Cerebral Cavernous Malformation, Familial

Clinical characteristics Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord comprising closely clustered, enlarged capillary channels (caverns) with a single layer of endothelium without mature vessel wall elements or normal intervening brain parenchyma. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase or decrease in size and increase in number over time. Hundreds of lesions may be identified, depending on the person's age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades with findings such as seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with FCCM remain symptom free throughout their lives. Cutaneous vascular lesions are found in 9% of those with familial cerebral cavernous malformations (FCCM; see Diagnosis/testing) and retinal vascular lesions in almost 5%. Diagnosis/testing The diagnosis of familial cerebral cavernous malformation (FCCM) is established in a proband with either or both of the following: Multiple CCMs, or one CCM and at least one other family member with one or more CCMs A heterozygous pathogenic variant in KRIT1, CCM2, or PDCD10 Management Treatment of manifestations: Surgical removal of lesions associated with intractable seizures or focal deficits from recurrent hemorrhage or mass effect may be considered. Treatment of seizures and epilepsy is symptomatic. Headaches are managed symptomatically and prophylactically. Acute and chronic neurologic deficits may be managed through rehabilitation. Surveillance: Brain MRI imaging with gradient echo (GRE) or susceptibility-weighted imaging (SWI) is indicated in individuals experiencing new neurologic symptoms. Agents/circumstances to avoid: Agents that increase risk of hemorrhage: aspirin, NSAIDs, heparin, and sodium warfarin (Coumadin®). Note: When these medications are necessary for treatment of life-threatening thrombosis, careful consideration and close medical monitoring of dosage are warranted. Radiation to the central nervous system may lead to new lesion formation. Evaluation of relatives at risk: Asymptomatic at-risk relatives of all ages may be evaluated by molecular genetic testing (if the family-specific pathogenic variant is known) to allow early diagnosis and monitoring of those at high risk of developing CCMs. Symptomatic relatives may undergo brain MRI with special sequences (GRE or SWI) to determine presence, size, and location of lesions. Pregnancy management: Baseline MRI one year prior to delivery is recommended to determine lesion locations; pregnant women with FCCM who have had recent brain or spinal cord hemorrhage, epilepsy, or migraine require closer monitoring during pregnancy; individulas with FCCM are at a higher risk for symptomatic cerebral hemorrhage during pregnancy than those with sporadic CCM; seizure is the most common symptom of CCM hemorrhage during pregnancy; exposure to antiepileptic medication during pregnancy may increase the risk for adverse fetal outcome but is generally recommended because the fetal risk is typically less than that associated with fetal exposure to an untreated maternal seizure disorder. Genetic counseling Familial CCM is inherited in an autosomal dominant manner. The proportion of affected individuals with a de novo pathogenic variant is unknown. Each child of an individual with FCCM has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.