Cerebral Cavernous Malformation

Cerebral cavernous malformation is a cluster of dilated, thin walled capillary like vascular channels with no intervening brain tissue and little flow, causing seizures, haemorrhage and focal deficits. Many are found incidentally.

Prevalence is about 0.4 to 0.5% of the population on MRI. Most are sporadic, and about 20% are familial.

Genetics. Familial disease is autosomal dominant with variants in CCM1 (KRIT1), CCM2 or CCM3 (PDCD10). A founder CCM1 variant is common in people of Hispanic descent from the southwestern United States. Familial cases have multiple lesions.

Associations. Sporadic lesions are often solitary and linked to a developmental venous anomaly; radiotherapy can induce lesions.

Classification. Zabramski types I to IV by MRI appearance, from acute or subacute haemorrhage (type I) to punctate microbleeds (type IV).

Natural history. Annual haemorrhage risk is about 0.2 to 1% in lesions without a previous bleed and several times higher after a bleed, with highest risk in the first 2 years. Brainstem lesions have higher risk.

Pathophysiology.

Loss of function of the CCM proteins disrupts endothelial junctions and increases signalling through MEKK3 and KLF2/4, leading to leaky, enlarged vascular channels.

Repeated microhaemorrhage and iron deposition cause gliosis and seizure.

• Seizures in about 50% of supratentorial lesions.
• Haemorrhage with sudden headache and focal deficit; brainstem lesions cause cranial nerve or long tract signs.
• Progressive focal deficit or headache.
• Incidental finding on imaging in many people.

Red flags.

• Sudden headache with new deficit.
• Brainstem or spinal lesion with new neurological signs.
• Rapid lesion growth on imaging.

• MRI with gradient echo or susceptibility weighted sequences: popcorn lesion with a haemosiderin rim; multiple lesions suggest familial disease.
• CT is insensitive except for acute haemorrhage and calcification.
• Catheter angiography is usually normal and is only needed to exclude other lesions.
• EEG for seizures; genetic testing and counselling when there are multiple lesions or a family history.
• Screening MRI of first degree relatives in familial disease.

Differential diagnosis. Arteriovenous malformation, haemorrhagic tumour, amyloid angiopathy, capillary telangiectasia, haemorrhagic metastasis, calcified granuloma and old haemorrhage.

• Incidental or minimally symptomatic lesions: observation with clinical and MRI follow up.
• Seizures: levetiracetam 500 mg orally twice daily, increased by 500 mg twice daily every 2 weeks as needed to a maximum of 1500 mg twice daily. Monitor mood, behaviour and renal function. Reduce dose when creatinine clearance is 50 to 80 mL/min (500 to 1000 mg twice daily), 30 to 50 mL/min (250 to 750 mg twice daily) and under 30 mL/min (250 to 500 mg twice daily); use with caution in pregnancy and breastfeeding. Refer for epilepsy surgery if seizures are drug resistant after 2 adequate drug regimens.
• Surgical resection for accessible symptomatic lesions with recurrent haemorrhage or drug resistant epilepsy, and for selected brainstem lesions after repeated bleeds in an experienced centre.
• Stereotactic radiosurgery has uncertain benefit and is considered only in selected deep, symptomatic lesions after repeat bleeds.
• Antithrombotic drugs are not absolutely contraindicated and are used when there is a clear indication; avoid high risk combinations where possible.
• Avoid unnecessary radiation exposure in familial disease; control blood pressure.

Monitoring. MRI at 6 to 12 months after diagnosis, then as clinically needed; yearly clinical review in familial disease.

Referral and escalation. Neurosurgical and epilepsy referral for symptomatic lesions; urgent review for haemorrhage; clinical genetics for familial disease.

Special groups. Pregnancy: not contraindicated; haemorrhage risk does not appear clearly higher, and delivery mode follows obstetric indication. Children: seizures and haemorrhage are managed similarly, with surgery in a specialist centre.