Cerebral Cavernous Malformation, Familial

Clinical characteristics.

Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord comprising closely clustered, enlarged capillary channels (caverns) with a single layer of endothelium without mature vessel wall elements or normal intervening brain parenchyma. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase or decrease in size and increase in number over time. Hundreds of lesions may be identified, depending on the person's age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades with findings such as seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with FCCM remain symptom free throughout their lives. Cutaneous vascular lesions are found in 9% of those with familial cerebral cavernous malformations (FCCM; see Diagnosis/testing) and retinal vascular lesions in almost 5%.

Diagnosis/testing.

The diagnosis of familial cerebral cavernous malformation (FCCM) is established in a proband with either or both of the following:

• Multiple CCMs, or one CCM and at least one other family member with one or more CCMs
• A heterozygous pathogenic variant in KRIT1, CCM2, or PDCD10

Management.

Treatment of manifestations: Surgical removal of lesions associated with intractable seizures or focal deficits from recurrent hemorrhage or mass effect may be considered. Treatment of seizures and epilepsy is symptomatic. Headaches are managed symptomatically and prophylactically. Acute and chronic neurologic deficits may be managed through rehabilitation.

Surveillance: Brain MRI imaging with gradient echo (GRE) or susceptibility-weighted imaging (SWI) is indicated in individuals experiencing new neurologic symptoms.

Agents/circumstances to avoid: Agents that increase risk of hemorrhage: aspirin, NSAIDs, heparin, and sodium warfarin (Coumadin^®). Note: When these medications are necessary for treatment of life-threatening thrombosis, careful consideration and close medical monitoring of dosage are warranted. Radiation to the central nervous system may lead to new lesion formation.

Evaluation of relatives at risk: Asymptomatic at-risk relatives of all ages may be evaluated by molecular genetic testing (if the family-specific pathogenic variant is known) to allow early diagnosis and monitoring of those at high risk of developing CCMs. Symptomatic relatives may undergo brain MRI with special sequences (GRE or SWI) to determine presence, size, and location of lesions.

Pregnancy management: Baseline MRI one year prior to delivery is recommended to determine lesion locations; pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine require closer monitoring during pregnancy; individulas with FCCM are at a higher risk for symptomatic cerebral hemorrhage during pregnancy than those with sporadic CCM; seizure is the most common symptom of CCM hemorrhage during pregnancy; exposure to antiepileptic medication during pregnancy may increase the risk for adverse fetal outcome but is generally recommended because the fetal risk is typically less than that associated with fetal exposure to an untreated maternal seizure disorder.

Genetic counseling.

Familial CCM is inherited in an autosomal dominant manner. The proportion of affected individuals with a de novo pathogenic variant is unknown. Each child of an individual with FCCM has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.

Suggestive Findings

Familial cerebral cavernous malformation (FCCM) should be suspected in individuals with the following clinical findings, brain imaging, histopathology, and family history.

Clinical findings

• Seizure disorder with onset at any age, but most typically between the second and fifth decades
• Focal neurologic deficits
• Nonspecific headaches
• Cerebral hemorrhage
• Vascular skin lesions (capillary malformations, hyperkeratotic cutaneous capillary venous malformations, venous malformations, red macules, and/or nodular venous malformations)
• Retinal cavernomas and rare choroidal hemangiomas

Brain imaging. Brain MRI using either gradient echo (GRE) or susceptibility-weighted imaging (SWI) demonstrating one or more cerebral cavernous malformations [Bulut et al 2014]:

• The characteristic lesion is of mixed signal intensity with a central reticulated core surrounded by a dark ring, which is presumed to be hemosiderin deposition from prior hemorrhage [Rigamonti et al 1987] (see Table 2).
• Lesions may appear as black dots, mixed signal intensity, or with rims of hemosiderin, fresh hemorrhage, or edema [Al-Shahi Salman et al 2008, de Souza et al 2008, Nikoubashman et al 2013, Nikoubashman et al 2015].

Note: Intravenous gadolinium contrast administration is not needed for identification of cavernous malformations, but is useful in identifying complex vascular malformations with arterial and venous components (which on rare occasion are associated with CCMs) and other types of vascular brain malformations including telangiectasias, arteriovenous malformations, and aneurysms.

Histopathology

• Closely clustered enlarged capillary channels (caverns) ranging from two to 55 mm (mean: 8 mm) with a single layer of endothelium without normal mature vessel wall elements or intervening brain parenchyma
• Thrombosis and intra- and extralesional hemorrhage. Edema may surround lesions with recent hemorrhage.

Family history. Two or more family members (including the proband) with cerebral cavernous malformations (CCM). Note: Individuals with a single CCM may have familial CCM; therefore, the presence of a single CCM in an individual with no family history of CCM (i.e., a simplex case) does not exclude the diagnosis of familial CCM (FCCM).

Establishing the Diagnosis

The diagnosis of familial cerebral cavernous malformation (FCCM) is established in a proband with either or both of the following:

• Multiple CCMs, or one CCM and at least one other family member with one or more CCMs
• A heterozygous pathogenic variant in KRIT1, CCM2, or PDCD10 identified by molecular genetic testing (see Table 1)

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and genomic testing.

Serial single-gene testing. Sequence analysis of KRIT1, CCM2, and PDCD10 is performed first (either sequentially or concurrently) followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

Several founder pathogenic variants that are useful for stratifying genetic testing in specific populations have been identified:

• In individuals with ancestry from northern Mexico and the American Southwest, the pathogenic p.Gln455Ter variant in KRIT1 is common.
• Gene-targeted deletion/duplication analysis for the CCM2 exon 2-10 deletion may be performed as part of the first tier of the testing strategy in individuals from the US, where up to 22% of affected individuals will have this pathogenic variant [Liquori et al 2007, Stahl et al 2008].
• In individuals of Ashkenazi Jewish descent a recurrent pathogenic variant in CCM2, c.30+5_30+6delGCinsTT, has been identified in multiple unrelated kindreds [Gallione et al 2011].

A multigene panel that includes KRIT1, CCM2, and PDCD10 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Neurologic findings. In familial CCM, up to 50% of individuals with a heterozygous pathogenic variant in either KRIT1, CCM2, or PDCD10 are clinically asymptomatic, although at least half of these individuals have identifiable CCM lesions on head imaging [Battistini et al 2007, Fischer et al 2013]. However, based on CCMs ascertained on autopsy, approximately 90% of individuals with either sporadic CCM or FCCM were asymptomatic [Otten et al 1989].

Cerebral cavernous malformation (CCM) has been reported in infants and children, but the majority of individuals with FCCM present with symptoms between the second and fifth decades. In one study, 9% of individuals were symptomatic before age ten years, 62%-72% between ages ten and 40 years, and 19% after age 40 years [Gunel et al 1996]. A more recent study of affected individuals found that 20% were younger than age ten years and 33% younger than age 18 years at the time of referral for genetic testing; the age of symptom onset was not cited [Spiegler et al 2014].

Clinically affected individuals most often present with seizures (40%-70%), focal neurologic deficits (35%-50%), nonspecific headaches (10%-30%), and cerebral hemorrhage (32%) [Denier et al 2004b]. Five percent of individuals with intractable temporal lobe epilepsy have CCM [Spencer et al 1984], although it is unknown how many of these individuals have FCCM.

Central nervous system hemorrhages may be intralesional or extend beyond the lesion [Al-Shahi Salman et al 2008]. In children, hemorrhage and an aggressive presentation were thought to be more likely than in adults [Lee et al 2008]; however, Al-Holou et al [2012] evaluated hemorrhage risk in affected individuals younger than age 25 years and found that it was similar to the rates in adults. In general, symptom onset in children with FCCM is earlier than in children with sporadic (i.e., non-genetic) CCM [Acciarri et al 2009].

Cavernous malformation can lead to death from intracranial hemorrhage or from complications of surgery [Acciarri et al 2009] particularly when found in the brain stem [Bhardwaj et al 2009, Abla et al 2010]. Of note, severe hemorrhage from CCM is less common than hemorrhage from arteriovenous malformations (AVM) [Selman et al 2000].

Brain MRI. Either gradient echo (GRE) or susceptibility-weighted imaging (SWI) is the imaging modality of choice. While larger, complex lesions are visible on routine T₁- and T₂- weighted MRI sequences, GRE MRI sequences reveal up to triple the number of lesions and SWI MRI sequences reveal an additional doubling or tripling [Cooper et al 2008, de Souza et al 2008]. Use of these sensitive imaging techniques may reveal hundreds of lesions [Petersen et al 2010].

Four characteristic types of lesions have been described [Zabramski et al 1994] by MRI and histology (see Table 2). Dividing CCM into these radiologic and histologic types is clinically useful in predicting hemorrhage risk [Nikoubashman et al 2015].

The medical significance of small lesions (classified as type 4) seen on MRI (sometimes referred to as cerebral dot-like cavernomas or black spot lesions) is unclear. For these lesions, a mean bleeding rate of 0.7% per lesion–year was found over a period of 5.5 years in 18 children with either an inherited or a de novo heterozygous pathogenic variant in KRIT1 or PDCD10. Of the ten inidividuals who had hemorrhages, only two were symptomatic [Nikoubashman et al 2013, Nikoubashman et al 2015].

FCCM is a dynamic disease on neuroimaging studies. Brunereau et al [2000] and Labauge et al [2001] determined that new lesions appear at a rate of between 0.2 and 0.4 lesions per patient-year. In both FCCM and sporadic CCM lesions may change in size and signal characteristics over time.

It had been assumed that individuals with familial CCM generally have multiple lesions while individuals who represent simplex cases (i.e., a single occurrence of a CCM in a family) have a single lesion; however, in a study of 138 individuals (62 symptomatic and 76 asymptomatic) with a heterozygous KRIT1 pathogenic variant, Denier et al [2004b] found that 26 (20%) appeared to have only one lesion when evaluated with T₂-weighted MRI sequences. Further examination with GRE sequence MRI of 12 of the apparently symptom-free individuals revealed multiple lesions in eight (66%) and a single detectable lesion in four (33%). Additionally, eight of the symptom-free individuals showed no lesion at all. Thus, approximately 13% of individuals with a heterozygous KRIT1 pathogenic variant had only one lesion detected when examined with T₂-weighted MRI and about 2% had only one lesion detected when examined with GRE sequence MRI. Since lesions are more readily identifiable using SWI, the number of clinically asymptomatic affected individuals is likely to increase as longitudinal studies using SWI are published.

Some studies have identified an increasing number of lesions in families by generation: five to 12 lesions in children and adolescents; 20 lesions in parents; and more than 100 lesions in grandparents [Horowitz & Kondziolka 1995]. This is likely related to ascertainment bias; it has not been borne out by subsequent studies.

Brunereau et al [2000] and Labauge et al [2001] determined that in familial CCM 76%-86% of lesions were supratentorial and 16%-24% infratentorial. Of the infratentorial lesions, almost half occurred in the brain stem. Brain stem lesions are frequently associated with symptoms [Fritschi et al 1994].

Spinal cord lesions are considered rare, reportedly occurring in fewer than 5% of affected individuals [Deutsch et al 2000, Badhiwala et al 2014]. In one large family with a known heterozygous KRIT1 pathogenic variant, spinal cavernous angiomas, either alone or associated with vertebral hemangiomas, were found in five of eight individuals studied using spinal MRI [Toldo et al 2009]. Cohen-Gadol et al [2006] found that 40% of persons presenting with a spinal CM had a similar intracranial lesion (CCM). In this same study 40% of persons with both spinal and intracranial CMs were simplex cases. Molecular genetic testing was not done in this study; however, multiplicity of spinal cord cavernous malformations are strongly suggestive of FCCM.

Other. Vascular lesions found outside of the central nervous system have been reported in association with multiple intracranial cavernomas (cavernous malformations) with and without confirmed heterozygous pathogenic variants in KRIT1, CCM2, or PDCD10.

• Vascular skin lesions have been reported in 9% of individuals with a heterozygous pathogenic variant in KRIT1 and less commonly in individuals with a heterozygous pathogenic variant in CCM2 or PDCD10 [Eerola et al 2000, Zlotoff et al 2007, Sirvente et al 2009, Toldo et al 2009, Kurlemann 2012, Campione et al 2013, Brownlee & Roxburgh 2014, Cigoli et al 2014, Bilo et al 2016].
  • In the 38 individuals with FCCM and cutaneous vascular malformations reported by Sirvente et al [2009], the skin lesions were classified as capillary malformations (13); hyperkeratotic cutaneous capillary venous malformation (15); venous malformations (8); and unclassified (2).
  • Bluish nodules and other subcutaneous nodules have been described in the venous malformations.
  • Some affected individuals have skin lesions removed secondary to bleeding, pain, protrusion, concern about cosmesis, or concern for malignancy.
• Retinal vascular lesions, reported in 5% of affected individuals, may include retinal cavernomas and (rarely) choroidal hemangiomas [Wood et al 1957, Sarraf et al 2000, Labauge et al 2006].
• Liver cavernoma have been reported in two Italian families with a heterozygous pathogenic variant in CCM2 but have not been confirmed to occur with an increased frequency in individuals with FCCM compared to individuals in the general population [Drigo et al 1994, Toldo et al 2009].
• Renal angioma has been reported in one affected individual of Italian descent [Battistini et al 2007].
• Atrial myxoma [Ardeshiri et al 2008, Sharma et al 2011] is rare and has not yet been definitively attributed to FCCM [Dobyns et al 1987, Drigo et al 1994, Labauge et al 1999, Eerola et al 2000, Chen et al 2002, Toldo et al 2009, Lanfranconi et al 2014].

Phenotype Correlations by Gene

The clinical course of FCCM varies within and between families; therefore, the following are generalizations.

KRIT1. Individuals with a heterozygous pathogenic variant in KRIT1 may have a less severe clinical phenotype than those with a heterozygous pathogenic variant in either CCM2 or PDCD10 [Gault et al 2006].

• Up to 50% of persons with FCCM caused by a heterozygous pathogenic variant in KRIT1 ultimately become symptomatic.
• Skin lesions may be more common in persons with a heterozygous KRIT1 pathogenic variant [Sirvente et al 2009, Campione et al 2013].

CCM2. Individuals with a heterozygous pathogenic variant in CCM2 have fewer brain lesions on GRE MRI, and the rate of lesion development is slower than in individuals with a heterozygous pathogenic variant in KRIT1 [Denier et al 2006].

PDCD10. Individuals with a heterozygous pathogenic variant in PDCD10 are most likely to present with hemorrhage and to have symptom onset before age 15 years [Denier et al 2006, Shenkar et al 2015].

• Individuals with pathogenic variants in this gene generally have the most severe clinical phenotype [Riant et al 2013, Shenkar et al 2015], including a higher risk of the following:
  • Lesion burden
  • Skin lesions
  • Scoliosis
  • Brain tumors (meningioma, astrycytoma, acoustic neuroma)
  • Cognitive disability unrelated to lesion burden or hemorrhage

Penetrance

KRIT1. Among 64 families with 202 individuals who were heterozygous for a KRIT1 pathogenic variant [Denier et al 2004b]:

• 62% were symptomatic;
• 58% of those who were at least age 50 years had symptoms related to CCM;
• 45 of 53 symptom-free individuals had lesions on MRI (3 had indications of a type 4 lesion; see Table 2) and five had no clinical or MRI findings of CCM.
  Note: SWI MRI, the most sensitive imaging technique for identifying CCMs, was not performed in this study.

PDCD10. Penetrance may be decreased in families with a heterozygous pathogenic variant in PDCD10 compared to families with a heterozygous pathogenic variant in KRIT1 [Denier et al 2006]. Penetrance may be specific to the pathogenic variant [Gianfrancesco et al 2007].

Prevalence

Based on autopsy studies, approximately 0.4%-0.5% of the general population have either sporadic CCM or FCCM [Otten et al 1989, Del Curling et al 1991, Robinson et al 1991]. The fairly common occurrence of asymptomatic vascular lesions in individuals with FCCM suggests that the population incidence of FCCM has been routinely underestimated [Verlaan et al 2002a, Johnson et al 2004].

There is a high incidence of FCCM in individuals of Mexican descent who have the pathogenic p.Gln455Ter variant in KRIT1 – a finding that could be attributable to inheritance from a common ancestor [Johnson et al 1995, Gunel et al 1996].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with familial cerebral cavernous malformation (FCCM), the following evaluations are recommended:

• MRI imaging of the brain and/or spinal cord if not already performed
  • Cerebral angiography may be considered to better define a complex lesion with arterial or venous components identified on brain MRI; however, caution should be used as cerebral angiography carries a small but appreciable risk of stroke.
• In those with epilepsy:
  • Electoencephalogram (EEG) and/or video-EEG
  • Wada testing (to determine which hemisphere is language dominant)
  • Magnetoencephalography to confirm the localization of the epilepsy and to exclude other epileptogenic lesions
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Recurrent hemorrhage or mass effect. Surgical removal of lesions associated with intractable seizures or focal deficits from recurrent hemorrhage or mass effect has traditionally been recommended [Heros & Heros 2000, Selman et al 2000, Folkersma & Mooij 2001]; however, a recent large prospective study in Scotland reported that surgical excision increased the overall risk of short-term neurologic disability, symptomatic intracranial hemorrhage, and new focal neurosurgical deficits [Moultrie et al 2014], calling this practice into question.

• Neuropsychological testing may be considered prior to any neurosurgical procedure.
• Microsurgical techniques rely on intraoperative examination for precise localization.
• Even when a large number of lesions are present, a surgical approach may be justified.

Gamma knife surgery or radiosurgery, while effective, appears to increase the risk of recurrent hemorrhage and remains unproven [Wang et al 2010, Steiner et al 2010]. Very large single lesions can be difficult to ablate, especially in the brain stem. In these instances, radiosurgery may be an option [Monaco et al 2010].

• In a group of individuals with symptomatic cavernous malformations studied in Japan, radiosurgery using varying doses of radiation for deep lesions was compared with conservative (nonsurgical) management. Doses less than 15 Gray (Gy) were associated with the lowest level of complications. Complications were also lower when the lesions were of smaller size, with overall hemorrhage rates reduced initially but reverting to a rate similar to that of the natural history after the first two years post-radiosurgery [Kida et al 2015].
• A study that carefully reviewed post-radiosurgery changes in individuals with CCM or AVM found that more than 30% developed radiation necrosis [Blamek et al 2010].

Seizures. Standard treatment for focal seizures using antiepileptic medication with early evaluation for surgical resection is appropriate (see Recurrent hemorrhage or mass effect).

Headaches. Standard treatment and management of headaches is indicated unless the headache is severe, prolonged, or progressive, or associated with new or worsening neurologic deficits. In this circumstance, urgent brain imaging could lead to surgical management.

Neurologic deficits. Rehabilitation is indicated for those with temporary or permanent neurologic deficits.

Surveillance

Brain MRI imaging with GRE or SWI is indicated in individuals experiencing new neurologic symptoms. Interpretation can be difficult because new hemorrhages may be asymptomatic.

Agents/Circumstances to Avoid

Limited evidence suggests an increased risk of hemorrhage with certain analgesic medications such as nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen) and aspirin. Individuals with headaches and other pain should avoid these medications if suitable substitutes are available.

Other medications that increase risk of hemorrhage (e.g., heparin, sodium warfarin [Coumadin^®]) should be avoided or, when such medications are necessary for treatment of life-threatening thrombosis, should be closely monitored by the affected individual's medical team [Schneble et al 2012, Flemming et al 2013, Erdur et al 2014].

The use of narcotic pain medications is also discouraged in chronic pain conditions because of the potential for addiction and because of their association with rebound headaches.

Radiation to the central nervous system is associated with de novo lesion formation in FCCM [Larson et al 1998, Nimjee et al 2006, Golden et al 2015]. The pathology of these lesions appears to be histologically different from the cavernomas found prior to radiation [Cha et al 2015].

Evaluation of Relatives at Risk

It is appropriate to evaluate both symptomatic and apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of screening and preventive measures.

Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known.
• Brain and/or spinal cord MRI imaging including GRE or SWI if the pathogenic variant in the family is not known

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine will require closer observation during pregnancy. Baseline MRI one year prior to delivery is recommended to determine lesion locations [De Jong et al 2012, Witiw et al 2012, Yamada et al 2013].

Simonazzi et al [2014] reported six women with CCM who had symptoms such as seizure or focal neurologic deficit during pregnancy or within six weeks post-delivery. Reviewing the literature they found ten further cases in which pregnancy outcome was published. Of the 16 women, hemorrhage occured in ten. Preterm delivery occurred in four of six cases, one because of neurologic symptoms at 30 weeks. Cæsarean (C-)section was performed in nine cases, eight of which were for concern over CCM.

Affected women and obstetricians are frequently concerned that the risk of increased blood pressure and intrathoracic pressure during stage 3 labor (pushing phase) could lead to CCM hemorrhage. However, in a study of 168 pregnancies (64 women), 28 with sporadic CCM and 36 with FCCM, only five symptomatic cerebral hemorrhages were reported, most commonly manifesting as seizures. Nineteen deliveries in this study were by C-section, mostly due to fear of possible intracranial hemorrhage. The risk of CCM hemorrhage was higher in the familial cases (3.6% compared with 1.8% in sporadic cases) [Kalani & Zabramski 2013].

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Recent advances in the understanding of the pathobiology and molecular signaling of the CCM proteins (see Molecular Genetics) has identified several pathways which may be amenable to drug targeting. These are being investigation in in vitro assays and in live animal models.

Fasudil, a specific Rho kinase inhibitor, has been demonstrated in Krit1(+/-) and Ccm2 (+/-) mouse models of FCCM to reduce both lesion size and number, as well as to lesson hemorrhage, proliferation, and inflammation [Stockton et al 2010, McDonald et al 2012]. Fasudil is approved in Japan for treatment of vasodilation; it is not currently available with FDA approval in the United States.

Statin medications are nonspecific Rho kinase inhibitors and may be suitable for repurposing to treat CCM lesions. Strong in vitro data [Whitehead et al 2009] led to simvastatin being studied in people with CCM who are eligible to take this medication for other indications such as hyperlipidemia. This trial is in the final data collection and analysis phase (ClinicalTrials.gov identifier: NCT01764451). However, a Ccm2 knockout mouse model treated with simvastatin did not show a significant decrease in lesion burden, raising questions about dosing and efficacy of statin drug therapy [Gibson et al 2015]. A further proof-of-concept human trial is planned for atorvastatin therapy (ClinicalTrials.gov identifier: NCT02603328).

The chemotherapeutic drug sorafenib [Wüstehube et al 2010] has been investigated in murine models of FCCM caused by mutation of KRIT1 with the finding of reduced capillary sprouting.

Loss of function of KRIT1 leads to an increase in signaling of the TGFβ pathway leading to an inappropriate endothelial-to-mesenchymal cellular transition (EndMT): endothelial cells change to become more proliferative, with increased invasiveness and sprouting. Chemical inhibition of TGFβ decreases both the size and number of CCM lesions in mouse models [Maddaluno et al 2013]. Furthermore, inhibition of upstream Wnt/B-Catenin signaling related to EndMT with the drug sulindac restores junctional integrity between endothelia, and also reduces number and size of CCM lesions in a Pdcd10 knockout mouse model [Bravi et al 2015]. Sulindac is used clinically in humans for other indications, including for the treatment of colon cancer.

A repurposing drug screen identified vitamin D₃ (cholecalciferol) and tempol (a superoxide scavenger) as potential therapeutic drugs for CCM. Both of these molecules reduced lesion number in mouse models of CCM [Gibson et al 2015]. Vitamin D₃ inhibits the signaling activation of RHOA, while tempol targets superoxide, suggesting a role for oxidative stress in CCM disease pathogenesis.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.