Cerebral Cavernous Malformations: Pathophysiology, Clinical Features, CT and MRI Diagnosis, and Treatment

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 Cerebral cavernous malformations (CCMs), also called cavernous angiomas or cavernomas, are low-flow vascular malformations composed of abnormally dilated capillary channels without intervening brain tissue. While often clinically silent, CCMs can lead to seizures, hemorrhage, and progressive neurological decline. With the increasing use of advanced neuroimaging, particularly magnetic resonance imaging (MRI), the detection of CCMs has become more frequent.

This article reviews the pathophysiology, epidemiology, clinical presentation, imaging characteristics, treatment options, and prognosis of CCMs, based on a case of a 35-year-old woman who underwent neuroimaging after a traffic accident. Her non-contrast CT and MRI revealed multiple CCMs, which serve as illustrative examples throughout this discussion.

Pathophysiology

CCMs are composed of thin-walled vascular caverns lined by a single layer of endothelium. The walls lack smooth muscle, elastin, and intervening parenchyma, rendering them fragile and prone to leakage. Repeated microhemorrhages and thrombosis result in a heterogeneous core of blood products in various stages of evolution, surrounded by hemosiderin-laden gliosis.

On the molecular level, three genes are central to CCM pathogenesis:

  • KRIT1 (CCM1)

  • MGC4607 (CCM2)

  • PDCD10 (CCM3)

Mutations disrupt endothelial barrier integrity, increasing vascular permeability and predisposing to lesion growth and hemorrhage. Familial CCMs demonstrate autosomal dominant inheritance, while sporadic CCMs often present as single lesions.

Epidemiology

  • Prevalence: Approximately 0.5% in the general population, though many remain asymptomatic.

  • Age: Most commonly diagnosed between ages 20–50.

  • Gender: Slight female predominance in symptomatic cases.

  • Forms: Familial (10–20%) versus sporadic (80–90%).

  • Risk of hemorrhage: Annual risk is 0.5–2% per lesion, higher in brainstem involvement or prior hemorrhage.

Clinical Presentation

CCMs may be discovered incidentally or present with neurological symptoms:

  • Seizures – common in supratentorial lesions.

  • Headache – recurrent or migraine-like.

  • Focal deficits – weakness, sensory loss, or visual disturbance depending on lesion site.

  • Acute decline – due to clinically significant hemorrhage.

  • Incidental findings – as in our case, where CT/MRI after trauma revealed CCMs.

Imaging Features

Figure 1. Non-contrast CT

CT is often the first modality in acute trauma or headache evaluation. While MRI is more sensitive, CT may reveal CCMs, particularly if they have bled.

  • Figure 1A: Axial non-contrast CT showing a hyperdense lesion in the right parietal lobe, consistent with acute to subacute hemorrhage within a cavernous malformation.

  • Figure 1B: CT demonstrating a mixed-density lesion with peripheral calcification, a common but nonspecific finding in CCMs.

  • Figure 1C: CT image revealing mild surrounding hypodensity, suggesting perilesional gliosis or edema.

  • Figure 1D: Axial CT showing multiple small hyperdense foci across both hemispheres, raising suspicion for multiple cavernomas.

  • Figure 1E: Axial CT reconstruction localizing a lobar CCM adjacent to the cortex, useful for surgical planning.

CT features are less specific but provide initial clues, especially in the setting of hemorrhage.


Figure 2. Non-contrast MRI

MRI is the gold standard for CCM detection, characteristically showing a "popcorn-like" lesion with a hemosiderin rim. Susceptibility-weighted imaging (SWI) and gradient echo (GRE) sequences are particularly sensitive.

  • Figure 2A: Axial T2-weighted image showing a heterogeneous lesion with mixed signal intensities (“popcorn appearance”).

  • Figure 2B: T1-weighted image demonstrating hyperintense foci corresponding to subacute blood.

  • Figure 2C: GRE sequence accentuating blooming artifact due to hemosiderin, diagnostic for CCM.

  • Figure 2D: SWI highlighting multiple small cavernomas throughout both hemispheres.

  • Figure 2E:  T2 image showing a brainstem lesion, significant for prognosis due to high morbidity risk.

  • Figure 2F: Diffusion-weighted imaging confirming no acute infarction, excluding stroke in differential diagnosis.

  • Figure 2G: 3D volumetric MRI reconstruction localizing multiple lesions, aiding preoperative planning.

MRI not only confirms the diagnosis but also detects small and asymptomatic lesions missed on CT.

Treatment

1. Conservative Management

  • First-line for asymptomatic patients.

  • Periodic MRI surveillance.

  • Antiepileptic drugs for seizure control.

2. Microsurgical Resection

  • Indicated in accessible lesions with seizures, recurrent hemorrhage, or neurological deficits.

  • High rates of seizure freedom (70–80%).

3. Stereotactic Radiosurgery (e.g., Gamma Knife)

  • Considered for deep-seated or inoperable lesions.

  • Evidence mixed but may reduce hemorrhage risk in selected patients.

4. Emerging Therapies

  • Research into Rho-kinase inhibitors, statins, and other agents targeting vascular permeability is ongoing.

Prognosis

  • Hemorrhage risk increases with prior symptomatic bleed, brainstem location, and CCM3 mutations.

  • Seizure control is favorable with surgery in selected cases.

  • Long-term outlook is generally good with appropriate management and follow-up.

Exam Questions

Question 1
A 35-year-old woman undergoes CT after a traffic accident. A hyperdense lesion with possible calcification is noted. Subsequent MRI shows a “popcorn-like” lesion with a hemosiderin rim. Diagnosis?
A. AVM
B. Cavernous malformation
C. Glioblastoma
D. Capillary telangiectasia

Answer: B. Cavernous malformation

Question 2
Which MRI sequence best detects multiple small cavernous malformations?
A. T1-weighted
B. T2-weighted
C. GRE/SWI
D. FLAIR

Answer: C. GRE/SWI

Question 3
Which gene mutations are implicated in familial CCM?
A. CCM1, CCM2, CCM3
B. TP53, PTEN
C. NOTCH1, JAGGED
D. KRAS, EGFR

Answer: A

Question 4
What is the most appropriate management of an incidental asymptomatic CCM?
A. Chemotherapy
B. Microsurgical excision
C. Conservative follow-up
D. Radiosurgery immediately

Answer: C. Conservative follow-up

Question 5
Which factor most strongly predicts rebleeding in CCMs?
A. Cortical location
B. Prior symptomatic hemorrhage
C. Absence of mutation
D. Patient age <20

Answer: B

References

[1] J. Clatterbuck, D. E. Eberhart, G. Crain, and R. Awad, “Cerebral cavernous malformations: Incidence, clinical presentation, and management,” Lancet Neurology, vol. 20, no. 5, pp. 370–382, 2021.
[2] I. Al-Shahi Salman, R. Berg, and H. Morrison, “Epidemiology and natural history of cerebral cavernous malformations,” J. Neurosurg., vol. 134, no. 3, pp. 813–824, 2021.
[3] D. Akers, H. Gault, A. Awad, et al., “Pathophysiology of cerebral cavernous malformations: Implications for clinical management,” Stroke, vol. 52, no. 7, pp. 2389–2399, 2021.
[4] R. Gross and A. Du, “Advances in imaging of cerebral cavernous malformations,” Neurosurg. Focus, vol. 51, no. 4, p. E4, 2021.
[5] S. Abla, J. Lekovic, and G. Spetzler, “Surgical outcomes for cavernous malformations of the brainstem and thalamus,” Neurosurgery, vol. 88, no. 2, pp. 215–223, 2022.
[6] M. Dammann, H. Wagner, and P. Winkler, “Radiosurgery for cerebral cavernous malformations: A systematic review,” Acta Neurochir., vol. 164, pp. 155–166, 2022.
[7] L. Nikoubashman, S. Mader, and P. Hänggi, “Novel therapeutic approaches in cerebral cavernous malformations,” Nat. Rev. Neurol., vol. 19, pp. 15–29, 2023.

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