Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study

Abstract

SummaryBackgroundCerebral cavernous malformations (CCMs) are prone to bleeding but the risk of intracranial haemorrhage and focal neurological deficits, and the factors that might predict their occurrence, are unclear. We aimed to quantify these risks and investigate whether they are affected by sex and CCM location.MethodsWe undertook a population-based study using multiple overlapping sources of case ascertainment (including a Scotland-wide collaboration of neurologists, neurosurgeons, stroke physicians, radiologists, and pathologists, as well as searches of registers of hospital discharges and death certificates) to identify definite CCM diagnoses first made in Scottish residents between 1999 and 2003, which study neuroradiologists independently validated. We used multiple sources of prospective follow-up both to identify outcome events (which were assessed by use of brain imaging, by investigators masked to potential predictive factors) and to assess adults' dependence. The primary outcome was a composite of intracranial haemorrhage or focal neurological deficits (not including epileptic seizure) that were definitely or possibly related to CCM.Findings139 adults had at least one definite CCM and 134 were alive at initial presentation. During 1177 person-years of follow-up (completeness 97%), for intracranial haemorrhage alone the 5-year risk of a first haemorrhage was lower than the risk of recurrent haemorrhage (2·4%, 95% CI 0·0–5·7 vs 29·5%, 4·1–55·0; p<0·0001). For the primary outcome, the 5-year risk of a first event was lower than the risk of recurrence (9·3%, 3·1–15·4 vs 42·4%, 26·8–58·0; p<0·0001). The annual risk of recurrence of the primary outcome declined from 19·8% (95% CI 6·1–33·4) in year 1 to 5·0% (0·0–14·8) in year 5 and was higher for women than men (p=0·01) but not for adults with brainstem CCMs versus CCMs in other locations (p=0·17).InterpretationThe risk of recurrent intracranial haemorrhage or focal neurological deficit from a CCM is greater than the risk of a first event, is greater for women than for men, and declines over 5 years. This information can be used in clinical practice, but further work is needed to quantify risks precisely in the long term and to understand why women are at greater risk of recurrence than men.FundingUK Medical Research Council, Chief Scientist Office of the Scottish Government, and UK Stroke Association.

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

“…Lifetime risk of clinically overt hemorrhage is >30%. 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].…”

“…While the CCM3 genotype portends more aggressive disease, the clinical behavior of CCM cases, regardless of genotype, remains widely unpredictable [3]. 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].…”

Vascular Permeability in Cerebral Cavernous Malformations

“…1,2 A CCM lesion consists of clusters of hemorrhagic dilated anomalous vessels ('caverns') lined by endothelium with defective intercellular junctions, and devoid of mature vessel wall angioarchitecture. 3,4 Multifocal CCM lesions arise in familial cases with autosomal dominant mutations in CCM1 (KRIT1), CCM2, or CCM3 (PDCD10) genes.…”

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

“…6 Other authors identified prior hemorrhage as an important risk factor for subsequent hemorrhage by comparing hemorrhage rates of CCMs with and without prior hemorrhage. 1,2,5,[7][8][9] According to these studies, hemorrhage rates ranged from 0%-6% and 4.5%-60%, depending on whether prior hemorrhage was or was not present, respectively. 1,2,5,7-9 However, these articles have a lack of comparability because of differing hemorrhage definitions.…”