Natural History and Management Options of Cerebral Cavernous Malformation

18 Natural History and Management Options of Cerebral Cavernous Malformation

Juri Kivelev, Jaakko Rinne, Mika Niemela, and Juha Hernesniemi

Abstract

Natural history of cavernous malformations may be affected by genetic mutational status, ultrastructural features, location along the neural axis, and, probably, perifocal hemodynamic environment. Patients with familial forms frequently harbor multiple cavernomas, whereas those with sporadic forms mostly present with a single lesion. Low blood flow inside the cavernous malformations predisposes to stasis and thrombosis, making profuse extralesional bleeding unlikely. In current clinical practice, cavernous malformations are anticipated mostly as asymptomatic incidental findings. In general, disease is characterized by three main clinical patterns: hemorrhage, seizures, and focal neurological deficits. An acute clinical manifestation is prevalently related to hemorrhage. The risk of this event, in average 1% per patient-year, depends on the location of the cavernoma and increases in deeper lesions of the brain and in brainstem. Seizure activity occurs in up to 80% of symptomatic patients with supratentorial cavernomas most probably due to hemosiderotic impregnation of perifocal brain. Focal neurological deficits are common for lesions located in eloquent areas. In summary, modern data suggest cavernomas to be fairly benign lesions which, however, may carry risks of neurological deterioration.

Keywords: cavernoma cavernous malformation cavernous hemangioma venous malformation

18.1 Introduction

Cavernous malformations, or cavernomas, are not common but are increasingly detected as incidental findings due to widespread availability of neuroimaging. Their incidence in the general population is estimated to range between 0.16 and 0.8%.1^, ²^, ³^, ⁴^, ⁵^, ⁶^, ⁷ Population-based annual detection rate of cavernomas has been estimated at 0.56 per 100,000 person-years for adults older than 16 years.⁸ Most are diagnosed between the second and fifth decades of life and can be either sporadic or familial.⁴^, ⁹^, ¹⁰ They occur in both genders with equal frequency.¹¹ Most patients present with a sporadic single lesion. However, 10 to 40% of cases are familial (or hereditary).⁷^, ¹² Familial cavernomas affect Hispanic-Americans more frequently and are typically characterized by multiple lesions. In hereditary cases, cavernomas are characterized by an autosomal dominant pattern of inheritance with incomplete penetrance. Three genes, namely, CCM1, CCM2, and CCM3, responsible for development of the cavernomas have been identified to date.¹

Natural history of the disease is predetermined by cavernoma genetics, ultrastructural features, location along the neural axis, and hemodynamic alterations in the lesion and surrounding brain. Fig. 18.1 demonstrates the histological view of a cavernoma. Blood flow inside the lesions is low, predisposing to intraluminal stasis and thrombosis. Due to its fragility, a cavernoma causes repetitive microhemorrhages into the surrounding neural tissue with formation of perifocal hemosiderosis and reactive gliosis. Such local homeostatic instability produced by either genetic or reactive environmental factors (inflammation, breakdown of the blood–brain barrier, gliosis) may provoke intensive neoangiogenesis and proliferation of the sinusoids constituting cavernoma. Subsequently, lesions enlarge and grow, which may coexist with clinical progression.

Fig. 18.1 Microscopic view of a cavernoma. The dilated vessels without intervening neural parenchyma are lined by thin endothelium and surrounded by collagenous fibrotic tissue with blue deposits of iron (hemosiderin) after hemorrhages.

Up to 40% of patients are asymptomatic.¹³^, ¹⁴ The most frequent clinical manifestations are seizures, focal neurological deficits (FNDs), and hemorrhage. Seizure activity occurs in up to 80% of patients with supratentorial cavernomas most probably being evoked by perilesional intraparenchymal changes. FNDs are typical for cavernomas located close to eloquent regions of the brain and for spinal lesions. Headaches are a common complaint in many cavernoma patients, and usually lead to further clinical and radiological workup. However, due to their unspecific nature, it is generally accepted that headaches are not linked to the cavernoma.

18.2 Selected Papers on the Natural History of Cavernous Malformations

●Del Curling O Jr, Kelly DL Jr, Elster AD, Craven TE. An analysis of the natural history of cavernous angiomas. J Neurosurg 1991;75(5):702–708

●Kondziolka D, Lunsford LD, Kestle JR. The natural history of cerebral cavernous malformations. J Neurosurg 1995;83(5):820–824

●Horne MA, Flemming KD, Su IC, et al; Cerebral Cavernous Malformations Individual Patient Data Meta-analysis Collaborators. Clinical course of untreated cerebral cavernous malformations: a meta-analysis of individual patient data. Lancet Neurol 2016;15(2):166–173

18.3 Natural History of Cavernous Malformation

18.3.1 Risk of Hemorrhage

For supratentorial cavernomas, the estimated annual risk of hemorrhage is 1% per patient-year (range: 0.25–2.5%; Table 18.1).³^, ⁸^, ¹⁵^, ¹⁶^, ¹⁷^, ¹⁸^, ¹⁹^, ²⁰^, ²¹ In familial cases, bleeding rates may vary depending on the cavernoma genotype. CCM3 carriers are more prone than CCM2 and CCM1 patients to develop cerebral hemorrhages, especially at a younger age.²² Furthermore, the authors showed that in patients with multiple cavernomas CCM1 was associated with a higher number of lesions than CCM2 and CCM3. Thus, the overall risk of hemorrhage in these patients is increased due to cumulative risks from each lesion.

Table 18.1 Reported symptomatic hemorrhage rates of cerebral cavernomas

Study	Annual hemorrhage rate (%)	Study design
Del Curling et al²⁴	0.1	Retrospective
Robinson et al⁷⁶	0.7	Prospective
Zabramski et al⁹⁵	1.2	Prospective
Kondziolka et al⁵¹	1.3	Retrospective
	2.6	Prospective
	0.6	For incidental lesion
Aiba et al³	0–0.4	Prospective
Porter et al⁷³	5	Retrospective
Porter et al⁷³	5	Brainstem lesion
Labauge et al⁵³	2.5	Retrospective, familial forms
Kupersmith et al⁵²	2.46	Brainstem lesions
Labauge et al., 2001	4.3	Prospective, familial forms
Cantu et al¹⁸	1.7	Retrospective, Hispanic population
Al-Shahi Salman et al⁷	0.5	Prospective
Jeon et al⁴⁴	4.5	Prospective

Infratentorial cavernomas have a higher bleeding rate with estimated annual risk ranging from 2.5 to 13.6% per patient-year.²⁹ This seems to be unrelated to eloquence of the region and thus easier detecting of symptomatic decline after ictus. Interestingly, larger lesion size (> 1 cm), early age at presentation (< 35 years), and coexistence of developmental venous malformation (DVA) were found to be associated with higher hemorrhage rates.²⁵ Nevertheless, the mechanisms of higher bleeding risk of cavernomas in the infratentorial compartment remain unclear.

Vascular permeability and iron leakage seem to play a central role in the pathogenesis of cavernomas when considering the natural history of the disease.³⁰ According to Girard et al, significant lesional permeability increases at follow-up correlated with interval hemorrhage or growth.³⁰ This corresponds with the hypothesis that enhanced vascular permeability is associated with and may drive hemorrhagic proliferation of cavernomas. Using a high magnetic resonance imaging (MRI) sensitivity technique, the authors showed higher regional brain permeability than contralateral homologous regions in anatomical locations initially lacking cavernomas, which later developed de novo lesions.

18.3.2 Risk of Rebleeding

After initial decline, caused by extralesional bleeding, many patients recover well, but some can experience rebleeding. Lesions of the brainstem seem to be more prone to rebleed. The risk of having recurrent extralesional hemorrhage in this selected group varies from 5.1 to 60% per patient-year.²⁹ Aiba et al found that younger women exhibited a higher incidence of rebleeding, possibly caused by hormonal factors.²⁶ Of note, Kalani et al in 2013 showed no increased hemorrhage risk during pregnancy, thus concluding that a history of cavernoma is not a contraindication to pregnancy or vaginal delivery.³¹

In contrast to previous studies, Barker et al proposed the concept of temporal clustering of the hemorrhages after the initial event.³² Using sophisticated statistical analysis in 141 patients, the authors discovered quantitative evidence of a spontaneous decline in the hazard of cavernoma rehemorrhage approximately 2 years after the first hemorrhage.

Xie et al summarized published data on hemorrhage risk factors subdividing them into three groups³³:

●Hemorrhage risk factors: History of previous ictus and location in brainstem.

●Possible risk factors: Female sex, younger age, perilesional edema on MRI, large lesion size, coexistence of DVA, hemodynamic change, or high blood pressure.

●No risk factors: Pregnancy, multiplicity, and antiplatelet or antithrombotic use.

This simple classification reflects modern understanding of factors that may affect cavernoma natural history. According to hese data, only a history of previous hemorrhage and brainstem location constitutes “true” increased risk of rehemorrhage, whereas other variables are not strong enough to change the natural history of the disease. Obviously further larger international multicenter prospective studies are needed to have unbiased data on disease course.

18.3.3 Risk of Seizures

Seizures are the most frequent clinical presentation of supratentorial cavernomas, occurring in 41 to 80% of patients.¹^, ³⁴

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