Familial Cerebral Aneurysms

An intracranial aneurysm is a hernia, usually in the form of a small sack, in the wall of a cerebral artery. The main complication is rupture, as this leads to a subarachnoid haemorrhage.

The disease is considered as « familial » when at least two members of the same family have an intracranial aneurysm.

Definition

An intracranial aneurysm is a hernia, usually in the shape of a small sack, within the wall of a cerebral artery. The main complication is its rupture than can lead to a subarachnoid haemorrhage.

The disease is considered as « familial » when at least two members of the same family have an intracranial aneurysm.

Epidemiology

Intracranial aneurysms are common. They are present in 1 to 2% of the general population (when they are systematically looked for at autopsy or with angiography).   Most aneurysms are small and 80% of them do not rupture. The incidence of subarachnoid haemorrhage (number of new cases) varies between 5 and 15 cases per 100,000 people per year.

The familial forms of intracranial aneurysm is thought to account for between 5% and 20% of the total number of cases with aneurysms. The frequency of the disease varies according to the population. In more than 80% of familial cases, patients with a family history of aneurysm report no more than 2 to 3 cases in the family. Within families, women seem to be affected more often than men (there are until 4 times more women than men among patients with aneurysm).

Clinical presentation

In most cases, the first case within a family is detected as a result of a subarachnoid haemorrhage (escape of blood because of a rupture in the aneurysm sac).

A subarachnoid haemorrhage is the most frequent cause of clinical manifestations with:

• In most cases, a sudden unusual headache (like a « thunderclap ») that is extremely severe, associated with vomiting and neck pain
• A sudden comaoccurs in one out of every three cases
• Epileptic seizuresoccur in 5% of cases
• A deficitsuch as paralysis or speech difficulties is observed when the subarachnoid haemorrhage is accompanied by a cerebral haemorrhage (i.e. inside the tissue of the brain)

In 5% to 10% of   cases, clinical manifestations are less obvious. The headache can be sudden but not severe.

A subarachnoid haemorrhage may be associated with symptoms indicating the compression of certain nerves in the brain by the aneurysmal sack. Such compression may be accompanied by diplopia (double vision) because of damage to the nerves responsible for eye movements (paralysis of the 3rd or 6th cranial nerve).

A subarachnoid haemorrhage is a serious symptom because, on average, one in every two patients suffering a subarachnoid haemorrhage dies during the first month. Of the survivors, approximately one in three suffers long-term effects.

On average, a subarachnoid haemorrhage occurs most frequently between the ages of 40 and 50 years. However, it can occur at any age.

In the familial forms, the mean age of cases with subarachnoid haemorrhage appears to be lower by 2 to 10 years, compared to the average age among the general population.

The aneurysm may be discovered during an imaging exam (CT or MRI scan) in the absence of any symptom. This is then referred to as an « asymptomatic » aneurysm.

Etiology – Pathophysiology    

An examination of the aneurysmal sack shows that its wall is abnormal and thin. In many cases, the normal elastic fibres of the vessel wall and muscle cells within the central part of the wall (the media) have disappeared. The thinning of the vessel wall explains its fragility and the rupture that can occur, especially when the aneurysmal sack continues to swell under pressure from the circulating blood in the artery. 

The fragility of the wall varies from one vessel to another depending on the pressure from blood flow, which is variable. This is probably why aneurysms are usually located in certain arteries or their bifurcations. Aneurysms at the top of the internal carotid artery, in the middle cerebral artery and in the anterior cerebral artery account for approximately 90% of all intracranial aneurysms. About 10% of aneurysms are bilateral.

Various types of abnormality in the vascular wall are responsible for the development and growth of an arterial aneurysm.

In familial forms of intracranial aneurysm, the diagnosis of an associated hereditary disease has been reported in approximately 15% of cases in a major study carried out in Finland.

The cause is almost always familial Autosomal Dominant Polycystic Kidney Disease or, more rarely, an autosomal recessive form of the same disease. The disease causes kidney cysts. The autosomal dominant form is the most frequent genetic kidney disease, affecting 1 in 2,000 of the population. Anomalies in two genes are responsible: PKD1 on chromosome 16 and PKD2 on chromosome 4. Renal cysts may be responsible for hypertension, pain (resulting mainly from the increased size of the kidneys), UTIs and, more rarely, kidney stones. The number of cysts increases with age. The disease can lead to kidney failure requiring dialysis, or transplant in 50% of cases. Symptoms of cysts in other organs are less frequent (liver, pancreas). Approximately 10% of patients with polycystic kidney disease also prove to have an intracranial aneurysm when it is looked for but in more than 80% of cases, the aneurysm is small with a diameter of less than 6 mm.

The diagnosis of an aneurysm in a patient suffering from diseases affecting the vascular wall might also suggest a familial form of aneurysm. However, this has not yet been sufficiently well documented.

This is the case for:

• The Ehlers Danlos Syndromecaused by mutations in the COL3A1 gene on chromosome 2 (which codes for collagen 3, a large protein that ensures the strength of the collagen within blood vessel walls and in various organs). This rare autosomal dominant disease (with a prevalence of 1 case in 10,000 to 20,000 people) is responsible for the fragility of the arterial wall, leading to aneurysms as well as arterial-venous dissections or fistulae.  Patients suffering from Ehlers Danlos Syndrome may, in particular, have several large aneurysms. One-half of intracranial haemorrhages observed in the disease are related to the rupture of an aneurysm. This represents approximately 2% of patients suffering from the disease. Other signs or symptoms are present in the syndrome: hyperelasticity of the skin, fragility and transparency of the skin, bruising, acrogeria, intestinal perforations, pneumothorax, rupture of the uterine wall during labour and, more rarely, subluxations of joints. The clinical signs of the disease appear in 25% of cases before the age of 20 and in 80% of cases before the age of 40. For further information on this disease, contact the centre for rare vascular diseases at the « Hôpital Européen Georges Pompidou » (maladiesvasculairesrares.com).
• Fibromuscular dysplasiais a disease affecting medium-sized arteries. It leads to a succession of stenosis (narrowing) and dilatations (ectasia) of the blood vessels. Fibromuscular dysplasia affects mainly the renal arteries, more rarely the cervical arteries. On average, 7% of patients with fibromuscular dysplasia have an arterial aneurysm. The familial forms of fibromuscular dysplasia are, however, rare, affecting approximately 5% of cases. The association of an aneurysm and familial fibromuscular dysplasia is exceptional (only one case has been reported).

Aneurysms have been associated with other rare genetic diseases such as Type 1 neurofibromatosis, elastic pseudoxanthoma or Marfan’s disease in a few case reports in the medical literature. However, these associations may be fortuitous given the high frequency of aneurysms in the general population.

Only 3 cases of subarachnoid haemorrhage associated with aneurysm have been described in brittle bone disease secondary to mutations in the collagen genes (Col1A1, col1A2).

Screening for hereditary diseases that weaken the wall of blood vessels usually returns a totally negative result.

Diagnosis

The diagnosis of an intracranial aneurysm requires a scan of the cerebral arteries, using one of the following techniques:

• Conventional angiography, which is the standard examination, for detecting aneurysms of all sizes.  This examination requires the injection of a contrast medium through an artery into the vessel. Imaging of all the cerebral arteries are obtained to search for one or more aneurysms.   This technique is also used for treatment of aneurysms in cases of subarachnoid haemorrhage (cf. Treatment).
• Magnetic resonance imaging (MRI)that can display both the brain tissue and the meninges (envelopes of the brain) as well as the large and medium-sized arteries, using a sequence called magnetic resonance angiography (MRA).  This examination can be used to detect aneurysms that are more than 3 mm in diameter.
• CT scanswith and without the injection of contrast medium can reveal both the brain and the intracranial arteries using CT angiography. The detection threshold for aneurysms is also 3 mm with this technique.

When the rupture of aneurysm occurs, the diagnosis of subarachnoid haemorrhage should be confirmed in emergency using a CT scan without injection of contrast medium. This exam can display the accumulation of blood around the brain. When the examination is normal (small subarachnoid bleed), a lumbar puncture is carried out to collect the CSF containing blood or blood derivatives. A detailed display of all arteries is immediately required after the occurrence of a subarachnoid bleed; this is done using conventional angiography.   This examination displays the aneurysm responsible for the bleed and allows for treatment of the lesion (cf. Treatment).

In familial cases, when a subarachnoid bleed occurs, the aneurysms are usually larger than those observed in non-familiar cases (greater than 10 mm in diameter in 40% of cases, compared to 20%) and multiple (more than two in 25% of cases compared to 10%).

Treatment

When a subarachnoid bleed occurs, the aim of treatment is first to remove the cause of the recent haemorrhage.

There are currently two means of doing this:

• Surgical treatmentwhich consists of placing a clip on the neck of the aneurysm sack. The surgical treatment is also allows for the removal of the blood that has accumulated around the brain. The treatment is carried out by a neurosurgeon.
• Endovascular treatmentwhich consists of depositing a material within the aneurysm sack to cause thrombosis (the formation of a blood clot) in the sack. The aneurysm is then no longer visible and is excluded from the blood circulation. This treatment does not require the opening of the skull. It is done using a probe introduced into an artery in the leg and directed towards the affected cerebral artery. An interventional neuroradiologist carries out the treatment.

The choice of treatment (surgical or endovascular) or the decision to refrain from treatment is made on an individual basis depending on a large number of parameters such as the potential risk of invasive treatment, the type of aneurysm, its position, the presence or absence of other aneurysms, the patient’s general condition etc. It often requires discussion by several specialists (interventional neuroradiologists, neurosurgeons and anaesthetists).

Genetics

The frequency of familial types varies between 5% and 20%.

Several patterns of transmission have been suggested i.e. autosomal dominant or autosomal recessive. More importantly, there is a non-Mendelian polygenic type.

No specific gene has been identified yet except for familial aneurysms occurring in a well-defined nosological framework such as Autosomal Dominant Polycystic Kidney Disease. Current data suggest that several genes might be involved. Some of them have been located on chromosomes 2, 7, 11, 14, 19 and X but this is yet to be confirmed.

In the absence of any family history, the frequency with which an aneurysm is discovered in the relatives of a patient with an intracranial aneurysm is, on average, between 1% and 2%. This does not seem to differ from the frequency of aneurysm in the general population. In a recent study, the risk of subarachnoid bleed in a first-degree relative was estimated at between 0.03% and 0.1% per year. The risk is halved for a second-degree relative.

If at least two members of the same family have an aneurysm (familial aneurysm), the frequency with which an aneurysm is discovered in a first-degree relative is approximately 9% to 10%. This means that the risk of discovering an aneurysm is multiplied by approximately 4 compared to the same search carried out in a sporadic case.

Where there are at least two cases of subarachnoid bleed in a family, the risk of occurrence of a subarachnoid bleed is estimated to be as follows:

• approximately 0.7% per yearfor a person with two first-degree relatives (sibling, mother, father) who have had a subarachnoid bleed
• approximately 0.2% per yearfor a person with one first-degree relative and one second-degree relative (uncle, aunt, grandparents) who have had a subarachnoid bleed
• approximately 0.1% per yearfor a person with two second-degree relatives (uncle, aunt, grandparents) who have had a subarachnoid bleed

A non-invasive examination (MRI with MRA or CT Angiography) is sometimes requested by a relative because of the presence within the family of at least two identified cases of intracranial aneurysm. A consultation with, clinical examination and questionnaire are then needed to check the absence of any symptom or neurological sign. The usefulness and the risks of a screening imaging examination for aneurysm are detailed to the person requesting these consultations and examinations.  The meaning of a positive or negative result and of any appropriate therapeutic possibilities will be described in detail, with their limitations. The examination will be carried out, after obtaining the patient’s consent and, only after this specific consultation.

Prognosis

In the absence of a subarachnoid bleed, when the aneurysm is discovered by chance or during a family investigation but has produced no symptoms, the decision on whether or not to treat is discussed on an individual basis and depends mainly on the risk of a spontaneous bleed. The risk is mainly related to the size of the lesion (the risk of bleeding is extremely low for very small aneurysms but increases linearly with size as measured during the examination (angio-scanner, MRA or conventional angiography):

• The risk is probably less than 0.04% per yearwhen the aneurysm has a diameter of less than 7 mm. The risk rises to 0.5% per year for diameters between 7 and 12 mm, 3% per year between 13 and 24 mm and 8% per year for aneurysms with a diameter greater than 25 mm.
• Location also seems to influence the risk of rupture, is the risk would be slightly greater for aneurysms in posterior vessels.

Certain factors appear related to the enlargement or to the rupture of aneurysms e.g. age, smoking, drinking and hypertension.

Apart from the size of the aneurysm, various factors can increase the risk of rupture e.g. the location of the lesion, age, smoking, drinking and hypertension.

Some studies suggest that the aneurysm might increase in size more rapidly in the familial forms of intracranial aneurysms.

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