of promising circulation and imaging biomarkers for risk prediction and early therapeutic intervention. While microsurgery remains the mainstay, the role of emerging therapies like stereotactic radiosurgery, LITT, and other minimally invasive approaches requires head-to-head comparison versus surgery and conservative management, especially for high-risk locations. Given the complexities of care, establishment of comprehensive, multidisciplinary CCM treatment centers with concentrated experience may optimize outcomes through coordinated multispecialty approaches, imaging, treatment planning, and sponsorship of clinical trials. Finally, most studies have prioritized radiographic, clinical, and safety outcomes, but dedicated qualitative and quantitative assessment of patient/parent-reported outcomes and quality of life in pediatric CCM patients is still needed to better determine quality-adjusted life expectancies and guide family counseling. In summary, this review reveals key gaps in evidence that highlight an urgent need for dedicated, prospective, multicenter studies to optimally care for pediatric CCM patients through accurate risk stratification, biomarker development, improved therapies, and coordinated multidisciplinary treatment paradigms.

Limitations

This study has several important limitations that should be considered. First, as a systematic review, our study was restricted to published studies written in English, which may have led to language bias and the exclusion of potentially relevant papers. Additionally, most included studies were retrospective in nature, which are prone to bias and confounding compared to prospective studies. The lack of prospective, controlled clinical trials severely limits the strength of evidence regarding optimal management of pediatric CCMs. Several of the studies included mixed populations of pediatric and adult patients, which complicated extraction of pediatric-specific data. Outcomes were often not stratified based on patient age at diagnosis or lesion characteristics, making it difficult to tease out unique risk factors and prognostic indicators for the pediatric population. Furthermore, there was substantial heterogeneity across studies in terms of data collected, definitions used (e.g. for hemorrhage), and duration of follow-up, limiting the ability to perform quantitative meta-analyses. Our illustrative case highlights the challenges and nuances in pediatric CCM management but represents just a single patient’s experience. Finally, the literature search was conducted in January 2023, so more recent publications were not captured. Despite these limitations, this review synthesizes the most comprehensive evidence to date on this rare pediatric condition and highlights critical knowledge gaps that require further dedicated prospective research.

Conclusions:

CCMs present with a diverse array of neurologic symptoms, and the management approach is influenced by factors such as lesion size, location, and multiplicity. In pediatric patients, treatment decisions should consider these factors as well as consider overall health status and hemorrhage risk. Cases that are asymptomatic or exhibit minimal symptoms may be best managed conservatively. Microsurgery, facilitated by imaging and frameless stereotactic navigation, presents an effective treatment avenue with limited morbidity for many CCMs. Each approach carries inherent limitations and associated risks.

Acknowledgements:

We would like to express our sincere gratitude to Children’s Health and University of Texas Southwestern Medical Center’s Neurosurgery Department for their invaluable contributions to this research project. Their support, guidance, and expertise have been instrumental in shaping the direction and outcomes of this work.

Author Contributions:

Cesar A. Ramirez, BA*: Conceptualization, Methodology, Formal Analysis, Investigation, Resources, Data Curation, Writing – Original Draft, Writing – Review & Editing, Visualization

Umaru Barrie, PhD*: Conceptualization, Methodology, Formal Analysis, Investigation, Resources, Data Curation, Writing – Original Draft, Writing – Review & Editing, Visualization

Pooja Venkatesh, BS: Conceptualization, Methodology, Writing – Original Draft, Writing – Review & Editing, Visualization

Emerson Lout, BS: Methodology, Data Curation, Writing – Review & Editing, Visualization

Momodou G. Bah, BS: Methodology, Data Curation, Writing – Review & Editing

Sanjay V. Neerukonda, BS: Methodology, Data Curation, Writing – Review & Editing

Usama AlDallal, BS: Data Curation, Writing – Review & Editing

Abigail Jenkins, BA: Methodology, Data Curation, Writing – Review & Editing

Jonathan Tao, BS: Methodology, Data Curation, Writing – Review & Editing

Donald Detchou, BA: Methodology, Data Curation, Writing – Review & Editing

Soummitra Anand, BSA: Methodology, Data Curation, Writing – Review & Editing

Faraaz Azam, BS: Methodology, Data Curation, Writing – Review & Editing, Administration

Anant Naik, MD: Methodology, Data Curation, Writing – Review & Editing

Brett Whittemore, MD: Resources, Writing – Review & Editing, Project administration, Supervision

*Co-first authors: contributed equally to this manuscript

Conflict of interest Statement:
The authors have no personal or institutional interest with regards to the authorship and/or publication of this manuscript.

Funding Disclosures:
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

IRB compliance statement and ethical adherence:
This study was written in compliance with our institutional ethical review board. IRB approval was waived given the de-identified nature of the information presented.

References:

  1. Paddock M, Lanham S, Gill K, Sinha S, Connolly DJ. Pediatric cerebral cavernous malformations. Pediatric Neurology. 2021;116:74-83. 
  2. Flemming KD, Kumar S, Brown Jr RD, Lanzino G. Predictors of initial presentation with hemorrhage in patients with cavernous malformations. World neurosurgery. 2020;133:e767-e773. 
  3. Gross BA, Du R. Hemorrhage from cerebral cavernous malformations: a systematic pooled analysis. Journal of Neurosurgery. 2017;126(4):1079-1087. 
  4. Santos AN, Rauschenbach L, Saban D, et al. Natural Course of Cerebral Cavernous Malformations in Children: A Five-Year Follow-Up Study. Stroke. Mar 2022;53(3):817-824. doi:10.1161/STROKEAHA.121.035338
  5. Horne MA, Flemming KD, Su I-C, et al. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. The Lancet Neurology. 2016;15(2):166-173. 
  6. Gross BA, Du R, Orbach DB, Scott RM, Smith ER. The natural history of cerebral cavernous malformations in children. Journal of Neurosurgery: Pediatrics. 2016;17(2):123-128. 
  7. Gross BA, Smith ER, Goumnerova L, Proctor MR, Madsen JR, Scott RM. Resection of supratentorial lobar cavernous malformations in children. Journal of Neurosurgery: Pediatrics. 2013;12(4):367-373. 
  8. Gross BA, Smith ER, Scott RM. Cavernous malformations of the basal ganglia in children. Journal of Neurosurgery: Pediatrics. 2013;12(2):171-174. 
  9. Gross BA, Lin N, Du R, Day AL. The natural history of intracranial cavernous malformations. Neurosurgical focus. 2011;30(6):E24. 
  10. Bigi S, Mori AC, Steinlin M, Remonda L, Landolt H, Boltshauser E. Cavernous malformations of the central nervous system in children: presentation, treatment and outcome of 20 cases. European journal of paediatric neurology. 2011;15(2):109-116. 
  11. Al-Shahi Salman R, Berg MJ, Morrison L, Awad IA. Hemorrhage from cavernous malformations of the brain: definition and reporting standards. Stroke. 2008;39(12):3222-3230. 
  12. Awad IA, Polster SP. Cavernous angiomas: deconstructing a neurosurgical disease: JNSPG 75th Anniversary Invited Review Article. Journal of neurosurgery. 2019;131(1):1-13. 
  13. Abdulrauf SI, Kaynar MY, Awad IA. A comparison of the clinical profile of cavernous malformations with and without associated venous malformations. Neurosurgery. 1999;44(1):41-46. 
  14. Bergametti F, Denier C, Labauge P, et al. Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. The American Journal of Human Genetics. 2005;76(1):42-51. 
  15. Craig HD, Günel M, Cepeda O, et al. Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15–13 and 3q25. 2–27. Human molecular genetics. 1998;7(12):1851-1858. 
  16. Gault J, Sain S, Hu L-J, Awad IA. Spectrum of genotype and clinical manifestations in cerebral cavernous malformations. Neurosurgery. 2006;59(6):1278-1285. 
  17. Günel M, Awad IA, Anson J, Lifton RP. Mapping a gene causing cerebral cavernous malformation to 7q11. 2-q21. Proceedings of the National Academy of Sciences. 1995;92(14):6620-6624. 
  18. Günel M, Awad IA, Finberg K, et al. A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. New England Journal of Medicine. 1996;334(15):946-951. 
  19. Couteulx SL-l, Jung HH, Labauge P, et al. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nature genetics. 1999;23(2):189-193. 
  20. Liquori CL, Berg MJ, Siegel AM, et al. Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. The American Journal of Human Genetics. 2003;73(6):1459-1464. 
  21. Li D, Hao S-Y, Tang J, et al. Clinical course of untreated pediatric brainstem cavernous malformations: hemorrhage risk and functional recovery. Journal of Neurosurgery: Pediatrics. 2014;13(5):471-483. 
  22. D’Angelo R, Marini V, Rinaldi C, et al. Mutation analysis of CCM1, CCM2 and CCM3 genes in a cohort of Italian patients with cerebral cavernous malformation. Brain Pathology. 2011;21(2):215-224. 
  23. Dammann P, Jabbarli R, Wittek P, et al. Solitary sporadic cerebral cavernous malformations: risk factors of first or recurrent symptomatic hemorrhage and associated functional impairment. World Neurosurgery. 2016;91:73-80. 
  24. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. OriginalPaper. Systematic Reviews. 2021-03-29 2021;10(1):1-11. doi:doi:10.1186/s13643-021-01626-4
  25. Acciarri N, Galassi E, Giulioni M, et al. Cavernous malformations of the central nervous system in the pediatric age group. Pediatric neurosurgery. 2009;45(2):81-104. 
  26. Alexiou GA, Mpairamidis E, Sfakianos G, Prodromou N. Surgical management of brain cavernomas in children. Pediatric Neurosurgery. 2009;45(5):375-378. 
  27. Amato MCM, Madureira JFG, Oliveira RSd. Intracranial cavernous malformation in children: a single-centered experience with 30 consecutive cases. Arquivos de Neuro-Psiquiatria. 2013;71:220-228. 
  28. Bhardwaj RD, Auguste KI, Kulkarni AV, Dirks PB, Drake JM, Rutka JT. Management of pediatric brainstem cavernous malformations: experience over 20 years at the hospital for sick children. Journal of Neurosurgery: Pediatrics. 2009;4(5):458-464. 
  29. Bilginer B, Narin F, Hanalioglu S, Oguz KK, Soylemezoglu F, Akalan N. Cavernous malformations of the central nervous system (CNS) in children: clinico-radiological features and management outcomes of 36 cases. Child’s Nervous System. 2014;30:1355-1366. 
  30. Consales A, Piatelli G, Ravegnani M, et al. Treatment and outcome of children with cerebral cavernomas: a survey on 32 patients. Neurological sciences. 2010;31:117-123. 
  31. Di Rocco C, Iannelli A, Tamburrini G. Cavernomas of the central nervous system in children: a report of 22 cases. Acta neurochirurgica. 1996;138:1267-1274. 
  32. Giulioni M, Acciarri N, Padovani R, Frank F, Galassi E, Gaist G. Surgical management of cavernous angiomas in children. Surgical neurology. 1994;42(3):194-199. 
  33. Hirschmann D, Czech T, Roessler K, et al. How can we optimize the long-term outcome in children with intracranial cavernous malformations? A single-center experience of 61 cases. Neurosurgical Review. 2022;45(5):3299-3313. 
  34. Hugelshofer M, Acciarri N, Sure U, et al. Effective surgical treatment of cerebral cavernous malformations: a multicenter study of 79 pediatric patients. Journal of Neurosurgery: Pediatrics. 2011;8(5):522-525. 
  35. Jaman E, Abdallah HM, Zhang X, Greene S. Clinical characteristics of familial and sporadic pediatric cerebral cavernous malformations and outcomes. J Neurosurg Pediatr. Oct 1 2023;32(4):506-513. doi:10.3171/2023.5.PEDS22397
  36. Knerlich-Lukoschus F, Steinbok P, Dunham C, Cochrane DD. Cerebellar cavernous malformation in pediatric patients: defining clinical, neuroimaging, and therapeutic characteristics. J Neurosurg Pediatr. Sep 2015;16(3):256-66. doi:10.3171/2015.1.Peds14366
  37. Lee J-W, Kim D-S, Shim K-W, et al. Management of intracranial cavernous malformation in pediatric patients. Child’s Nervous System. 2008;24(3):321-327. 
  38. Li D, Hao S-Y, Tang J, et al. Surgical management of pediatric brainstem cavernous malformations. Journal of Neurosurgery: Pediatrics. 2014;13(5):484-502. 
  39. Mazza C, Scienza R, Beltramello A, Da Pian R. Cerebral cavernous malformations (cavernomas) in the pediatric age-group. Childs Nerv Syst. Jun 1991;7(3):139-46. doi:10.1007/BF00776709
  40. Noh JH, Cho KR, Yeon JY, Seol HJ, Shin HJ. Microsurgical treatment and outcome of pediatric supratentorial cerebral cavernous malformation. J Korean Neurosurg Soc. Sep 2014;56(3):237-42. doi:10.3340/jkns.2014.56.3.237
  41. Prolo LM, Jin MC, Loven T, et al. Recurrence of cavernous malformations after surgery in childhood. J Neurosurg Pediatr. May 1 2020;26(2):179-188. doi:10.3171/2020.2.PEDS19543
  42. Samanci Y, Ardor GD, Peker S. Management of pediatric cerebral cavernous malformations with gamma knife radiosurgery: a report of 46 cases. Child’s Nervous System. 2022;38(5):929-938. 
  43. Velz J, Özkaratufan S, Krayenbühl N, et al. Pediatric brainstem cavernous malformations: 2-center experience in 40 children. Journal of Neurosurgery: Pediatrics. 2022;29(6):612-623. 
  44. Xia C, Zhang R, Mao Y, Zhou L. Pediatric cavernous malformation in the central nervous system: report of 66 cases. Pediatric neurosurgery. 2009;45(2):105-113. 
  45. Zimmerman RS, Spetzler RF, Lee KS, Zabramski JM, Hargraves RW. Cavernous malformations of the brain stem. Journal of neurosurgery. 1991;75(1):32-39. 
  46. Washington CW, McCoy KE, Zipfel GJ. Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation. Neurosurg Focus. Sep 2010;29(3):E7. doi:10.3171/2010.5.FOCUS10149
  47. Aslan A, Börcek AÖ, Demirci H, Erdem MB. Cerebral cavernous malformation presenting in childhood: a single-centered surgical experience of 29 cases. Clinical neurology and neurosurgery. 2020;194:105830. 
  48. Moultrie F, Horne MA, Josephson CB, et al. Outcome after surgical or conservative management of cerebral cavernous malformations. Neurology. 2014;83(7):582-589. 
  49. Snellings DA, Hong CC, Ren AA, et al. Cerebral cavernous malformation: from mechanism to therapy. Circulation research. 2021;129(1):195-215. 
  50. Taslimi S, Modabbernia A, Amin-Hanjani S, Barker FG, Macdonald RL. Natural history of cavernous malformation: systematic review and meta-analysis of 25 studies. Neurology. 2016;86(21):1984-1991. 
  51. Moore SA, Brown RD, Christianson TJ, Flemming KD. Long-term natural history of incidentally discovered cavernous malformations in a single-center cohort. Journal of neurosurgery. 2014;120(5):1188-1192. 
  52. Salman RA-S, Hall JM, Horne MA, et al. Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. The Lancet Neurology. 2012;11(3):217-224. 
  53. Kupersmith MJ, Kalish H, Epstein F, et al. Natural history of brainstem cavernous malformations. Neurosurgery. 2001;48(1):47-54. 
  54. Aiba T, Tanaka R, Koike T, Kameyama S, Takeda N, Komata T. Natural history of intracranial cavernous malformations. Journal of neurosurgery. 1995;83(1):56-59. 
  55. Kearns KN, Chen CJ, Yagmurlu K, et al. Hemorrhage Risk of Untreated Isolated Cerebral Cavernous Malformations. World Neurosurg. Nov 2019;131:e557-e561. doi:10.1016/j.wneu.2019.07.222
  56. Akers A, Al-Shahi Salman R, A. Awad I, et al. Synopsis of guidelines for the clinical management of cerebral cavernous malformations: consensus recommendations based on systematic literature review by the angioma alliance scientific advisory board clinical experts panel. Neurosurgery. 2017;80(5):665-680. 
  57. Dillon WP. Cryptic vascular malformations: controversies in terminology, diagnosis, pathophysiology, and treatment. AJNR: American Journal of Neuroradiology. 1997;18(10):1839. 
  58. Wilms G, Marchal G, Van Hecke P, Van Fraeyenhoven L, Decrop E, Baert A. Cerebral venous angiomas: MR imaging at 1.5 Tesla. Neuroradiology. 1990;32:81-85. 
  59. De Souza JM, Domingues FS, Chimelli L, Gault J. Spinal root arteriovenous malformations and same-segment cord cavernous malformation in familial cerebral cavernous malformation: Case report. Journal of Neurosurgery: Spine. 2008;9(3):249-252. 
  60. Rigamonti D, Drayer BP, Johnson PC, Hadley MN, Zabramski J, Spetzler RF. The MRI appearance of cavernous malformations (angiomas). Journal of neurosurgery. 1987;67(4):518-524. 
  61. Lyne SB, Girard R, Koskimaki J, et al. Biomarkers of cavernous angioma with symptomatic hemorrhage. JCI Insight. Jun 20 2019;4(12)doi:10.1172/jci.insight.128577
  62. Lopez-Ramirez MA, Pham A, Girard R, et al. Cerebral cavernous malformations form an anticoagulant vascular domain in humans and mice. Blood. Jan 17 2019;133(3):193-204. doi:10.1182/blood-2018-06-856062
  63. Girard R, Fam MD, Zeineddine HA, et al. Vascular permeability and iron deposition biomarkers in longitudinal follow-up of cerebral cavernous malformations. Journal of neurosurgery. 2016;127(1):102-110. 
  64. Cavalcanti DD, Kalani MYS, Martirosyan NL, Eales J, Spetzler RF, Preul MC. Cerebral cavernous malformations: from genes to proteins to disease. Journal of neurosurgery. 2012;116(1):122-132. 
  65. Riant F, Bergametti F, Ayrignac X, Boulday G, Tournier‐Lasserve E. Recent insights into cerebral cavernous malformations: the molecular genetics of CCM. The FEBS journal. 2010;277(5):1070-1075. 
  66. McDonald DA, Shi C, Shenkar R, et al. Lesions from patients with sporadic cerebral cavernous malformations harbor somatic mutations in the CCM genes: evidence for a common biochemical pathway for CCM pathogenesis. Human molecular genetics. 2014;23(16):4357-4370. 
  67. Akers AL, Johnson E, Steinberg GK, Zabramski JM, Marchuk DA. Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis. Human molecular genetics. 2009;18(5):919-930. 
  68. Fischer A, Zalvide J, Faurobert E, Albiges-Rizo C, Tournier-Lasserve E. Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis. Trends in molecular medicine. 2013;19(5):302-308. 
  69. Yadla S, Jabbour PM, Shenkar R, Shi C, Campbell PG, Awad IA. Cerebral cavernous malformations as a disease of vascular permeability: from bench to bedside with caution. Neurosurgical focus. 2010;29(3):E4. 
  70. Haasdijk RA, Cheng C, Maat-Kievit AJ, Duckers HJ. Cerebral cavernous malformations: from molecular pathogenesis to genetic counselling and clinical management. European journal of human genetics. 2012;20(2):134-140. 
  71. Agosti E, Flemming KD, Lanzino G. Symptomatic cavernous malformation presenting with seizure without hemorrhage: analysis of factors influencing clinical presentation. World neurosurgery. 2019;129:e387-e392. 
  72. Dalyai RT, Ghobrial G, Awad I, et al. Management of incidental cavernous malformations: a review. Neurosurg Focus. Dec 2011;31(6):E5. doi:10.3171/2011.9.FOCUS11211
  73. Mostofi A, Gurusinghe NT. Multiple cerebral cavernous malformations in association with a Dubowitz-like syndrome. J Cerebrovasc Endovasc Neurosurg. Mar 2020;22(1):15-19. doi:10.7461/jcen.2020.22.1.15
  74. Chen B, Lahl K, Saban D, et al. Effects of medication intake on the risk of hemorrhage in patients with sporadic cerebral cavernous malformations. Front Neurol. 2022;13:1010170. doi:10.3389/fneur.2022.1010170
  75. Abla AA, Lekovic GP, Garrett M, et al. Cavernous malformations of the brainstem presenting in childhood: surgical experience in 40 patients. Neurosurgery. 2010;67(6):1589-1599. 
  76. Pollock BE, Garces YI, Stafford SL, Foote RL, Schomberg PJ, Link MJ. Stereotactic radiosurgery for cavernous malformations. J Neurosurg. Dec 2000;93(6):987-91. doi:10.3171/jns.2000.93.6.0987
  77. Ogasawara C, Watanabe G, Young K, et al. Laser Interstitial Thermal Therapy for Cerebral Cavernous Malformations: A Systematic Review of Indications, Safety, and Outcomes. World Neurosurg. Oct 2022;166:279-287 e1. doi:10.1016/j.wneu.2022.06.052
  78. Satzer D, Tao JX, Issa NP, et al. Stereotactic laser interstitial thermal therapy for epilepsy associated with solitary and multiple cerebral cavernous malformations. Neurosurg Focus. Apr 1 2020;48(4):E12. doi:10.3171/2020.1.Focus19866
  79. Polster SP, Stadnik A, Akers AL, et al. Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial. Neurosurgery. Dec 1 2019;85(6):843-853. doi:10.1093/neuros/nyy539
  80. Wildi S, Nager S, Akeret K, et al. Impact of Long-Term Antithrombotic and Statin Therapy on the Clinical Outcome in Patients with Cavernous Malformations of the Central Nervous System: A Single-Center Case Series of 428 Patients. Cerebrovasc Dis. 2023;52(6):634-642. doi:10.1159/000529511
  81. collaboration Cpt. Medical management and surgery versus medical management alone for symptomatic cerebral cavernous malformation (CARE): a feasibility study and randomised, open, pragmatic, pilot phase trial. Lancet Neurol. Jun 2024;23(6):565-576. doi:10.1016/S1474-4422(24)00096-6
  82. Batra S, Lin D, Recinos PF, Zhang J, Rigamonti D. Cavernous malformations: natural history, diagnosis and treatment. Nat Rev Neurol. Dec 2009;5(12):659-70. doi:10.1038/nrneurol.2009.177
  83. Ferroli P, Casazza M, Marras C, Mendola C, Franzini A, Broggi G. Cerebral cavernomas and seizures: a retrospective study on 163 patients who underwent pure lesionectomy. Neurol Sci. Feb 2006;26(6):390-4. doi:10.1007/s10072-006-0521-2
  84. Fritschi JA, Reulen HJ, Spetzler RF, Zabramski JM. Cavernous malformations of the brain stem. A review of 139 cases. Acta Neurochir (Wien). 1994;130(1-4):35-46. doi:10.1007/BF01405501
  85. Wang CC, Liu A, Zhang JT, Sun B, Zhao YL. Surgical management of brain-stem cavernous malformations: report of 137 cases. Surg Neurol. Jun 2003;59(6):444-54; discussion 454. doi:10.1016/s0090-3019(03)00187-3
  86. Santos AN, Rauschenbach L, Saban D, et al. Natural course of cerebral cavernous malformations in children: a five-year follow-up study. Stroke. 2022;53(3):817-824.

Figure and Table Legends

Figure 1: PRISMA Flow diagram showcasing the methodology employed in conducting the systemic review. Created with BioRender.com.

Figure 2(A,B) Axial T1W and coronal T2W MRI imaging identifying a hemorrhagic lesion located in the right hemipons. (C,D) Axial T1W and coronal T2W MRI imaging showing re-hemorrhage of the cavernous malformation. (E,F) Axial FLAIR and coronal T2W MRI imaging taken at last follow-up showing complete resection of the cavernoma with mild surrounding edema.

Table 1. Demographics and patient characteristics of non-comparative retrospective studies included in the systematic review.

Table 2. Management and neurological outcome of non-comparative retrospective studies included in the systematic review.

Table 3. Demographics and patient characteristics of retrospective studies comparing surgical versus conservative management in pediatric cavernomas.

Table 4. Management and neurological outcomes of retrospective studies comparing surgical versus conservative management in pediatric cavernomas.

Pediatric Cerebral Cavernous Malformations

Pediatr Stroke. 2025;11: 1-50

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