What is the management approach for familial cerebral cavernous malformation syndrome?

Management of Familial Cerebral Cavernous Malformation Syndrome

The management of familial cerebral cavernous malformation syndrome requires a comprehensive approach including genetic testing, imaging surveillance, treatment of symptomatic lesions, and genetic counseling, with surgical intervention reserved primarily for symptomatic or hemorrhagic lesions. 1

Diagnostic Evaluation

• Brain MRI with gradient echo or susceptibility-weighted sequences is the recommended imaging modality for diagnosis and follow-up of suspected or known CCMs to determine if there are single or multiple lesions 2
• Obtain a 3-generation family history at the time of diagnosis, focusing on symptoms of headache, stroke, abnormal MRI scan, or other neurological complications 1
• Consider genetic testing of CCM1-3 genes by sequencing followed by deletion/duplication analysis in patients with multiple CCMs without an associated developmental venous anomaly (DVA) or with a positive family history 1
• The mutation detection rate is at least 75% of all cases with multiple CCMs, with approximately 53-65% due to mutations in CCM1, 20% in CCM2, and 10-16% in CCM3 1

Imaging Surveillance

• Brain imaging should be performed as soon as possible after the onset of clinical symptoms to demonstrate hemorrhage or new CCM formation 1
• Some clinicians advise baseline MRI of the spinal cord at diagnosis and follow-up brain MRI every 1-2 years 3
• Familial CCM is a dynamic disease with potential for new lesion formation; serial MRI may reveal changes in number, size, and imaging characteristics consistent with acute or resolving hemorrhage 4
• MRI should be performed in patients who develop new neurological symptoms during follow-up 2

Management of Asymptomatic Lesions

• Conservative management is recommended for asymptomatic CCMs, particularly those in eloquent or deep locations 2
• The natural history risk of death or nonfatal stroke for an asymptomatic CCM is approximately 2.4% over 5 years 2
• Surgical resection is not generally recommended for asymptomatic CCMs, especially those in eloquent, deep, or brainstem regions 2
• Radiosurgery is not recommended for asymptomatic CCMs 2
• Prophylactic resection of asymptomatic lesions does not appear to be indicated 4

Management of Symptomatic Lesions

Seizures

• Antiepileptic therapy is reasonable for first seizure thought to be due to a CCM (class I, level B) 1, 2
• Approximately 50-60% of patients become seizure-free on medication after first diagnosis of CCM-related epilepsy 1, 2
• Surgery may be considered early if seizures were associated with a hemorrhagic CCM or in patients who may not be compliant with medications 1, 2

Hemorrhagic Lesions

• For easily accessible, symptomatic CCMs, surgical resection may be considered 2
• For deep CCMs, surgical resection may be considered if symptomatic or after prior hemorrhage 2
• For brainstem CCMs, surgical resection may be offered after a second symptomatic bleed (class IIb, level B) 2
• Radiosurgery may be considered for solitary CCMs with previous symptomatic hemorrhage if located in eloquent areas with unacceptably high surgical risk (class IIb, level B) 2, 5
• The recommended prescription dose for stereotactic radiosurgery is between 11-13 Gy to reduce radiation-induced adverse effects 2, 5

Special Considerations

Pregnancy

• Patients with multiple CCMs should consider genetic counseling prior to pregnancy (class I, level C) 1
• Patients may be counseled that the risk of neurological symptoms during pregnancy is likely not different than the non-pregnant state (class IIa, level B) 1
• In patients with a seizure disorder due to CCM, discussion of appropriate antiepileptic drugs to reduce teratogenic side effects and folate supplementation should occur prior to pregnancy 1
• MRI without contrast should be considered if focal neurological deficits, acute severe headache, or seizure flare-ups occur during pregnancy 1
• Vaginal delivery is appropriate in most patients unless there is a neurological deficit that precludes it or recent hemorrhage 1

Medications and Activities

• Statins should be used only for approved cholesterol-lowering and cardiovascular indications with close monitoring of CCMs, not specifically for treating CCM 1
• Most studies suggest the likely safety of antiplatelet medication and a low risk of bleeding from existing CCM in patients on antithrombotics, though these studies were uncontrolled 1
• There is no evidence that vitamin D supplementation prevents future CCM disease manifestations, despite an association between vitamin D deficiency and historically aggressive CCM disease behavior 1
• Activities that could result in potential injury should a seizure occur (scuba diving, caving, skydiving, surfing, solo airplane flying) should be avoided 1
• The influence of physical activity on CCM behavior is largely unknown (class IIb, level C) 1

Genetic Counseling

• In the setting of a positive mutation in a proband, counsel the individual and family about autosomal dominant inheritance and identify at-risk individuals based on the pedigree 1
• Genetic testing of adult at-risk family members can be offered, though ethical issues should be considered when testing asymptomatic individuals 1
• Even asymptomatic siblings should be considered for screening MRI, as there may be an increased risk of hemorrhage spontaneously or due to certain medications 3
• CCM3 mutation carriers have a greater chance of spontaneous mutation, increased CCM burden, younger mean age of presentation, and significant association with other manifestations including skin CCMs, scoliosis, spinal cord cavernous malformations, cognitive disability, and benign brain tumors 1

Common Pitfalls and Caveats

• Radiosurgery has no immediate effect on the CCM and may take 2-3 years to reduce hemorrhage risk 2, 5
• Higher radiosurgery doses (>13 Gy) are associated with increased risk of radiation-induced adverse effects 2, 5
• Radiosurgery is not recommended in familial CCM because of concern about de novo CCM genesis 2
• Children may develop CCM in response to therapeutic radiation over 300 Gy in the first decade of life, raising concerns about frequent CT scans or dental radiographs in carriers of CCM mutations 1
• Familial CCM can sometimes be mistaken for cerebral amyloid angiopathy (CAA), but can be distinguished by age of onset, presence of cognitive complaints, family history, and distribution of hemorrhagic lesions 6