Cerebral cavernous malformations (CCMs) are intracranial lesions comprised of low flow and abnormally dilated capillary endothelial channels with increased permeability that predispose these vessels to episodes of thrombosis and focal hemorrhage, resulting in seizures and neurologic deficits.
There are two forms: familial and sporadic.
Familial CCMs, which account for at least 20% of all cases, can be passed from parent to child. Individuals with familial CCMs typically have multiple lesions. Familial CCMs are passed through families in an autosomal dominant manner, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Each child of an individual with familial CCM has a 50% chance of inheriting the mutation.
Sporadic CCMs occur in people with no family history of the disorder. These individuals tend to have only one CCM. Those with sporadic CCM do not have a greater chance of having a child with a CCM than anyone else in the general population.
Cavernomas comprise 8%-15% of intracranial vascular lesions, usually supratentorial in location and superficial.
Of 164 cerebral cavernous hemangiomas may be found in every age group including the neonatal period. The sex incidence is equal. In 126 cases (76.8%) the cavernomas were of supratentorial, in 34 cases (20.7%) of infratentorial site, and in 4 more cases (2.5%) there was multiple occurence of supratentorial and posterior fossa cavernous haemangiomas 1).
Although several natural history reports exist for adults with CMs, similar data for pediatric patients are limited.
Gross et al reviewed hospital databases to identify children with CMs who had not been treated surgically and who had clinical and radiological follow-up. Annual hemorrhage rates were calculated in lesion-years, and risk factors were assessed using the Cox regression.
In a cohort of 167 patients with 222 CMs, the mean patient age at the time of diagnosis was 10.1 years old (SD 6.0). Ninety patients (54%) were male. One hundred four patients (62%) presented with hemorrhage from at least 1 CM, 58 (35%) with seizures with or without CM hemorrhage, and 43 (26%) with incidental lesions. Twenty-five patients (15%) had multiple CMs, 17 (10%) had a family history of CMs, and 33 (20%) had radiologically apparent developmental venous anomaly (DVAs). The overall annual hemorrhage rate was 3.3%. Permanent neurological morbidity was 29% per hemorrhage, increasing to 45% for brainstem, thalamic, or basal ganglia CM and decreasing to 15% for supratentorial lobe or cerebellar lesions. The annual hemorrhage rate for incidental CMs was 0.5%; for hemorrhagic CMs, it was 11.3%, increasing to 18.2% within the first 3 years. Hemorrhage clustering within 3 years was statistically significant (HR 6.1, 95% CI 1.72-21.7, p = 0.005). On multivariate analysis, hemorrhagic presentation (HR 4.63, 95% CI 1.53-14.1, p = 0.007), brainstem location (HR 4.42, 95% CI 1.57-12.4, p = 0.005), and an associated radiologically apparent DVA (HR 2.91, 95% CI 1.04-8.09, p = 0.04) emerged as significant risk factors for hemorrhage, whereas age, sex, CM multiplicity, and CM family history did not.
Prior hemorrhage, brainstem location, and associated DVAs are significant risk factors for symptomatic hemorrhage in children with CMs. Hemorrhage clustering within the first 3 years of a bleed can occur, a potentially important factor in patient management and counseling 2)
Cerebral Cavernous malformation (CCM) diagnosis occurs more frequently than some years ago, due to the increased diffusion of magnetic resonance imaging. Progress in knowledge on genetical and molecular pathogenesis may change management strategy of these patients allowing more tailored approaches 3).
Macroscopic calcifications of cerebral cavernomas were found only in 18 cases (11%). Cerebral angiography was done in 31 cases (18.9%). In 9 cases angiography was totally normal, and in 11 cases the cavernoma presented only as an avascular mass. In the remaining cases there was no conformity in the angiographic appearance of cerebral cavernous haemangiomas. Operative extirpation is the treatment of choice if a solitary lesion is favourably located. In addition to our patient there are now 21 cases (12.8%) in which cavernomas were treated successfully by operative extirpation 4).
MRI is the modality of choice, demonstrating a characteristic “popcorn” or “berry” appearance with a rim of signal loss due to hemosiderin, which demonstrates prominent blooming on susceptibility weighted sequences.
Gradient echo or T2* sequences are able to delineate these lesions better than T1 or T2 weighted images. In patients with familial or multiple cavernous angiomas GRE T2* sequences are very important in identifying the number of lesions missed by conventional Spin echo sequences.
The SWI sequence, being more sensitive to substances which distort the local magnetic field than the GRE T2*W sequence, showed a higher sensitivity in identifying cerebral cavernous malformations. Thus, routine clinical neuroimaging protocol should contain SWI sequences to evaluate patients with (or suspected) cerebral cavernous malformations 5).
Susceptibility weighted imaging (SWI) may have sensitivity equal to that of GRE in detecting these capillary telangiectasias in the brain. SWI is also highly sensitive in detecting calcification as compared to T1 and T2 images.
If a recent bleed has occurred then surrounding oedema may be present.
The lesions generally do not enhance, although enhancement is possible.
Quantitative Susceptibility Mapping (QSM) MRI allows accurate assessment of iron content in cerebral cavernous malformations (CCM), and a threshold increase by 6% in QSM has been shown to reflect new symptomatic hemorrhage (SH) in previously stable lesions.
It is unclear how lesional QSM evolves in CCMs after recent SH, and whether this could serve as a monitoring biomarker in clinical trials aimed at preventing rebleeding in these lesions.
In 16 CCM patients who experienced a SH within the past year, whose lesion was not resected or irradiated.
The data acquisition was performed using QSM sequence implemented on a 3T MRI system ASSESSMENT: The lesional QSM assessments at baseline and yearly during 22 patient-years of follow-up were performed by a trained research staff including imaging scientists.
Biomarker changes were assessed in relation to clinical events. Clinical trial modeling was performed using two-tailed tests of time-averaged difference (assuming within-patient correlation of 0.8, power = 0.9 and alpha = 0.1) to detect 20%, 30% or 50% effects of intervention on clinical and biomarkers event rates during two years of follow-up.
The change in mean lesional QSM of index hemorrhagic lesions was +7.93% per patient-year in the whole cohort. There were 5 cases (31%) of recurrent SH or lesional growth, and twice as many instances (62%) with a threshold (6%) increase in QSM. There were no instances of SH hemorrhage or lesional growth without an associated threshold increase in QSM during the same epoch 6).
There have been few comparative studys of microsurgical excision vs conservative treatment of cerebral cavernous malformations (CCM) and none of them has reliably demonstrated a statistically and clinically significant difference.
A prospective, population-based study to identify and independently validate definite CCM diagnoses first made in 1999-2003 in Scottish adult residents, used multiple sources of prospective follow-up to assess adults' dependence and to identify and independently validate outcome events.
Moultrie et al., used univariate and multivariable survival analyses to test the influence of CCM excision on outcome, adjusted for prognostic factors and baseline imbalances.
Of 134 adults, 25 underwent CCM excision; these adults were younger (34 vs 43 years at diagnosis, p = 0.004) and more likely to present with symptomatic intracranial hemorrhage or focal neurological deficit than adults managed conservatively (48% vs 26%; odds ratio 2.7, 95% confidence interval [CI] 1.1-6.5). During 5 years of follow-up, CCM excision was associated with a deterioration to an Oxford Handicap Scale score 2-6 sustained over at least 2 successive years (adjusted hazard ratio [HR] 2.2, 95% CI 1.1-4.3) and the occurrence of symptomatic intracranial hemorrhage or new focal neurologic deficit (adjusted HR 3.6, 95% CI 1.3-10.0).
CCM excision was associated with worse outcomes over 5 years compared to conservative management. Long-term follow-up will determine whether this difference is sustained over patients' lifetimes. Meanwhile, a randomized controlled trial appears justified.
CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CCM excision worsens short-term disability scores and increases the risk of symptomatic intracranial hemorrhage and new focal neurologic deficits 7).
Alvarez de Eulate-Beramendi et al. selected 17 consecutive cases anatomopathologically diagnosed as cavernoma during 9 years. Immunohistochemical staining was performed for HIF-1alpha and MMP-9. We evaluated the relation between seizures and the scale of uptake of different tissues surrounding cavernoma. RESULTS. Cases with seizures had HIF-1alpha positive uptake in vascular endothelium in 31%, 17% in fibrous tissue and 34% in inflammatory tissue. Besides, it also shows MMP-9 positive uptake in vascular endothelium in 86%, 100% in fibrous tissue and 43% of brain tissue. Statistical analysis by chi-square and odds ratio shows a positive trend towards seizures and the presence of HIF-1alpha and MMP-9 in vascular tissue, fibrous tissue and brain tissue, but no for inflammatory tissue. CONCLUSION. HIF-1alpha and MMP-9, valued by immunohistochemical methods, are related to complications as seizures 8).
A patient who underwent subtotal resection of posterior fossa medulloblastoma with subsequent chemotherapy and radiotherapy at the age of 10 years. A new lesion in the region of the left foramen of Monro appeared 16 years later. Based on the imaging results, metastasis or radiation-induced cavernoma was considered. The lesion had the same appearance on imaging as a rarely published intraventricular cavernoma of the foramen of Monro. Unlike the cavernoma of the foramen of Monro, this lesion was subependymal and intraforniceal. Using electromagnetic navigation and neuroendoscopy, the lesion was completely removed. Histopathological examination revealed a cavernous haemangioma.
This is a unique case of intraforniceal paraforaminal cavernoma that was successfully removed endoscopically using electromagnetic neuronavigation and without neurological sequelae. 9).