Continuing Education Activity

Cerebral cavernous malformations (CCMs), also known as cavernomas or cavernous hemangiomas, are clusters of abnormal capillaries lacking intervening brain tissue. Hemosiderin deposits and gliosis often surround these low-flow, low-pressure vascular lesions due to recurrent microhemorrhages and thrombosis. CCMs can be asymptomatic or present with seizures, headaches, focal neurological deficits, or symptomatic hemorrhages. While most are sporadic, up to 20% have a familial autosomal dominant inheritance pattern. The average annual risk increases after a prior hemorrhage with factors, eg, location, presence of associated developmental venous anomalies, and patient demographics influencing hemorrhage risk. 

CCMs range in diameter from under a millimeter to several centimeters and may occur anywhere in the central nervous system, with up to 20% located in the brainstem. CCM may be diagnosed in both young children and adults and may develop de novo or even regress spontaneously during a patient's lifetime. Diagnosis is typically made through characteristic lesions on imaging. Management includes conservative observation for asymptomatic lesions, while symptomatic cases may warrant surgical resection or, in specific cases, stereotactic radiosurgery. Genetic testing and counseling are recommended for familial cases. The natural history and treatment strategies for CCMs continue to evolve, emphasizing the importance of individualized care. This activity for healthcare professionals is designed to enhance the learner's competence in recognizing CCMs, performing the recommended evaluation, and implementing an appropriate interprofessional management approach to improve patient outcomes.

Objectives:

• Identify clinical features of cerebral cavernous malformations.

• Determine appropriate diagnostic studies when evaluating patients with cerebral cavernous malformations.

• Implement recommended management approaches for patients with cerebral cavernous malformation.

• Apply interprofessional team strategies to improve care coordination and outcomes in patients with cerebral cavernous malformations.

Introduction

Cerebral cavernous malformations (CCMs) are abnormally large collections of "low flow" vascular channels without brain parenchyma intervening between the sinusoidal vessels (see Images. Pons Cavernoma, Head CT, Cavernous Malformation).[1][2] McCormick (1966) recognized CCMs as a class of cerebral vascular malformations, which include arteriovenous malformations, developmental venous anomalies (DVA), and capillary telangiectasia. Due to recurrent microhemorrhages and thrombosis, they are typically surrounded by hemosiderin deposits and gliosis. These lesions have slow flow and low pressure, causing the average rupture risk to be much lower than some other vascular malformations, eg, arteriovenous malformations. Cavernomas are often found incidentally but can also present during the evaluation of headaches, seizures, focal neurologic deficits, or symptomatic hemorrhage.[3] 

Clinically, CCMs are highly variable in both symptomatic presentation and natural history. Adding to the confusion, CCM is referred to by various terms in the medical literature, including cavernomas, cavernous angiomas, and cavernous hemangiomas, although CCM is the preferred nomenclature (see Image. Cerebral Cavernous Hemangioma).[2] CCMs range in size from punctate to several centimeters in diameter and may occur anywhere in the central nervous system, with up to 20% of them located in the brainstem.[4] CCM may be diagnosed in both young children and adults and may develop de novo or even regress spontaneously during a patient's lifetime. A thorough understanding of this entity's natural history is paramount to avoid unnecessary and potentially morbid interventions. Given the heterogeneity of this condition, the ontogenesis, diagnosis, and management strategies for CCMs are subjects of ongoing debate among neuroscientists, and treatment paradigms continue to evolve.

Etiology

Experts do not fully understand the pathogenesis of CCMs, but the genetic underpinnings have been clarified in recent years. CCMs may be sporadic or have a familial cause. Some studies report that up to 20% of cases follow a familial, autosomal dominant inheritance pattern, while others estimate that between 40% and 60% of cases are familial.[3][5][6] Sporadic cases tend to present with a single CCM, while familial cases are characterized by multiple CCMs in a single patient.

Evolving understanding of genetic associations with CCMs has led to identifying 3 homologically distinct genes responsible for CCM development: CCM1/KRIT1, CCM2/Malcavernin, and CCM3/PDCD10 genes located on the 7q, 7p, and 3p chromosomes, respectively.[7][8][9][8] Those expressed genes encoded by the CCM genes interact in neural tissue with capillary endothelial tight junctions and cytoskeletal proteins during angiogenesis.[3] A common deletion in CCM2 was found to be responsible for clustering among Ashkenazi Jews.[10] Many authors have proposed a "2-hit" hypothesis of familial CCM wherein epigenetic or environmental exposure (the second hit) results in CCM gene loss-of-function and may account for the proclivity of these lesions to accumulate over time and with radiation exposure.[11] Studies of sporadic CCM support a common pathway involving de novo mutations of CCM genes.[9]

Interactions occur between various CCM protein products as well as between these products and other cellular machinery responsible for a range of functions, including cell-cell communication and angiogenesis. The most critical dysfunction identified in CCM mutations is endothelial junction permeability, an effect mediated by Notch1 and Rho kinase activity.[12] This correlates with the characteristic histopathological appearance of CCM, which lacks mature vessel wall architecture and a mature blood-brain barrier.[13] CCMs are distinguished from other cerebral vascular malformations by the absence of direct arteriovenous communication and lack of intervening brain parenchyma.

Recently, genetic studies on the surgically resected lesions from sporadic cases lacking inherited germline mutations have shown somatic mutations of the same 3 CCM genes. This could point towards identical molecular mechanisms in both familial and sporadic CCMs.[14]

Cerebral Cavernous Malformation Risk Factors

The average annual hemorrhage rate is estimated at 0.7% to 1.1% per lesion in patients without a history of prior hemorrhage.[7] However, this risk rises to approximately 4.5% in patients who have sustained previous intracerebral hemorrhage.[7] Approximately 2 to 3 years after a hemorrhagic event, the risk of hemorrhage is thought to decrease. Furthermore, rupture risk varies based on the CCM's location, associated developmental venous anomalies, and gender.[15] Infratentorial location, deep location, young age, and female gender are associated with increased risk.[7][16] Asymptomatic familial cases are also thought to have a higher annual hemorrhage rate than asymptomatic sporadic cases.[16] CCMs may also arise de novo and grow, shrink, or remain stable over time.[17][18]  Brainstem lesions and CCM3 familial cases with PDCD10/CCM3 mutations are associated with a greater risk of bleeding. Cavernous angiomas with symptomatic hemorrhage (CASH) include lesions that impact a patient’s life and merit clinical intervention.

Epidemiology

The incidence of CCMs is approximately 0.4% to 0.8% in the general population.[7] Though uncommon, CCMs are the most common cerebral vascular abnormality, accounting for 10% to 25% of all vascular malformations.[7] Moreover, CCMs are the second most common incidental vascular finding, after aneurysms, on brain magnetic resonance imaging (MRI), with a prevalence of 1 in 625 neurologically asymptomatic people.[19][20][21][22]

Clinical presentation is bimodal, with a significant number of cases detected in both adolescents and middle-aged adults. No discernible sex difference in prevalence has been noted; however, conflicting research has been reported on whether prognosis differs among men and women.[23] Familial CCM is notably prevalent among persons of northern Mexican ancestry, compared with other populations, with rates as high as 50%, an effect traced to a common founder mutation.[8][1] The incidence of incidentally detected CCM has increased substantially due to the widespread use of MRI.[24] The majority (approximately 75%) of CCMs are found in the supratentorial compartment in predictable proportion to the volume of neural tissue present.[25]

Pathophysiology

The chief mechanism underlying the clinical manifestations of CCM is the propensity for intralesional and extralesional hemorrhage. Sluggish blood flow through dysplastic channels results in recurrent thrombosis, calcification, and hemosiderin deposition along the lesion's margins. Hemorrhage into adjacent brain parenchyma can produce focal neurologic deficits (FND), seizure, or headache, prompting the patient to present for evaluation. 

Clinical and lifestyle risk factors for a first symptomatic episode of CCM hemorrhage are unknown, but risk factors for repeated hemorrhage are well-studied.[2] The pathogenesis of CCM-related epilepsy has been attributed to perilesional reactive gliosis due to clinically silent microhemorrhages, which alter the conduction of adjacent white matter pathways. The observation that seizure-free outcomes are improved when the entire lesion is resected, including the surrounding hemosiderin rim, supports this.[26]

Histopathology

Histopathologically, CCMs are well-circumscribed, multilobate vascular lesions consisting of sinusoidal channels lined by a single layer of epithelium, devoid of smooth muscle and lacking intervening brain parenchyma. Gliosis and hemosiderin deposits are seen along the margins. On gross inspection, CCMs appear "mulberry-like." Light microscopy shows an absence of a smooth muscle wall layer, and electron microscopy shows abnormalities in endothelial gap junctions.[27][25]

History and Physical

Clinical Features of Cerebral Cavernous Malformations

While the clinical presentation of symptomatic CCMs varies by location, the most common clinical manifestations are seizures (50%), intracranial hemorrhage (25%), and FND without radiographic evidence of recent hemorrhage (25%).[2][28] A review by Ene and colleagues found that the most common presentation of CCMs was seizures at an average of 40.6% of CCM cases.[16] Supratentorial lesions are most commonly present with seizures, whereas FND or ataxia is the most common presentation in patients with infratentorial lesions.[29] Between 6% and 65% of patients are asymptomatic and diagnosed incidentally on brain MRI.[2][20][24][3]

When CCM is diagnosed, clinicians should perform a thorough history for evidence of prior symptomatic hemorrhage and a comprehensive neurologic exam to assess for the deficit, which may otherwise have been unrecognized. Headaches are common in patients with CCM, and determining a causal relationship may be difficult. Similarly, CCM-related epilepsy (CRE) can present a diagnostic challenge as seizure focus may be challenging to localize. The criteria for CRE have been defined by expert consensus and can be broadly categorized as "definite," "probable," or "unrelated to CCM" based on the proximity of localized seizure focus to the CCM.[30] 

Given the high prevalence of familial CCM, the Angioma Alliance advocates obtaining a detailed 3-generation family history when MRI diagnoses new CCM. When multiple CCMs are present or the family history is positive, genetic screening for CCM1, CCM2, and CCM3 should be considered. Given the autosomal dominant nature of CCM inheritance, appropriate counseling regarding familial risk is warranted, and risk-benefit discussion regarding testing asymptomatic relatives should be offered.[2]

Evaluation

Imaging Modalities and Diagnostic Features

The American College of Radiology (ACR) Appropriateness Criteria provide expert consensus recommendations for acute neurologic symptoms, including a headache, FND, and altered consciousness.[31] Guidelines for imaging follow-up of known CCM are not well-established, but imaging is generally recommended that new symptoms warrant repeat imaging to assess for acute or subacute hemorrhage.[2][6]

CCMs are low-flow vascular lesions that present diagnostic challenges due to their small vessel size and angiographically occult nature. Recognition of these lesions is vital for appropriate management. A detailed understanding of imaging and diagnostic criteria, supported by advanced techniques, enhances the clinician's capability to manage CCMs effectively while minimizing unnecessary interventions. 

The Angioma Alliance has established standardized definitions for CCM-related hemorrhage, emphasizing symptom-imaging concordance and biomarker identification to improve diagnostic consistency among neuroimagers and clinicians.[6]

Magnetic resonance imaging

When parenchymal hemorrhage is diagnosed, follow-up imaging with contrast-enhanced MRI is indicated to assess for an underlying vascular lesion. Whether symptomatic or incidentally detected, the majority of CCMs are diagnosed by MRI (see Images. Cortical Cavernoma, Third Ventricular Cavernoma, and Third Ventricular Cavernoma, Sagittal View).[6][24][1][32] MRI is nearly 100% sensitive for CCM detection, making it the diagnostic modality of choice. MRI is particularly effective in familial CCM, where multiple lesions are often present. T2-weighted imaging reveals the characteristic "popcorn" core with a hypointense hemosiderin rim.[25] Gradient-echo (GRE) and susceptibility-weighted imaging (SWI) sequences highlight the "blooming" artifact caused by hemosiderin deposition, though this may exaggerate lesion size.[2][6]

Advanced MRI techniques, such as diffusion tensor imaging (DTI) and functional MRI, aid preoperative planning by mapping critical white matter tracts and eloquent brain regions.[7][3][33] Functional MRI techniques, eg, blood oxygen level-dependent task-activation mapping of language function, are highly accurate and noninvasive tools that have proven useful in the preoperative workup of CCM.[34] New techniques like high-field SWI and advanced MR imaging are improving lesion characterization and risk stratification, particularly for surgically complex cases. Emerging techniques like quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) are under investigation as biomarkers for disease activity.[35][36]

Computed tomography imaging

Computed tomography (CT) is less sensitive and specific for CCM but can identify hemorrhage or amorphous calcifications in symptomatic patients. Contrast enhancement may highlight the lesions, but significant edema or mass effect is rare unless a recent hemorrhage has occurred (see Image. Pons Cavernoma, Head CT). CT is primarily used to rule out acute hemorrhage, with MRI needed for definitive diagnosis unless contraindicated.[37]

Angiography

CCMs are characteristically angiographically occult lesions due to the slow transit of blood via the dysplastic channels. However, associated DVAs may be visible on CT angiography or digital subtraction angiography, often enhancing briskly and serving as indirect evidence of CCM (see Image. Cavernous Malformation).[38] The presence of DVAs can impact surgical planning and hemorrhage risk assessment. Multiple CCMs associated with a single DVA suggest a sporadic origin rather than familial.

Zabramski Classification and Hemorrhage Risk

The Zabramski classification categorizes CCMs according to the following types based on their MRI appearance (see Image. Cavernoma, Zabramski Classification):

1. Type I: Hyperintense on T1 and T2 due to subacute hemorrhage
2. Type II: The classic "popcorn" lesion with mixed signal intensities reflecting hemorrhages at various stages
3. Type III: Chronic resolved hemorrhage presenting with an isointense core
4. Type IV: Small capillary telangiectasias only visible on GRE sequences [39][3]

Type I and II lesions may carry a higher risk of hemorrhage, sometimes prompting consideration of surgical intervention.[39][3]

Treatment / Management

Management of Cerebral Cavernous Malformations

The clinical course of CCMs is highly variable and primarily determined by lesion location.[25] This variability necessitates a thorough evaluation of patient-specific factors, including risk tolerance and lesion characteristics, to guide management and therapeutic decisions. Interprofessional discussions are essential for determining the optimal approach for each patient. CCM management requires a tailored approach balancing surgical risks, natural disease progression, and patient-specific factors. Conservative management, surgical intervention, and advanced techniques form the foundation of current treatment paradigms, with ongoing research expanding therapeutic options.

Conservative management

For asymptomatic patients with solitary lesions, observation is the preferred strategy.[2] This approach is supported for cases with supratentorial lesions in noneloquent areas and for patients whose risk of surgery outweighs the potential benefits. Conservative management typically includes clinical and radiographic surveillance.

Surgical management

Microsurgical resection remains the only definitive treatment for CCMs but is associated with significant challenges and potential postoperative morbidity, which can sometimes exceed the risks posed by the untreated lesion.[40] The following considerations are involved with surgical management:

• Indications for surgery
  • Symptomatic lesions: Surgery is often considered for symptomatic lesions, especially in noneloquent, supratentorial locations where resection is associated with high success rates and low complication rates.[41]  
  • Medically refractory epilepsy: Early surgery is favored for patients whose epilepsy is linked to a solitary CCM confirmed as the epileptogenic focus. This approach may prevent a "kindling" effect, improving seizure outcomes.[2][26][30]
  • Brainstem lesions: CCMs located in the deep gray nuclei and brainstem pose a much more significant challenge. Studies using DTI and diffusion tensor tractography have shown that up to 82% of patients with brainstem lesions have involvement of the corticospinal tract and other major fiber tracts[42], highlighting the extreme difficulty neurosurgeons face with patient and approach selection (see Images. Brainstem Cavernoma, Pontine Cavernoma, and Pontine Cavernoma, Sagittal). While good outcomes may be achieved in surgically resected brainstem lesions at high-volume, specialized centers, complication rates are high, and new postoperative neurologic deficits are expected (53% of cases).[43] While surgery is not typically recommended for brainstem CCMs due to a significant risk of complications, many recommend operating after a second symptomatic bleed due to a potentially aggressive natural course. Indications for resection of brainstem CCMs after a single disabling hemorrhage or spinal CCMs are more controversial.[2] Favorable outcomes are more likely for pial-presenting brainstem lesions. With image guidance, appropriate patient and approach selection, and detailed knowledge of the intrinsic brainstem anatomy, these lesions can be safely resected with good outcomes.[44]

• Surgical techniques

  • Complete lesionectomy is the primary goal, with resection of hemosiderin-stained gliotic brain when seizures are the indication.[26] Techniques include frameless stereotactic guidance, electrocorticography, and intraoperative MRI for precision.[45]
  • DVAs, which often coexist with CCMs, must be preserved to avoid venous infarction.
  • Surgical strategies depend on lesion size; smaller lesions may be excised en bloc, while larger ones often require piecemeal excision.[25]
  • Postoperative MRI within 72 hours is recommended to confirm complete resection, as incomplete removal is associated with a high rebleeding risk (approximately 40%).

Stereotactic radiosurgery

Stereotactic radiosurgery (SRS) is a noninvasive alternative for treating anatomically inaccessible or high-risk symptomatic lesions. SRS is highly accurate and allows targeted delivery of high-dose radiation (typically 11 to 15 Gy) with sparing of adjacent, healthy brain parenchyma. The mechanism of therapeutic SRS is uncertain; lesion size may decrease, remain stable, or even increase, and no reliable imaging biomarker for successful CCM obliteration has been established, as with metastasis and high-flow vascular lesions.[46] SRS is most effective after a latency period of about 2 years, during which hemorrhage risk reduction is observed. While it may reduce annualized hemorrhage rates (eg, from 33% to 12.3% within 2 years and <1% after).[47]  A recent meta-analysis found a modest reduction in hemorrhage rates with a substantial incidence of radiation-related complications (11%), including new focal neurologic deficits, hydrocephalus, and painful paresthesia.[46] SRS is also strongly linked to the development of de novo CCM, although such cases rarely become symptomatic.[48] Because radiation-induced damage in the brainstem can be devastating, SRS is not recommended as a treatment option for brainstem CCMs.[44]

Complications include radiation-induced FND, hydrocephalus, and paresthesia (approximately 11% incidence). Brainstem CCMs are generally not treated with SRS due to the potential for devastating complications. SRS is still seen with an eye of suspicion as its benefit is not conferred for at least 2 to 3 years after treatment, concurrent with the period of temporal hemorrhage clustering. New techniques, such as MRI-guided laser interstitial thermal therapy (LIIT), show promise as minimally invasive alternatives for select cases.[49]

Medical management and experimental therapies

Medical treatment for CCMs remains investigational. Preclinical studies suggest that Rho-kinase inhibitors, statins, and vitamin D may reduce symptoms and lesion progression.[50][51] Anticoagulant and antiplatelet therapies have not been associated with increased hemorrhage risk in patients with CCMs treated for other conditions.[52]

Genetic considerations

Genetic testing is advised for patients with multiple CCMs or a family history of the condition. Genetic counseling should be offered to the patient and their family if mutations are identified.[2] Screening MRIs are recommended for first-degree relatives of patients with familial CCMs.

Special considerations and guidelines

The following recommendations should be kept in mind in the management of CCMs:

• According to the 2017 Angioma Alliance Care Guidelines, surgical resection is not recommended for asymptomatic lesions, particularly those in eloquent or deep brain regions.
• Surgery may be considered for solitary, asymptomatic CCMs in accessible, noneloquent locations to prevent future hemorrhages and alleviate psychological burden or lifestyle restrictions.
• Brainstem CCMs may warrant surgery after a second symptomatic bleed due to their potentially aggressive natural history.
• The risks of surgical morbidity should be weighed against the natural history of the disease. While microsurgical resection is curative for intractable cases, most patients with supratentorial CCMs are managed conservatively either with radiographic and clinical observation alone or in addition to antiepileptic drugs, as the current first-line management strategy.[25] 

Differential Diagnosis

Classic CCM rarely poses a diagnostic dilemma as the radiographic differential diagnosis for isolated T2 artifact, a nonenhancing lesion on MRI, is limited. When numerous small CCMs are present, as is often the case with familial CCM, the differential diagnosis is broad and includes other etiologies of diffuse cerebral microbleeds, including cerebral amyloid angiopathy, chronic hypertension, and hemorrhagic or previously treated metastases, among others. Lesion calcification, which can be detected on routine noncontrast head CT, favors the diagnosis of CCM over other types of microbleeds. Finally, the coexistence of a DVA strongly supports the diagnosis of CCM.[38]

Prognosis

The natural history of CCM has been characterized in several large studies.[5][23][39][28] The overall annualized hemorrhage rate in untreated CCM is estimated at 2.4%, with a predicted cumulative 5-year risk of hemorrhage of 15.8% from the time of diagnosis.[32][22] For patients with incidentally detected CCM, the risk of hemorrhage is substantially lower, estimated to be 0.33% per year.[5] 

Rates of epilepsy in incidental lesions are similarly low at 1% to 2%.[30] Conversely, patients who have a documented history of CCM hemorrhage are at significantly greater risk of repeat hemorrhage (23% 5-year rate), a finding which has been replicated in multiple large case series and meta-analyses to date.[5][24][32][53] CCMs display a phenomenon termed temporal clustering wherein hemorrhage tends to reoccur within the first 2 to 3 years after a prior hemorrhage. After this initial clustering of hemorrhage events, a relatively quiescent period where no overt hemorrhages occur may be seen.[25][54] Prior hemorrhage is a significant risk factor for future hemorrhagic events.[25] 

Several factors have been associated with CCM rupture, including lesion location, size, multiplicity, and an associated DVA.[55][53][32] Studies have shown that supratentorial lobar CCMs have a much more benign prognosis than deep lesions in the thalamus, basal ganglia, or posterior fossa. In one study, the event rate for superficial lesions was 0% per year, while that for deep lesions was 10.6% per year (P = .0001).[25][56] Brainstem CCMs are the most dangerous and have a high relative event rate (4- to 7-times more likely to rupture than isolated supratentorial lesions).[53][43] In one meta-analysis, nonbrainstem hemorrhage rates were reported to be 0.3% per year vs. 2.8% per year for brainstem lesions.[53] 

Also of note, the initial presentation of patients with intracranial hemorrhage or FND and brainstem location was independently associated with a hemorrhage over the 5 years after the initial diagnosis.[22][25]  Female gender as a risk factor for hemorrhage remains a topic of debate.[23][22] In familial CCM, more aggressive CCM behavior has been observed in CCM3 mutants, contrasting with a more benign clinical course in CCM1 deletions.[57][9]

Complications

The risks and benefits of surgical or radiotherapeutic intervention must be assessed on a case-by-case basis, and the prospective risks of untreated CCM must be balanced with the anticipated intervention morbidity. The overall mortality associated with CCM hemorrhage is low, estimated at 2.2%, but progressive neurologic deficits can accumulate and reduce a patient's quality of life.[53] In the hands of experienced surgeons with appropriate patient selection, postoperative morbidity can be quite low, with a recent estimate of 1.5%.[58] Nonetheless, when feasible, conservative management may be favorable, as shown in a recent prospective study in which CCM excision worsened short-term disability and increased the risk of neurologic deficit or recurrent hemorrhage.[40]

Postoperative and Rehabilitation Care

Although there are no guidelines on the role of antiepileptics following surgical resection of CCM, patients are typically maintained on antiepileptic monotherapy following surgery.[59] Seizure-free outcomes following surgery are dependent on various factors such as preoperative seizure frequency, the extent of CCM resection, the extent of perilesional "hemosiderin-ring" resection, and timing of surgery relative to the initial presentation.[60][61] Antiepileptic drug withdrawal following surgery should be planned with appropriate dose tapering to reduce the risk of seizure recurrence.[62][63]

Consultations

Neurosurgery consultation is recommended for the management of patients with a cerebral or spinal CCM.

Deterrence and Patient Education

Patients with CCM are encouraged to explore the official website of the multidisciplinary Angioma Alliance. The Angioma Alliance is dedicated to providing up-to-date patient resources, including educational videos. Information is provided regarding genetic testing, participation in ongoing clinical research, and tissue banking. The Angioma Alliance also offers social support via online forums and social media sites, allowing patients and family members to support one another and share their experiences with CCM.

Some activity restrictions, including mountain climbing above 10,000 feet, smoking, water activities, and contact sports, may be considered for people with CCMs, though the effectiveness of these recommendations is not proven. Most studies suggest that antiplatelet medications (for other conditions, if needed) are safe in these patients.

Pearls and Other Issues

RhoA/Rho kinase pathway is seen as a potential target for the pharmacotherapeutic treatment of CCMs. Normally, CCM2 and CCM1 act together to suppress RhoA. CCM1 and CCM2 deficiency leads to constitutively active Rho-kinase (ROCK), destabilizing endothelial cell junctions and vascular permeability.[64] ROCK suppressants have been experimentally shown to enable vasculogenesis in CCM1-, CCM2-, and CCM3-deficient cells.[65] Fasudil, a ROCK inhibitor, has been shown to decrease the lesion burden in CCM1-deficient mice.[66]

While CCM1, CCM2, or CCM3 deficiencies have been shown to activate bone morphogenic protein (BMP) and transform growth factor-beta (TGF-beta), causing an endothelial-to-mesenchymal transition (EndoMT), inhibiting either BMP or TGF-beta was found to decrease the lesion burden in CCM1-deficient mice representing another avenue of research in CCM therapy.[67] Similarly, suppressing Beta-catenin was also found to reduce the number and size of CCMs in a CCM3-deficient mice model.[68] These findings demonstrate the importance of a thorough understanding of the molecular biology underpinning CCM.

Enhancing Healthcare Team Outcomes

Effective management of CCMs relies on a collaborative, patient-centered approach involving physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals. Each team member contributes specialized skills and assumes distinct responsibilities, emphasizing interprofessional communication and care coordination to enhance patient safety, clinical outcomes, and team performance. Physicians, including neurologists and neurosurgeons, play a central role in diagnosing CCMs, determining treatment plans, and performing surgical interventions when indicated. They work closely with advanced practitioners, who provide detailed patient education, conduct follow-ups, and coordinate care transitions, ensuring continuity and adherence to the chosen management strategy.

Nurses are pivotal in providing bedside care, monitoring symptoms, and offering psychosocial support, particularly for patients undergoing observation or recovering from surgery. Pharmacists contribute by reviewing medication regimens to prevent interactions, optimizing treatment for comorbid conditions, and exploring emerging pharmacological interventions, eg, Rho-kinase inhibitors and statins, currently in trial for CCM management. Genetic counselors are essential for patients with familial or multiple CCMs, offering guidance on genetic testing and implications for the patient and their family members.

Interprofessional communication ensures a seamless flow of information between team members, facilitating shared decision-making and personalized care. Neurosurgical consultations are integral to evaluating treatment options, including observation with serial imaging, surgical resection, or stereotactic radiosurgery. Care coordination across disciplines is vital for managing complex cases, such as those involving brainstem CCMs or refractory epilepsy, requiring alignment on risk-benefit analyses and tailored intervention strategies. This collaborative approach extends to patient education and empowerment, ensuring that patients and their families are informed about their condition and involved in care decisions. By leveraging the collective expertise of the healthcare team and maintaining open lines of communication, care delivery is optimized to enhance patient outcomes, improve safety, and promote a cohesive and effective care environment for individuals with CCMs.