Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 2.0.0
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: KRIT1, CCM2, PDCD10
• Condition: Cerebral cavernous malformations 1, 2, and 3
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• KRIT1 ⇔ 0020724 (cerebral cavernous malformation 1): Limited Actionability
• CCM2 ⇔ 0011304 (cerebral cavernous malformation 2): Limited Actionability
• PDCD10 ⇔ 0011305 (cerebral cavernous malformation 3): Limited Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: KRIT1 ⇔ 0020724 (OMIM:116860) CCM2 ⇔ 0011304 (OMIM:603284) PDCD10 ⇔ 0011305 (OMIM:603258)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality due to familial cerebral cavernous malformation-related complications including hemorrhage / Referral to specialist to guide MRI surveillance and treatment (surgery and/or pharmacotherapy)	2	2D	1D	2	7DD

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

It is estimated that 1/111 to 1/1,000 individuals in the general population has a cerebral cavernous malformation (CCM). Familial CCM (FCCM) represents about 20% of all CCM cases with an estimated prevalence of 1/5,000 to 1/10,000. Common occurrence of asymptomatic vascular lesions in individuals with FCCM suggests that the population prevalence of FCCM may be underestimated. This is supported by a recent population-based study estimating the prevalence of FCCM at 0.07% (1/1429 individuals). [1, 2, 3]

Clinical Features

FCCM is a vascular malformation disorder characterized by multiple closely clustered irregular dilated capillaries (caverns) that can be asymptomatic or can cause variable neurological manifestations such as seizures, nonspecific headaches, progressive or transient focal neurologic deficits, and/or cerebral hemorrhages. The number of lesions can vary from one or two to hundreds (typical number 6-20 CCMs), depending on age and the quality and type imaging. The diameter of CCMs can range from a few millimeters to several centimeters. CCMs typically occur in the brain and the spinal cord, but have also been reported in vertebra, skin, retina, and choroid. There are rare reports of liver hemangiomas, renal angiomas, and adrenal gland calcifications. Brain tumors and scoliosis have been reported in one study of individuals with pathogenic variants (PVs) in the PDCD10 gene. However, the full phenotypic characteristics of FCCM may not be known because of the limited number of individuals undergoing genetic testing. [1, 2, 3, 4]

Natural History

FCCM is a dynamic disease, with CCM size increasing or decreasing over time and new lesions estimated to appear at a rate of 0.2 to 1.0 lesions per person per year. Although CCMs have been reported in infants and children, the majority of cases become evident between the second and fifth decades. One study of 79 genetically confirmed consecutive probands reported that up to 20% of index cases in FCCM are in children younger than 10 years and 33% younger than 18 years. Up to 60% of individuals with FCCM are clinically asymptomatic, although at least half of these individuals have identifiable lesions on brain imaging.
Clinically affected individuals most often present with seizures (20%-70%), focal neurologic deficits (25-50%), nonspecific headaches (10%-30%), cerebral hemorrhage (30%-41%), spinal cord malformations (16%-70%), and cutaneous vascular malformations (9%-20%). The hemorrhagic event rate is estimated at 2-5% per lesion per year, and the new onset seizure rate is 2.4%. In a prospective study of 479 individuals with FCCM, the cumulative incidence of first seizure was 20% by age 18 years (95% CI 17%-23%) and 60% by age 80 years (95% CI 54%-66%). Functional outcome is mostly determined by the location of CCM, with brainstem and basal ganglia lesions having a worse prognosis. The long-term prognosis of FCCM is not well known, but an estimated 80% of cases have preserved autonomy.
The clinical course can vary by genotype. Individuals with a PV in PDCD10 in general have the most severe clinical phenotype and are most likely to present with hemorrhage and have symptom onset before age 15 years. One study reported age of onset of symptomatic cerebral hemorrhage based on genotype to be 12.9 ± 11.6 years in individuals with PVs in PDCD10 versus 22.9 ± 13.9 years in individuals with PVs in KRIT1 and 38.5 ± 21.9 years in individuals with PVs in CCM2. PDCD10 PV carriers are more likely to have higher hemorrhage rates compared with individuals with PVs in either KRIT1 or CCM2. Individuals with a PV in CCM2 typically have fewer brain lesions and slower lesion development compared to individuals with a PV in KRIT1. Some studies indicate that individuals with a PV in KRIT1 may have a less severe clinical phenotype but are more likely to have skin lesions than those with a PV in CCM2 or PDCD10. [1, 2, 3, 5]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs of an individual diagnosed with FCCM, the following evaluations are recommended:
• Consultation with a genetics professional
• If epilepsy is of concern:
• Electroencephalogram (EEG) to help establish diagnosis of epilepsy or aid in seizure localization (CCM vs alternate pathologies) that may facilitate surgical planning
• Neuropsychological evaluation to determine which hemisphere is language dominant, and overall eligibility for surgical resection
• Baseline eye exam for retinal cavernous malformations. (Tier 4) [1]

Supportive care to improve quality of life, maximize function, and reduce complications is recommended for all forms of CCM. This ideally involves multidisciplinary care by specialists in relevant fields. (Tier 4) [1]

For initial diagnosis of a CM in an individual with FCCM, MRI of the brain and spine with recommended sequences should be performed. This investigates nonspecific neurological symptoms and provides a baseline CM burden for future follow-up. MRI is the preferred imaging test for the confirmation, detection, and evaluation of CMs and suspected bleeding (Tier 2) [2]

Surgical Considerations (all ages)
Many recommendations for the surgical and medical treatment of CMs do not distinguish between treatment of sporadic CMs and those due to FCCM. There are no randomized clinical trials to guide the indication for surgery, and most of the available literature is based on single-center cohorts limited by referral and reporting biases, often without independent, third-party assessment of outcome. Moreover, these series are from highly specialized centers, making their conclusions not immediately generalizable. This is especially true when CMs in highly eloquent areas like the brainstem and the thalamus are considered. (Tier 2) [2]

Below are recommendations regarding the surgical management of CMs:
•In general, early surgical resection of CM for seizure control can be useful, especially with medically refractory epilepsy, if the epileptogenic CM responsible for epilepsy is identified. When considering surgery in FCCM patients with seizure and nonhemorrhagic CM, a careful review by a neurologist and EEG should be considered to assure that the relationship of the CM to the seizure and that the appropriate CM is being considered for resection or ablation when multiple CMs are present.
•Surgical resection of intracranial CMs may be considered in the following specific circumstances:
oCM lesions that are symptomatic and easily accessible
oDeep CM lesions if symptomatic
oBrainstem CM after one or more symptomatic bleed(s)
oA solitary asymptomatic CM if easily accessible in a noneloquent area, to prevent future hemorrhage.
•Surgical resection of spinal CMs may be considered in the following specific circumstances:
oDorsal or dorsolateral CMs that meet specific criteria
Intramedullary, embedded, or ventral spinal CMs after one or more neurological impairing events or progressive neurological deterioration. (Tier 2) [2]

A systematic review and reconstructed time-to-event meta-analysis was conducted to evaluate effectiveness of surgical intervention versus conservative management in patients with symptomatic CCMs. Four eligible studies with a total of 290 patients (children and adults) were included. Surgical intervention showed 43 events over a mean time to focal neurological deficit (FND)/intracranial hemorrhage (ICH) of 6.372 years (95 % CI: 3.536–8.005), while observational management had 48 events with a significantly longer mean time of 10.992 years (95 % CI: 6.070–8.005). No significant difference was found at 2 years (p = 0.910), but at 5 and 10 years, surgical intervention had more events and shorter mean times (p < 0.0001). Sensitivity analysis for previously bleeding CCMs showed no significant difference in events < (p =0.131). (Tier 1) [6]

One study assessed conservative or surgical treatment of patients with new-onset cavernoma-related epilepsy (CRE). This comparative observational study included 79 consecutive patients, each with a single sporadic CCM and new-onset CRE. Forty-one patients underwent initial surgery (IS), and 38 patients underwent initial conservative (IC) treatment. Of those in the latter group, 19 underwent delayed surgical (DS) treatment. At the last follow-up, 88%, 32%, and 79% of patients in the respective groups had been seizure free for at least 2 years (p < 0.0001) and 78%, 8%, and 58%, respectively, had been off AEDs (p < 0.0001). The cumulative probability of staying seizure free during a 5-year period was 73% (mean seizure-free follow-up 49.8 ± 2.7 months, 95% CI 44.4-55.1 months) for the IS group, 22% (mean 31.8 ± 3.6 months, 95% CI 24.8-38.8 months) for the IC group, and 68% (mean 48.6 ± 4.3 months, 95% CI 40.1-57.1 months) for the DS group (IS vs IC p < 0.001). Long-term operative morbidity was 3%, and long-term morbidity in the conservatively treated group was also 3%. Half of the patients who started with conservative treatment underwent subsequent surgical treatment; however, a longer duration of epilepsy prior to surgery did not worsen postoperative seizure outcome. (Tier 2) [2]

Surgical Considerations (specific to pediatric patients)
Treatment of CM in children with either sporadic or familial disease, is either surgical resection or observation, with data supporting excision as first line therapy for symptomatic lesions (seizure, focal headache, neurological deficits), lesions with recurrent hemorrhage, or lesions with high risk of neurological deficit (e.g., large lesions or those located in the posterior fossa). (Tier 2) [2, 4]

In children with FCCM, symptomatic or enlarging supratentorial or cerebellar CMs can be assessed for treatment with surgical resection. However, brainstem CMs in children, regardless of whether the child has familial or sporadic disease, should generally be observed. (Tier 2) [4]

Non-Surgical Interventions
In individuals with FCCM, propranolol can be used for reducing CM hemorrhage or preventing new CM formation. Although it is safe and tolerable at low doses in patients with familial CM, long-term efficacy is not clear. One randomized placebo-controlled trial including 83 symptomatic adults with familial CM and symptoms assessed new symptomatic hemorrhages or focal neurological deficits attributed to the CM over 24 months. The incidence of symptomatic intracerebral hemorrhage or focal neurological deficit was 1.7 (95% CI 1.4 to 2.0) cases per 100 person-years (two [4%] of 57 participants) in the propranolol group and 3.9 (3.1-4.7) per 100 person-years (two [8%] of 26) in the standard care alone group (univariable hazard ratio [HR] 0·43, 80% CI 0·18-0·98). Most patients with new symptomatic hemorrhage during the trial had nondisabling symptoms. Seizure rates and de novo CM rates did not differ between groups.
nter value here... (Tier 2) [2]

A statin can be considered in patients with CM and elevated cholesterol according to standard medical use guidelines. However, the long-term efficacy of statins for reducing CM hemorrhage risk or preventing new CM development is not known. (Tier 2) [2]

Seizures due to CMs are treated with standard anti-seizure medications (ASMs). (Tier 2) [2]

Neurologic deficits can be addressed with rehabilitation services. (Tier 4) [1]

However, if the headache is severe, prolonged, or progressive, or associated with new or worsening neurologic deficits. In this circumstance, urgent brain imaging could lead to prompt management. (Tier 4) [1]

If the individual has a stable focal neurologic deficit, physical therapy & rehabilitation should be considered. (Tier 4) [1]

For persistent lower motor neuron facial weakness or double vision, facial reanimation &/or ophthalmologic surgeries to restore function can be considered. (Tier 4) [1]

Pre-pregnancy/Pregnancy Management
Patients with known FCCM should consider genetic counseling before pregnancy. (Tier 2) [2]

For both familial and sporadic CCM:
•If a pregnant individual suffers a seizure disorder due to CM, discuss appropriate ASMs to reduce teratogenic side effects.
•If focal neurological deficits, an acute, severe headache, or a flare-up in seizures occur during pregnancy or while lactating, an MRI scan without contrast can be considered.
•If a patient has a brain hemorrhage during pregnancy, the severity of symptoms and risk of recurrent hemorrhage need to be weighed against the risk of surgical intervention at that point in the pregnancy.
•It is generally agreed that vaginal delivery is appropriate in most patients unless there is a neurological deficit that precludes such or recent hemorrhage.
Data from several large series suggest that pregnancy does not increase the risk of clinical symptoms and hemorrhage rate compared with nonpregnant CM patients, although some controversy remains. A review of 349 pregnancies with 49 hemorrhages during childbearing
years found only 3 hemorrhages occurred during pregnancy. The study compared the number of clinically significant hemorrhages divided by the time in the pregnant state
vs the number of hemorrhages during the nonpregnant state between the ages of 15 and 44 years. The hemorrhage rate for pregnant women was 1.15% per person-year compared with
1.01% per person-year for nonpregnant women. The authors concluded that hemorrhage rate did not differ dependent on pregnancy. This conclusion assumes that the CM was present between the ages of 15 and 44 years. Similarly, another study found a low hemorrhage rate in 64 patients with CM (28 sporadic; 36 familial) who had 168 pregnancies. This study agreed that there is no increased risk during pregnancy. This study was limited
in that confirmation of clinical events radiologically was not always possible. Given that many patients are diagnosed with CM after childbearing years, another study looked at patients with pregnancy after CM diagnosis. In this study, no symptomatic hemorrhages occurred in 32 patients with pregnancy after the diagnosis of CM was made. This study was limited by the small number of patients with pregnancies after CM diagnosis. (Tier 2) [2]

Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or headaches require close monitoring during pregnancy. (Tier 4) [1]

Surveillance

Changes in symptoms or new symptoms in individuals with FCCM warrant imaging, ideally by MRI and within two weeks of onset. Depending on symptom severity, presentation, and emergent availability of MRI, these may warrant CT to evaluate for large hemorrhage and mass effect prior to MRI availability. Routine scheduled follow-up MRI may be useful to document the stability of CMs which have previously bled or enlarged or in other situations per the clinical judgment (Tier 2) [2]

There is recent evidence that subclinical changes on surveillance MRIs may herald subsequent symptomatic hemorrhages (SH), while the impact on clinical decisions remains controversial. A study including 59 genetically confirmed FCCM patients and 25 individuals with multifocal lesions but unknown genotype, followed patients that had had follow-up MRI surveillance after diagnosis for a median for 2 years per patient. During the follow-up period (total of 212 patient-years) in patients with familial/multifocal disease, a total of 86 new lesions were identified. Approximately 19% of FCCM/multifocal patients with new SH during follow-up underwent resection of the hemorrhagic lesion. Two of the 28 (7.1%) patients with FCCM with asymptomatic changes (ACs) chose to undergo resection. (Tier 2) [2]

In children with FCCM, brain MRI should be performed when investigating any neurological symptoms, but it is unclear at what age imaging should be performed in asymptomatic children. On follow-up imaging for foci of susceptibility in children with FCCM, it is important to focus on any change since prior imaging, including new CMs, change in size of a CM, change in blood signal characteristics, and development of edema in the surrounding parenchyma. (Tier 2) [2]

Careful skin examinations should be done for vascular birthmarks in children with FCCM. (Tier 2) [4]

Regular check-ups are recommended, as additional asymptomatic lesions may appear with time. (Tier 4) [3]

If a person has an exacerbation of a previously quiescent seizure disorder, EEG, and possibly neurosurgical evaluation should be considered. (Tier 4) [1]

Spinal imaging should be repeated if the affected person has recurrent or worsening symptoms. (Tier 4) [1]

Circumstances to Avoid

Radiation exposure, including radiosurgery, is not recommended for asymptomatic CCMs, nor in FCCM, as radiation exposure may enhance the genesis of new CMs. (Tier 2) [2]

The pathology of these radiation-induced lesions appears to be histologically different from the cavernomas found prior to radiation. A case study of 2 patients with FCCM reported that, following therapeutic radiation, both patients developed very high numbers of CCMs within the radiation ports, supporting radiation as an accelerator of lesion formation and suggesting implications for risks of radiation in this disease. (Tier 3) [1]

Similar to sporadic CCM, surgical resection should not be performed in those with FCCM for asymptomatic, stable CM if located in eloquent, deep or brainstem areas, nor in cases with multiple asymptomatic CMs (Tier 2) [2]

For individuals with either sporadic CCM of FCCM, sex hormones (including exogenous oral estrogen and progesterone) may increase risk of CM hemorrhage and caution regarding their use is recommended. (Tier 2) [2]

Caution is recommended with medications such as analgesics such as NSAIDs, antithrombotic medications such as heparin and warfarin (Coumadin), and thrombolytic agents. This recommendation includes certain analgesic medications such as nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen). Individuals with headaches and other pain should avoid these medications if suitable substitutes are available. Antithrombotic medications including anticoagulants and antiplatelet agents should be avoided or, when such medications are necessary for treatment of life-threatening thrombosis with close monitoring by the individual’s medical team. In a study, 40 patients with CCMs, 5 who presented with hemorrhage, were placed on antiplatelets alone (n=32), anticoagulants alone (n=6), or both (n=2) for the treatment of cardiovascular disease. One patient developed a prospective hemorrhage over 258 person-years of follow-up (prospective hemorrhage rate 0.41% per person-year). Within a hospital thrombolysis registry, 1 of 9 patients with CCM versus 11 of 341 without CCM had a symptomatic intracerebral hemorrhage (p=0.27). Parenchymal hemorrhage occurred in 2 of the 9 patients with CCM versus 27 of 341 patients without CCM (p=0.17). (Tier 3) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [1, 2, 3]

Prevalence of Genetic Variants

Following stringent inclusion criteria for FCCM (multiple lesions and/or family history consistent with FCCM), genetic testing of individuals with FCCM by direct sequencing and deletion/duplication analysis of KRIT1, CCM2, and PDCD10 results in a diagnostic rate between 75% and 98%. (Tier 3) [2, 4]

The exact prevalence of pathogenic variants (PVs) that lead to FCCM is unknown, though 53%-65% of cases of FCCM are attributable to PVs in KRIT1, 20% of cases are attributable to CCM2, and approximately 10-16% are attributable to PDCD10. (Tier 4) [1, 2]

Non-inherited de novo PVs are frequently identified in pediatric cases with PVs, particularly those with PVs in PDCD10. In a cohort of 16 children PDCD10 carriers with parental genetic screening, 44% were affected by de novo variants. (Tier 4) [2]

Penetrance

It is estimated that up to 60% of people with FCCM caused by a PV in KRIT1, CCM2, or PDCD10 are clinically asymptomatic, although many asymptomatic individuals have identifiable CCM lesions on head imaging. (Tier 3) [1, 5]

One study of 202 individuals (64 probands and 138 relatives, mean age at follow-up 42 years) who had a PV in KRIT1 reported a mean age of clinical onset of 30 years. Of all, 62% were symptomatic. Among the 138 non-proband relatives, 62 (45%) were asymptomatic; however, upon imaging 85% of asymptomatic relatives were found to have CMs. In all, 58% of those who were at least age 50 years had symptoms related to CM (Tier 3) [1]

In FCCM, 70%-86% of lesions are supratentorial and 16%-24% infratentorial in location. Of the infratentorial lesions, almost half occur in the brain stem (Tier 3) [1]

A meta-analysis of prospective studies evaluating the natural history of CMs, including 4 studies on FCCM, found 76% to 92% of individuals with FCCM (symptomatic and asymptomatic combined) had multiple lesions. Any hemorrhage rate was found to be 4.3% per person-year (either asymptomatic or symptomatic), and symptomatic hemorrhage as reported to be 1.43% per person-year (1 study, n=33). Mixed hemorrhage and rehemorrhage rates, both asymptomatic and symptomatic combined were 11% per person-year, whereas symptomatic rate ranged from 1.8% to 6.5% per person-year (3 studies, N=84). The annual hemorrhage rate in brainstem cavernomas was 1.43% (1 study, n=33). New lesion development was 32.1% per person-year (3 studies, N=80). Incidence rate of size change was 8% per person-year (95% CI 5.2% - 12.2%) (3 studies, N=84). (Tier 1) [7]

A prospective study that enrolled 386 FCCM individuals (300 with KRIT1 PVs) reported an overall symptomatic ICH rate of 2.8% per person-year (95% CI 1.9-4.1%). The median age at enrollment was 42 (IQR=21–55, range=0–85) and 236 (61%) were female. Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). (Tier 3) [2]

A retrospective review of 131 pediatric patients with CCM (mean age 8.4 years), including 35 cases with familial CCM, found that patients with familial CCM were noted to have a larger lesion size on average (5.26 cm3 vs 1.6 cm3, p = 0.047). These patients also had a shorter progression-free follow-up interval, with 50% of patients showing progression by 888 days, compared with only 15% of sporadic CCM patients during the same period (p=0.0019). Familial etiology of the disease and larger average lesion volume were independent, significant predictors of disease progression (p = 0.001, HR 3.29, 95% CI 1.65-6.54) and future hemorrhage (p = 0.023, HR 1.1, 95% CI 1.01-1.10), respectively. (Tier 5) [8]

A retrospective cohort study with 1592 patients with suspected FCCM (600 patients with FCCM confirmed via genetic testing) with a mean age of 37.6 years (SD 17.1), found that the lifetime risk of first symptomatic hemorrhage was ~80%, with an event rate that remained constant beyond age 20. The lifetime risk of a first seizure was ~45%. (Tier 5) [9]

Retinal vascular lesions have been reported in 5% of individuals with FCCM (Tier 3) [1]

Several studies have reported penetrance based on genotype:
•In one study of 18 individuals with PVs in PDCD10 whose mean age of first clinical symptom was 12.6 years (range 0.25-52 years), ICH rates per patient-year of 20% (95% CI 14%-28%) were reported since onset of symptoms and 24% (95% CI: 16%-35%) for recurrent hemorrhage. Correlation with CM count revealed that the annual risk of hemorrhage per CM (0.3%, 95% CI 0.2%-0.4%) is similar to other genotypes, indicating that the higher hemorrhage risk in individuals with PVs in PDCD10 was largely due to greater CM burden. (Tier 3) [2]

•In one cohort study of 29 individuals with known KRIT1 PVs, at least one spinal cord cavernous malformations was found in up to 70% of individuals. (Tier 3) [1]

•Vascular skin lesions have been reported in 9% of individuals with a PV in KRIT1. (Tier 3) [1]

Relative Risk

Information on relative risk was not available.

Expressivity

In general, the penetrance of all 3 FCCMs is greater in adults than children, and when using certain types of MR imaging. (Tier 4) [2]

For all three FCCM disorders, clinical severity is highly variable both within and between families. While patients with any of the three genetic disorders may suffer serious clinical sequelae, evidence suggests that, in general, KRIT1 PVs cause less severe clinical course and PDCD10 PVs cause more severe disease manifestations. (Tier 3) [2]

Individuals with a PV in PDCD10 have a greater chance of having increased CM burden, a younger mean age of presentation, and a younger mean age of presentation of symptomatic cerebral hemorrhage. (Tier 4) [2]

The penetrance of all three FCCM disorders is incomplete and dependent on age. Variable expressivity within families also occurs. (Tier 4) [2]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions included in this report include regular MRI surveillance, surgical excision of CMs, enhanced pregnancy monitoring, avoidance of antithrombotic and certain analgesic medications, and avoidance of radiation. Depending on the location of the CM being excised (e.g., brainstem), there can be high risks of early postoperative morbidity and mortality.
Surgical outcomes in children are generally excellent, with most pediatric series reporting a nearly 0% mortality rate and a 4% to 5% rate of new permanent deficit. Surgical
resection of the most common type of CM in children, supratentorial lobar lesions, provides
98% resection rates and abrogation of seizures in 96% of patients, with a 5% complication rate. Recurrence rates were lower with single lesions and greater in patients with multiple CMs or acute hemorrhage at time of surgery.
Long-term residual/recurrence rates vary from 11% to 23%, with higher rates reported in pediatric patients. Based on an average of 6 years follow-up, delayed postoperative hemorrhage has been found on follow-up in 5.6% of all cases and 29% of all known residual/recurrent CMs. A single center study of 126 patients who underwent resection of a CM reported that 24 out of 126 individuals (19%) had a CM post-surgical remnant. Of these, 7 had at least one post-operative hemorrhagic event. CM post-surgical remnant bleeding presented mostly with acute headache (50%) and focal neurological deficit (25%). [2, 4]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Most CCMs are detected incidentally or suspected when symptoms become evident. Although up to 60% of individuals are clinically asymptomatic, at least half of these individuals have identifiable lesions on brain imaging. (Tier 3) [1]

FCCM can be confused with an atrial myxoma embolizing to the brain. (Tier 4) [1]

Date of Search: 04.04.2017 (updated 07.29.2025)

Reference List

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2. Akers, Amy L. Albanese, John Alcazar-Felix, Roberto J. Al-Shahi Salman, Rustam Awad, Issam A. Connolly, Edward S. Danehy, Amy Flemming, Kelly D. Gordon, Errol Hage, Stephanie Kim, Helen Lanzino, Giuseppe Lee, Cornelia H. McCormick, Paul C. Mabray, Marc C. Marchuk, Douglas A. Smith, Edward Smith, Kelsey M. Srivastava, Siddharth Taylor, J. Michael Vadivelu, Sudhakar. Guidelines for the Diagnosis and Clinical Management of Cavernous Malformations of the Brain and Spinal Cord: Consensus Recommendations Based on a Systematic Literature Review by the Alliance to Cure Cavernous Malformation Clinical Advisory Board Experts Panel. Neurosurgery. (2025) Website: https://journals.lww.com/neurosurgery/fulltext/9900/guidelines_for_the_diagnosis_and_clinical.1651.aspx

3. Familial cerebral cavernous malformation. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=221061

4. Ferriero, Donna M. Fullerton, Heather J. Bernard, Timothy J. Billinghurst, Lori Daniels, Stephen R. DeBaun, Michael R. deVeber, Gabrielle Ichord, Rebecca N. Jordan, Lori C. Massicotte, Patricia Meldau, Jennifer Roach, E. Steve Smith, Edward R. on behalf of the American Heart Association Stroke, Council Council on, Cardiovascular Stroke, Nursing. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke. (2019) Website: https://doi.org/10.1161/STR.0000000000000183

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. CEREBRAL CAVERNOUS MALFORMATIONS; CCM. MIM: 116860: 2021 Oct 05. World Wide Web URL: http://omim.org.

6. da Fontoura Galvão G, Verly G, Valença P, Domingues FS, da Silva MR, Marcondes J. Early and long-term outcome of surgical versus conservative management for intracranial cerebral cavernous malformation: Meta-analysis of reconstructed time-to-event data. Clin Neurol Neurosurg. (2024) 246(1872-6968):108567.

7. Taslimi S, Ku JC, Modabbernia A, Macdonald RL. Hemorrhage, Seizures, and Dynamic Changes of Familial versus Nonfamilial Cavernous Malformation: Systematic Review and Meta-analysis. World Neurosurg. (2019) 126(1878-8769):241-246.

8. Jaman E, Abdallah HM, Zhang X, Greene S. Clinical characteristics of familial and sporadic pediatric cerebral cavernous malformations and outcomes. J Neurosurg Pediatr. (2023) 32(1933-0715):506-513.

9. Dammann P, Santos AN, Mavarani L, Guey S, Chabriat H, Herve D, Croft J, Renteria M, Jang D, Zhang J, Li D, Wu Z, Weng JC, Petracca A, Fusco C, D'Agruma L, Castori M, Rath M, Pilz RA, Felbor U, Steinberg GK, Gu J, Bervini D, Goldberg J, Raabe A, Cervio A, Villamil F, Rosales J, Rauschenbach L, Riess C, Oppong MD, Karadachi H, Ahmadipour Y, Wrede KH, Jabbarli R, Deuschl C, Li Y, Santos Piedade G, Köhrmann M, Frank B, Wälchli T, Schmidt B, Overstijns M, Beck J, Fung C, Al-Shahi Salman R, Flemming KD, Lanzino G, Zafar A, Weinsheimer S, Nelson J, Zabramski JM, Akers A, Morrison L, McCulloch CE, Kim H, Sure U, Brain Vascular Malformation Consortium Cerebral Cavernous Malformation Investigator Group. Lifetime Risk of First Symptomatic ICH or Seizure in Familial Cerebral Cavernous Malformations: A Multicenter Patient Data Analysis. Neurology. (2025) 105(1526-632X):e213798.