Small vessel disease in the CNS:
an overview
Alex Easton
Capital Health and Dalhousie
University, Halifax
Injury to the CNS
• Reduced cerebral blood flow (due to occlusion)
causes ischemic injury (stroke)
• Increased cerebral blood flow (eg due to acute
hypertension) causes vessel rupture and hemorrhage
• Primary rupture (eg because the wall is weakened as
in an aneurysm) also leads to hemorrhage
• Hemorrhage can result in secondary vasospasm
(more ischemia) and both hemorrhage and ischemia
increase vessel permeability (cerebral edema)
Diseases of perforating arteries
• This refers to perforating arteries with a
diameter between 40 to 900 microns
• The vessel wall can be structurally abnormal
• The vessel wall can be inflamed
• The vessel can be malformed or focally dilated
The vessel wall can be structurally
abnormal
• There are 4 structural pathologies:
–
–
–
–
Atherosclerosis (hypertension, diabetes)
Fibrinoid necrosis (hypertension)
Arteriolosclerosis (aging)
Microaneurysms (hypertension)
• The vessel wall is thickened in 3 main categories:
– Arteriolosclerosis
– Cerebral amyloid angiopathy
– CADASIL
The vessel wall can be inflamed (CNS
vasculitis)
• CNS vasculitis can be classified as:
– Infectious
– Non-infectious
• Or as due to:
– Immune injury
– Direct infection
The vessel wall can be malformed or
dilated:
• The two main categories are:
– Vascular malformations
– Aneurysms
Structural pathologies
• Atherosclerosis
– Hypertension, diabetes and aging lead to
extension of atherosclerosis into small vessels
– The point of stenosis and occlusion is reached
earlier than in larger vessels
Structural pathologies
Fibrinoid necrosis versus
arteriolosclerosis
• Both look very similar on H&E sections
• Fibrinoid necrosis
– Associated with hypertension
– With atherosclerosis it tends to cause lacunar infarcts or
primary brain hemorrhage
• Arteriolosclerosis
– Associated with aging
– Tends to cause subcortical ischemic vascular dementia
– These vessels tend NOT to rupture and bleed
Microaneurysms
• They may not exist
Microaneurysms
• They can rupture and bleed
• But many patients don’t have hypertension
• And the majority of hypertensive bleeds in
some series don’t have microaneurysms
Thickening of small arteries
• Arteriolosclerosis
• Cerebral amyloid angiopathy
• CADASIL
Cerebral amyloid angiopathy
Cerebral amyloid angiopathy
CAA – take home points
• In most cases the amyloid is beta amyloid, a cleavage
product of amyloid beta precursor protein encoded
on chromosome 21
• Most cases are sporadic with or without Alzheimer’s
disease
• Familial causes include Down’s syndrome (Trisomy
21), familial Alzheimer’s disease, and hereditary
cerebral hemorrhage with amyloid angiopathy of the
Dutch and Flemish types
CAA – take home points
• Sporadic Aβ-CAA not associated with
Alzheimer’s is rare under 60, with a 30%
prevalence over 60 in autopsy series
• 80-90% of Alzheimer patients have Aβ-CAA
• In most people the disease is clinically silent
CAA – take home points
• Complications include:
– Lobar hemorrhage (usually frontal and parietal
lobes)
– Isolated subarachnoid hemorrhage
– Infarcts or white matter ischemia
– Amyloid-beta related angiitis (a form of CNS
vasculitis)
CAA – take home points
• Other forms of CAA are due to mutated
precursor proteins giving rise to fragments
that are prone to form amyloid:
– Cystatin C
– Gelsolin
– ABri precursor protein (Bri=British)
– ADan precursor protein (Dan=Danish)
– Transthyretin
– Prion protein
CADASIL
• Cerebral autosomal dominant arteriopathy
with subcortical infarcts and
leucoencephalopathy
Vasculitis
• Non-infectious or infectious
Non-infectious v infectious
• Non-infectious
Either primary cranio-cerebral diseases
Or related to systemic disease
Primary diseases
•
•
•
•
Primary CNS angiitis (and variants)
Giant cell (temporal) arteritis
Takayasu’s arteritis
Kawasaki’s disease
Systemic diseases
• Systemic lupus erythematosis
• Polyarteritis nodosa
• ANCA-associated vasculitides (Wegener’s and ChurgStrauss)
• Sjögren’s syndrome
• Behçet’s syndrome
• Rheumatoid arthritis
• Hodgkin’s disease
• Drug-induced
Etc…
Infectious causes
• Bacterial
– Spirochetal (eg borrelia/Lyme disease)
– Purulent (eg streptococcal)
– Granulomatous (eg due to TB)
• Viral
– Eg herpes zoster, Epstein-Barr virus
• Other
– Fungal, protozoal, mycoplasmal, rickettsial