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

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 Churg- Strauss) 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