33 Familial Cerebral Aneurysms

Hosam Al-Jehani and Richard Leblanc

Fig. 33.1 Pedigree demonstrating familial history of cerebral and peripheral aneurysms. (From Leblanc R. De novo formation of familial cerebral aneurysms. Neurosurgery 1999;44:871–877. Reprinted with permission.)

Clinical Presentation

A 24-year old white female was admitted to the hospital because of an episode of transient global amnesia, headache, nausea, and neck pain.

The patient gave a family history of intracranial and peripheral aneurysms (Fig. 33.1),¹ but the review of systems was unremarkable.
She was normotensive and the remainder of the general and neurologic examinations were normal.
A complete blood count, serum electrolytes, liver function tests, and urinalysis were normal. A chest x-ray, electrocardiogram, and ultrasound examination of the kidneys were unremarkable.
A contrast-enhanced computed tomographic (CT) scan demonstrated a right internal carotid artery aneurysm, which was confirmed by four-vessel intraarterial cerebral angiography (Fig. 33.2).¹ No other aneurysms were seen, but both posterior communicating arteries (PCOMs) had an infundibular origin.
The patient underwent a right pterional craniotomy and uneventful clipping of the aneurysm.
The patient remained well until 10 years later when, at the age of 34 years, she was readmitted to the hospital because of severe headache. Cerebral angiography showed the presence of de novo aneurysms of the right internal carotid artery between the posterior communicating and anterior choroidal arteries, of the right middle cerebral artery at its bifurcation, of the anterior communicating artery, and on the left middle cerebral artery at the distal aspect of its first segment (M1) and at the bifurcation of its second segment (M2). The previously clipped aneurysm did not fill (Fig. 33.3).¹
The anterior communicating artery (ACOM) aneurysm was clipped, and the right internal carotid artery aneurysm was treated with detachable coils. The patient made an uneventful recovery. She was discharged home and returned to her previous occupation.
The patient remained well for another 10 years when, at the age of 44 years, she underwent CT scanning for investigation of chronic, nonspecific facial pain. The CT scan showed that the previously untreated aneurysm of the second segment of the left middle cerebral artery had enlarged, a finding confirmed by intraarterial angiography. Angiography also demonstrated new aneurysms of the proximal and distal right middle cerebral artery, of the right ACOM and of the distal right superior cerebellar artery.

Fig. 33.2 Right carotid artery angiogram demonstrating the presence of a 1 × 1.5 cm aneurysm of the right internal carotid artery at the level of its bifurcation into anterior and middle cerebral arteries. (From Leblanc R. De novo formation of familial cerebral aneurysms. Neurosurgery 1999;44:871–877. Reprinted with permission.)

Fig. 33.3 Right internal carotid artery angiogram performed during compression of the left internal carotid artery (top) demonstrating the anterior communicating artery aneurysm and the aneurysms of the left middle cerebral artery at its bifurcation and at the origin of its second segment (arrowheads). The later two aneurysms are further illustrated at the bottom right image after the performance of a left internal carotid artery angiogram. The aneurysm at the origin of the right middle cerebral artery is illustrated at the bottom left of the figure. (From Leblanc R. De novo formation of familial cerebral aneurysms. Neurosurgery 1999; 44:871–877. Reprinted with permission.)

Questions

What are the risk factors of subarachnoid hemorrhage (SAH)?
What is the prognosis of aneurysmal SAH?
What are some of the common genetically determined conditions associated with intracranial aneurysms?
What is the incidence of familial aneurysms that are not associated with other genetically determined conditions?
What are the features of familial aneurysms compared with sporadic ones?
What have been the results of genetic studies of familial cerebral aneurysms?
What are the limitations to the genetic studies of familial intracranial aneurysm?
How can genetic factors interact with other risk factors in familial aneurysms?
What are your recommendations for screening for familial intracranial aneurysms?

Answers

What are the risk factors of SAH?

Risk factors for aneurysmal SAH include 2–4

Cigarette smoking (odds ratio of 3.1)

Arterial hypertension (odds ratio of 2.6)

Excessive use of alcohol

A family history of aneurysmal SAH

Advancing age

The use of cocaine
What is the prognosis of aneurysmal SAH?
- Subarachnoid hemorrhage from a ruptured intracranial aneurysm has a poor prognosis: In population-based studies mortality is of the order of 50% and 20% of survivors remain severely disabled.⁵
What are some of the common genetically determined conditions associated with intracranial aneurysms?
- Syndromes associated with intracranial aneurysms include^6,7
  - Autosomal dominant polycystic kidney disease
  - Ehlers–Danlos syndrome type I and IV
  - Marfan syndrome
  - Fibromuscular dysplasia
  - Neurofibromatosis type 1
  - Tuberous sclerosis
  - Osteogenesis imperfecta type 1
  - Achondroplasia
  - α1-Antitrypsin deficiency
What is the incidence of familial aneurysms that are not associated with other genetically determined conditions?
- Up to 15% of individuals with a ruptured aneurysm in the absence of other familial conditions associated with cerebral aneurysms will have a first-degree relative who also has a cerebral aneurysm compared with ~5% for age-matched controls.⁸
- The risk of harboring intracranial aneurysm is proportional to the number of affected first-degree relatives.^9–12
What are the features of familial aneurysms compared with sporadic ones?
- In initial studies comparing familial cerebral aneurysms and sporadic cerebral aneurysms, it was found that familial aneurysms rupture at a younger age, especially in women, and at a smaller size than sporadic aneurysms. Familial aneurysms tend to rupture within the same decade in families, and within 5 years of each other in identical twins.^11,13,14
- Others have suggested that familial aneurysms may be diagnose when they are a larger size than sporadic ones, that they more often occur on the middle cerebral artery and that patients that harbor them are more likely to have multiple aneurysms than individuals with sporadic aneurysms. Familial aneurysms have been shown to have a worse outcome following rupture than sporadic aneurysms.^11,15
What have been the results of genetic studies of familial cerebral aneurysms?
- Initial studies aimed at identifying genetic factors associated with cerebral aneurysms not associated with other well–defined genetic conditions have been largely negative. We were unable to identify a link to the human leucocyte antigen (HLA) system in our cases, and sequencing of the type III collagen gene showed that it is was preserved in our patients.^16,17
- Others have suggested a linkage to the 7q11 locus near the elastin gene, to the collagen type 1A2 gene,¹⁸ and to 19q12–13 and 9p21, which contain several loci related to cerebrovascular disease that may be important for aneurysm formation. The loci 1p34.3–p36.13 and Xp22 were found to be associated with familial intracranial aneurysms across diff erent populations.^19,20
What are the limitations to the genetic studies of familial intracranial aneurysm?
- The limitations to genetic studies are multiple. Varying definitions of what constitutes a familial incidence of aneurysms are in use. This implies a different genetic load in the families studied that may lead to diff erent findings.
- The mode of inheritance is unknown and is most likely heterogeneous. It is difficult to determine whether a sibling is not affected because aneurysms may develop after a negative screening examination.
- Finally, large cooperative international studies probably are not applicable because diff erent populations and diff erent ethnic groups have diff erent risks for SAH and thus probably also have diff erent genetic determinants for intracranial aneurysms.^19,21–23
How can genetics factors interact with other risk factors in familial aneurysms?
- The interaction between genetic and other risk factors such as atherosclerosis, arterial hypertension, and cigarette smoking may predispose to weakening of the arterial wall. This would be expected to result in a higher risk of developing large and multiple aneurysms in familial cases, or more fragile aneurysms that might rupture at a smaller size.
- The possibility of such interactions is supported by the findings that cerebral aneurysms are associated with several loci related to cerebrovascular disease that could predispose to atherosclerosis, hypertension, and aneurysm formation²⁰ and by the observation that polymorphic variants of the eNOS allele, which are associated with cigarette smoking, are more frequent in patients with SAH than in patients with unruptured aneurysms.^18,24–26
What are your recommendations for screening for familial intracranial aneurysms?
- The possible usefulness of elective screening of asymptomatic relatives of individuals with familial intracranial aneurysms is controversial and is best evaluated by decision analysis.
- However, most of the studies fail to support a role for systematic screening of individuals felt to be at risk of harboring a cerebral aneurysm because of their family history or at best suggest a very limited role for this practice, which may benefit only the young.10,27–29
- More recently, some have suggested that screening may be of benefit for first-degree relatives who are in their fourth decade or older and who have a history of cigarette smoking or of arterial hypertension, especially if they are female; and others have suggested that magnetic resonance angiography (MRA) screening is cost-effective, especially for patients 50 years and older.^30,31
- One of the factors that militate against elective screening of asymptomatic individuals with a family history of cerebral aneurysms is the risk attendant to intraarterial angiography.
- However, less invasive diagnostic procedures, such as CT or MRA are becoming well established in the non-invasive diagnosis of individuals suspected of having even a small aneurysm.^32,33
- Thus, we currently recommend MRA to our patients with a family history of cerebral aneurysms who desire screening, but we usually wait until the patient is 20 years old or older.
- This is followed by conventional angiography if the results are equivocal or if an aneurysm that warrants treatment is found.
- A negative examination, however, does not rule out that an aneurysm may develop in the future.
- There are currently no firm guidelines to suggest that screening should be repeated if an initial examination is negative. We have previously suggested that periodic reexamination should be considered for individuals with a treated aneurysm who have a family history of cerebral aneurysms because, as illustrated by the case of the patient described here, new aneurysms can develop decades later.^1,34