Simultaneous and sequential hemorrhage of multiple cerebral cavernous malformations: a case report

Cerebral cavernous malformations (CCMs), also known as cavernomas or cavernous angiomas, are classically defined as low pressure hamartomatous berrylike vascular lesions with minimal to no intervening brain parenchyma composed of thin-walled endothelial-lined sinusoidal spaces devoid of smooth muscle [1‐4]. It has been suggested that CCMs arise from failure of vascular stabilization in angiogenesis which promotes the development of capillary dysplasia, weak intercellular junctions, and defective smooth muscle recruitment [5]. An estimated 0.5 % of the population has CCMs [3, 6]. While many patients remain asymptomatic, others tend to develop epilepsy, neurological deficits, or hemorrhage [1, 4, 6]. Sporadic and inherited forms of CCM have been described. The sporadic form often results in single isolated lesions while the inherited form is associated with multiple lesions and mutations of the endothelial genes CCM1, CCM2 or CCM3 [5, 7].

The etiology of CCM rupture is not well understood. It has been demonstrated that CCM lesions elicit inflammatory responses that involve tumor necrosis factor alpha (TNF-α) and interleukins (ILs). Upregulation of angiogenic factors such as vascular endothelial growth factor (VEGF) have also been described. These processes are implicated in the promotion of angiogenesis and breakdown of the blood–brain barrier (BBB) leading to the progression and rupture of CCM [5]. CCM2 and CCM3 mutations have also been linked to higher hemorrhage rates [1, 8]. Simultaneous hemorrhages of multiple CCM lesions are anecdotally common but few have been reported [7, 9, 10]. Causative physiologic parameters preceding hemorrhagic CCM events are often not described even in case reports. We present a case of an individual with simultaneous and sequential hemorrhages in multiple CCMs with a new onset diagnosis of hypertension.

Cerebral cavernomas are estimated to occur in 1 out of every 200 individuals in the general population [3, 6, 7]. They are hypothesized to develop due to failure of vascular stabilization in angiogenesis of cerebral blood vessels [5]. In a large series studying the natural history of cavernomas, 18.7 to 20 % of patients had multiple lesions [9, 12, 13]. Multiple lesions are mostly seen in familial CCM (FCCM) forms [7]. FCCM has been associated with mutations of CCM1, CCM2 and CCM3 genes. Nevertheless, 22 % of multiple lesions occur without any evidence of gene mutation [8].

CCMs have a hemorrhage rate of 0.7 to 1.1 % per lesion per year [4, 7]. Most cases of hemorrhages reported in the literature tend to involve one lesion, even in patients with multiple CCMs. Personal communication from Issam Awad suggests that multiple simultaneously hemorrhagic CCM lesions are more common (July 2015). However, to date there have been a total of only three reports on simultaneous hemorrhages of multiple cavernomas (Table 1). Our report is different in that the presented case exhibited simultaneous and sequential rupture patterns in the setting of new onset hypertension. What would lead to such a phenomenon remains an enigma, as the exact cause of CCM hemorrhage has yet to be determined. Many studies have focused on the genetic and inflammatory mechanisms contributing to CCM rupture, but few have investigated the potential role chronic hypertension may play in this complex multifactorial disease process.

Genetic and inflammatory causes have clearly been shown to influence CCM hemorrhage. In mouse model experiments, Cunningham et al. observed that conditional inactivation of the CCM2 gene in adult mice produced a cerebral hemorrhage similar to that observed in adult human CCMs [1]. Mutation of the CCM3 gene in humans has been linked to a hereditary variant of CCM and demonstrates early-onset cerebral hemorrhage patterns [8]. Shi et al. have reported CCMs to be active inflammation sites infiltrated with B cells and plasma cells [14]. Our patient did not have any familial past medical history of intracerebral hemorrhage or relatives with a diagnosis of CCM. However, he was being treated for sinusitis and it is possible that there was an increased release of inflammatory cytokines, TNF-α and ILs. These inflammation mediators stimulate angiogenesis and BBB breakdown and are thought to contribute to CCM rupture [5]. It is also possible that rupture of one of the CCMs enhanced recruitment of the inflammatory processes that contributed to the sequential pattern that was observed in our patient. However, inflammation and genetics may be only part of this complex multifactorial disease process and hypertension may play a role.

The studies that have addressed hemodynamic effects on CCMs are narrowly focused and limited. A recent study on the association of cardiovascular risk factors with CCM severity in 185 Hispanic individuals with CCM1 mutation failed to find any positive correlation between CCM rupture and cardiovascular risks, including hypertension [15]. However, an experiment by Little et al. demonstrated that cavernomas are affected by changes in mean arterial blood pressure (MABP) and venous pressure. Direct angioma pressure measurements showed that a mean reduction of 14.7±2.1 mmHg in MABP resulted in a 7.0±0.5 mmHg drop in angioma pressure. Mechanical jugular compression induced real measurable changes in CCM pressure up to 9 mmHg [2]. Although the study did not investigate changes caused by increased MABP, the data clearly demonstrate that systemic blood pressure changes significantly affect CCM pressures.

Few studies to date have directly measured cerebral capillary pressure or determined the direct effects of systemic blood pressure on capillary physiology. Classical studies of cerebral blood flow show that the pial arterioles autoregulate until systolic blood pressure exceeds approximately 160 mmHg above which smaller pial arterioles are differentially affected, become dilated, and lose regulatory control; this results in increases in blood flow [16, 17]. Direct measurement of cerebral capillary pressure is problematic but pressure characteristics can be extrapolated from peripheral limb vasculature experiments which demonstrate that significantly higher apex pressures are measured in patients with essential hypertension when compared to age-matched and sex-matched normotensive controls [18, 19]. Structural abnormalities can also occur in peripheral capillaries as a result of essential hypertension with loss or reduction in the density of vessels per volume of tissue, which is a process known as rarefaction [18, 20]. When considering the histopathological features of CCM architecture, chronic hypertensive changes alter arterial flow and vessel physiology, which could cause meaningful alterations in capillary anatomy as well as hemorrhage propensity and patterns.

Many vascular disease processes are influenced by multifactorial systemic corporeal changes. An example of this is the development and rupture of cerebral aneurysms. Inflammation, genetics, hypertension, smoking, and age are known risk factors that contribute to the development of aneurysm rupture and hemorrhage [21‐25]. Models have been developed to describe the pathophysiology for aneurysm induction and progression and include endothelial damage and degeneration of the elastic lamina, inflammatory cell recruitment and infiltration, and chronic remodeling of vascular wall [26]. Similarly, we argue that chronic high blood pressure may be a factor in capillary physiology that alters architectural features of abnormal capillary anatomy in CCM which increases the propensity for hemorrhage.

This case report is unusual in that hypertension may have played a role in the simultaneous and sequential hemorrhage pattern noted in this individual. Notwithstanding the many advances made in understanding the structure, formation and evolution of CCMs, there is still a lack of understanding concerning the effect of hemodynamic changes on cerebral capillary physiology and cavernomas. Investigative work focusing on the role of hypertension and other hemodynamic factors in CCM rupture is much needed, especially experiments in order to better determine if blood pressure changes affect the incidence of CCM hemorrhage.

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.