Neurosurgery notes/Vascular/Haemorrhagic diseases/SAH/Pathophysiology of aneurysms

Pathophysiology of aneurysms

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SAH

General

  • Cerebral aneurysms are pathological acquired dilatations of the arterial wall
  • All aneurysm being discussed here are saccular aneurysm
  • 80– 90% of intracranial aneurysms (IAs) are saccular or berry aneurysms

Numbers

  • Intracranial aneurysms prevalence (adult)
    • Radiological: 1– 2%
    • Autopsy : 1- 5%
  • Intracranial aneurysms are responsible for about 80– 85% of all cases of spontaneous SAH
  • The commonest age of presentation of aneurysms is in the fifth decade of life
  • Slight female preponderance of 3:2.

Theories regarding aneurysm formation and development

Vessel wall biology
  • Intracranial aneurysms are often located at bifurcation points where there are more collagen than elastin fibres, and where the muscular layer is less developed.
  • Raised BP --> increase wall sheer stress --> Endothelial cell acts as mechanosensor to stimulate Smooth muscle cell (SMC) apoptosis and increase elastin/ collagen fibre --> weakening of vessel wall
  • Vascular extracellular matrix enzymes such as gelatinase, elastase or matrix metalloproteinase can contribute to the formation as well.
Genetic factors
  • Genetic factors are implicated in the genesis of intracranial aneurysms.
  • Intracranial aneurysms are more prevalent in
    • Siblings of patients with a history of IAs in another first- degree relative.
  • Most common heritable disorders associated with intracranial aneurysms
      • Disorder
      Inheritance pattern
      Gene
      Gene product
      Prevalence
      ADPKD
      AD
      PKD1
      Polycystin 1
      >1/1000
      EDS
      AD
      COL3A1
      Collagen type III
      1–9/100 000
      MfS
      AD
      FBN1
      Fibrillin 1
      1–5/10 000
      NF 1
      AD
      NF1
      Neurofibromin
      1–5/10 000
      PXE
      AD and AR
      ABCC6
      ATP binding cassette
      1–9/100 000
      ADPKD, autosomal dominant polycystic kidney disease; EDS, Ehlers–Danlos syndrome; MfS, Marfan’s syndrome; NF1, neurofibromatosis type 1; PXE, pseudoxanthoma elasticum.
Haemodynamic factors
  • Increased risk of aneurysm formation in situations of increased haemodynamic stress such as
    • An ‘unbalanced’ anterior communicating artery (Acom) complex (dominant A1 segment of the anterior cerebral artery on one side with hypoplasia of the contralateral one),
    • Low- pressure shunts such as high- flow arteriovenous malformations,
    • Along the collateral pathway after spontaneous or iatrogenic carotid occlusion
  • Rhoton’s rules for aneurysm formation:
    • They arise from a branch point of a parent artery and arise from the convex side of turns or curves, where wall shear stresses are greatest
  • The aneurysms also tend to point in the direction that blood would flow if the turn or curve was not present
Environmental (modifiable) factors
  • Only convincing evidence exists only for
    • Cigarette smoking
      • The HUNT study, prospectively conducted in Norway between 1983 and 1986, showed that current smokers (hazard ratio (HR) 6.1) and, to less extent former smokers (HR 2.7), have a higher incidence of aneurysmal SAH than those that have never smoked.
      • Smoking triggers an inflammatory response through various mechanisms resulting in aneurysm formation and/ or rupture
    • Hypertension.
      • Systolic blood pressure
      • In the HUNT study, the risk of aneurysmal SAH was significantly higher in people with systolic blood pressure between 130 and 139 mmHg than in the reference population (<130 mmHg systolic).
        • If sBP > 170mmHg: a HR of 3.
    • Hypertension + smoking combined have an additive interaction:
      • HR for Smoker + HTN: 13.3x vs without these two factors
  • Other factors that are more controversial:
    • Alcohol consumption, hormonal factors

Location

  • Rhoton 3 rules about the location of saccular aneurysms:
    • Aneurysms arise at branching sites of the parent artery (e.g. PComA, middle cerebral artery (MCA) bifurcation, basilar bifurcation)
    • Aneurysms arise from a turn or curve of the artery
    • Dome lays in the direction of the maximal haemodynamic flow.
        • Higher flows means what? Flow impingement at translucent tissues Flow impingement means what? microscopic reRair (thrombus) upon microscopic injury (tear) Thick wall Proliferating multilayer Cell alive at least Low w41 stres High wall stress Thin wall Necrotic monolayer Cell death cluster Flow-induced Pressure-induced • High wall stress • Impingement • Low wall stress • Nonimpingement
        notion image
  • Non-branching aneurysms (located at non- branching sites of the artery)
    • Are less common
    • Often are not berry aneurysms.
  • Anterior cerebral circulation
    • About 90% of saccular aneurysms
    • Among ruptured aneurysms,
  • Posterior circulation
    • Basilar bifurcation is the most common site.

Size and morphology

  • Size of an aneurysm is very important because it correlates with
    • The risk of aneurysm rupture
    • The risk of treatment.
  • IA size classification (based on the maximum diameter of the dome):
    • Small (< 10 mm)
    • Large (11 - 25 mm)
    • Giant (> 25 mm)
  • Components of a saccular aneurysm
    • Neck
      • The portion of the aneurysm connected to the parent artery
      • With the development of endovascular techniques, determination of the size of the neck has become especially important.
      • Aneurysms with a neck > 4 mm are considered wide- neck aneurysms.
      • Neck/ dome ratio
        • Another important morphological feature affecting endovascular treatment.
        • Computational fluid dynamic studies assessment of risk of rupture
          • Aspect ratio (aneurysm cranio- caudal dimension divided by transverse diameter)
          • Aneurysm angle
    • Fundus (sac)
      • Secondary outpouching
        • AKA: blebs/daughter sacs/lobulations
        • Not uncommon.
        • In ruptured aneurysms, these are often the point of rupture
        • Commonly located on the dome opposite to the point of maximal inflow.
        • In unruptured aneurysms, they are associated with
          • An increased risk of rupture
            • Their presence or absence is one of the important factors in deciding whether or not to treat.
        H = Height W = Width N = Neck dimension O = Aneurysm angle H/N = Aspect ratio WIN = Dome/Neck ratio Fig. 47.1 Schematic illustration of a cerebral aneurysm and morphological parameters.
        Schematic illustration of a cerebral aneurysm and morphological parameters

Intracranial aneurysm progression and risk of rupture

  • Aneurysm growth is reflected in
    • Radiological (macroscopic) change
    • Structural wall variations (microscopic) at the molecular levels.
  • Aneurysms progression depends on a balance between
    • Wall repair
    • Wall destruction
      • This can be accelerated in patients who
        • Smoke
        • Arterial hypertension
  • Brinjikji et al. 2016 Meta- analysis of nearly 13 000
    • Overall proportion of growing aneurysms was 3%/aneurysm/year.
    • Most important risk factors for growth included
      • Age > 50 years,
      • Female sex
      • Smoking history
      • Non- saccular shape
    • Aneurysm growth = a high risk of rupture
      • Rupture rate of 3.1% per year VS 0.1% per year for stable IAs)
  • Villablanca et al. 2013: Annual rupture rate was 12x higher in growing compared with non- growing IAs
  • Mehan et al. 2014 IAs growth was associated with an OR 55.9 for rupture on a multivariate analysis

Multiple aneurysms (MIAs)

  • Number
    • 30% of SAH pts
  • Mainly associated with HTN
  • To localise which aneurysm bleed:
    • Epicentre: look for greatest concentration of blood
    • Area of focal vasospams on angiogram
    • Irregularities in shape of aneurysm (murphy’s tit): bleeding pint
    • If still cant figure out then suspect the largest one#
    • Most common cause of post secured aneurysmal bleeding is from rebleeding from the original aneurysm that was missed on initial angiogram
  • Numbers
    • Variable incidences in different studies:
      • 13.9% in the UCAS Japan study (Morita et al., 2012),
      • 35% in the ISUIA study (Wiebers et al., 2003).
    • In patients presenting with SAH, MIAs are found in 15– 45% of patients.
  • In patients with MIAs, each aneurysm is not at increased risk of rupture, but the cumulative risk of rupture is higher than in patients with only one aneurysm (Morita et al., 2012).
  • The exact mechanism of MIAs’ formation is not completely understood.
  • Higher risk of developing MIAs
    • Cigarette smoking
    • Hypertension
    • Age
    • Female sex

Cerebral aneurysm

A diagram of a human body AI-generated content may be incorrect.
Numbers:
  • 5% of population
  • Ratio of rupture to unruptured= 1:1 (50% not ruptured)
  • 2% of aneurysm present during childhood
Pathophysiology
  • Vs extracranial blood vessels cerebral blood vessels have
    • Less elastic in the tunica media and adventitia of ,
    • Media has less muscle
    • Adventitia is thinner
    • Internal elastic lamina is more prominent
    • Less supporting connective tissue: Large cerebral blood vessels lie within the subarachnoid space
  • Aneurysms tend to arise in areas where there is
    • A curve in the parent artery, in the angle between it
    • A significant branching artery,
  • Aneurysms Point in the direction that the parent artery would have continued had the curve not been present
Aetiology
  • Congenital predisposition (e.g. defect in the muscular layer of the arterial wall, referred to as a medial gap )
  • “Atherosclerotic” or hypertensive: presumed aetiology of most saccular aneurysms, probably interacts with congenital )
  • Embolic: as in atrial myxoma
  • Infectious: “mycotic aneurysms”
  • Traumatic
  • Associated with other conditions (See SAH)
    • ADPKD
      • 3-15%
    • FMD
    • AVM
    • Connective tissue: Marfan, Ehlers danlos, pseudoxanthoma elasticum
    • FIA (Familial intracranial aneurysm syndrome)
      • >2 relatives with SAH or Unruptured aneurysm
    • Coarctation of aorta
    • Osler-weber-Rendu syndrome
    • Atherosclerosis
    • Bacterial endocarditis
Presentation:
Major bleed: Rupture
  • SAH
  • ICH: 30%
    • Commonly in aneurysm distal to circle of Willis (MCA aneurysm)
  • IVH: 20%
    • Worse prognosis: 64% mortality: larger the ventricles the poorer the outcome
    • Mechanism:
      • Distal PICA aneurysm rupture --> blood enter foramen of Luschka --> bld enter into 4th ventricle
      • ACOM rupture --> blood enter lamina terminalis --> blds enter 3rd and lateral ventricles
      • Distal basilar artery/carotid terminus aneurysm: may rupture through floor of the 3rd (RARE)
  • SDH: 5%
Minor Bleed:
  • Warning/sentinel haemorrhage
  • Short latency: 10days
Non bleed
  • Mass effect
    • Brain stem: hemiparesis due to giant aneurysm
    • Cranial neuropathy: long latency: time between CN signs and SAH =110 days
      • CN3 palsy
        • 9% of PCOM, less so with basilar apex aneurysm
        • Presented as
          • Pupil down and out
          • Dilated pupil that is unreactive (Giant aneurysm compressing)
            • Parasympathetic nerve running on the outside
            • Core of the nerve has motor function which is lost on DM or vascular related diseases. Blood vessels go from out to in
          • Ptosis
        • Medical emergency: pending rupture
      • Visual Loss
        • Nasal quadrantanopsia: Ophthalmic
        • Chiasmal syndrome: Ophthalmic, ACOM, Basilar apex
      • CN5 pain
        • Facial pain: due to ICA aneurysm:
          • Intracavernous
          • Supra-clinoid aneurysm
    • Pituitary dysf(x)
      • Intra-/supra-sellar aneurysm
      • Endocrine dysf(x) due to compression of pituitary stalk or gland
  • Infarcts/TIA
    • Present: amaurosis fugax (transient blindness), homonymous hemianopsia
    • Latency: 21 days
    • Distal embolization of clotted blood from aneurysm
  • Seizures
    • Area of encephalomalacia due to gliosis next to aneurysm
  • H/A w/o haemorrhage
    • Reduces after tx in most cases
    • Acute
      • Thunderclap
      • Due to aneurysmal expansions, thrombosis or intramural bleeding
    • Chronic:
      • >2 weeks
      • 50% pts:
        • Unilateral
        • Retro/peri-orbital due to irritation of overlying dura
      • 50% pts:
        • Diffuses or bilateral
        • Mass effect causing inc. ICP

Conditions with inc. of aneurysm

  • AVM:
  • Moyamoya
  • Osler Weber Rendu syndrome
    • Hereditary haemorrhagic telangiectasia (HHT)
    • Mutations found in HHT disrupt TGF-beta-mediated pathways in vascular endothelial cells. Disruption in this pathway results in aberrant blood vessel development leading to extreme fragility and arteriovenous malformations.
  • Atherosclerosis
  • Bacterial endocarditis
  • Familial aneurysms
    • 15- fold increase
      • 1st - degree relatives,
      • People with two or more relatives
      • In the presence of hypertension and/ or smoking,
    • Screening of family members of patients with aneurysmal SAH without additional affected relatives is controversial.
    • Screening of family members older than 30 is recommended if two or more relatives are affected in a given family (Thompson et al., 2015).
      • Before screening, counselling regarding the implications of a diagnosis of IAs is indicated since not all unruptured aneurysms warrant treatment.
  • Conditions associated with IA include:
      • Autosomal dominant polycystic kidney disease (ADPKD):
      • Mutation of PKD1 (Chr 16p; 90%) and PKD2 (Chr 4q; 5-15%) gene —> form transmembrane proteins on endothelium (unsure mech)
        • Guide growth function: abnormal embryological development of blood vessel
        • Mechanosensor function: cannot sense the stress on the arterial wall —> vessel cannot contract to reduce stress on wall —> chronically dilation can occur
        • 100% penetrance by 80 yrs of age
      • Present with renal and visceral cysts associated
        • SAH present 10 yrs earlier when compared to non ADPKD patients
      • A spectrum of vascular abnormalities including cerebral aneurysms (often multiple).
      • Cerebral aneurysms are found in 25% of patients with this condition
      • Screening is recommended in patients with
        • Polycystic kidney disorder + a family history of IAs.
          • ADPKD increases the risk of IA by 10– 20- fold depending on whether there is also a family history of IAs.
        • ADPKD + HTN
          • ADPKD + hypertension may further facilitate the formation of IAs.
            • A recent study showed that ADPKD patients with IAs had higher blood pressure parameters (especially those older than 45 years of age), compared with ADPKD patients without IAs.
      • Mainly MCA
      • Inc. risk of aneurysm and Inc risk of rupture (20x more risk to rupture)
        • Renal f(x) normal for first few years of life.
        • Causes renal failure —> HTN
        • 60% rupture before 50 yrs old
      • Recommendation
        • Asymptomatic:
          • >25 yrs: Do not routinely angiography
          • ???<25 yrs
            • If have relative with cerebral aneurysm do 2-3 yrly screening
            • If no relatives with aneurysm do 5 yrly screening
        • Symptomatic: angiography and tx aneurysm >1cm
      Connective tissue disease
      • Collagenopathies (such as Ehlers- Danlos, Type IV):
        • Anomalies in type III collagen
        • Fragile skin and hypermobile joints, vascular fragility, disposition of supra- aortic vessel dissections, carotid– cavernous fistulas, and intracranial aneurysms.
        • Although rare, it is important to recognize this condition since these patients are at very high risk of complications from intravascular diagnostic and therapeutic catheterizations because of their vascular fragility.
        • Marfan’s syndrome:
          • Marfan: mutation of Fibrillin 1 gene (a scaffolding prot.) —> elastin cannot be bound well to tissue
          • Disorder of fibrillin (the major glycoproteic component of elastic tissues).
            • Chromosome 15
          • Tall + arachnodactyly and hypermobile joints
          • Higher risk of intra- and extracranial aneurysms development.
        • Type 4 Ehlers Danlos: type 3 collagen deficiency —> high rate of dissection too
        • Pseudoxanthoma elasticum: genetic disease
          • A protein not made and cannot help release ATP —> lack of ATP, means lack of Pyrophosphate release from ATP —> no Pyrophosphate to bind to ions like Ca —> Ca accumulate and deposit into elastin (at skin, eye, blood vessels) —> inc. brittleness (less flexible) of elastin —> elastin fragments —> unsure how but possibly due to arterial weaken —> Aneurysm to form
      Aortic coarctation:
      • Narrowing or constriction of the lumen of the aorta most commonly located distal to the origin of the left subclavian artery, near the insertion of the ligamentum arteriosum.
      • IAs are found more often in patients with aortic coarctation
        • 10.3% in an MR angiography series of 117 patients with aortic coarctation) (Curtis et al., 2012)
      Fibromuscular dysplasia:
      • Idiopathic, segmental, nonatherosclerotic, non- inflammatory vascular disease
      • Occurs predominantly in middle-aged women
      • Vessels affected
        • Cervical ICA (75%).
        • Vertebral (12%)
        • ECA
      • Disease is bilateral in 60% of cases.
      • Angiographic
        • Almost always with non-invasive techniques, demonstrate alternating luminal narrowing and dilatation, the resulting appearance often described as a “string of beads.”
          • This “corrugation” typically affects the mid ICA, usually 2 cm distal to bulb.
          • Uni- or multifocal tubular stenoses are less common, and where observed, the degree of stenosis is usually modest (less than 40%).
          notion image
      • FMD can occasionally be observed intracranially and is associated with aneurysms.
      • Weakening of wall
      • Intracranial fibromuscular dysplasia is rare.
      • Clinical features
        • Steno- occlusive disease of major arteries.
      • The incidence of IAs is higher in patients with fibromuscular dysplasia compared with the general population
        • 7.3% in a meta- analysis performed by Cloft et al. 1998
Familial intracranial aneurysm syndrome (FIA):
  • No recognised disorder causing aneurysm but family members common to have aneurysm
  • 7–20% of patients with detected aneurysms have other family members with aneurysms
  • 2 or more relatives 3rd degree or closer
    • With radiographically proven aneurysm
  • 1st degree relatives (esp siblings) should undergo screening MRI/MRA