Prospective Hemorrhage Rates of Cerebral Cavernous Malformations in Children and Adolescents Based on MRI Appearance

Prospective Hemorrhage Rates Based on the Zabramski Classification

When a CCM is diagnosed, the most important issue is to predict the risk for future hemorrhage and clinical symptoms. Thus, the aim of any classification should be to predict hemorrhage (and consequently clinical) risks. Prior hemorrhage has already been described as an important risk factor for subsequent hemorrhage.^1,2,7⇓–9 However, the term “hemorrhage” is used to describe both cerebral bleeding and a clinical symptom in the published literature, making accurate comparisons of hemorrhage rates difficult, with some authors calculating hemorrhage rates per patient and indicating clinical event rates instead of radiologic event rates (Table 3).¹⁰ While the assessment of clinical events appears practical, there is a distinct risk of false generalization: The same CCM will lead to different clinical event rates depending on whether it is located in the precentral or the middle frontal gyrus. Accordingly, hemorrhage of brain stem CCMs was more likely to be symptomatic than other CCMs in our series. Therefore, we advocate the assessment of lesion-based radiologic hemorrhage rates because the occurrence of clinical events (with the exception of seizures) depends primarily on lesion location and the extent of hemorrhage.^12,13 Clinical event rates can then be deduced when the localization and hemorrhage rate of a given CCM are known.¹¹

We analyzed hemorrhage rates on the basis of the most common CCM classification by Zabramski et al³ and found that it is possible to predict radiologic hemorrhage rates on the basis of this classification. Even though Zabramski type I, II, and (proposed) V CCMs have distinctive morphologic features, these lesions share statistically similar high annual hemorrhage rates of 20.1%–29.8%. Annual hemorrhage rates of type III and dot-sized CCM are significantly lower (3.4% and 1.3%, respectively). Our results imply that the presence of acute or subacute blood-degradation products, present in Zabramski type I, II, and V CCMs, is the strongest predictor of hemorrhage. These findings are highly in accordance with results provided by Jeon et al,⁵ who performed a comparable analysis on 410 mostly solitary-type I, II, and III CCMs in a population older than 18 years of age: The authors reported an increased annual hemorrhage risk of type I and II lesions (27.6% and 15.4%, respectively) compared with type III lesions (5.4%) (P < .001).⁵ Additionally, the authors found that female sex, age, infratentorial localization, multiplicity, size, and the presence of venous angioma were no risk factors for hemorrhage, which is also in accordance with our results.⁵ The outstanding role of signs of prior hemorrhage is also supported by previous published results, in which an increased risk for hemorrhagic CCM has been reported despite different definitions of hemorrhage (Table 3).^1,2,7⇓–9 A possible explanation might be the destruction of microstructural integrity after a first hemorrhagic event.¹⁴

Our findings and data from the literature imply that a simple tripartite classification might be more useful in clinical practice:

1. CCMs with acute or subacute blood-degradation products (Zabramski I, II, V). High hemorrhage risk of 23.4% (literature: 4.5%–60%).^1,2,5,8 Mean hemorrhage-free interval: 22.63 months. Association with acute or subacute clinical symptoms.

2. CCMs without acute or subacute blood-degradation products (Zabramski III). Intermediate annual hemorrhage risk of 3.4% (literature: 0%–6%).^{1,2,5,8,15⇓–17} Mean hemorrhage-free interval: 27.88 months. They may be symptomatic particularly in the context of seizures: Ten percent of seizures in our series were associated with these CCMs.

3. Dot-sized lesions, visible in T2* and not or barely visible in T1WI and T2WI (Zabramski IV). The lowest hemorrhage rate of 1.3%. Mean hemorrhage-free interval: 37.78 months. Appear to be asymptomatic unless they are hemorrhagic.⁶

Other Possible Risk Factors

Whereas univariate analyses implied that brain stem localization, the presence of a developmental venous anomaly, and a solitary CCM are associated with an increased hemorrhage risk, these factors did not prove significant in our multivariate analyses. In fact, data from various authors imply that an apparent increased hemorrhage risk of brain stem lesions is likely to be caused by a selection bias: Brain stem hemorrhage is more likely to be symptomatic than supratentorial hemorrhage and is therefore more likely to lead to MR imaging.^9,12,18,19 Furthermore, while the relationship between developmental venous anomalies and CCMs is not fully understood yet, neither Flemming et al²⁰ nor Jeon et al,⁵ who performed analyses comparable with ours found that the presence of developmental venous anomalies was associated with an increased hemorrhage risk. Finally, it has been reported that patients with multiple CCMs and patients with CCM3 mutations have a more aggressive clinical course. Flemming et al,²⁰ for example, indicated an odds ratio of 2.65 for hemorrhage in patients with multiple lesions. However, a more aggressive clinical course does not necessarily imply an increased hemorrhage risk. Current evidence suggests that a more aggressive clinical course is possibly caused by an increased cumulative hemorrhage rate rather than an increased hemorrhage rate of each CCM.^5,21,22 Paradoxically, our data demonstrated an increased long-term hemorrhage rate of solitary lesions. However, this result may have been biased because most of the solitary lesions were more likely to be resected early on and thus were absent from long-term radiologic follow-up analyses. Although there were limited patient data with mutations in our analyzed population, our results did not suggest that hemorrhage rates of each CCM type depended on a specific mutation type. Results in the literature suggest that those carrying the CCM3 mutation are likely to present with an increased number of CCMs at an early age.^6,22 Again, a more aggressive clinical course in patients with CCM3 mutations may be caused by an increased cumulative risk due to a high number of CCMs.^6,21,22

Limitations

Our retrospective approach involves a degree of selection bias. An ideal study dealing with hemorrhage rates should be prospective and standardized. However, examining a considerable number of patients with CCMs on a regular basis—ideally monthly to reliably diagnose new hemorrhage—can be a tedious task, which is reflected by the fact that all published prospective studies dealing with the natural history of CCMs are registry studies.^{1,8,15⇓–17}

Furthermore, it has been discussed controversially whether CCMs in children bear an increased hemorrhage risk.²³ Mottolese et al,⁴ for instance, reported that CCMs in children are more likely to be symptomatic. In the end, the sometimes reported lower proportion of asymptomatic incidental CCMs in children is likely to be caused by a selection bias because routine examinations of the brain are more common in adults than in children. Additionally, hemorrhage rates in the literature are commonly calculated under the assumption that CCMs are congenital, despite the proof of de novo lesions.^{7⇓–9,15⇓–17} Consequently, hemorrhage rates calculated under this assumption are always inversely proportional to the mean age of a patient population, leading to a higher hemorrhage rate in younger populations. In fact, Jeon et al,⁵ who performed a prospective hemorrhage rate calculation similar to ours, reported comparable hemorrhage rates for a population older than 18 years of age.

A further limitation of our study is a diagnostic uncertainty concerning dot-sized lesions.⁶ The size and signal of dot-sized lesions depend strongly on technical MR imaging parameters such as magnetic field strength and section thickness. It is conceivable that dot-sized CCMs simply correspond to small nonhemorrhagic CCMs.⁶ Nonetheless, our data suggest that these different CCM types have statistically significant distinctive clinical and radiologic features that justify differentiation of these lesions.

In summary, we believe that analyzing CCMs in children and adolescents with multiple CCMs is a practical approach in the absence of prospective studies with serial MR imaging examinations; examining CCMs in the context of multiple lesions allows a longitudinal analysis of different CCMs of varying types, sizes, and locations at the same time and underlying the same possible influence factors. Furthermore, differential diagnosis of dot-sized T2* lesions in adults comprises microangiopathic, amyloid angiopathic, or drug-induced (eg, anticoagulant therapy) microbleeds, which are rare in children and adolescents.