Clinical course of untreated pediatric brainstem cavernous malformations: hemorrhage risk and functional recovery

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>The aim of this study was to investigate the clinical appearance of untreated pediatric brainstem cavernous malformations (CMs) and to identify the hemorrhage risks and functional outcomes.</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>All pediatric patients with a diagnosis of brainstem CM between 1985 and 2012 were registered. The clinical chart and radiographs were recorded, and follow-up evaluations were obtained prospectively.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>A total of 85 patients (69.4% male) were included with a mean age of 12.7 years. Sixty-seven patients (78.8%) had prior hemorrhage, and 6 patients (7.1%) were asymptomatic. There were 15 midbrain lesions, 53 pons lesions, and 17 medulla lesions. The mean lesion size was 1.9 cm. During a total of 401.6 patient-years of follow-up, 47 hemorrhages occurred in 37 patients, and the annual hemorrhage rate was 11.7% per patient-year. The mean hemorrhage interval was 47.8 months. The hemorrhage risk declined over time, especially after the first 2 years. Both a lesion size ≥ 2 cm (hazard ratio [HR] 2.122, p = 0.037) and the presence of perilesional edema (HR 2.192, p = 0.039) predicted future hemorrhage and were associated with a high annual hemorrhage rate. The hemorrhage-free survival at 6 months was 85.7%, and at 1, 5, 10, and 15 years was 71.5%, 49.4%, 27.5%, and 13.7%, respectively. At the most recent functional evaluation, 33 patients (38.8%) had improved, 32 (37.6%) had stabilized, and 20 (23.5%) had worsened, without any deaths. Twenty-two patients (25.9%) obtained a full recovery. Prospective hemorrhage (HR 0.191, p = 0.003) was the adverse predictor for full recovery. Full recovery primarily occurred within the first 12 months, after which the chance of full recovery decreased. The cumulative percentage of complete recovery at 6 months was 32.7%, and at 1, 3, and 5 years was 40.8%, 43.6%, and 49.2%, respectively.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>In this study the hemorrhage rate was relatively high in pediatric brainstem CMs, although the functional outcome was acceptable. The decline in hemorrhage risk and the identified adverse predictors in this study were helpful for clinicians and patients when deciding on treatment. Referral bias and the insufficient follow-up period of the study were highlighted as limitations.</jats:p></jats:sec>

Peripheral Plasma Vitamin D and Non-HDL Cholesterol Reflect the Severity of Cerebral Cavernous Malformation Disease

“…The significant correlations were apparently driven mostly by early age of symptom onset, an acknowledged index of aggressive CCM disease [3,[5][6][7]27]. We recognize that the weaker correlations with other features may reflect small numbers of subjects with individual parameters of disease aggressiveness.…”

“…Given the small numbers of cases with each disease aggressiveness feature, and the known correlation among the different features (i.e., patients with earlier symptom onset are more likely to experience greater lesion burden and multiple hemorrhages, patients with recent hemorrhage are more likely to experience recent lesional growth) [3], we subsequently considered the respective features of disease aggressiveness in chronic or acute domains for our primary hypothesis testing. Since CCM disease beginning in pediatric patients has been shown to be more severe than when disease onset is in adults [3,[5][6][7], we used symptoms beginning at or before 18 years of age as a feature of chronic disease aggressiveness. We also considered more than 25 SWI lesions, more than five T2-weighted lesions and more than one hemorrhage as features of chronic disease aggressiveness because these same thresholds correlated with cerebral vascular permeability in patients with CCM [1].…”

“…Clinical disease aggressiveness is portended by early age of onset [3,27], high lesion burden [3] and multiple clinical bleeds resulting in disability [4]. Acute disease aggressiveness is characterized by recent clinical hemorrhage, which predicts a higher likelihood of future bleeding [5][6][7]. Lesion genesis and asymptomatic hemorrhagic proliferation (lesion growth) have been considered as features of disease aggressiveness in preclinical studies [10,11,28] with potential clinical implications.…”

“…Some patients remain asymptomatic, while others are disabled from recurrent bleeds and/or high lesion burden [4]. Early age of lesion onset, multiple hemorrhages and increased lesion burden have been correlated in various studies with chronic disease severity [5][6][7][8][9]. Features of acute disease aggressiveness include clinically overt hemorrhage, CCM lesion growth and the genesis of new lesions [10,11].…”

The natural history of cerebral cavernous malformations in children

“…2,10,13,20 In our analysis, 82% of brainstem CMs presented with hemorrhage along with a subsequent annual hemorrhage rate of 16.7%. While it is difficult to determine whether the high subsequent hemorrhage rate relates to the brainstem location or to the initial hemorrhagic presentation, this rehemorrhage rate is higher than that for hemorrhagic lesions presenting outside the brainstem.…”