Continuing Education Activity

A cerebral cavernous malformation (CCM) is an abnormally large collection of "low flow" vascular channels without brain parenchyma intervening between the sinusoidal vessels. Clinically, cerebral cavernous malformations have highly variable presentations. Adding to the confusion, they are also referred to as cavernomas, cavernous angiomas, and cavernous hemangiomas, though CCM is the preferred nomenclature. CCMs range in diameter from under a millimeter to several centimeters and may occur anywhere in the central nervous system with up to 20 percent 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. Thorough knowledge of the natural history of this entity is of paramount importance to avoid unnecessary and potentially morbid interventions. Given the heterogeneity of this condition, the ontogenesis, diagnosis, management strategies for CCM are subjects of ongoing debate and treatment paradigms continue to evolve. This activity reviews the pathogenesis, diagnosis, evaluation, and treatment of cerebral cavernous malformations and emphasizes the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Describe the most common signs and symptoms in patients with cerebral cavernous malformations.
• Summarize the diagnostic studies for cerebral cavernous malformations.
• Review how to thoroughly evaluate a patient with a new diagnosis of cerebral cavernous malformation.
• Explain the role of interprofessional, patient-centered care in the management of 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.[1][2] McCormick (1966) recognized CCMs as one of the four classes of cerebral vascular malformations which include arteriovenous malformations (AVM), developmental venous anomalies (DVA), and capillary telangiectasia. Clinically, CCMs are highly variable in both symptomatic presentation and natural history. Adding to the confusion, CCM has assumed a variety of names in the medical literature including cavernomas, cavernous angiomas, and cavernous hemangiomas, though CCM is the preferred nomenclature.[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% located in the brainstem.[3] 

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 the natural history of this entity is of paramount importance to avoid unnecessary and potentially morbid interventions. Given the heterogeneity of this condition, the ontogenesis, diagnosis, 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. The majority of CCMs are sporadic, but up to 20% follow a familial, autosomal dominant inheritance pattern characterized by the presence of multiple CCMs in a single patient.[4][5] This has led to the identification of three homologically distinct genes responsible for CCM development: CCM1, CCM2, and CCM3.[6] Mutations in any one of these genes can result in multifocal CCM and all three show relatively high genetic penetrance. Many authors have proposed a "two-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 exposure to radiation.[7] Studies of sporadic CCM support a common pathway involving de novo mutations of CCM genes.[6]

CCM protein products interact with each other and other cellular machinery responsible for a range of functions including cell-cell communication and angiogenesis. The most critical dysfunction found in CCM mutants is endothelial junction permeability, an effect mediated by Notch1 and Rho kinase activity.[8] This correlates with the characteristic histopathological appearance of CCM which lacks mature vessel wall architecture and mature blood-brain-barrier.[9] CCMs are distinguished from other cerebral vascular malformations by the absence of direct arteriovenous communication and lack of intervening brain parenchyma.

Epidemiology

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.[10][11][12][13] Clinical presentation is bimodal with a significant number of cases detected in both adolescents and middle-aged adults. There is no discernible sex difference in prevalence; however, there is conflicting research as to whether prognosis is different among men and women.[14] Familial CCM is notably prevalent among persons of northern Mexican ancestry, an effect that has been traced to a common founder mutation.[1] The incidence of incidentally detected CCM has increased substantially due to the widespread use of magnetic resonance imaging (MRI).[15] The majority (approximately 75%) of CCMs are found in the supratentorial compartment in predictable proportion to the volume of neural tissue present.[16]

Pathophysiology

The propensity for intra-lesional and extra-lesional hemorrhage is the chief mechanism underlying the clinical manifestations of CCM. Sluggish blood flow through dysplastic channels results in recurrent thrombosis, calcification, and deposition of hemosiderin along the margins of the lesion. Hemorrhage into adjacent brain parenchyma can produce focal neurologic deficits (FND), seizure, or a 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 re-hemorrhage are well-studied.[2] The pathogenesis of CCM-related epilepsy has been attributed to peri-lesional reactive gliosis due to clinically silent micro-hemorrhages which alters conduction adjacent white matter pathways. The observation that seizure-free outcomes are improved when the entire lesion, including the surrounding hemosiderin rim, is resected, supports this.[17]

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. On gross inspection, cavernous malformations appear "mulberry-like."[16]

History and Physical

While the clinical presentation of symptomatic cavernous malformations varies by location, the most common clinical manifestations are seizures (50%), intracranial hemorrhage (25%), and focal neurological deficits (FND) without radiographic evidence of recent hemorrhage (25%).[2][18] Supratentorial lesions most commonly present with seizures whereas FND or ataxia is the most common presentation in patients with infratentorial lesions.[19] Up to 20% to 50% of patients are asymptomatic and diagnosed incidentally on brain MRI.[2][11][15] 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 proximity of localized seizure focus to the CCM.[20] 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 CCM are present, or 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

The American College of Radiology (ACR) Appropriateness Criteria provide expert consensus recommendations for acute neurologic symptoms including a headache, FND, altered consciousness. [21] 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 which has been shown to have nearly 100% sensitivity.[5][15][1][22] MRI is particularly valuable in identifying multiple lesions in the case of familial CCM.[1] T2 weighted MRI typically demonstrates a characteristic mixed signal "popcorn" core with a hypointense rim.[16]

The hemosiderin rim lining the margins of CCMs generates a profound signal void on gradient-echo MRI due to the ferromagnetic dephasing of proton spins. The effect is a striking signal void or "blooming" artifact on gradient echo or susceptibility-weighted sequences (SWI) which is easily detected but can overestimate the actual size of the lesion. MRI has, therefore, become the gold standard tool for the diagnosis and staging of CCM. Guidelines for imaging follow-up of known CCM are not well-established, but it is generally recommended that new symptoms warrant repeat imaging to assess for acute or subacute hemorrhage.[2][5]

CCMs are characteristically angiographically occult lesions due to the slow transit of blood via the dysplastic channels save for the frequently associated developmental venous anomalies (DVA). CT angiography and digital subtraction angiography are therefore of limited utility in the workup of CCM however they may show indirect evidence of CCM by highlighting adjacent DVAs which typically enhance and opacify briskly on angiogram.[23]

CCM may present on non-contrast head CT (NCCT) as amorphous calcifications, but further imaging with MRI is warranted to confirm the diagnosis unless contraindicated. The principal role of NCCT is the identification of hemorrhage in symptomatic patients. The Angioma Alliance has defined standard definitions of CCM-related hemorrhage and recommended reporting criteria to improve diagnostic consistency and accuracy among neuroimagers and clinicians.[5] These guidelines define CCM hemorrhage by the temporal concordance of neurologic symptoms and quantitative imaging biomarkers seeking to avoid misattribution of symptoms to clinically silent CCM.

Advanced MR imaging is playing an increasingly important role in the management of surgically complex CCM. Diffusion tensor imaging (DTI) has been used to identify critical white matter tracts in preoperative planning for brainstem CCM.[24] Functional MRI techniques such as blood oxygen level-dependent (BOLD) task-activation mapping of language function are highly accurate and non-invasive tools that have proven useful in the preoperative workup of CCM.[25] Emerging work using high field strength SWI may provide detailed information on the angioarchitecture of CCM, potentially identifying at-risk lesions.[26]

Treatment / Management

Location is the most important factor that determines the natural history of CCM.[16] Because the clinical course of CCM is highly variable and location-dependent, management and therapeutic decision-making require multidisciplinary discussion and a thorough evaluation of the patient risk tolerance profile. When feasible, surgical resection is the preferred treatment option for symptomatic CCM. In select cases, targeted radiotherapy is used to treat lesions that are surgically inaccessible. There is no role for endovascular therapy in CCM.

Surgical excision is the only definitive treatment for CCM but the decision to operate remains challenging as postoperative morbidity may approach or exceed the complications of the untreated disease.[27] Conservative management and observation are therefore favored for all patients with solitary CCM who are asymptomatic.[2] For supratentorial lesions in non-eloquent regions, surgical excision can be curative with high success rates and relatively low complications.[28] Surgery should, therefore, be considered in this patient population for patients who present with symptomatic hemorrhage. In cases of medically refractory epilepsy, early surgery is favored for amenable lesions, especially if there is high confidence that a solitary CCM is an epileptogenic source.[2][17][20]

CCMs located in the deep gray nuclei and brainstem pose a much greater challenge. Studies using diffusion tensor imaging and diffusion tensor tractography have shown that up to 82% of patients with brainstem lesions have involvement of corticospinal tract and other major fiber tracts[29] highlighting the extreme difficulty neurosurgeons face with patient and approach selection. 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).[30] Long-term outcomes are better for lesions with a pial presentation which may facilitate resection and minimal collateral injury.[31] Aggressive intervention in the brainstem is therefore reserved only for patients who have suffered a single disabling bleed, or with long life expectancy which may pose a higher cumulative risk for future hemorrhage.[2][30][31] With the utilization of image guidance, appropriate patient and approach selection, and detailed knowledge of the intrinsic brainstem anatomy, these lesions can be safely resected with good outcomes.[32]

The technical goal of surgery should be, at a minimum, complete lesionectomy.[33] Seizure outcomes seem to be better if the surrounding hemosiderin-stained gliotic brain is also resected.[17] With selective adjuncts such as frameless stereotactic guidance, electrocorticography, and intraoperative MRI, microsurgical resection of CCMs has become much safer and more complete. If the lesion is not adjacent to eloquent areas, resecting the hemosiderin-laden gliotic 'pseudocapsule' surrounding the lesion should be strongly considered esp. if treatment indication is intractable seizures. CCM associated developmental venous anomalies (DVA) should be spared during microsurgical resection as they typically drain the surrounding normal brain. Each case demands a tailored resection technique. Large lesions can be tackled by piecemeal excision while smaller ones may be amenable for en-bloc resection.[16]

Stereotactic radiosurgery (SRS) has long served as an alternative to surgery in symptomatic patients with anatomically foreboding lesions or unfavorable risk profile. 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 there is no reliable imaging biomarker for successful CCM obliteration as with metastasis and high-flow vascular lesions.[34] Several series on SRS for CMs suggest that the greatest risk reduction in hemorrhage usually happens after a 2-year latency period. Hasegawa et al. showed that for patients with high-risk, symptomatic,  diencephalic or brainstem CCM, radiotherapy reduced re-hemorrhage rates from 33% to 12.3% in the 2-year post-treatment period with a further reduction in annualized hemorrhage rate to less than 1% after 2 years.[35] 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.[34] SRS is also strongly linked to the development of de novo CCM, although such cases rarely become symptomatic.[36] Because radiation-induced damage in the brainstem can be devastating, SRS is not recommended as a treatment option for brainstem CMs.[32]

CCM is a surgical disease, and the role of medical management is limited but the subject of much ongoing laboratory research. Preclinical animal model studies have recently shown that both statins and targeted Rho-kinase inhibitors may reduce symptoms and lesion progression.[37] The medical complications of CCM should be managed following evidence-based guidelines. Intraparenchymal hemorrhage due to CCM should follow standard evidence-based guidelines and protocols which have been well-described by expert consensus.[38] Recent prospective data found no increase in hemorrhage or other adverse events in patients with CCM who are treated with anticoagulant or antiplatelet medications for other purposes.[39]

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 cavernous malformations are managed conservatively either with radiographic and clinical observation alone or in addition to anti-epileptic drugs, as the current first-line management strategy.[16] Radiosurgery 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. Early results from the use of MRI-guided laser interstitial thermal therapy (LIIT) for cavernous malformation-related epilepsy are promising.[40] Further use and expansion of such minimally invasive therapies seem assured.[16]

Differential Diagnosis

Classic CCM rarely poses a diagnostic dilemma as the radiographic differential diagnosis for isolated T2* artifact, a non-enhancing lesion on MRI is limited. When numerous small CCM 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 non-contrast head CT, favors the diagnosis of CCM over other types of microbleed. Finally, the co-existence of a developmental venous anomaly (DVA) strongly supports the diagnosis of CCM.[23]

Staging

The most widely accepted tool for grading CCM was derived from early observations by Zabramski et al. on the MR manifestations of hemorrhage within the lesion.[41] This classification schema defines type I lesions by the presence of subacute hemorrhage (high T1 signal, days to weeks from ictus), type II lesions as "popcorn" lesions with central T2* blooming, type III as chronic hemorrhage (low T1 and T2 signal, more than 1-month-old) and lastly, type IV CCM corresponding to multiple punctate microhemorrhages visualized on gradient-echo sequences (T2*-weighted).

Prognosis

The natural history of CCM has been characterized in several large studies.[4][14][41][18] The overall annualized hemorrhage rate in untreated CCM is estimated at 2.4% with a predicted cumulative 5-year risk of hemorrhage 15.8% from the time of diagnosis.[22][13] For patients with incidentally detected CCM, the risk of hemorrhage is substantially lower, estimated to be 0.33% per year.[4] Rates of epilepsy in incidental lesions are similarly low at 1% to 2%.[20] 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.[4][15][22][42] CCMs display a phenomenon termed temporal clustering wherein re-hemorrhage tends to occur, 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.[16][43] Prior hemorrhage is a significant risk factor for future hemorrhagic events.[16] Several factors have been associated with CCM rupture including lesion location, size, multiplicity, and the presence of an associated DVA.[44][42][22] 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 = 0.0001).[16][45] 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).[42][30] In one meta-analysis, non-brainstem hemorrhage rates were reported to be 0.3% per year vs. 2.8% per year for brainstem lesions.[42] Also of note, the initial presentation of patients with intracranial hemorrhage (ICH) or focal neurological deficit and brainstem location was independently associated with a hemorrhage over the 5 years after the initial diagnosis.[13][16]  Female gender as a risk factor for hemorrhage remains a topic of debate.[14][13] In familial CCM, more aggressive CCM behavior has been observed in CCM3 mutants in contrast with a more benign clinical course in CCM1 deletions.[46][6]

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 morbidity of intervention. 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.[42] In the hands of experienced surgeons with appropriate patient selection, postoperative morbidity can be quite low with one recent estimate of 1.5%.[31] Nonetheless, when feasible, conservative management may be favorable as shown in one recent prospective study in which CCM excision worsened short-term disability and increased risk of neurologic deficit or recurrent hemorrhage.[27]

Postoperative and Rehabilitation Care

Although there are no guidelines on the role of anti-epileptics following surgical resection of CCM, patients are typically maintained on anti-epileptic monotherapy following surgery.[47] Seizure-free outcomes following surgery are dependent on various factors such as pre-operative seizure frequency, the extent of CCM resection, the extent of perilesional "hemosiderin-ring" resection, and timing of surgery relative to the initial presentation.[48][49] Anti-epileptic drug withdrawal following surgery should be planned with appropriate dose tapering to reduce the risk of seizure recurrence.[50][51]

Deterrence and Patient Education

Patients with CCM are encouraged to explore the official website of the multidisciplinary Angioma Alliance (AA). 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 provides social support via online forums and social media sites allowing patients and family members to support one another and share their experiences with CCM.

Pearls and Other Issues

RhoA/Rho kinase pathway is seen as a potential target for the pharmacotherapeutic treatment of cavernous malformations. Normally, CCM2 and CCM1 act together to suppress RhoA. CCM1 and CCM2 deficiency lead to constitutively active Rho-kinase (ROCK), which destabilizes endothelial cell junctions and vascular permeability.[52] ROCK suppressants have been experimentally shown to enable vasculogenesis in CCM1-, CCM2-, and CCM3-deficient cells.[53] Fasudil, a ROCK inhibitor has been shown to decrease the lesion burden in CCM1-deficient mice.[54]

While CCM1, CCM2 or CCM3 deficiencies have been shown to activate bone morphogenic protein (BMP) and transforming 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 CCM-1 deficient mice representing another avenue of research in CCM therapy.[55] Similarly, suppressing Beta-catenin was also found to reduce the number and size of cavernous malformations in a CCM3-deficient mice model.[56] These findings demonstrate the importance of a thorough understanding of the molecular biology underpinning CCM.

Enhancing Healthcare Team Outcomes

Comprehensive care for CCM requires an interprofessional effort involving neurosurgeons, epileptologists, neuroradiologists, mental health professionals, specialty certified nurses, and genetic counselors.

Given the complexity of this disease and its frequent presentation as an incidental finding, patient counseling and risk profile assessment should be performed at the time of diagnosis. Familial CCM follows an autosomal dominant inheritance pattern; thus, there is consensus agreement that detailed family history/pedigree and consideration of genetic screening for common mutations should be considered (Class I/Level C).[2] Ancillary care from social workers and mental health providers can address patient anxiety, and support groups such as the Angioma Alliance provide additional support mechanisms.

Neuroradiology reports should adhere to established reporting guidelines for CCM which clarify the clinical-radiologic correlation of symptoms and imaging findings.[5] An accurate radiographic description is critical for determining if patients are candidates for conservative or surgical treatment. Brain MRI with gradient echo and susceptibility-weighted sequences are the preferred tools for both diagnosis and follow-up imaging (Class 1/Level C).[2]

Evidence-based consensus guidelines for management have been described and are described in detail elsewhere (see references [2][20]). Conservative observation is favored for asymptomatic CCM, and curative surgical resection for CCM with recurrent hemorrhage or refractory epilepsy is supported by Class II/Level A evidence. For CCM with solitary hemorrhage, case-by-case consideration is warranted. The role of radiosurgery is the subject of ongoing debate for deep or brainstem CCM or lesions involving the eloquent cortex.