cavernous

Update: Cerebral cavernous malformation pathogenesis

Cerebral cavernous malformation pathogenesis

Genes mutated in cerebral cavernous malformation (CCM) encode proteins that modulate junction formation between vascular endothelial cells.

Most cerebral cavernous malformations are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2(MGC4607), or CCM3 (PDCD10).

How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 1).

Although a role for these three genes in the formation of these intracranial vascular lesions has been established since the 1990s, additional works have further elucidated the molecular mechanisms by which mutations in these genes and the resultant aberrant proteins interact, leading to the formation of CCMs.

Therefore, it is reasonable to assume that a molecular pathway exists that requires all three proteins to function together correctly for proper cellular function. Moreover, research is demonstrating how each component protein is capable of interacting with numerous other signaling and cytoskeletal molecules allowing for a diverse range of functions in molecular signaling pathways via unique protein–protein interactions.

Significant research findings from 2000 to 2015 have further enhanced our understanding of the pathogenesis of CCM formation. The use of advanced sequencing technologies to characterize genomic mutations and the identification of new signaling pathways and protein–protein interactions have led to great strides in understanding the molecular genetics involved in the development of CCMs. However, many unanswered questions remain, and future studies are clearly needed to improve our understanding of CCM pathogenesis. “Gene to protein to disease” mechanisms involved in the pathogenesis of CCMs should shed further light on potential therapeutic targets. 2).

The Phosphoinositide 3 kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression.

Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment 3).

Studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics 4).

CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3–KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified.

Tang et al. identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of cerebral cavernous malformationformation. Activation of TLR4 by Gram negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment 5).

In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need 6).

References

1) , 4)

Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30. Erratum in: Nature. 2016 May 25;536(7617):488. PubMed PMID: 27027284; PubMed Central PMCID: PMC4864035.
2)

Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral Cavernous Malformations: Review of the Genetic and Protein-Protein Interactions Resulting in Disease Pathogenesis. Front Surg. 2016 Nov 14;3:60. Review. PubMed PMID: 27896269.
3)

Kar S, Samii A, Bertalanffy H. PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev. 2015 Apr;38(2):229-36; discussion 236-7. doi: 10.1007/s10143-014-0597-8. Epub 2014 Nov 19. PubMed PMID: 25403688.
5)

Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 10. doi: 10.1038/nature22075. [Epub ahead of print] PubMed PMID: 28489816.
6)

Chohan MO, Marchiò S, Morrison LA, Sidman RL, Cavenee WK, Dejana E, Yonas H, Pasqualini R, Arap W. Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review. JAMA Neurol. 2018 Nov 26. doi: 10.1001/jamaneurol.2018.3634. [Epub ahead of print] PubMed PMID: 30476961.

UptoDate: Medulla Oblongata Cavernous Malformation

Medulla Oblongata Cavernous Malformation

see also Brainstem cavernous malformation.

53 patients underwent surgical treatment for Medulla Oblongata Cavernous Malformations between 2011 and 2017 in the Beijing Tiantan Hospital with a male-to-female ratio of 1.4 and a mean age of 32.6 years. Eighteen patients (34.0%) had respiratory failure, and two patients (3.8%) had cardiac instabilities, preoperatively. The mean mRS score was 2.7 upon admission. Gross total resection was achieved in 52 patients (98.1%). Postoperatively, twenty-three patients (43.4%) had respiratory dysfunction, and sixteen patients (30.2%) had dysphagia or coughing. The mean follow-up duration was 35.7 months. At the last follow-up evaluation, the mean mRS score was 1.7, and 42 patients (84%) had favorable outcomes, with mRS scores ≤ 2. The conditions of the patients improved in 34 cases (68%), remained unchanged in 10 cases (20%), and worsened in 6 cases (12%) relative to the preoperative baseline. The independent adverse factors for long-term outcome were age ≥ 50 years old and increased time of reservation of tracheal intubationafter surgery.

Surgical treatment of CMs involving the medulla oblongata was very challenging, notably, perioperative respiratory dysfunction, with which patients tend to have unfavorable long-term outcomes, especially for elderly patients 1).

A 28-year-old man who was presented with intractable hiccup for 15 days. It developed suddenly, then aggravated progressively and did not respond to any types of medication. On magnetic resonance images, a well-demarcated and non-enhancing mass with hemorrhagic changes was noted in the left medulla oblongata. Intraoperative findings showed that the lesion was fully embedded within the brain stem and pathology confirmed the diagnosis of cavernous hemangioma. The hiccup resolved completely after the operation. Based on the presumption that the medullary cavernoma may trigger intractable hiccup by displacing or compression the hiccup arc of the dorsolateral medulla, surgical excision can eliminate the symptoms, even in the case totally buried in brainstem 2).

A 61-year-old woman presented with vertigo and swallowing disturbance. T1-weighted magnetic resonance image (MRI) showed a low intensity mass in the dorsolateral portion of the medulla oblongata, and T2-weighted imaging revealed a hemosiderin rim surrounding the lesion. Angiography showed no abnormalities. Surgery using far lateral approach achieved complete removal of the mass and hematoma. Histological examination of the surgical specimen disclosed cavernous angioma. This case suggests that direct surgery can be recommended for cavernous angioma located in the dorsal or lateral medulla oblongata to remove the hematoma and angioma if bleeding clearly provokes neurological symptoms 3).

1)

Xie MG, Xiao XR, Li D, Guo FZ, Zhang JT, Wu Z, Zhang LW. Surgical Treatment of Cavernous Malformations Involving the Medulla Oblongata: 53 Cases. World Neurosurg. 2018 Jul 4. pii: S1878-8750(18)31429-3. doi: 10.1016/j.wneu.2018.06.213. [Epub ahead of print] PubMed PMID: 29981463.
2)

Lee KH, Moon KS, Jung MY, Jung S. Intractable hiccup as the presenting symptom of cavernous hemangioma in the medulla oblongata: a case report and literature review. J Korean Neurosurg Soc. 2014 Jun;55(6):379-82. doi: 10.3340/jkns.2014.55.6.379. Epub 2014 Jun 30. PubMed PMID: 25237438; PubMed Central PMCID: PMC4166338.
3)

Abe M, Ogawa A, Yoshida Y, Hidaka T, Suzuki M, Takahashi S. Surgical removal of cavernous angioma in the medulla oblongata. A case report. Neurosurg Rev. 1997;20(2):128-31. Review. PubMed PMID: 9226673.

Update: Familial cerebral cavernous malformation

Familial cerebral cavernous malformation

Familial cerebral cavernous malformations, 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.
It is an autosomal-dominant disease with incomplete penetrance. The pathogenic genes of FCCM have been mapped into three loci: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10.
see https://www.ncbi.nlm.nih.gov/books/NBK1293/.

Although the clinical course is unpredictable, symptoms typically present during adult life and include headaches, focal neurological deficits, seizures, and potentially fatal stroke. In addition to neural lesions, extraneural cavernous malformations have been described in familial disease in several tissues, in particular the skin 1).

In recent years there has been an increasing amount of publications linking FCCMs with other pathology, predominantly with extracranial and intracranial mesenchymal anomalies.
When faced with an unusual clinical feature in a patient with a Mendelian disorder, the clinician may entertain the possibilities of either the feature representing a novel manifestation of that disorder or the co-existence of a different inherited condition. Here we describe an individual with a submandibular oncocytoma, pulmonary bullae and renal cysts as well as multiple cerebral cavernous malformations and haemangiomas. Genetic investigations revealed constitutional mutations in FLCN, associated with Birt-Hogg-Dubé syndrome (BHD) and CCM2, associated with familial cerebral cavernous malformation. Intracranial vascular pathologies (but not cerebral cavernous malformation) have recently been described in a number of individuals with BHD (Kapoor et al. in Fam Cancer 14:595-597, 10.1007/s10689-015-9807-y , 2015) but it is not yet clear whether they represent a genuine part of that conditions’ phenotypic spectrum. We suggest that in such instances of potentially novel clinical features, more extensive genetic testing to consider co-existing conditions should be considered where available. The increased use of next generation sequencing applications in diagnostic settings is likely to lead more cases such as this being revealed 2).

A study described an unusual association between 2 independent hereditary diseases of confirmed genetic origin-a combination that has not been described previously 3).
Rosário Marques et al. documented a novel mutation on KRIT1 gene, and the second to be reported in a Portuguese family. This mutation consists in a two nucleotide insertion (c.947_948insAC) within the exon 10, resulting in premature protein termination (p.Leu317Argfs*2). These findings will hopefully contribute to a better clinical, imaging and genetic characterisation of this disease, particularly while trying to identify the factors that influence its treatment and prognosis 4).

Yang et al., investigated the genetic mutation in a Chinese family with FCCM.
The proband is a 29-year-old female presenting with a 1-month history of headache. Brain magnetic resonance imaging (MRI) revealed multiple intracranial lesions, the largest one showing a popcorn-like appearance. After a 4-year conservative observation, there was no significant clinical or radiological progression. Family investigation found five of her relatives had multiple CCM lesions. DNA sequencing analysis in the proband disclosed a novel heterozygous deletion mutation (c.1919delT; p.Phe640SerfsX21) in exon 17 of the CCM1/KRIT1 gene. This mutation leads to a frameshift and is predicted to cause a premature termination codon to generate a truncated Krev interaction trapped-1 (Krit1) protein of 659 amino acids. The mutation segregated with the disease in the family. C The current study identified a novel CCM1/KRIT1 heterozygous deletion mutation (c.1919delT) associated with FCCM. The findings expand the CCM gene mutation profiles in the Chinese population, which will be beneficial for genetic counseling 5).

A proband was hospitalized for sudden unconsciousness and underwent surgical treatment. The section of lesions showed classical cavernous-dilated vessels without intervening brain parenchyma, and hemosiderin-laden macrophages were accumulated in the surrounding tissue. In addition, magnetic resonance imaging (MRI) showed severe multiple cerebral cavernous malformation (CCM) lesions in cerebrum, brainstem, and cerebellum in other affected subjects. Especially, for the proband’s mother, hundreds of lesions were presented, and a few lesions were found in the expanded lateral ventricle (Evans’ index =0.33). Moreover, she showed the similar symptoms of hydrocephalus, including headache, dizziness, and diplopia. It was extremely rare in previous reports. To date, the genetic alterations leading to FCCM in Chinese population remain largely unknown. We investigated genetic defects of this family. Sequence analyses disclosed a novel heterozygous insertion mutation (c.1896_1897insT; p.Pro633SerfsTer22) in KRIT1/CCM1. Moreover, our real-time PCR results revealed that the mRNA level of KRIT1/CCM1 were significantly decreased in FCCM subjects (CCM family =0.42 ± 0.20 vs. healthy control =1.01 ± 0.16, P = 0.004). It indicated that this mutation could cause KRIT1/CCM1 functional mRNA deficiency. It may be closely related with the pathogenesis of FCCM. Our findings provided a new gene mutation profile which will be of great significance in early diagnosis and appropriate clinical surveillance of FCCM patients 6).

Case series

Fifty-seven familial CCM type-1 patients were included in this institutional review board-approved study. Baseline SWI (n = 57) and follow-up SWI (n = 17) were performed on a 3T Siemens MR scanner with lesions counted manually by the study neuroradiologist. We modified an algorithm for detecting radiation-induced microbleeds on SWI images in brain tumor patients, using a training set of 22 manually delineated CCM microbleeds from two random scans. Manual and automated counts were compared using linear regression with robust standard errors, intra-class correlation (ICC), and paired t tests. A validation analysis comparing the automated counting algorithm and a consensus read from two neuroradiologists was used to calculate sensitivity, the proportion of microbleeds correctly identified by the automated algorithm. RESULTS: Automated and manual microbleed counts were in strong agreement in both baseline (ICC = 0.95, p < 0.001) and longitudinal (ICC = 0.88, p < 0.001) analyses, with no significant difference between average counts (baseline p = 0.11, longitudinal p = 0.29). In the validation analysis, the algorithm correctly identified 662 of 1325 microbleeds (sensitivity=50%), again with strong agreement between approaches (ICC = 0.77, p < 0.001). CONCLUSION: The automated algorithm is a consistent method for counting microbleeds in familial CCM patients that can facilitate lesion quantification and tracking 7).

The authors retrospectively reviewed abdominal CT scans in 38 patients with fCCM, 38 unaffected age- and sex-matched control subjects, and 13 patients with sporadic, nonfamilial cerebral cavernous malformation (CCM). The size, number, and laterality of calcifications and the morphologic characteristics of the adrenal gland were recorded. Brain lesion count was recorded from brain magnetic resonance (MR) imaging in patients with fCCM. The prevalence of adrenal calcifications in patients with fCCM was compared with that in unaffected control subjects and those with sporadic CCM by using the Fisher exact test. Additional analyses were performed to determine whether age and brain lesion count were associated with adrenal findings in patients with fCCM. Results Small focal calcifications (SFCs) (≤5 mm) were seen in one or both adrenal glands in 19 of the 38 patients with fCCM (50%), compared with 0 of the 38 unaffected control subjects (P < .001) and 0 of the 13 subjects with sporadic CCM (P = .001). Adrenal calcifications in patients with fCCM were more frequently left sided, with 17 of 19 patients having more SFCs in the left adrenal gland than the right adrenal gland and 50 of the 61 observed SFCs (82%) found in the left adrenal gland. No subjects had SFCs on the right side only. In patients with fCCM, the presence of SFCs showed a positive correlation with age (P < .001) and number of brain lesions (P < .001). Conclusion Adrenal calcifications identified on CT scans are common in patients with fCCM and may be a clinically silent manifestation of disease 8).

1)

de Vos IJ, Vreeburg M, Koek GH, van Steensel MA. Review of familial cerebral cavernous malformations and report of seven additional families. Am J Med Genet A. 2017 Feb;173(2):338-351. doi: 10.1002/ajmg.a.38028. Epub 2016 Oct 28. Review. PubMed PMID: 27792856.
2)

Whitworth J, Stausbøl-Grøn B, Skytte AB. Genetically diagnosed Birt-Hogg-Dubé syndrome and familial cerebral cavernous malformations in the same individual: a case report. Fam Cancer. 2017 Jan;16(1):139-142. doi: 10.1007/s10689-016-9928-y. PubMed PMID: 27722904; PubMed Central PMCID: PMC5243871.
3)

Belousova OB, Okishev DN, Ignatova TM, Balashova MS, Boulygina ES. Hereditary Multiple Cerebral Cavernous Malformations Associated with Wilson Disease and Multiple Lipomatosis. World Neurosurg. 2017 Sep;105:1034.e1-1034.e6. doi: 10.1016/j.wneu.2017.06.002. Epub 2017 Jun 8. PubMed PMID: 28602929.
4)

Rosário Marques I, Antunes F, Ferreira N, Grunho M. Familial cerebral cavernous malformation: Report of a novel KRIT1 mutation in a Portuguese family. Seizure. 2017 Nov 10;53:72-74. doi: 10.1016/j.seizure.2017.10.020. [Epub ahead of print] PubMed PMID: 29145060.
5)

Yang C, Wu B, Zhong H, Li Y, Zheng X, Xu Y. A novel CCM1/KRIT1 heterozygous deletion mutation (c.1919delT) in a Chinese family with familial cerebral cavernous malformation. Clin Neurol Neurosurg. 2017 Nov 20;164:44-46. doi: 10.1016/j.clineuro.2017.11.005. [Epub ahead of print] PubMed PMID: 29169046.
6)

Wang H, Pan Y, Zhang Z, Li X, Xu Z, Suo Y, Li W, Wang Y. A Novel KRIT1/CCM1 Gene Insertion Mutation Associated with Cerebral Cavernous Malformations in a Chinese Family. J Mol Neurosci. 2017 Feb;61(2):221-226. doi: 10.1007/s12031-017-0881-5. Epub 2017 Feb 3. PubMed PMID: 28160210.
7)

Zou X, Hart BL, Mabray M, Bartlett MR, Bian W, Nelson J, Morrison LA, McCulloch CE, Hess CP, Lupo JM, Kim H. Automated algorithm for counting microbleeds in patients with familial cerebral cavernous malformations. Neuroradiology. 2017 Jul;59(7):685-690. doi: 10.1007/s00234-017-1845-8. Epub 2017 May 22. PubMed PMID: 28534135; PubMed Central PMCID: PMC5501247.
8)

Strickland CD, Eberhardt SC, Bartlett MR, Nelson J, Kim H, Morrison LA, Hart BL. Familial Cerebral Cavernous Malformations Are Associated with Adrenal Calcifications on CT Scans: An Imaging Biomarker for a Hereditary Cerebrovascular Condition. Radiology. 2017 Aug;284(2):443-450. doi: 10.1148/radiol.2017161127. Epub 2017 Mar 20. PubMed PMID: 28318403; PubMed Central PMCID: PMC5519414.

Update: Optic chiasma cavernous malformation

Optic chiasma cavernous malformation

Epidemiology

Suprasellar occurrences of cavernous malformations (CM) in the optic chiasm are extremely uncommon, representing less than 1% of all CNS CMs 1) 2).
To the best of the knowledge of Abou-Al-Shaar et al. less than 80 cases have been reported in the literature 3).

Clinical features

Patients with these lesions typically present with chiasmal apoplexy, characterized by sudden visual loss, acute headaches, retroorbital pain, and nausea 4).
These symptoms typically occur after a period of transient blurry vision and headaches. In addition, hypopituitarism from direct compression of the pituitary stalk has been reported in the literature 5) 6).

Diagnosis

On CT scan, optic pathway CMs appear as well-demarcated hyperdense lesions with or without calcifications 7).

MRI

MR imaging of cavernous hemangioma of the optic chiasm 8)
MRI is considered the most sensitive and specific imaging modality for the diagnosis of CM 9).
On T1-weighted images, CMs of the optic pathway demonstrate a hypointense to isointense appearance, whereas on T2-weighted images, they appear as heterogeneous “popcorn” lesions with mixed hyperintense and hypointense signals.
The hypointensity can be delineated further in the gradient-echo T2* images due to hemosiderin deposition in and around the CM. In addition, following intravenous gadolinium administration, minimal or no enhancement can be observed in the CM 10) 11).
It has been reported that CMs of the optic nerve and tract may show nerve thickening on coronal views, whereas CMs of the optic chiasm often appear as focal round masses 12).
Angiography is usually not helpful in diagnosing CMs because it does not delineate the lesion due to the low internal flow and high incidence of thrombosis 13).

Differential diagnosis

CMs of the optic pathway are commonly misdiagnosed as optic neuritis, optic glioma, meningioma, craniopharyngioma, venous angioma, arteriovenous malformation, thrombosed intracranial aneurysm, and pituitary apoplexy, histiocytosis, hypothalamic glioma, tuber cinereum hamartoma and metastasis 14) 15).
Cavernoma should be considered when a solid suprasellar mass has hemorrhage (mimicking cystic- adamantinomatous craniopharingioma).

Cavernoma and suprasellar meningioma are rarely associated. Holland and Symon report a patient, whose recovery after removal of the meningioma was complicated by haemorrhage from the cavernoma. This occurrence has not been previously reported 16).

Treatment

Surgical removal is the recommended treatment to restore or preserve vision and to eliminate the risk of future hemorrhage. However, the anatomical location and eloquence of nearby neural structures can make these lesions difficult to access and remove.
The surgical approach should allow optimal exposure of the lesion using the shortest route and with minimal brain retraction. Various surgical approaches have been reported in the literature including pterional, orbitozygomatic, supraorbital, subfrontal, and transbasal interhemispheric approaches. Almost half of the cases reported in the literature were managed through the frontotemporal approach 17).
Biopsy is contraindicated for these lesions due to the high risk of bleeding and symptomatic worsening 18) 19).

Reviews

2006

In their meticulous review of the literature, Lehner et al. found 42 previously reported patients with vascular malformations within optic nerves, chiasm, or optic tracts, 30 of them being cavernous hemangiomas. The optic chiasma was involved in 38 patients (90.5%) and a total excision of the tumor was performed in 21 cases 20).

Case reports

2016

A 33-year-old female presented 3 months postpartum with a headache of moderate severity and progressive visual loss in both eyes. On examination, the patient’s Glasgow coma scale (GCS) was 15/15. Visual field examination showed left homonymous incomplete hemianopia. Her visual acuity was 20/25 in the right eye and 20/30 in the left eye. Her discs and macula were healthy bilaterally. Extraocular movements were intact and pupils were reactive. The rest of her examination was unremarkable. Complete endocrine workup was normal.
Magnetic resonance imaging (MRI) revealed a large heterogeneous, hyperintense, hemorrhagic right suprasellar extra-axial complex cystic structure measuring 31 × 30 × 90 mm on T1-weighted images. There was mass effect on the adjacent hypothalamus and third ventricle displacing them toward the left and superiorly in addition to the optic pathway. The pituitary stalk was displaced toward the left. The lesion encased the right posterior cerebral artery and displaced the right carotid artery laterally.
Computed tomography (CT) arteriography demonstrated a completely thrombosed center. The imaging findings were compatible with suprasellar CM.
The patient underwent right frontal craniotomy and gross total resection of her suprasellar intrachiasmatic large infiltrative hemorrhagic CM. Organizing blood clots with reactive fibrohistiocytic and inflammatory reaction admixed with some ectatic vascular channels suggestive of a vascular malformation were noted. There were small foci admixed with granulation tissue, showing some dilated cavernous spaces that would be compatible with a vascular malformation such as cavernous angioma. On immunohistochemistry, the lesion was CD163+, CD20 rare, CD3+, CD34+, CD31+, CD38+, CTK−, EMA plasma cells, GFAP−, S100 dendritic cells, SMA vascular smooth muscle.
The patient had an uneventful operative course. Her visual acuity improved to 20/20 in both eyes. Extraocular muscles showed mild limitation of both eyes in an upward gaze. Otherwise, she was stable with no neurological deficits. Follow-up MRI at 12 months revealed complete removal of the suprasellar hemorrhagic CM with no evidence of a residual lesion or recurrence 21).

Cavernous malformation of the optic chiasm: Neuro-endoscopic removal 22).

Trentadue et al. report a case in which the finding was incidentally detected in a 49-year-old man. They describe the imaging characteristics of the lesion in such a rare location, highlighting the role of magnetic resonance imaging (MRI) (specifically 3 Tesla) in the management of asymptomatic patients 23).

2015

A 48-year-old female presented with an insidious history of progressive visual loss. Magnetic resonance imaging (MRI) showed a CM in the suprasellar region. The patient was operated via a right pterional approach with a complete lesion removal. The postoperative course was uneventful. Early postoperative ophthalmological examination revealed minimal improvement of the vision in the left eye 24).

2014

The case of a 60-year-old woman from our institution with acute-on-chronic visual disturbance secondary to visual pathway CM is presented. Including the current patient, 70 cases of anterior visual pathway CM have been published to our knowledge. The average patient age is 34.8 ± standard deviation of 14.2 years, with a female preponderance (n = 37, 52.9%). The majority of patients had an acute (n = 44; 62.9%; 95% confidence interval [CI] 0.51-0.73) onset of symptoms. In at least 55.6% (n = 40) of patients, the cause of visual disturbance was initially misdiagnosed. The majority (91.4%; n = 64) of patients underwent craniotomy, with complete resection and subtotal resection achieved in 53.1% (n = 34; 95%CI 0.41-0.65) and 17.2% (n = 11; 95%CI 0.10-0.28) of all surgical patients, respectively. Comparing surgically managed patients, complete resection improved visual deficits in 59.0% (n = 20; 95%CI 0.42-0.75), while subtotal resection improved visual deficits in 50.0% (n = 5; 95%CI 0.24-0.76; p = 0.62). CM is an important differential diagnosis for suprasellar lesions presenting with visual disturbance. A high index of suspicion is required in its diagnosis. Expeditious operative management is recommended to improve clinical outcomes 25).

2012

Ning et al. report a 28-year-old male presenting with left homonymous hemianopsia. Magnetic resonance imaging (MRI) revealed an occupied lesion located in the right side of the optic chiasm, and a clinical diagnosis of chiasmal CM was made. Microsurgical excision was performed via anterolateral pterional craniotomy. The patient showed good recovery with slight improvement of the visual field deficits after the operation. No CM recurrence was discovered during the follow-up MRI scans 26).

2011

Rheinboldt and Blase report the case of a 31-year-old male who presented to the ER with a 1-week history of progressively worsening, throbbing, left retro-orbital headache, ptosis, and subjective worsening of short-term memory function. Initial review of systems and laboratory data were noncontributory. Non-contrasted CT demonstrated a large hyperdense mass centered in the suprasellar cistern without evidence of dissecting extra-axial hemorrhage. Though the initial appearance mimicked a basilar tip aneurysm or another primary extra-axial suprasellar pathology such as a hemorrhagic or proteinaceous craniopharyngioma, germinoma, or optic glioma, a second smaller, clearly intra-axial, hyperdense lesion was observed in the left periventricular forceps major white matter. Consideration for multiple cavernomas versus hypervascular metastatic disease such as renal malignancy, thyroid malignancy, or melanoma was raised. CTA confirmed normal intracranial vasculature. Subsequent MRI images showed an acutely hemorrhagic mass centered at the left paramedian hypothalamus and tuber cinereum with numerous secondary foci, demonstrating mature hemorrhagic elements and confirming the diagnosis of multiple cavernomas 27).

2008

A 33-year-old female who suffered from a recurrence of an intrachiasmatic cavernous malformation is presented. She had already undergone surgery in 1991 and 2001 and was admitted to our hospital with reduced vision in the right eye. After MRI, and diagnosis of recurrence of the cavernoma, a neurosurgical operation was performed using the pterional approach. The intraoperative situation was documented with micro photographs. The postoperative course was uneventful. The female described a minimal improvement of her vision. No postoperative complications were observed. To our knowledge, microsurgically complete extirpation of a recurrence of an intrachiasmatic cavernoma has not yet been reported in the literature 28).

2007

Santos-Ditto et al. present the case of a female patient who developed chiasmatic apoplexy and menstrual alterations. CT scanning showed a suprasellar hemorrhage. She underwent surgery with the presumptive diagnosis of pituitary tumor. At surgery, we find a brown-grayish lesion involving left optic nerve and chiasm. Cavernous angioma was diagnosed by histopathology. Cavernous angiomas constitute nearly 15% of all central nervous system vascular malformations. Location at the optic pathway is very rare, but must to be ruled out in the diagnosis of a patient with chiasmatic and/or optic apoplexy. Surgery is useful in preventing worsening of the previous deficit or a new visual defect 29).

A 15-year-old boy presented with an extremely rare optochiasmatic cavernous angioma. He was admitted to a special hospital with the complaint of blurred vision persisting for 1 month. Magnetic resonance imaging and biopsy of the lesion were inconclusive. He was admitted to the neurosurgical clinic after worsening of the visual symptoms 9 months later. Repeat magnetic resonance imaging showed optochiasmatic cavernous angioma which had doubled in size. The lesion was removed completely without any problem. Postoperatively his visual complaints remained stable, but had improved after 1 year. Optochiasmatic cavernous malformation should be treated by surgical excision, whereas biopsy is useless and may result in enlargement 30).

A 38-year-old male patient who suffered from acute onset of severe headache and progressive loss of vision. The vascular malformation of the optic pathways was completely removed via a pterional approach. This is the first reported instance of complete resection of a cavernoma involving the optic nerve, the chiasm, and the optic tract 31).

2006

Muta et al. report a 14-year-old boy with cavernous malformation of the optic chiasm. He had a 2-year history of gradually worsening visual disturbance. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a suprasellar mass, findings compatible with craniopharyngioma. The mass was biopsied and histological examination confirmed cavernous malformation. On the second day after the biopsy, he suffered chiasmal apoplexy due to intratumoural haemorrhage, lost visual acuity and developed a field cut. Cavernous malformations arising from the optic nerve and chiasm are extremely rare; only 29 cases have been reported to date. Most patients manifested acute visual acuity and visual field disturbances. Although MRI findings of cavernous malformations in the brain parenchyma have been reported, MRI findings on the optic nerve and chiasm may not be completely diagnostic. Of the 29 documented patients, 16 underwent total resection of the lesion without exacerbation of their preoperative symptoms; in some cases, resection was complicated by risk of damage to the surrounding neural tissue. As patients may suffer intratumoural haemorrhage after biopsy or partial removal of the lesion, the advisability of surgical treatment of cavernous malformations of the optic nerve and chiasm must be considered carefully 32).

In their meticulous review of the literature, Lehner et al. found 42 previously reported patients with vascular malformations within optic nerves, chiasm, or optic tracts, 30 of them being cavernous hemangiomas. The optic chiasma was involved in 38 patients (90.5%) and a total excision of the tumor was performed in 21 cases. Lehner et al. published a patient with a cavernous haemangioma of the optic chiasma and left optic tract who presented with an acute defect of the right visual field and severe retro-orbital pain. They succeeded in total excision of the malformation via a neuronavigationally guided approach. In the postoperative course, vision of our patient improved immediately and was found to be completely normal three months after the surgical intervention. Considering this patient and the published cases in the literature, they are of the opinion that microsurgical excision is a safe and efficient treatment for these rare pathologies 33).

2005

Shkarubo et al. describe a rare case of chiasmatic apoplexy whose cause was chiasmatic cavernoma. In addition to acute visual disorders suggesting the involvement of the left optic nerve, chiasma, and left visual pathway, 23-year-old patient had endocrine disorders as polyuria, polydipsia, which first suggests craniopharyngioma and glioma of the chiasma. A capsule and hematomic clots were removed from the thickened left optic nerve and left chiasmatic half during surgery. Only did a morphological study involving immunohistochemical analysis permit identification of the process as hemorrhage from cavernous micromalformation with the formation of hematoma 34).

1989

Three patients with cavernomas of the optic nerve, chiasm, or optic tract are presented. All suffered progressive visual loss due to local hemorrhage and the space-occupying effects of the vascular malformation. Computed tomography scans revealed small lesions with mild contrast enhancement in the suprasellar and parasellar cisterns, whereas angiography was unremarkable. Magnetic resonance imaging was helpful in our cases both for diagnosis and for planning surgical approach, showing typical signs of cavernomas as confirmed by subsequent surgery and histological examination. The clinical and intraoperative findings are presented 35).

1984

Buonaguidi et al. report a very rare case of an intrasellar cavernous hemangioma mimicking, clinically and neuroradiologically, the presence of a nonfunctioning pituitary adenoma. It was possible to diagnose this benign, congenital vascular malformation only through a histological examination36).
1) , 4) , 12) , 14) , 17)

Liu JK, Lu Y, Raslan AM, Gultekin SH, Delashaw JB Jr. Cavernous malformations of the optic pathway and hypothalamus: analysis of 65 cases in the literature. Neurosurg Focus. 2010 Sep;29(3):E17. doi: 10.3171/2010.5.FOCUS10129. Review. PubMed PMID: 20809758.
2) , 15) , 25)

Tan T, Tee JW, Trost N, McKelvie P, Wang YY. Anterior visual pathway cavernous malformations. J Clin Neurosci. 2015 Feb;22(2):258-67. doi: 10.1016/j.jocn.2014.07.027. Epub 2014 Nov 11. Review. PubMed PMID: 25439746.
3) , 21)

Abou-Al-Shaar H, Bahatheq A, Takroni R, Al-Thubaiti I. Optic chiasmal cavernous angioma: A rare suprasellar vascular malformation. Surg Neurol Int. 2016 Aug 1;7(Suppl 18):S523-6. doi: 10.4103/2152-7806.187495. eCollection 2016. PubMed PMID: 27583178; PubMed Central PMCID: PMC4982351.
5) , 36)

Buonaguidi R, Canapicci R, Mimassi N, Ferdeghini M. Intrasellar cavernous hemangioma. Neurosurgery. 1984 Jun;14(6):732-4. PubMed PMID: 6462408.
6) , 27)

Rheinboldt M, Blase J. Exophytic hypothalamic cavernous malformation mimicking an extra-axial suprasellar mass. Emerg Radiol. 2011 Aug;18(4):363-7. doi: 10.1007/s10140-011-0940-0. Epub 2011 Feb 9. PubMed PMID: 21305332.
7)

Shibuya M, Baskaya MK, Saito K, Suzuki Y, Ooka K, Hara M. Cavernous malformations of the optic chiasma. Acta Neurochir (Wien). 1995;136(1-2):29-36. Review. PubMed PMID: 8748824.
8)

Tien R, Dillon WP. MR imaging of cavernous hemangioma of the optic chiasm. J Comput Assist Tomogr. 1989 Nov-Dec;13(6):1087-8. PubMed PMID: 2584493.
9)

Rigamonti D, Drayer BP, Johnson PC, Hadley MN, Zabramski J, Spetzler RF. The MRI appearance of cavernous malformations (angiomas). J Neurosurg. 1987 Oct;67(4):518-24. PubMed PMID: 3655889.
10)

Campbell PG, Jabbour P, Yadla S, Awad IA. Emerging clinical imaging techniques for cerebral cavernous malformations: a systematic review. Neurosurg Focus. 2010 Sep;29(3):E6. doi: 10.3171/2010.5.FOCUS10120. Review. PubMed PMID: 20809764; PubMed Central PMCID: PMC3708641.
11)

de Champfleur NM, Langlois C, Ankenbrandt WJ, Le Bars E, Leroy MA, Duffau H, Bonafé A, Jaffe J, Awad IA, Labauge P. Magnetic resonance imaging evaluation of cerebral cavernous malformations with susceptibility-weighted imaging. Neurosurgery. 2011 Mar;68(3):641-7; discussion 647-8. doi: 10.1227/NEU.0b013e31820773cf. PubMed PMID: 21164377.
13) , 19) , 30)

Ozer E, Kalemci O, Yücesoy K, Canda S. Optochiasmatic cavernous angioma: unexpected diagnosis. Case report. Neurol Med Chir (Tokyo). 2007 Mar;47(3):128-31. PubMed PMID: 17384496.
16)

Holland AJ, Symon L. Spontaneous haemorrhage in a cavernoma associated with a suprasellar meningioma: an unusual post-operative complication. Br J Neurosurg. 1994;8(1):109-11. PubMed PMID: 8011186.
18)

Deshmukh VR, Albuquerque FC, Zabramski JM, Spetzler RF. Surgical management of cavernous malformations involving the cranial nerves. Neurosurgery. 2003 Aug;53(2):352-7; discussion 357. Review. PubMed PMID: 12925251.
20) , 33)

Lehner M, Fellner FA, Wurm G. Cavernous haemangiomas of the anterior visual pathways. Short review on occasion of an exceptional case. Acta Neurochir (Wien). 2006 May;148(5):571-8; discussion 578. Epub 2006 Mar 2. Review. PubMed PMID: 16505967.
22)

Venkataramana NK, Rao SA, Arun LN, Krishna C. Cavernous malformation of the optic chiasm: Neuro-endoscopic removal. Asian J Neurosurg. 2016 Jan-Mar;11(1):68-9. doi: 10.4103/1793-5482.145114. PubMed PMID: 26889286; PubMed Central PMCID: PMC4732249.
23)

Trentadue M, Pozzi Mucelli R, Piovan E, Pizzini FB. Incidental optochiasmatic cavernoma: Case report of an unusual finding on 3 Tesla MRI. Neuroradiol J. 2016 Aug;29(4):289-94. doi: 10.1177/1971400916648335. Epub 2016 May 4. PubMed PMID: 27145992; PubMed Central PMCID: PMC4978328.
24)

Alafaci C, Grasso G, Granata F, Cutugno M, Marino D, Salpietro FM, Tomasello F. Cavernous malformation of the optic chiasm: An uncommon location. Surg Neurol Int. 2015 Apr 16;6:60. doi: 10.4103/2152-7806.155256. eCollection 2015. PubMed PMID: 25949848; PubMed Central PMCID: PMC4405893.
26)

Ning X, Xu K, Luo Q, Qu L, Yu J. Uncommon cavernous malformation of the optic chiasm: a case report. Eur J Med Res. 2012 Aug 14;17:24. doi: 10.1186/2047-783X-17-24. PubMed PMID: 22892383; PubMed Central PMCID: PMC3488017.
28)

Scholz M, Harders A, Lücke S, Pechlivanis I, Engelhardt M, Schmieder K. Successful resection of the recurrence of a cavernous malformation of the optic chiasm. Clin Ophthalmol. 2008 Dec;2(4):945-9. PubMed PMID: 19668450; PubMed Central PMCID: PMC2699781.
29)

Santos-Ditto RA, Santos-Franco JA, Pinos-Gavilanes MW. [Cavernous angioma of the second cranial nerve and chiasmatic apoplexy]. Neurocirugia (Astur). 2007 Feb;18(1):47-51. Review. Spanish. PubMed PMID: 17393047.
31)

Hempelmann RG, Mater E, Schröder F, Schön R. Complete resection of a cavernous haemangioma of the optic nerve, the chiasm, and the optic tract. Acta Neurochir (Wien). 2007;149(7):699-703; discussion 703. Epub 2007 May 16. PubMed PMID: 17502987.
32)

Muta D, Nishi T, Koga K, Yamashiro S, Fujioka S, Kuratsu J. Cavernous malformation of the optic chiasm: case report. Br J Neurosurg. 2006 Oct;20(5):312-5. PubMed PMID: 17129880.
34)

Shkarubo AN, Serova NK, Tropinskaia OF, Shishkina LV, Pronin IN. [Chiasmatic cavernoma]. Zh Vopr Neirokhir Im N N Burdenko. 2005 Apr-Jun;(2):20-1; discussion 21-2. Russian. PubMed PMID: 16078630.
35)

Hassler W, Zentner J, Wilhelm H. Cavernous angiomas of the anterior visual pathways. J Clin Neuroophthalmol. 1989 Sep;9(3):160-4. PubMed PMID: 2529273.

Update: Cerebral cavernous malformation etiology

Cerebral cavernous malformation (CM) is a sporadic vascular malformation occurring either as an autosomal dominant condition or as a well-known complication of radiation exposure.

see Radiation induced cerebral cavernous malformation.
CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 1).
Although a role for these three genes in the formation of these intracranial vascular lesions has been established since the 1990s, additional works have further elucidated the molecular mechanisms by which mutations in these genes and the resultant aberrant proteins interact, leading to the formation of CCMs.
The three CCM proteins coded by KRIT1, CCM2, and PDCD10 form a trimeric protein complex. Germline loss-of-function mutations in any of these genes may lead to the formation of CCMs. Therefore, it is reasonable to assume that a molecular pathway exists that requires all three proteins to function together correctly for proper cellular function. Moreover, research is demonstrating how each component protein is capable of interacting with numerous other signaling and cytoskeletal molecules allowing for a diverse range of functions in molecular signaling pathways via unique protein–protein interactions.
Significant research findings from 2000 to 2015 have further enhanced our understanding of the pathogenesis of CCM formation. The use of advanced sequencing technologies to characterize genomic mutations and the identification of new signaling pathways and protein–protein interactions have led to great strides in understanding the molecular genetics involved in the development of CCMs. However, many unanswered questions remain, and future studies are clearly needed to improve our understanding of CCM pathogenesis. “Gene to protein to disease” mechanisms involved in the pathogenesis of CCMs should shed further light on potential therapeutic targets. 2).

The Phosphoinositide 3 kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression.
Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment 3).

Studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics 4).
CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3–KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified.

Tang et al. identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of cerebral cavernous malformation formation. Activation of TLR4 by Gram negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment 5).

1) , 4)

Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30. Erratum in: Nature. 2016 May 25;536(7617):488. PubMed PMID: 27027284; PubMed Central PMCID: PMC4864035.
2)

Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral Cavernous Malformations: Review of the Genetic and Protein-Protein Interactions Resulting in Disease Pathogenesis. Front Surg. 2016 Nov 14;3:60. Review. PubMed PMID: 27896269.
3)

Kar S, Samii A, Bertalanffy H. PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev. 2015 Apr;38(2):229-36; discussion 236-7. doi: 10.1007/s10143-014-0597-8. Epub 2014 Nov 19. PubMed PMID: 25403688.
5)

Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 10. doi: 10.1038/nature22075. [Epub ahead of print] PubMed PMID: 28489816.

Update: Intraventricular cavernous malformation

Epidemiology

Intraventricular cavernomas (IVCs) are rare, and only occur in 2.8 to 10% of patients with cerebral cavernous malformations.
Reports concerning IVC are scarce and are limited mostly to sporadic case reports.
Till 2017, among 136 IVC cases, the mean age of the patients was 36.5 years; the male-to-female ratio was 0.8. The most frequent location was the lateral ventricle (52.6%), and most of the clinical symptoms (74%) were related to mass effects on adjacent brain tissues. Intraventricular hemorrhage occurred in 22.9% of cases 1).

Till 2003, only 10 pediatric cases out of 46 well-documented cases have been published 2).

Types

In a review of literature by Reyns et al., of the 45 cases reported in literature, 44% of intraventricular cavernomas were found to be located in the third ventricle, 27% in the lateral ventricle, 20% in the trigone, and 9% in the fourth ventricle 3).

Third ventricle cavernous malformation

see Third ventricle cavernous malformation.

Foramen of Monro

see Foramen of Monro cavernous malformation

Trigone cavernous malformation

Of intraventricular CM, only about 20% are located in the trigone of the lateral ventricle 4).
The first report of trigonal CM was published in 1977 by Coin 5).

Ohbuchi et al., conducted a PubMed search for trigonal CM and found 17 cases 6).

Clinical features

Although IVCs share some common characteristics with intraparenchymal cavernomas, they also have some distinct features involving structure, clinical symptoms, radiologic appearance, and onset of symptoms 7).

Differential diagnosis

The important differentials of the lesions occurring at the foramen of Monro include colloid cyst, central neurocytoma, giant cell astrocytoma, and oligodendroglioma. Cystic and hemorrhagic metastases, however uncommon, may also occur at the foramen of Monro 8).
Colloid cysts are oval-to-round lesions. Approximately two thirds are homogeneously hyperdense compared to brain on plain scans and one-third of them are isodense. On MRI, the signal characteristics of colloid cysts vary. Most commonly, these appear hyperintense on T1WI and hypointense on T2WI. Central neurocytomas are inhomogeneous, partially calcified, and mildly enhancing lateral ventricular masses. On MRI, these are seen to be inhomogeneously isointense on T1WI with variable appearance on T2WI. Giant cell astrocytomas are seen in association with tuberous sclerosis and appear iso-to- hypodense on CT scans with focal areas of calcification and cyst formation. These demonstrate hypo- to isointense signal on T1WI and are iso- to hyperintense on T2WI. Oligodendrogliomas most commonly show dense areas of calcification. These appear hypo- to isointense on T1WI and hyperintense on T2WI, showing moderate patchy enhancement 9).

Jin et al., report a case of trigonal cavernous malformation (CM) radiologically mimicking meningioma. The computed tomographic (CT) head angiography and magnetic resonance imaging (MRI) showed a partially calcified lesion with slight contrast enhancement located in the area of the left atrium of lateral ventricle. The lesion was completely removed using microsurgery with a parieto-occipital transcortical approach. The resected mass was histologically confirmed as CM. CM should be considered as differential diagnosis in case of the atrial mass lesion due to lack of hemosiderin ring characteristically seen other seated CM 10).

Dey et al., present the first report of an intraventricular encapsulated hematoma, mimicking cavernous malformation on imaging and gross lesion appearance. A 47-year-old female on anticoagulation therapy for atrial fibrillation presented with left upper extremity apraxia, neglect, and mild gait imbalance. Her brain CT scan and MRI revealed multilobulated lesions involving the choroid plexus in the atria of both lateral ventricles. The intraoperative appearance was that of encapsulated mass, with blood clots at different stages of liquefaction and organization, all consistent with the gross appearance of a cavernous malformation. However, histopathologic examination demonstrated hematoma with components at different ages, and normal vessel infiltration without any hint of cavernous malformation histology, or underlying neoplasia. Encapsulated hematoma should be considered in the differential diagnosis of hemorrhagic intraventricular masses 11).

Treatment

Most of the articles concluded that complete surgical resection is the treatment of choice.The microsurgical approach is currently considered the gold standard for IVC resection 12).

Neuroendoscopy

As neuroendoscopy evolves, we see that lesions considered impossible to be managed by neuroendoscopy before today are being treated with the advantages that the minimally invasive surgery offers 13).
However, tumor size and vascular nature are considered restrictive factors.
Till 2013, there are two cases in the literature of intraventricular cavernoma resection done by neuroendoscopy.
Giannetti describe a case of a man who presented with hydrocephalus secondary to a mesencephalic cavernoma and a second cavernous angioma located at the dorsum thalamus. This second lesion was successfully removed using a pure neuroendoscopic technique at the same time as a third ventriculostomy was performed 14).
Using the neuroendoscope and neuronavigational guidance and based on the biological characteristics of the IVC, proper lesion size, and dilated ventricles, Shirvani et al., totally resected the lesion in all his three cases. Neuroendoscopy can be considered as an alternative to microsurgery of IVCs. However, Shirvani et al., believe a larger series of cases is necessary to demonstrate when microsurgery and when neuroendoscopy should be performed for IVC resection 15).

Reviews

2009

Stavrinou et al., performed a search of the literature of the last 30 years and identified all cases of intraventricular cavernous angiomas. Trigonal cavernomas were separately identified and analysed. Our search yielded a total of 13 trigonal cavernomas.
A total of 61 intraventricular cases, 13 were located in the trigone of the lateral ventricles. The most prominent presenting symptom was intracranial hypertension (68.9%), followed by seizures (18.2%) and hemorrhage (13.1%).The literature review revealed a trend of intraventricular cavernomas to present with intracranial hypertension rather than seizures or focal neurologic deficit, unlike their intraparenchymal counterparts. We feel that this difference has received little attention in the international literature. We discuss a possible pathogenetic mechanism for the presence of intracranial hypertension and address different aspects of diagnosis and treatment of this benign lesion.
Trigonal cavernomas are benign lesions that have an excellent outcome after radical excision. Symptoms and signs of intracranial hypertension and hydrocephalus may be the prominent initial presentation of this rare ailment. 16).

Case series

2015

Faropoulos et al., present there experience, consisting of five IVC cases over a period of 11 years. They describe the symptoms leading to hospital admission, the main radiologic findings, the management of each ICV case, and the patients’ clinical status after surgery. They also reviewed the international literature on IVC, presenting the main demographic characteristics, their most common location in the ventricular system, and the main signs and symptoms. Finally, They present the management options according to the current literature, the advantages and disadvantages of every management option, accompanied by a brief follow-up of most IVC cases, whether the cavernoma was treated surgically or conservatively 17).

2010

Kivelev et al., present a series of 12 patients with IVCs that were treated at a single neurosurgical department. In addition, the authors reviewed the literature.
All clinical data were analyzed retrospectively. Follow-up questionnaires were sent to all patients. Outcome was assessed using the Glasgow Outcome Scale. The authors also conducted a PubMed search and found 77 cases of IVC.
The patients’ median age was 47 years, and the male/female ratio was 2:1. A cavernoma occurred in the lateral ventricle in 6 patients, in another 5 it was in the fourth ventricle, and 1 had a lesion in the third ventricle. Almost all patients presented with acute headache on admission and in more than half, the symptoms were related to cavernoma bleeding. In total, 8 rebleedings occurred in 5 patients during a median of 0.4 years. Three patients with a cavernoma of the fourth ventricle presented with a cranial nerve deficit. In 8 cases, a cavernoma was surgically treated an average of 1.3 years after the diagnosis. Only 1 patient underwent surgery in the acute phase after a major intraventricular/intracerebral hemorrhage. The median follow-up time was 2 years. No patient was lost to follow-up, and no patient died. In total, on follow-up 9 patients improved and 3 had a persistent neurological deficit, of which 2 existed before surgery.
In the present series, the IVCs had a high tendency for rehemorrhage. Surgery is advocated when hemorrhages are frequent, and the mass effect causes progressive neurological deficits. Microsurgical removal of the IVC is safe, but in the fourth ventricle it can carry increased risk for cranial nerve deficits 18).

1985

The clinical and radiographic presentations of 3 patients with intraventricular cavernous hemangioma are described. The accumulated total of 19 cases from the literature are compared to determine whether there is a common clinical and radiographic presentation for this benign intraventricular lesion. The differential diagnosis of intraventricular cavernous hemangioma includes intraventricular meningioma, choroid plexus papilloma, arteriovenous malformation, low grade astrocytoma, and ependymoma 19).

Case reports

2017

Shirvani et al., describe three IVC cases and briefly review previously documented IVC cases in PubMed. Among 136 IVC cases, the mean age of the patients was 36.5 years; the male-to-female ratio was 0.8. The most frequent location was the lateral ventricle (52.6%), and most of the clinical symptoms (74%) were related to mass effects on adjacent brain tissues. Intraventricular hemorrhage occurred in 22.9% of cases. Most of the articles concluded that complete surgical resection is the treatment of choice.The microsurgical approach is currently considered the gold standard for IVC resection. Using the neuroendoscope and neuronavigational guidance and based on the biological characteristics of the IVC, proper lesion size, and dilated ventricles, we totally resected the lesion in all three cases. Neuroendoscopy can be considered as an alternative to microsurgery of IVCs. However, we believe a larger series of cases is necessary to demonstrate when microsurgery and when neuroendoscopy should be performed for IVC resection 20).

2015

A 64-year-old woman who was evaluated after being found unresponsive. Imaging revealed a foramen of Monro cavernoma resulting in hydrocephalus. Supratentorial cavernomas are most frequently found in the cerebral cortex, and although ventricular cavernomas do occur, they are rarely located in the foramen of Monro. Foramen of Monro cavernomas are extremely dangerous, requiring aggressive management when identified 21).

2013

Bhatia et al., present a case of cavernous hemangioma located at foramen of Monro, with its radiopathological confirmation 22).

2012

A case of trigonal cavernous malformation (CM) with intraventricular hemorrhage. This 67-year-old woman experienced sudden onset of loss of consciousness and her Glasgow Coma Scale (GCS) was 5 points (E1V1M3) on admission. CT scan demonstrated intraventricular hemorrhage and acute hydrocephalus. Angiography did not demonstrate any vascular abnormality. Ventricular drainage was performed for acute hydrocephalus and the postoperative course was good. CT showed a hyperdense lesion in the left trigone, which was contrast-enhanced on T1-weighted MR. Removal of CM was performed via the left middle temporal sulcus 23).

2010

Intraventricular cavernous malformation with superficial siderosis 24).

2009

A case of intraventricular cavernoma in the region of the foramen of Monro with the aim of illustrating the difficulties involved in the diagnosis of this rare lesion 25).

2008

Jin et al., report a case of trigonal cavernous malformation (CM) radiologically mimicking meningioma. The computed tomographic (CT) head angiography and magnetic resonance imaging (MRI) showed a partially calcified lesion with slight contrast enhancement located in the area of the left atrium of lateral ventricle. The lesion was completely removed using microsurgery with a parieto-occipital transcortical approach. The resected mass was histologically confirmed as CM. CM should be considered as differential diagnosis in case of the atrial mass lesion due to lack of hemosiderin ring characteristically seen other seated CM 26).

Muccio et al., report the MRI findings and histological features of an uncommon case of a single giant (maximum diameter: >6 cm) cystic CCM of the left lateral ventricle occurring in a 26-year-old man who had undergone 30 Gy cranial irradiation for acute leukemia at the age of six years. Large cystic CCMs must be included in the neuroradiological differential diagnosis of intraventricular hemorrhagic cystic lesions 27).

A 56 years old patient was admitted with progressive and intractable headache of 10 days of evolution. He was known to suffer familial multiple cavernomatosis. Magnetic resonance imaging (MRI), revealed obstructive hydrocephalus due to a cavernoma located in the area of the left foramen of Monro. Under neuronavigation guidance, complete endoscopic resection of the cavernoma was performed and normal ventricular size achieved. The patient experienced transient recent memory loss that resolved within a month after surgery. In the literature attempted endoscopic resection is reported to be abandoned due to bleeding and ineffectiveness of piecemeal endoscopic resection. In this case, the multiplicity of the lesions made it advisable to resect the lesion endoscopically, to avoid an open procedure in a patient with multiple potentially surgical lesions. Endoscopic resection was uneventful with easy control of bleeding with irrigation, suction, and bipolar coagulation despite dense vascular appearance of the lesion. During the procedure, precise visualization of the vascular structures around the foramen of Monro allowed complete resection with satisfactory control of the instruments. To the best of the authors’ knowledge, this is the first published cavernoma of foramen of Monro successfully resected using an endoscopic approach 28).

2007

A 25-year-old male patient presented with a predominantly intralesional haemorrhage. Neuroimaging led to an accurate preoperative diagnosis although the typical low intensity perilesional ring of gliosis and hemosiderin was not present. The lesion was microsurgically removed using an stereotactically guided posterior temporal transsulcal approach 29).

2006

A eight-year old boy with a rare third ventricular cavernous angioma that hemorrhaged presenting with symptoms of acute hydrocephalus. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) showed a heterogenous ill-defined, solid and cystic intraventricular mass in the third ventricle which was mildly enhanced with contrast and there was associated hydrocephalus. The mass was removed with success and follow up after two years revealed no neurological abnormalities 30).

Longatti et al., report on a patient who presented with an intraventricular mass located at the level of the foramen of Monro. The clinical presentation and neuroimaging appearance of the mass led to an initial diagnosis of colloid cyst. A neuroendoscopic approach offered a direct view of the ventricular lesion, which was found to be a cavernous angioma partially occluding the foramen of Monro. The lesion was then removed using microsurgery. In this report the authors highlight possible pitfalls in the diagnosis of some lesions of the third ventricle, and the possible advantages of using a combined endoscopic and microsurgical technique when approaching such lesions 31).

Three cases of trigonal cavernous angiomas who presented with raised intracranial pressure or seizures and who underwent total excision with a good recovery. We also review the literature and discuss surgical approaches.
On magnetic resonance imaging, intraventricular cavernous angiomas lack the hemosiderin ring characteristically seen around parenchymal cavernous angiomas. This explains why trigonal cavernous angiomas can mimic malignant neoplasm on imaging, and they should be considered in the differential diagnosis of intraventricular masses. Total excision should be the goal of surgery 32).

A 47-year-old woman presented with unilateral ventricular enlargement detected by magnetic resonance imaging during a medical checkup. Neuroendoscopic exploration identified a multilocular lesion in which dark red fluid formed a niveau near the right side of the foramen of Monro. The diagnosis was intraventricular cavernous angioma. Restricted flow of cerebrospinal fluid at the foramen of Monro was observed. Xanthochromia, which seemed to be due to previous bleeding, was observed at the fornix. When the neuroendoscope touched the angioma, the wall collapsed and bled. Endoscopic removal of the angioma was abandoned, and craniotomy and resection of the angioma were performed. No new neurological anomalies were observed after surgery. Preoperative diagnosis of intraventricular cavernous angioma is difficult based on neuroimaging. Neuroendoscopy is effective for diagnosis and the decision-making process regarding treatment 33).

A 51-year-old woman was admitted with obstructive hydrocephalus-related symptoms. The computed tomography (CT) and magnetic resonance imaging (MRI) revealed a partly calcified lesion with slight contrast enhancement located in the area of the right foramen of Monro. The lesion was completely removed by surgical resection with a transfrontal transventricular approach. The resected mass was histologically diagnosed as cavernous hemangioma. The patient’s symptoms resolved immediately after operation. Cavernous hemangioma at the foramen of Monro in the present case had common MRI features as previously reported. Although MRI can provide initial diagnosis for such unusually localized tumor, it should be confirmed histopathologically 34).

2003

Tatsui et al., present two cases with diagnosis made only by histopathologic examination, due to a lack of classic image findings. Cavernous hemangiomas must be included in the differential diagnosis of intraventricular tumors, and total surgical resection is the treatment of choice. Perilesional ring as demonstrated by MRI, must not be expected when dealing with such lesions 35).

A 11-year-old girl operated on for a voluminous cavernoma at the ventricular trigone which was diagnosed after absence seizures.
Interestingly, the case we report showed a hypointense rim on T2-weighted magnetic resonance images which has not been a common finding in the cases previously reported 36).

A clinicopathological review of a giant intraventricular cavernous malformation 37).

2002

Intraventricular cavernoma in the region of the foramen of monro 38).

2000

A 15-years-old female patient, who suffered of mild chronic headache for 8 months, followed by two episodes of sudden intensive headache and stupor with complete recovery after 48 hours. CT scan was performed and revealed a voluminous size, hiperdense mass in the frontal horn of the lateral ventricle. The surgical access to site was through transcallosal interhemisphere approach. The patient had a good recovery without complications.
Although lateral ventricle cavernomas are rare they should be considered in the differential diagnosis of intraventricular tumors. A wrong preoperative diagnosis has sometimes induced a wrong therapy, such as radiotherapy, for these surgically curable benign 39).

1999

A 16-year-old female patient presented with a sudden distal deficit of the left superior limb. She had a voluminous tumor involving the two lateral ventricles, with radiological evidence of recent hemorrhage. A 30-year-old man presented with generalized seizures and a right hemiplegia related to a 4-cm-diameter cavernoma in the two lateral ventricles involving the interhemispheric scissure through the corpus callosum and left centrum ovale. The radiological appearance was not typical and did not allow the diagnosis. A 42-year-old man had a cavernoma in the third ventricle, which was responsible for his short-term memory loss. This cavernoma had been revealed by computed tomography that was performed after intracerebral hemorrhage related to another cavernoma in the right parietal lobe occurred.
Stereotactic biopsies allowed the diagnosis of intraventricular cavernoma in the first case. Surgical removal via a right transcortical transventricular approach and a transcallosal approach in the first and second cases, respectively, was complete, resulting in good outcomes. Surgical removal via a right transcortical transventricular approach in the third case was partial.
Intraventricular cavernomas are so uncommon that only 42 well-documented cases have been previously reported in the literature. It seems that their radiological diagnosis may be difficult because of their uncommon location in the ventricular system and their voluminous size. A wrong preoperative diagnosis has sometimes been the cause of inefficient therapy, such as radiotherapy, for these surgically curable benign lesions 40).

1997

A case of a cavernous haemangioma that appeared as an intraventricular mass at the foramen of Monro. Despite the unusual location the diagnosis was established by MRI because of the typical appearance. The differential diagnosis included primary and secondary neoplasms at the foramen of Monro 41).

1995

Four cases of cavernous malformations of the third ventricle. Patients presented with symptoms of hydrocephalus, memory loss, and signs of hypothalamic dysfunction. Magnetic resonance imaging and computed tomography provided characteristic images of the three lesions preoperatively. All patients underwent direct surgical excision of the malformations. Two patients had a transcallosal, transventricular approach, the third underwent a transcortical, transventricular approach, and the fourth had an infratentorial supracerebellar approach. Postoperatively, the patient with hypothalamic dysfunction has not improved and underwent ventriculoperitoneal shunting. The second patient did well initially; however, 8 days postoperatively, she became comatose and later died. The presumed cause of her deterioration was a hypothalamic venous infarction. The third and fourth patients have returned to their normal neurological baseline. The presenting signs and symptoms, magnetic resonance imaging and computed tomography findings, and treatment options for this rare lesion are discussed and illustrated 42).

1994

A 54-year-old female presented with a cryptic arteriovenous malformation (AVM) of the choroid plexus of the fourth ventricle causing intraventricular hemorrhage. Computed tomography and magnetic resonance imaging disclosed the lesion near the fourth ventricle, but bilateral vertebral angiograms showed no abnormalities. The preoperative diagnosis was cavernous angioma. The mass was removed completely, and histological examination demonstrated an AVM of the choroid plexus. Vascular malformations of the choroid plexus of the fourth ventricle are extremely rare. The possibility of this lesion being the cause of primary intraventricular hemorrhage of unknown origin should always be considered 43).

1993

A case located in the trigone of the lateral ventricle in the dominant hemisphere and drained into the longitudinal caudate vein of Schlesinger via deep medullary veins. By a transsylvian transventricular approach, the CM was totally removed with successful preservation of the medullary venous malformation. This approach is available for trigonal lesions, especially in cases with enlarged inferior horn. They stress that CM removal can be conducted with preservation of the adjacent medullary venous malformation 44).

1991

Since the availability of CT diagnosis 23 cases of intraventricular cavernous angioma (IVCA) have been published in the literature till 1991. Three additional cases have been operated upon in the Neurochirurgische Klinik, Krankenhaus Nordstadt, Hannover, Federal Republic of Germany. Based on these 26 cases the clinical data, radiological findings, treatment and outcome of IVCAs are reviewed 45).

A rare case of cavernous angioma located in the fourth ventricular floor occurred in a 44-year-old female complaining of occipital headache, vomiting, diplopia, and dysarthria. Computed tomographic scans demonstrated a high-density area in the fourth ventricle and slight hydrocephalus. Magnetic resonance (MR) imaging showed a mixed intensity mass on T2-weighted images and high- or isointensity regions on T1-weighted images. The tumor was totally removed and histologically diagnosed as cavernous angioma. Postoperatively, ataxic gait, nausea, and vomiting disappeared gradually. MR imaging was useful to accurately evaluate the anatomic relationship between the lesion and the brainstem 46).

1990

Cavernous angioma arising in the third ventricle is an extremely rare disease. Ogawa et al., reviewed five cases previously reported, as well as they own two cases, and discuss the clinical characteristics of and surgical approach to cavernous angioma at this site. The bifrontal craniotomy and interhemispheric translamina terminalis approach minimize the damage to the brain and allow for an approach to the third ventricle in a wide operative field with minimal compression of the brain itself. They have found this approach to be suitable for surgery on angiomas of the anterior half of the third ventricle 47).
1) , 15) , 20) Shirvani M, Hajimirzabeigi A. Intraventricular Cavernous Malformation: Review of the Literature and Report of Three Cases with Neuroendoscopic Resection. J Neurol Surg A Cent Eur Neurosurg. 2017 Jan 9. doi: 10.1055/s-0036-1594235. [Epub ahead of print] PubMed PMID: 28068754.
2) , 36) Nieto J, Hinojosa J, Muñoz MJ, Esparza J, Ricoy R. Intraventricular cavernoma in pediatric age. Childs Nerv Syst. 2003 Jan;19(1):60-2. PubMed PMID: 12541090.
3) , 4) , 40) Reyns N, Assaker R, Louis E, Lejeune JP. Intraventricular cavernomas: three cases and review of the literature. Neurosurgery. 1999 Mar;44(3):648-54; discussion 654-5. Review. PubMed PMID: 10069603.
5) Coin CG, Coin JW, Glover MB. Vascular tumors of the choroid plexus: diagnosis by computed tomography. J Comput Assist Tomogr. 1977 Jan;1(1):146-8. PubMed PMID: 615888.
6) , 23) Ohbuchi H, Osaka Y, Ogawa T, Nanto M, Nakahara Y, Katsura K, Tenjin H, Kasuya H. Trigonal cavernous malformation with intraventricular hemorrhage: a case report and literature review. J Med Invest. 2012;59(3-4):275-9. Review. PubMed PMID: 23037200.
7) , 17) Faropoulos K, Panagiotopoulos V, Partheni M, Tzortzidis F, Konstantinou D. Therapeutic management of intraventricular cavernoma: case series and review of the literature. J Neurol Surg A Cent Eur Neurosurg. 2015 May;76(3):233-9. doi: 10.1055/s-0034-1389093. Review. PubMed PMID: 25798802.
8) Lee BJ, Choi CY, Lee CH. Intraventricular cavernous hemangiomas located at the foramen of monro. J Korean Neurosurg Soc. 2012 Aug;52(2):144-7. doi: 10.3340/jkns.2012.52.2.144. Erratum in: J Korean Neurosurg Soc. 2012 Nov;52(5):505. PubMed PMID: 23091674; PubMed Central PMCID: PMC3467373.
9) , 22) Bhatia S, Kapoor AK, Gupta R, Sahni T. Cavernous hemangioma located at the foramen of Monro: Radiopathological correlation. Indian J Radiol Imaging. 2013 Jul;23(3):202-4. doi: 10.4103/0971-3026.120259. PubMed PMID: 24347847; PubMed Central PMCID: PMC3843325.
10) , 26) Jin SC, Ahn JS, Kwun BD, Kwon DH. Intraventricular cavernous malformation radiologically mimicking meningioma. J Korean Neurosurg Soc. 2008 Nov;44(5):345-7. doi: 10.3340/jkns.2008.44.5.345. PubMed PMID: 19119474; PubMed Central PMCID: PMC2612575.
11) Dey M, Turner MS, Pytel P, Awad IA. A “pseudo-cavernoma” – an encapsulated hematoma of the choroid plexus. J Clin Neurosci. 2011 Jun;18(6):846-8. doi: 10.1016/j.jocn.2010.09.018. PubMed PMID: 21435884; PubMed Central PMCID: PMC3094469.
12) Alves de Sousa A. [Deep-seated (corpus callosum, intraventricular, basal ganglia and insula) and brain stem cavernous angiomas. Experience in Brazil]. Neurochirurgie. 2007 Jun;53(2-3 Pt 2):182-91. Review. French. PubMed PMID: 17507054.
13) , 14) Giannetti AV. Purely neuroendoscopic resection of an intraventricular cavernous angioma: case report. J Neurol Surg A Cent Eur Neurosurg. 2013 Jan;74(1):47-50. doi: 10.1055/s-0032-1325632. PubMed PMID: 23027434.
16) Stavrinou LC, Stranjalis G, Flaskas T, Sakas DE. Trigonal cavernous angioma: a short illustrated review. Acta Neurochir (Wien). 2009 Nov;151(11):1517-20. doi: 10.1007/s00701-009-0252-2. Review. PubMed PMID: 19300903.
18) Kivelev J, Niemelä M, Kivisaari R, Hernesniemi J. Intraventricular cerebral cavernomas: a series of 12 patients and review of the literature. J Neurosurg. 2010 Jan;112(1):140-9. doi: 10.3171/2009.3.JNS081693. Review. PubMed PMID: 19408982.
19) Chadduck WM, Binet EF, Farrell FW Jr, Araoz CA, Reding DL. Intraventricular cavernous hemangioma: report of three cases and review of the literature. Neurosurgery. 1985 Feb;16(2):189-97. PubMed PMID: 3974830.
21) Winslow N, Abode-Iyamah K, Flouty O, Park B, Kirby P, Howard M 3rd. Intraventricular foramen of Monro cavernous malformation. J Clin Neurosci. 2015 Oct;22(10):1690-3. doi: 10.1016/j.jocn.2015.03.043. PubMed PMID: 26113004.
24) Sabat SB. Intraventricular cavernous malformation with superficial siderosis. Arch Neurol. 2010 May;67(5):638-9. doi: 10.1001/archneurol.2010.53. PubMed PMID: 20457968.
25) Meilán Martínez A, Vega Valdés P, Santamarta Liébana E, Rial Basalo JC. [Intraventricular cavernoma in the foramen of Monro: particularities due to its atypical location]. Radiologia. 2009 Nov-Dec;51(6):605-9. doi: 10.1016/j.rx.2009.04.009. Spanish. PubMed PMID: 19646725.
27) Muccio CF, Catapano G, Di Blasi A, Esposito G, Cerase A. Giant cystic intraventricular cerebral cavernous malformation: MRI with pathologic correlation. A case report. Neuroradiol J. 2008 Oct 1;21(4):547-50. PubMed PMID: 24256962.
28) Prat R, Galeano I. Endoscopic resection of cavernoma of foramen of Monro in a patient with familial multiple cavernomatosis. Clin Neurol Neurosurg. 2008 Sep;110(8):834-7. doi: 10.1016/j.clineuro.2008.05.011. PubMed PMID: 18584950.
29) González-Darder JM, Pesudo-Martínez JV, Merino-Peña J. [Trigonal cavernous angioma: case report]. Neurocirugia (Astur). 2007 Aug;18(4):330-2. Spanish. PubMed PMID: 17882341.
30) Zakaria MA, Abdullah JM, George JP, Mutum SS, Lee NN. Third ventricular cavernous angioma. Med J Malaysia. 2006 Jun;61(2):229-32. PubMed PMID: 16898318.
31) Longatti P, Fiorindi A, Perin A, Baratto V, Martinuzzi A. Cavernoma of the foramen of Monro. Case report and review of the literature. Neurosurg Focus. 2006 Jul 15;21(1):e13. PubMed PMID: 16859251.
32) Kumar GS, Poonnoose SI, Chacko AG, Rajshekhar V. Trigonal cavernous angiomas: report of three cases and review of literature. Surg Neurol. 2006 Apr;65(4):367-71, discussion 371. PubMed PMID: 16531197.
33) Sato K, Oka H, Utsuki S, Shimizu S, Suzuki S, Fujii K. Neuroendoscopic appearance of an intraventricular cavernous angioma blocking the foramen of monro – case report. Neurol Med Chir (Tokyo). 2006 Nov;46(11):548-51. PubMed PMID: 17124371.
34) Chen CL, Leu CH, Jan YJ, Shen CC. Intraventricular cavernous hemangioma at the foramen of Monro: Case report and literature review. Clin Neurol Neurosurg. 2006 Sep;108(6):604-9. Review. PubMed PMID: 15916846.
35) Tatsui CE, Koerbel A, Prevedello DM, Hanel RA, Grande CV, Moro MS, Araújo JC. [Magnetic resonance imaging of the intraventricular cavernomas: diagnostic aspects]. Arq Neuropsiquiatr. 2003 Mar;61(1):79-82. Portuguese. PubMed PMID: 12715024.
37) Anderson RC, Connolly ES Jr, Ozduman K, Laurans MS, Gunel M, Khandji A, Faust PL, Sisti MB. Clinicopathological review: giant intraventricular cavernous malformation. Neurosurgery. 2003 Aug;53(2):374-8; discussion 378-9. PubMed PMID: 12925254.
38) Suess O, Hammersen S, Brock M. Intraventricular cavernoma: unusual occurrence in the region of the foramen of monro. Br J Neurosurg. 2002 Feb;16(1):78-9. PubMed PMID: 11926476.
39) Fagundes-Pereyra WJ, Marques JA, Sousa LD, Carvalho GT, Sousa AA. [Cavernoma of the lateral ventricle: case report]. Arq Neuropsiquiatr. 2000 Sep;58(3B):958-64. Review. Portuguese. PubMed PMID: 11018841.
41) Kaim A, Kirsch E, Tolnay M, Steinbrich W, Radü EW. Foramen of Monro mass: MRI appearances permit diagnosis of cavernous haemangioma. Neuroradiology. 1997 Apr;39(4):265-9. PubMed PMID: 9144673.
42) Sinson G, Zager EL, Grossman RI, Gennarelli TA, Flamm ES. Cavernous malformations of the third ventricle. Neurosurgery. 1995 Jul;37(1):37-42. Review. PubMed PMID: 8587688.
43) Tamaki M, Ohno K, Asano T, Niimi Y, Uchihara T, Hirakawa K. Cryptic arteriovenous malformation of the choroid plexus of the fourth ventricle–case report. Neurol Med Chir (Tokyo). 1994 Jan;34(1):38-43. Review. PubMed PMID: 7514753.
44) Miyagi Y, Mannoji H, Akaboshi K, Morioka T, Fukui M. Intraventricular cavernous malformation associated with medullary venous malformation. Neurosurgery. 1993 Mar;32(3):461-4; discussion 464. PubMed PMID: 8455774.
45) Tatagiba M, Schönmayr R, Samii M. Intraventricular cavernous angioma. A survey. Acta Neurochir (Wien). 1991;110(3-4):140-5. Review. PubMed PMID: 1927606.
46) Itoh J, Usui K. Cavernous angioma in the fourth ventricular floor–case report. Neurol Med Chir (Tokyo). 1991 Feb;31(2):100-3. PubMed PMID: 1715036.
47) Ogawa A, Katakura R, Yoshimoto T. Third ventricle cavernous angioma: report of two cases. Surg Neurol. 1990 Dec;34(6):414-20. Review. PubMed PMID: 2244306.

Gamma Knife Radiosurgery of Brainstem Cavernous Malformations

Gamma knife radiosurgery for brainstem cavernous malformation

Case series

2016

All patients who underwent GKS for the treatment of a hemorrhagic brainstem CM(s) in the Department of Neurosurgery, Lille University Hospital, CHU Lille, Université de Lille, Lille, France. between January 2007 and December 2012. The GKS was privileged when the surgical procedure was evaluated as very risky. The mean dose of radiation was 14.8 Gy, and the mean target volume was 0.282 cm3. All patients participated in a scheduled clinical follow-up. The posttreatment MRI was performed after 6 months and after 1 year, and then all patients had an annual MRI follow-up.
There were 19 patients with a mean age of 36.7 years. The mean follow-up period was 51.2 months. The annual hemorrhage rate (AHR) was 27.31% before GKS, 2.46% during the first 2 years following the GKS, and 2.46% after the first 2 years following the GKS. The decrease in AHR after GKS was significant (p < 0.001).
GKS should be suggested when the surgical procedure harbors a high risk of neurological morbidity in patients with brainstem CM. Compared to prior literature results, a lower dose than applied in this study could be discussed 1).

Between January of 2009 and December of 2014, 43 patients (20 males and 23 females) with brainstem cavernous malformations were treated at the West China Hospital, Sichuan University, Gamma Knife Center. The mean age of these patients was 41.7 years. All of the patients experienced 1 or more episodes of symptomatic bleeding (range 1-4) before undergoing GKS. The mean volume of the malformations at the time of GKS was 442.1mm3, and the mean prescribed marginal radiation dose was 11.9Gy. The mean follow-up period after radiosurgery was 36 months (range 12-120 months).
Before GKS, 50 hemorrhages (1.2 per patient) were observed (25.0% annual hemorrhage rate). Three hemorrhages following GKS were observed within the first 2 years (3.92% annual hemorrhage rate), and 1 hemorrhage was observed in the period after the first 2 years (1.85% annual hemorrhage rate). In this study of 43 patients, new neurological deficits developed in only 1 patient (2.32%; permanent paresthesia on the left side of the face and the right lower limb of the patient). There were no deaths in this study.
GKS is a favorable alternative treatment for brainstem CMs. Using a low marginal dose treatment might reduce the rate of hemorrhage and radiation-induced complications2).

2014

From 1992 to 2011, 49 patients with brainstem CMs were treated with Gamma Knife radiosurgery (GKS). Lee et al., classified patients into two groups: Group A (n = 31), patients who underwent GKS for a CM following a single symptomatic bleed, and group B (n = 18), patients who underwent GKS for a CM following two or more symptomatic bleeds. The mean marginal dose of radiation was 13.1 Gy (range 9.0-16.8 Gy): 12.8 Gy in group A and 13.7 Gy in group B. The mean follow-up period was 64.0 months (range 1-171 months).
In group A, the annual hemorrhage rate (AHR) following GKS was 7.06 % within the first 2 years and 2.03 % after 2 years. In group B, four patients (22.2 %) developed new or worsening neurologic deterioration as a result of repeat hemorrhages. In group B, the AHR was 38.36 % prior to GKS, 9.84 % within the first two years, and 1.50 % after two years. There was no statistically significant difference in the AHRs at each follow-up period after GKS between the two groups. Adverse radiation effects (AREs) developed in a total of four patients (8.2 %); among them, one patient (2.0 %) developed a permanent case of diplopia. No mortality occurred in this series.
In this study, GKS was demonstrated to be a safe and effective alternative treatment for brain stem CMs that resulted in a reduction in the AHR. Consequently, we suggest that even CM patients who have suffered only a single bleed should not be contraindicated for SRS 3).

39 patients (16 males, 23 females) were treated with GKS for BSCA from January 1997 to September 2012. Clinical data were analyzed retrospectively. The mean age was 41.5 years. All patients had a history of symptomatic bleeding once or more before performing GKS. Mean volume of BSCA was 1095.3mm(3) and median prescribed marginal dose was 13 Gy.
Mean follow-up period since diagnosis was 4.1 years. The number of hemorrhagic events between initial diagnosis and GKS was 5 over a total of 14.9 patients-years with annual hemorrhagic rate of 33.6%. Following GKS, there were five hemorrhagic events within the first 2 years (8.1%/year) and two after the first 2 years (2.4%/year). The difference was not statistically significant. Neurologic status improved in 24 patients (61.5%), and stationary in eleven (28.2%). 4 patients (10.3%) experienced the exacerbation of symptoms at the last follow-up and none of them were related to the radiation injury. Significant volume reduction after GKS was observed in 24 patients (61.5%). Surgical excision was performed in one patient due to swelling and rebleeding after GKS. Age at presentation, sex, mass size of BSCA, and location, GKS dose did not affect post-GKS hemorrhage.
GKS for BSCA using relatively low marginal dose is safe and effective. Long-term prospective study is needed to confirm the optimal dose for BSCA 4).

1) Aboukais R, Estrade L, Devos P, Blond S, Lejeune JP, Reyns N. Gamma Knife Radiosurgery of Brainstem Cavernous Malformations. Stereotact Funct Neurosurg.2016 Dec 20;94(6):397–403. [Epub ahead of print] PubMed PMID: 27992870.
2) Liu HB, Wang Y, Yang S, Gong FL, Xu YY, Wang W. Gamma knife radiosurgery for brainstem cavernous malformations. Clin Neurol Neurosurg. 2016 Oct 11;151:55-60. doi: 10.1016/j.clineuro.2016.09.018. [Epub ahead of print] PubMed PMID: 27794267.
3) Lee SH, Choi HJ, Shin HS, Choi SK, Oh IH, Lim YJ. Gamma Knife radiosurgery for brainstem cavernous malformations: should a patient wait for the rebleed? Acta Neurochir (Wien). 2014 Oct;156(10):1937-46. doi: 10.1007/s00701-014-2155-0. PubMed PMID: 24965071.
4) Kim BS, Yeon JY, Kim JS, Hong SC, Lee JI. Gamma knife radiosurgery of the symptomatic brain stem cavernous angioma with low marginal dose. Clin Neurol Neurosurg. 2014 Nov;126:110-4. doi: 10.1016/j.clineuro.2014.08.028. PubMed PMID: 25238102.

The Role of Hemosiderin Excision in Seizure Outcome in Cerebral Cavernous Malformation Surgery: A Systematic Review and Meta-Analysis

The T2-weighted image show a cavernous malformation as heterogeneous and “popcorn-like” with a mixed signal intensity core and a hypointense hemosiderin rim.


T2WI and T2* gradient echo show multiple cavernomas. Notice the popcorn appearance with peripheral rim of hemosiderin on the T2WI. The lesions are almost completely black on the gradient echo due to blooming artefacts. T2* and susceptibility weighted imaging (SWI) markedly increase the sensitivity of MRI to detect small cavernomas. The five black dots in the left cerebral hemisphere on the T2* are also cavernomas and are not visible on the T2WI.

Importance

In ten studies comparing extended hemosiderin excision with only lesion resection were identified by searching the English-language literature. Meta-analyses, subgroup analyses and sensitivity analysis were conducted to determine the association between hemosiderin excision and seizure outcome after surgery.
Patients who underwent extended surrounding hemosiderin excision could exhibit significantly improved seizure outcomes compared to patients without hemosiderin excision. However, further well-designed prospective multiple-center RCT studies are still needed 1).
Previous works showed that extent of resection and its surrounding hemosiderin rim were found to consistently correlate with a more favorable post-operative seizure-free outcome 2) 3).
Patients with short duration of epilepsy associated with cavernous malformations could benefit greatly from complete resection of hemosiderin rim and cavernous malformations 4).
High field intraoperative MRI imaging (iopMRI) and neuronavigation might play a crucial role to achieve both goals 5).
26 patients (14 female, 12 male, mean age 39·1 years, range: 17-63 years) with CM related epilepsy were identified. Eighteen patients suffered from drug resistant epilepsy (69·2%). Mean duration of epilepsy was 11·9 years in subjects with drug resistant epilepsy (n = 18) and 0·3 years in subjects presenting with first-time seizures (n = 8).
24 lesionectomies and two lesionectomies combined with extended temporal resections were performed.
Seven lesions were located extratemporally.
Complete CM removal was documented by postsurgical MRI in all patients. As direct consequence of iopMRI, refined surgery was necessary in 11·5% of patients to achieve complete cavernoma removal and in another 11·5% for complete resection of additional adjacent epileptogenic cortex. Removal of the hemosiderin rim was confirmed by iopMRI in 92% of patients. Two patients suffered from mild (7·7%) and one from moderate (3·8%) visual field deficits. Complete seizure control (Engel class 1A) was achieved in 80·8% of patients with a mean follow-up period of 47·7 months 6).
1) Ruan D, Yu XB, Shrestha S, Wang L, Chen G. The Role of Hemosiderin Excision in Seizure Outcome in Cerebral Cavernous Malformation Surgery: A Systematic Review and Meta-Analysis. PLoS One. 2015 Aug 25;10(8):e0136619. doi: 10.1371/journal.pone.0136619. eCollection 2015. PubMed PMID: 26305879.
2) Stavrou I, Baumgartner C, Frischer JM, Trattnig S, Knosp E. Long-term seizure control after resection of supratentorial cavernomas: a retrospective single-center study in 53 patients. Neurosurgery. 2008 Nov;63(5):888-96; discussion 897. doi: 10.1227/01.NEU.0000327881.72964.6E. PubMed PMID: 19005379.
3) Kim W, Stramotas S, Choy W, Dye J, Nagasawa D, Yang I. Prognostic factors for post-operative seizure outcomes after cavernous malformation treatment. J Clin Neurosci. 2011 Jul;18(7):877-80. doi: 10.1016/j.jocn.2010.12.008. Epub 2011 May 10. Review. PubMed PMID: 21561775.
4) Jin Y, Zhao C, Zhang S, Zhang X, Qiu Y, Jiang J. Seizure outcome after surgical resection of supratentorial cavernous malformations plus hemosiderin rim in patients with short duration of epilepsy. Clin Neurol Neurosurg. 2014 Apr;119:59-63. doi: 10.1016/j.clineuro.2014.01.013. Epub 2014 Jan 25. PubMed PMID: 24635927.
5) Xie HW, Wang DM, Yuan QG, Sha C, Yang YM, Jiang HZ. [The utility of neuronavigation in the microsurgery for cerebral cavernous malformations]. Zhonghua Wai Ke Za Zhi. 2011 Aug 1;49(8):712-5. Chinese. PubMed PMID: 22168935.
6) Sommer B, Kasper BS, Coras R, Blumcke I, Hamer HM, Buchfelder M, Roessler K. Surgical management of epilepsy due to cerebral cavernomas using neuronavigation and intraoperative MR imaging. Neurol Res. 2013 Oct 23:0. [Epub ahead of print] PubMed PMID: 24070413.

Outcome after surgical or conservative management of cerebral cavernous malformations

There have been few comparative studies of microsurgical excision vs conservative management 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 1).
1) Moultrie F, Horne MA, Josephson CB, Hall JM, Counsell CE, Bhattacharya JJ, Papanastassiou V, Sellar RJ, Warlow CP, Murray GD, Al-Shahi Salman R; Scottish Audit of Intracranial Vascular Malformations (SAIVMs) steering committee and collaborators. Outcome after surgical or conservative management of cerebral cavernous malformations. Neurology. 2014 Aug 12;83(7):582-9. doi: 10.1212/WNL.0000000000000684. Epub 2014 Jul 3. PubMed PMID: 24994841.