Update on the natural history of cavernous malformations and factors predicting aggressive clinical presentation

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  • 1 Departments of Neurological Surgery and
  • | 2 Neurology, Washington University Center for Stroke and Cerebrovascular Disease, Washington University School of Medicine, Saint Louis, Missouri
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Cavernous malformations (CMs) are angiographically occult, low-pressure neurovascular lesions with distinct imaging and clinical characteristics. They present with seizure, neurological compromise due to lesion hemorrhage or expansion, or as incidental findings on neuroimaging studies. Treatment options include conservative therapy, medical management of seizures, surgical intervention for lesion resection, and in select cases stereotactic radiosurgery. Optimal management requires a thorough understanding of the natural history of CMs including consideration of issues such as mode of presentation, lesion location, and genetics that may impact the associated neurological risk. Over the past 2 decades, multiple studies have been published, shedding valuable light on the clinical characteristics and natural history of these malformations. The purpose of this review is to provide the reader with a concise consolidation of this published material such that they may better understand the risks associated with CMs and their implications on patient treatment.

Abbreviation used in this paper:

CM = cavernous malformation.

Cavernous malformations (CMs) are angiographically occult, low-pressure neurovascular lesions with distinct imaging and clinical characteristics. They present with seizure, neurological compromise due to lesion hemorrhage or expansion, or as incidental findings on neuroimaging studies. Treatment options include conservative therapy, medical management of seizures, surgical intervention for lesion resection, and in select cases stereotactic radiosurgery. Optimal management requires a thorough understanding of the natural history of CMs including consideration of issues such as mode of presentation, lesion location, and genetics that may impact the associated neurological risk. Over the past 2 decades, multiple studies have been published, shedding valuable light on the clinical characteristics and natural history of these malformations. The purpose of this review is to provide the reader with a concise consolidation of this published material such that they may better understand the risks associated with CMs and their implications on patient treatment.

Cerebral CMs, also referred to as cavernous angiomas, cavernous hemangiomas, or cavernomas, are vascular malformations consisting of thin hyalinized vascular channels without interposed brain. These lesions are also referred to as angiographically occult vascular malformations due to the fact that they are low-pressure systems that do not shunt blood and are not generally apparent on diagnostic catheter angiography.8,29 Prior to the development of MR imaging, diagnosis of CMs was uncommon; only 163 cases had been presented in the literature by 1976, the vast majority of which presented as symptomatic lesions.54 However, with the ever-increasing availability and fidelity of MR imaging technology, the diagnosis of CMs has become exceedingly more common. Another byproduct of the MR imaging era has been a dramatic increase in the number of CMs being diagnosed prior to symptom onset, with at least 40% of CMs now being identified incidentally.5 Our ability to make appropriate clinical judgments regarding the management of these lesions is predicated on our understanding of the hemorrhagic and neurological risk associated with CMs and what factors potentially impact this risk. The purpose of this paper is to consolidate the current body of knowledge of the natural history of CMs into a form that helps the cerebrovascular practitioner with patient treatment.

Methods

A literature search using the online database PubMed provided through the National Center for Biotechnology was performed. Search terms were “natural history,” “cavernous malformation,” “cavernoma,” “cavernous angioma,” and “cavernous hemangioma.” The search was limited to studies in the English language and specific to humans. Articles were reviewed along with any pertinent citations provided by these articles. Studies of interest included those that provided information regarding modes of presentation, hemorrhage rates, and factors affecting prognosis (for example, age, sex, size, and genetic components to the disease).

Epidemiology

Cavernous malformations occur in sporadic and familial forms.21,47 They are the second most common vascular lesion behind developmental venous anomalies and account for 10%–15% of all vascular malformations.5 Based on autopsy and MR imaging studies, the incidence ranges from 0.4% to 0.8%,5,34,42,48 with 25% of these occurring in children.34 The average age of adult presentation is in the 4th or 5th decade of life. Children present in a bimodal pattern with peaks at 0–2 years of age and 13–16 years of age.34,41

The familial form of CMs comprises approximately 6%–50% of all cases, and a higher prevalence has been noted in people with Mexican-American ethnicity. Based on current imaging studies, more than 50% of patients with familial CMs have multiple lesions compared with only 12%–20% in those with the sporadic form.5,40,47,57 In regard to sex, the prevalence of CMs appears equal among men and women. However, some studies (see detailed discussion below) have raised the question of an increased incidence of symptomatic lesions in women.2,27,40,44,49,53,54

Presentation

Cavernous malformations have a wide range of presenting symptoms. These can vary from mild symptoms such as headache to more severe symptoms including seizure, focal neurological deficit, and even death. In addition, since the introduction of MR imaging, more and more CMs are being found incidentally. With supratentorial lesions, the most common presenting symptom is new onset seizure, representing 23%–79% of cases.1,2,12,25–27,40,43–45,48,51,56,57 With infratentorial lesions, most patients present with either a focal neurological deficit (for example, cranial nerve palsy, hemiparesis, and hemisensory deficits) or gait ataxia.20,30,44,52,55 Brainstem CMs have also been reported to cause symptoms such as cardiovascular instability, respiratory compromise, and hiccups.55 Cavernous malformations located in the basal ganglia and/or thalamus most commonly present with sensorimotor deficits, but less common presentations of hemiballismus and hydrocephalus have also been reported.17

All of the above symptoms can be found with or without acute hemorrhage. The definition of hemorrhage varies greatly from study to study, thus creating difficulty in quantifying bleeding rates. Some consider a lesion as having hemorrhaged only when there is a new neurological event in association with positive imaging findings. Others consider only the imaging. Given this, there is a wide range in percentage of patients presenting with hemorrhage, from a low of 9% to a high of 88%.1,2,12,14,15,26,27,30,38,40,43–45,50–52,55,56

As noted above, there is also a growing group of patients with CMs that are being diagnosed incidentally or during workup for chronic headaches. Patients in the pre–MR imaging era, such as those presented by Voigt and Yaşargil,54 were 100% symptomatic. Currently, the percentage of CM patients with incidental presentation is 2%–32%, and the percentage of patients with chronic headache presentation is 6%–65%.1,12,25–27,30,37,40,43–45,48,52,56,57 Table 1 shows the breakdown of presenting symptoms and location of CMs.

TABLE 1:

Summary of presenting symptoms and locations of CMs in the literature*

Authors & YearType of StudyNo. of PatientsMean Age (yrs)Presenting Symptom (%)Location (%)
HemorrhageSeizureFNDGNDHAIncidentalSupratentorialInfratentorial
Xia et al., 2009retro6611.620.047.712.3NA46.2NA83.39.1
Kivelev et al., 2009retro3344.046.043.018.0NA21.06.070.030.0
Hauck et al., 2009retro4437.5NANA86.057.0NANA0.0100.0
Acciarri et al., 2009retro42<18.040.559.5NA14.326.2NA87.512.5
Tarnaris et al., 2008retro2136.857.1NA23.8NANA19.00.0100.0
Wang et al., 2003retro13733.567.2NA51.1NANANA0.0100.0
Kupersmith et al., 2001retro3737.573.0NANANA43.05.00.0100.0
Porter et al., 1999retro10037.097.0NA69.039.037.0.NA0.0100.0
Moriarity et al., 199940pro6834.613.049.046.0NA65.01.573.027.0
Moran et al., 1999review/retro690NA16.079.0NANANANA100.00.0
Porter et al., 1997retro17337.525.036.020.0NA6.012.063.037.0
Kim et al., 1997retro6232.2NA40.88.232.66.112.269.430.6
Pozzati et al., 1996retro14530.018.046.9NA20.710.34.186.913.1
Aiba et al., 1995retro110NA56.422.7NANANA20.967.832.2
Kondziolka et al., 1995retro/pro12237.350.023.0NANA18.0NA48.052.0
Zabramski et al., 1994pro3125.0NA39.0NA26.052.039.091.09.0
Robinson et al., 1993retro6634.6NA51.545.5NA30.313.684.215.8
Del Curling et al., 1991retro3242.09.050.022.0NA34.019.086.014.0
Simard et al., 1986review/retro138NA28.735.5NANANANANANA

* FND = focal neurological deficit; GND = global neurological deficit; HA = headache; NA = not available; pro = prospective; retro = retrospective.

Natural History

Overall Hemorrhage Risk

In the early 1990s (corresponding to the increase in MR imaging availability and usage), a rapid increase in the knowledge of the hemorrhage risk associated with CMs occurred. Del Curling et al.12 were one of the first groups to report on this risk. In their study, MR images from 8000 patients were retrospectively reviewed. Symptoms in these patients included seizure (50%), headache (34%), and focal neurological symptoms (16%). Thirty-two patients with CMs were identified, for an MR imaging–based incidence of 0.39%. They reported symptomatic hemorrhage rates of 0.25% per patient-year and 0.10% per lesion-year. Robinson et al.48 retrospectively reviewed MR images from over 14,000 patients. Symptoms in these patients included seizure (52%), focal neurological deficit (46%), headache (30%), and incidental (14%). Sixty-six patients with 76 CMs were identified, for an MR imaging–based incidence of 0.47%. They reported a symptomatic hemorrhage rate of 0.7% per lesion-year. Kim et al.25 retrospectively reviewed 62 patients with 108 CMs. Most lesions were symptomatic, but 12% were incidental. They reported symptomatic hemorrhage rates of 2.3% per patient-year and 1.4% per lesion-year. Zabramski et al.57 reported on 21 asymptomatic patients in whom familial CM was diagnosed who were prospectively observed (including serial MR imaging studies) for an average of 2.2 years. They reported symptomatic hemorrhage rates of 6.5% per patient-year and 1.1% per lesion-year. They also identified numerous asymptomatic hemorrhages by MR imaging and calculated asymptomatic hemorrhage rates of 13% per patient-year and 2% per lesion-year. Numerous other natural history studies have been reported over the years, most of which have documented hemorrhage rates ranging from 0.7% to 6% per patient-year (see Table 2 for a complete listing of reported hemorrhage rates).

TABLE 2:

Summary of initial hemorrhage and rehemorrhage rates found in the literature*

Authors & YearType of StudyNo. of PatientsMean Age (yrs)Hemorrhage Rate/Patient-Yr (%)Rehemorrhage Rate/Patient-Yr (%)Hemorrhage Rate/Lesion-Yr (%)Rehemorrhage Rate/Lesion-Yr (%)
Hauck et al., 2009retro4437.5NA42.0NANA
Tarnaris et al., 2008retro2136.8NA0.05NANA
Ghannane et al., 2007retro390.0136.27NANA
Wang et al., 2003retro13733.56.060.0NANA
Mathiesen et al., 2003pro342 incidental/7 symptomaticNANANA
Sandalcioglu et al., 2002retro1229.26.81.9NANA
Labauge et al., 2001pro3340.84.30.6NANA
Kupersmith et al., 2001retro3737.52.465.1NANA
Labauge et al., 2000retro3716.5NA2.5NA
Porter et al., 1999retro10037.05.030.0NANA
Moriarity et al., 199940pro6834.63.1NANANA
Moran et al., 1999review/retro6900.7NANANA
Porter et al., 1997retro17337.51.60.4 infratentorial/3.8 supratentorialNANA
Kim et al., 1997retro6232.22.33.81.42.6
Aiba et al., 1995retro110NANANA0.39 no hemorrhage hx/22.9 hemorrhage hx
Kondziolka et al., 1995retro/pro12237.31.30.6 no hemorrhage hx/4.5 hemorrhage hxNANA
Zabramski et al., 1994pro3125.06.5 symptomatic/13 MRI basedNA1.1 symptomatic/2 MRI basedNA
Fritschi et al., 1994retro13931.82.721.02.721.0
Robinson et al., 1993retro6634.6NANA0.7NA
Del Curling et al., 1991retro3242.00.25NA0.1NA

* hx = history.

Risk Factors That Increase Hemorrhage Risk

Hemorrhagic Presentation

Aiba et al.2 were the first to provide evidence that hemorrhagic presentation negatively impacts the natural history of CMs. In their retrospective review of 110 patients with CMs, they found that patients presenting with hemorrhage were at higher risk for new hemorrhage than those presenting with incidental findings or with seizure (22.9% per patient-year vs 0.39% per patient-year, respectively). Other investigators have documented similar findings. Kondziolka et al.27 performed a combined retrospective/prospective evaluation of 122 patients with conservatively managed CMs, documenting a symptomatic hemorrhage rate of 0.6% per patient-year in patients without hemorrhagic presentation versus 4.5% per patient-year for patients with hemorrhagic presentation. Mathiesen et al.37 performed a retrospective analysis of 34 patients, reporting a symptomatic hemorrhage rate of 2% per year for patients with incidental lesions versus 7% per year in patients with symptomatic presentation. Moriarity et al.40 prospectively evaluated 68 patients with 228 CMs and reported an overall hemorrhage rate of 3.1% per patient-year. While they did not identify hemorrhagic presentation as a standalone risk factor, they did find that patients who presented with hemorrhagic or nonhemorrhagic focal neurological deficits had higher hemorrhage rates than those who presented without focal neurological deficits (8.9% vs 0.4% per patient-year, respectively).

It should be noted, however, that although patients with CMs who present with symptomatic hemorrhage are at an increased risk for new hemorrhage after diagnosis, this period of higher risk appears time limited. This phenomenon, known as “temporal clustering,” was suspected by several early clinicians; however, in 2001 Barker et al.4 provided compelling evidence for temporal clustering when they studied the hazard curve of rehemorrhage for 141 patients with CMs with a history of previous hemorrhage. They noted a spontaneous decline in the hazard risk of CM rehemorrhage approximately 2 years after a previous hemorrhage. Since this report, other investigators have also documented temporal clustering of hemorrhages in patients with CMs.55

Deep Anatomical Location

In the aforementioned study by Robinson et al.,49 a higher incidence of neurological disability was noted in patients with infratentorial than in those with supratentorial CMs. Similar findings have been noted by other investigators. Porter et al.43 retrospectively analyzed 173 patients with CM and categorized the CMs by location: 1) infratentorial versus supratentorial, and 2) deep versus superficial (brainstem, thalamus, and basal ganglia CMs were considered deep; the remaining CMs were considered superficial). They reported a higher rate of recurrent symptomatic hemorrhage in infratentorial than in supratentorial lesions (3.8% per patient-year vs 0.4% per patient-year) as well as in deep than in superficial lesions (4.1% per patient-year vs 0% per patient-year). Others provided evidence indicating that brainstem CMs have a particularly poor natural history. Fritschi et al.14 presented their series of 139 patients with brainstem CMs along with a literature review. They calculated a relatively high symptomatic hemorrhage rate of 2.7% per patient-year and a very high rehemorrhage rate of 21% per patient-year. Porter et al.44 retrospectively reviewed their experience with 100 patients with brainstem CMs, documenting a symptomatic hemorrhage rate of 5% per patient-year and a symptomatic rehemorrhage rate of 30% per patient-year. Kupersmith et al.30 retrospectively evaluated 37 brainstem CMs, finding a symptomatic hemorrhage rate of 2.5% per patient-year and symptomatic rehemorrhage rate of 5.1% per patient-year. Kim et al.25 retrospectively analyzed 62 patients with 108 CMs including 10 whose lesions were located within the brainstem. They found that brainstem CMs had a significantly higher frequency of presenting with a major neurological deficit compared with other lesion locations (80% of brainstem CMs presented with major neurological deficit vs 123% of cortical lesions). Although most studies suggested that brainstem CMs carry higher risk of symptomatic hemorrhage, at least one study by Tarnaris et al.52 suggests otherwise, as their retrospective analysis of 21 patients with brainstem CMs documented surprisingly low rates of rebleeding and neurological deterioration (0.05% and 0.1% per patient-year, respectively).

Female Sex

Vaquero et al.53 were one of the first groups to document a female predominance in symptomatic CMs (female/male ratio 2:1). Many studies since have found an increase in the frequency of symptomatic lesions in women. Robinson et al.48 found a significant increase in hemorrhage rate in females. This was reiterated by studies presented by Aiba et al.3 and Porter et al.44 In fact, Porter and colleagues went further to question the effect of pregnancy on hemorrhage risk. Kupersmith et al.30 found a higher risk of rehemorrhage in women (5.9%) than in men (3.3%). Not all studies, however, have documented a difference in hemorrhage rates between male and female patients.14,27,43

Other Factors Affecting Natural History

Seizure

The most common presenting symptom for patients with CMs is seizure (25%–79%).38,39 These seizures are thought to be induced by recurrent microhemorrhages from the CM, resulting in perilesional gliosis and inflammation, both of which are epileptogenic.3 In a retrospective review by Kondziolka et al.,27 4.3% of patients developed new seizures after initial CM diagnosis. In a retrospective review by Del Curling et al.,12 1.5% of patients developed new seizures after initial CM diagnosis. In the retrospective review by Moriarity et al.,40 the risk of developing seizures following CM diagnosis was 2.4% per patient-year for patients not initially presenting with seizures. If the presenting symptom was seizure, the rate of having recurrent seizures was 5.5% per patient-year. While the presumed etiology of seizures in this patient population is recurrent microhemorrhages, there is no evidence to date suggesting that seizure (either at presentation or in follow-up) impacts the risk of CM hemorrhage.

De Novo Formation

Initially it was believed that CMs were developmental anomalies that were present since birth; however, there is now compelling evidence that CMs—in the sporadic and familiar forms—can develop de novo.22,47 Several studies have quantified the incidence of de novo CM development, with results ranging from 0.1 to 0.6 new lesions per patient-year.23,32,57 This phenomenon is much more common in the familial than the sporadic forms of the disease, as 27.5%–30% of patients with familial forms develop de novo CM formation while only 4.1% of patients with sporadic lesions develop de novo CM formation over time.31,32,45

Size Dynamics

De novo formation is not the only dynamic aspect of CMs. Lesion size can also vary substantially over time. Pozzati et al.46 were the first to demonstrate the dynamic nature of CMs when they presented 3 cases in which the CM grew substantially over time. They theorized the mechanism to be serial microhemorrhages followed by organization, fibrosis, and calcification. Others have shown that CMs can decrease in size over time. In the retrospective series by Kim et al.,25 the average CM size was 14.2 mm at initial diagnosis and 9.1 mm on repeat imaging. Perhaps the best study demonstrating the dynamic nature of CMs over time is that by Clatterbuck et al.10 who observed 68 patients with 114 CMs with serial imaging over a mean period of 3.7 years. Over this follow-up period, they found that 22% of lesions were stable in size, 43% of lesions increased in size, and 35% of lesions decreased in size. Many of these lesions had periods of both increase and decrease in size. To date, no study has correlated CM growth with risk of symptomatic hemorrhage.

Familial Inheritance and Genetics

It was long suspected that a genetic link to CMs existed;7,9,24,28 however, definitive evidence remained elusive until 1982 when Hayman et al.21 published their seminal paper on CM inheritance. They reported on a kindred of 122 individuals, of whom 5 had cerebral vascular malformations and 3 had CMs. They documented autosomal dominant inheritance with variable expressivity. This report was followed by the studies of Rigamonti et al.47 and Mason et al.36 who found that familial inheritance was especially high in Hispanic-American families.

This newly found information provided a patient population through which genetic mapping was used to elucidate the genetic cause of familial CMs. Dubovksy et al.13 and Gil-Nagel et al.16 were able to map the responsible gene to 7q. Guenl et al.18 discovered through analysis of genetic markers a founder mutation among familial and sporadic cases in Hispanic-Americans of Mexican descent, suggesting a common ancestor among these patients. This mutation was later identified as truncating mutations in CCM1.33 Further studies found that CCM1 was likely not the only responsible gene.11,19 Subsequently, Craig et al.11 discovered 2 additional loci associated with familial CMs, CCM2 on 7p and CCM3 on 3q. They also found that Caucasian forms of familial CMs were 40% linked to CCM1, 20% linked to CCM2, and 40% linked to CCM3. Recent data suggest that a fourth gene may be present.6,35

The identification of familial inheritance and the genetic mutations that underlie it not only shed light on the underlying molecular mechanisms leading to CM formation, but also impacted clinical management. First, the number of cases of familial CMs appears higher than initially reported, with several studies showing that as many as 50% of patients with CMs have familial inheritance.33,47,57 A detailed family history is therefore imperative when evaluating all patients with CMs, and genetic testing should be considered in those with evidence of familial inheritance. Second, the incidence of CM multiplicity is far higher in familial than in sporadic forms of the disease, with a reported incidence as high as 96% in patients with familial inheritance.57 Third, the rate of de novo CM formation is much higher in familial than in sporadic forms of the disease.31,32,45 This observation suggests that additional MR imaging studies over time may be appropriate for patients with familial CMs. Finally, familial inheritance appears to have some impact on the risk of hemorrhage. Although no study has thus far documented a higher than expected hemorrhage rate per lesion, the high incidence of CM multiplicity and the high rate of de novo CM formation strongly suggests that the greater overall CM burden in patients with familial forms leads to an increased risk of hemorrhage per patient. Consistent with this notion, annual hemorrhage rates of 4.3% per patient-year have been reported for patients with familial but asymptomatic CMs31 compared with 0.6% per patient-year for patients with sporadic forms but asymptomatic CMs.27 Vigilant counseling of familial patients with familial forms regarding the signs and symptoms of hemorrhage is therefore necessary.

Conclusions

Based on our review of the literature, CMs have symptomatic hemorrhage rates ranging from 0.1% to 2.7% per lesion-year and 0.013% to 16.5% per patient-year. Although the hemorrhage rates per patient-year at first appear broad, the majority of studies report rates of hemorrhage that fall within a narrower range of 0.7% to 6% per patient-year. In addition, many studies have identified risk factors that increase the risk of hemorrhage including presenting with a symptomatic hemorrhage, deep or infratentorial location, and perhaps female sex. Seizures are also a significant source of patient morbidity. The reported rates of new seizure following CM diagnosis range from 1.5% to 4.3% per patient-year, and history of a previous seizure increases this rate to 5.5% per patient-year. Finally, available evidence suggests that the greater overall CM burden found in familial versus sporadic forms of CMs leads to a higher annual risk of symptomatic hemorrhage for patients with familial inheritance.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Similarly, none of the authors have any personal or institutional financial interest related to this submission.

Author contributions to the study and manuscript preparation include the following. Conception and design: Zipfel, Washington. Acquisition of data: Washington, McCoy. Analysis and interpretation of data: all authors. Drafting the article: all authors. Critically revising the article: Zipfel, Washington. Reviewed final version of the manuscript and approved it for submission: all authors. Study supervision: Zipfel.

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    Laberge-le Couteulx S, , Jung HH, , Labauge P, , Houtteville JP, , Lescoat C, & Cecillon M, et al.: Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 23:189193, 1999

    • Search Google Scholar
    • Export Citation
  • 34

    Lanzino G, & Spetzler RF: Cavernous Malformations of the Brain and Spinal Cord New York, Thieme, 2008

  • 35

    Liquori CL, , Berg MJ, , Squitieri F, , Ottenbacher M, , Sorlie M, & Leedom TP, et al.: Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat 27:118, 2006

    • Search Google Scholar
    • Export Citation
  • 36

    Mason I, , Aase JM, , Orrison WW, , Wicks JD, , Seigel RS, & Bicknell JM: Familial cavernous angiomas of the brain in an Hispanic family. Neurology 38:324326, 1988

    • Search Google Scholar
    • Export Citation
  • 37

    Mathiesen T, , Edner G, & Kihlström L: Deep and brainstem cavernomas: a consecutive 8-year series. J Neurosurg 99:3137, 2003

  • 38

    Moran NF, , Fish DR, , Kitchen N, , Shorvon S, , Kendall BE, & Stevens JM: Supratentorial cavernous haemangiomas and epilepsy: a review of the literature and case series. J Neurol Neurosurg Psychiatry 66:561568, 1999

    • Search Google Scholar
    • Export Citation
  • 39

    Moriarity JL, , Clatterbuck RE, & Rigamonti D: The natural history of cavernous malformations. Neurosurg Clin N Am 10:411417, 1999

  • 40

    Moriarity JL, , Wetzel M, , Clatterbuck RE, , Javedan S, , Sheppard JM, & Hoenig-Rigamonti K, et al.: The natural history of cavernous malformations: a prospective study of 68 patients. Neurosurgery 44:11661173, 1999

    • Search Google Scholar
    • Export Citation
  • 41

    Mottolese C, , Hermier M, , Stan H, , Jouvet A, , Saint-Pierre G, & Froment JC, et al.: Central nervous system cavernomas in the pediatric age group. Neurosurg Rev 24:5573, 2001

    • Search Google Scholar
    • Export Citation
  • 42

    Otten P, , Pizzolato GP, , Rilliet B, & Berney J: [131 cases of cavernous angioma (cavernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies.]. Neurochirurgie 35:8283, 1989. (Fr)

    • Search Google Scholar
    • Export Citation
  • 43

    Porter PJ, , Willinsky RA, , Harper W, & Wallace MC: Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 87:190197, 1997

    • Search Google Scholar
    • Export Citation
  • 44

    Porter RW, , Detwiler PW, , Spetzler RF, , Lawton MT, , Baskin JJ, & Derksen PT, et al.: Cavernous malformations of the brainstem: experience with 100 patients. J Neurosurg 90:5058, 1999

    • Search Google Scholar
    • Export Citation
  • 45

    Pozzati E, , Acciarri N, , Tognetti F, , Marliani F, & Giangaspero F: Growth, subsequent bleeding, and de novo appearance of cerebral cavernous angiomas. Neurosurgery 38:662670, 1996

    • Search Google Scholar
    • Export Citation
  • 46

    Pozzati E, , Giuliani G, , Nuzzo G, & Poppi M: The growth of cerebral cavernous angiomas. Neurosurgery 25:9297, 1989

  • 47

    Rigamonti D, , Hadley MN, , Drayer BP, , Johnson PC, , Hoenig-Rigamonti K, & Knight JT, et al.: Cerebral cavernous malformations. Incidence and familial occurrence. N Engl J Med 319:343347, 1988

    • Search Google Scholar
    • Export Citation
  • 48

    Robinson JR, , Awad IA, & Little JR: Natural history of the cavernous angioma. J Neurosurg 75:709714, 1991

  • 49

    Robinson JR Jr, , Awad IA, , Magdinec M, & Paranandi L: Factors predisposing to clinical disability in patients with cavernous malformations of the brain. Neurosurgery 32:730736, 1993

    • Search Google Scholar
    • Export Citation
  • 50

    Sandalcioglu IE, , Wiedemayer H, , Secer S, , Asgari S, & Stolke D: Surgical removal of brain stem cavernous malformations: surgical indications, technical considerations, and results. J Neurol Neurosurg Psychiatry 72:351355, 2002

    • Search Google Scholar
    • Export Citation
  • 51

    Simard JM, , Garcia-Bengochea F, , Ballinger WE Jr, , Mickle JP, & Quisling RG: Cavernous angioma: a review of 126 collected and 12 new clinical cases. Neurosurgery 18:162172, 1986

    • Search Google Scholar
    • Export Citation
  • 52

    Tarnaris A, , Fernandes RP, & Kitchen ND: Does conservative management for brain stem cavernomas have better long-term outcome?. Br J Neurosurg 22:748757, 2008

    • Search Google Scholar
    • Export Citation
  • 53

    Vaquero J, , Leunda G, , Martínez R, & Bravo G: Cavernomas of the brain. Neurosurgery 12:208210, 1983

  • 54

    Voigt K, & Yaşargil MG: Cerebral cavernous haemangiomas or cavernomas. Incidence, pathology, localization, diagnosis, clinical features and treatment. Review of the literature and report of an unusual case. Neurochirurgia (Stuttg) 19:5968, 1976

    • Search Google Scholar
    • Export Citation
  • 55

    Wang CC, , Liu A, , Zhang JT, , Sun B, & Zhao YL: Surgical management of brain-stem cavernous malformations: report of 137 cases. Surg Neurol 59:444454, 2003

    • Search Google Scholar
    • Export Citation
  • 56

    Xia C, , Zhang R, , Mao Y, & Zhou L: Pediatric cavernous malformation in the central nervous system: report of 66 cases. Pediatr Neurosurg 45:105113, 2009

    • Search Google Scholar
    • Export Citation
  • 57

    Zabramski JM, , Wascher TM, , Spetzler RF, , Johnson B, , Golfinos J, & Drayer BP, et al.: The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422432, 1994

    • Search Google Scholar
    • Export Citation
  • 1

    Acciarri N, , Galassi E, , Giulioni M, , Pozzati E, , Grasso V, & Palandri G, et al.: Cavernous malformations of the central nervous system in the pediatric age group. Pediatr Neurosurg 45:81104, 2009

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    Gil-Nagel A, , Dubovsky J, , Wilcox KJ, , Stewart JM, , Anderson VE, & Leppik IE, et al.: Familial cerebral cavernous angioma: a gene localized to a 15-cM interval on chromosome 7q. Ann Neurol 39:807810, 1996

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    Gross BA, , Batjer HH, , Awad IA, & Bendok BR: Cavernous malformations of the basal ganglia and thalamus. Neurosurgery 65:719, 2009

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    Günel M, , Awad IA, , Finberg K, , Anson JA, , Steinberg GK, & Batjer HH, et al.: A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. N Engl J Med 334:946951, 1996

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    Günel M, , Awad IA, , Finberg K, , Steinberg GK, , Craig HD, & Cepeda O, et al.: Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery 38:12651271, 1996

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    Hauck EF, , Barnett SL, , White JA, & Samson D: Symptomatic brainstem cavernomas. Neurosurgery 64:6171, 2009

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    Hayman LA, , Evans RA, , Ferrell RE, , Fahr LM, , Ostrow P, & Riccardi VM: Familial cavernous angiomas: natural history and genetic study over a 5-year period. Am J Med Genet 11:147160, 1982

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    Johnson EW: Cerebral cavernous malformation, familial (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ccm) [Accessed June 14, 2010]

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    Kattapong VJ, , Hart BL, & Davis LE: Familial cerebral cavernous angiomas: clinical and radiologic studies. Neurology 45:492497, 1995

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    Kim DS, , Park YG, , Choi JU, , Chung SS, & Lee KC: An analysis of the natural history of cavernous malformations. Surg Neurol 48:918, 1997

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    Kivelev J, , Niemelä M, , Kivisaari R, , Dashti R, , Laakso A, & Hernesniemi J: Long-term outcome of patients with multiple cerebral cavernous malformations. Neurosurgery 65:450455, 2009

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    Kondziolka D, , Lunsford LD, & Kestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 83:820824, 1995

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    Kufs H: Uber heredofamiliare Aniogmatose des Gehirns und der Retina, ihr Beziehungen zueinander und zur Angiomatose der haut. Ztschr Neurol Psych 113:651686, 1928

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    Kumar V, , Abbas AK, , Fausto N, , Robbins SL, & Cotran RS: Robbins and Cotran Pathologic Basis of Disease ed 7 Philadelphia, Elsevier Saunders, 2005

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    Kupersmith MJ, , Kalish H, , Epstein F, , Yu G, , Berenstein A, & Woo H, et al.: Natural history of brainstem cavernous malformations. Neurosurgery 48:4754, 2001

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    Labauge P, , Brunereau L, , Laberge S, & Houtteville JP: Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations. Neurology 57:18251828, 2001

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    Labauge P, , Brunereau L, , Lévy C, , Laberge S, & Houtteville JP: The natural history of familial cerebral cavernomas: a retrospective MRI study of 40 patients. Neuroradiology 42:327332, 2000

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  • 33

    Laberge-le Couteulx S, , Jung HH, , Labauge P, , Houtteville JP, , Lescoat C, & Cecillon M, et al.: Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 23:189193, 1999

    • Search Google Scholar
    • Export Citation
  • 34

    Lanzino G, & Spetzler RF: Cavernous Malformations of the Brain and Spinal Cord New York, Thieme, 2008

  • 35

    Liquori CL, , Berg MJ, , Squitieri F, , Ottenbacher M, , Sorlie M, & Leedom TP, et al.: Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat 27:118, 2006

    • Search Google Scholar
    • Export Citation
  • 36

    Mason I, , Aase JM, , Orrison WW, , Wicks JD, , Seigel RS, & Bicknell JM: Familial cavernous angiomas of the brain in an Hispanic family. Neurology 38:324326, 1988

    • Search Google Scholar
    • Export Citation
  • 37

    Mathiesen T, , Edner G, & Kihlström L: Deep and brainstem cavernomas: a consecutive 8-year series. J Neurosurg 99:3137, 2003

  • 38

    Moran NF, , Fish DR, , Kitchen N, , Shorvon S, , Kendall BE, & Stevens JM: Supratentorial cavernous haemangiomas and epilepsy: a review of the literature and case series. J Neurol Neurosurg Psychiatry 66:561568, 1999

    • Search Google Scholar
    • Export Citation
  • 39

    Moriarity JL, , Clatterbuck RE, & Rigamonti D: The natural history of cavernous malformations. Neurosurg Clin N Am 10:411417, 1999

  • 40

    Moriarity JL, , Wetzel M, , Clatterbuck RE, , Javedan S, , Sheppard JM, & Hoenig-Rigamonti K, et al.: The natural history of cavernous malformations: a prospective study of 68 patients. Neurosurgery 44:11661173, 1999

    • Search Google Scholar
    • Export Citation
  • 41

    Mottolese C, , Hermier M, , Stan H, , Jouvet A, , Saint-Pierre G, & Froment JC, et al.: Central nervous system cavernomas in the pediatric age group. Neurosurg Rev 24:5573, 2001

    • Search Google Scholar
    • Export Citation
  • 42

    Otten P, , Pizzolato GP, , Rilliet B, & Berney J: [131 cases of cavernous angioma (cavernomas) of the CNS, discovered by retrospective analysis of 24,535 autopsies.]. Neurochirurgie 35:8283, 1989. (Fr)

    • Search Google Scholar
    • Export Citation
  • 43

    Porter PJ, , Willinsky RA, , Harper W, & Wallace MC: Cerebral cavernous malformations: natural history and prognosis after clinical deterioration with or without hemorrhage. J Neurosurg 87:190197, 1997

    • Search Google Scholar
    • Export Citation
  • 44

    Porter RW, , Detwiler PW, , Spetzler RF, , Lawton MT, , Baskin JJ, & Derksen PT, et al.: Cavernous malformations of the brainstem: experience with 100 patients. J Neurosurg 90:5058, 1999

    • Search Google Scholar
    • Export Citation
  • 45

    Pozzati E, , Acciarri N, , Tognetti F, , Marliani F, & Giangaspero F: Growth, subsequent bleeding, and de novo appearance of cerebral cavernous angiomas. Neurosurgery 38:662670, 1996

    • Search Google Scholar
    • Export Citation
  • 46

    Pozzati E, , Giuliani G, , Nuzzo G, & Poppi M: The growth of cerebral cavernous angiomas. Neurosurgery 25:9297, 1989

  • 47

    Rigamonti D, , Hadley MN, , Drayer BP, , Johnson PC, , Hoenig-Rigamonti K, & Knight JT, et al.: Cerebral cavernous malformations. Incidence and familial occurrence. N Engl J Med 319:343347, 1988

    • Search Google Scholar
    • Export Citation
  • 48

    Robinson JR, , Awad IA, & Little JR: Natural history of the cavernous angioma. J Neurosurg 75:709714, 1991

  • 49

    Robinson JR Jr, , Awad IA, , Magdinec M, & Paranandi L: Factors predisposing to clinical disability in patients with cavernous malformations of the brain. Neurosurgery 32:730736, 1993

    • Search Google Scholar
    • Export Citation
  • 50

    Sandalcioglu IE, , Wiedemayer H, , Secer S, , Asgari S, & Stolke D: Surgical removal of brain stem cavernous malformations: surgical indications, technical considerations, and results. J Neurol Neurosurg Psychiatry 72:351355, 2002

    • Search Google Scholar
    • Export Citation
  • 51

    Simard JM, , Garcia-Bengochea F, , Ballinger WE Jr, , Mickle JP, & Quisling RG: Cavernous angioma: a review of 126 collected and 12 new clinical cases. Neurosurgery 18:162172, 1986

    • Search Google Scholar
    • Export Citation
  • 52

    Tarnaris A, , Fernandes RP, & Kitchen ND: Does conservative management for brain stem cavernomas have better long-term outcome?. Br J Neurosurg 22:748757, 2008

    • Search Google Scholar
    • Export Citation
  • 53

    Vaquero J, , Leunda G, , Martínez R, & Bravo G: Cavernomas of the brain. Neurosurgery 12:208210, 1983

  • 54

    Voigt K, & Yaşargil MG: Cerebral cavernous haemangiomas or cavernomas. Incidence, pathology, localization, diagnosis, clinical features and treatment. Review of the literature and report of an unusual case. Neurochirurgia (Stuttg) 19:5968, 1976

    • Search Google Scholar
    • Export Citation
  • 55

    Wang CC, , Liu A, , Zhang JT, , Sun B, & Zhao YL: Surgical management of brain-stem cavernous malformations: report of 137 cases. Surg Neurol 59:444454, 2003

    • Search Google Scholar
    • Export Citation
  • 56

    Xia C, , Zhang R, , Mao Y, & Zhou L: Pediatric cavernous malformation in the central nervous system: report of 66 cases. Pediatr Neurosurg 45:105113, 2009

    • Search Google Scholar
    • Export Citation
  • 57

    Zabramski JM, , Wascher TM, , Spetzler RF, , Johnson B, , Golfinos J, & Drayer BP, et al.: The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422432, 1994

    • Search Google Scholar
    • Export Citation

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