CASE 16308 Published on 15.11.2018

Familial Cerebral Cavernous malformation Syndrome: A Silent Threat

Section

Neuroradiology

Case Type

Clinical Cases

Authors

Lady Hardinge Medical College and associated Hospitals, India Email:gargnavni@gmail.com
W Pratiksha Hospital, India Email: dr.nimesh.gupta88@gmail.com

Patient

44 years, female

Categories

Area of Interest Neuroradiology brain ; Imaging Technique MR

Procedure Diagnostic procedure ; Special Focus Congenital ;

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Clinical History

A 44-year-old female presented to the Neurology clinic complaining of chronic headache. She had no other complaint. There was no history of any associated aura or nausea. Patient refused for a Computed tomography of brain due to radiation hazard and underwent a non contrast MRI of brain.

Imaging Findings

MRI brain revealed multiple, popcorn like lesions in bilateral cerebral hemispheres and cerebellum appearing hyperintense on T1W, mixed signal intensity on T2W with peripheral hemosiderin rim. The lesions showed blooming on susceptibility weighted images. No perilesional edema was seen. A diagnosis of familial Cerebral Cavernous Malformation syndrome was considered.
Patient was counselled about the associated risk of haemorrhage and managed conservatively. Screening MRI of other family members was advised. Genetic testing was not possible due to high cost and limited availability. The patient had lost both parents in an accident. One brother of patient was found to have similar lesions but was asymptomatic. The younger sister of patient had no cerebral lesions.

Discussion

Cerebral cavernous malformations (CCM) are low flow vascular malformations in brain and/or the spinal cord having haemorrhage in various stages of evolution. They represent 5-13 % of central nervous system vascular malformations [1,2]. These are usually single and asymptomatic, however multiple CCM may occur in familial form associated with CCM genes.
These CCM may be asymptomatic or may cause headache, epilepsy, intracerebral hemorrhage, and/or focal neurologic deficits [3]). Repeated hemorrhages can result in degeneration. Death may occur due to haemorrhage in lesions particularly brainstem lesions.
CCM can occur anywhere in the brain and the spinal cord, most common location being supratentorial brain parenchyma (75%) [4].

Familial form of CCM is inherited in an autosomal dominant manner and has been associated with three genes, CCM1 (KRIT1), CCM2 and CCM3 (PDCD10). CCM1 and CCM2 are located on chromosome 7q and CCM3 is located on chromosome 3 [5, 6].

Familial CCM is defined as the occurrence of CCMs in at least two family members, and/or the presence of a disease-causing mutation in one of the genes associated with CCM and/or the presence of multiple CCMs (typically five or more) [7]. These may be associated with developmental venous anomalies, cutaneous vascular lesions, retinal hemangiomas or vertebral hemangiomas [8-13].

Younger patients might have few lesions with new lesions appearing at the rate of 0.2 -0.4 per patient year [4].

MRI is the imaging modality of choice for diagnosis as well as for monitoring the evolution of lesions. Both spin echo and gradient echo sequences can be used though gradient echo sequences can pick up more lesions [3]. On T2W sequences, CCM appear as well defined, popcorn like lesions with mixed signal intensity due to haemorrhage in various stages. A peripheral low signal intensity hemosiderin ring is seen on T2W sequences and gradient echo images [14]. Contrast MRI is usually not required for diagnosis of CCM, however it helps in characterization of other associated vascular malformations like capillary telangiectasia, aneurysms, and arteriovenous malformations.

The lesions demonstrating T1W/T2W hyperintense signal and/or perilesional edema are suggestive of recent bleed. It is important to identify these lesions as they are associated with recurrent bleeding.

People with familial CCM should be cautious in taking medications which may cause haemorrhage like analgesics and anticoagulants. Screening MRI of symptomatic as well as asymptomatic siblings should be advised to find out the number, location and size of lesions.

Written informed patient consent for publication has been obtained.

Differential Diagnosis List

FAMILIAL CEREBRAL CAVERNOUS MALFORMATION SYNDROME

Amyloid angiopathy

Hypertensive bleed

Final Diagnosis

FAMILIAL CEREBRAL CAVERNOUS MALFORMATION SYNDROME

References

[1] McCormick WF, Hardman JM, Boulter TR (1968) Vascular malformations (“angiomas”) of the brain, with special reference to those occurring in the posterior fossa. J Neurosurg 28(3):241–251

[2] Giombini S, Morello G (1978) Cavernous angiomas of the brain: account of fourteen personal Fact cases and review of the literature. Acta Neurochir (Wien) 40(1–2):61–82 (PMID: 654971)

[3] Brunereau L, Labauge P, Tournier-Lasserve, Laberge S, Levy C, Houtteville J (2000) Familial Form of Intracranial Cavernous Angioma: MR Imaging Findings in 51 Families. Radiology 214:209-216

[4] Brunereau, L, Levy, C, Laberge, S, et al (2000) De novo lesions in familial form of cerebral cavernous malformations: clinical and MR features in 29 non-Hispanic families. Surg. Neurol 53: 475–82

[5] Liquori CL, Berg MJ, Siegel AM, et al (2003) Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73(6):1459-64

[6] Craig HD, Gunel M, Cepeda O, et al (1998) Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum Mol Genet 7(12):1851-8

[7] Denier, C, Labauge, P, Brunereau, L, et al (2004) Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. Ann Neurol 55: 213-20

[8] Labauge P, Enjolras O, Bonerandi JJ, et al (1999) An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families. Ann Neurol 45(2):250–254 (PMID: 9989629)

[9] Labauge P, Krivosic V, Denier C, Tournier Lasserve E, Gaudric A (2006) Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas: a clinical and genetic study. Arch Ophthalmol 124(6):885–886

[10] Toll A, Parera E, Giménez-Arnau AM, et al (2009) Cutaneous venous malformations in familial cerebral cavernomatosis caused by KRIT1 gene mutations. Dermatology 218(4):307–313

[11] Toldo I, Drigo P, Mammi I, Marini V, Carollo C (2009) Vertebral and spinal cavernous angiomas associated with familial cerebral cavernous malformation. Surg Neurol 71(2): 167–171

[12] Lanfranconi S, Ronchi D, Ahmed N, et al. (2014) A novel CCM1 mutation associated with multiple cerebral and vertebral cavernous malformations. BMC Neurol 14:158

[13] Abe, T, Crowley, RS, Marks, MP, et al (1998) Coexistence of occult vascular malformations and developmental venous anomalies in the central nervous system: MR evaluation. AJNR 19: 51–7 (PMID: 9432157)

[14] Hallam DK, Russell EJ (1998) Imaging of angiographically occult cerebral vascular malformations. Neuroimaging Clin N Am 8(2):323-47 (PMID: 9562592)

Case information

URL:	https://www.eurorad.org/case/16308
DOI:	10.1594/EURORAD/CASE.16308
ISSN:	1563-4086

License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Figure 1

MRI BRAIN

T1W axial image shows a well defined hyperintense lesion in right frontal region.

T2W axial image shows a well defined mixed signal intensity lesion in right frontal region with surrounding hemosiderin rim.

Figure 2

MRI BRAIN

T1W axial image shows well defined hyperintense lesions in right fronto-parietal and left parietal regions

T2W axial image shows multiple well defined mixed signal intensity lesions in right fronto-parietal and left parietal regions with surrounding hypointense hemosiderin rim.

Figure 3

MRI BRAIN