microvascular diseases of the brain: an update

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Microvascular Diseases of the Brain: AnUpdate

Essay for partial fulfillment of Master degree ofNeurology and psychiatry

BY

Mohamed Ragab Ali MohamedM.B.B.CH

Benha faculty of medicineSupervisors

PROF. Mohamed Yasser MetwallyProfessor of neurologyAin Shams University

www.yassermetwally.com

PROF. Ahmed Abdel moneim GaberProfessor of neurologyAin Shams University

Dr. Ramez Reda MoustafaAssistant professor of neurology

Ain Shams University

Ain Shams UniversityFaculty of Medicine

2013

Professor Yasser Metwallywww.yassermetwally.com


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list of content

Introduction 3 Aim of the work 7 Chapter 1: overview of microvascular

diseases of the brain 8

Chapter 2: classification and risk factors ofmicrovascular diseases of the brain

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Chapter 3:effect of microvascular diseasesof the brain on cognition and disability

57

Chapter 4:neuroimaging of microvasculardisease of the brain

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Chapter 5:treatment and prevention ofmicrovascular diseases of the brain

88

Discussion 109 Recommendation 139 Summary and conclusion 131 References 142



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Intoduction

Microcirculatory brain disease is a collective terminology that

comprises vascular arteriolar pathology, metabolic endocrinal

abnormalities and haemorheological abnormalities. Clinically it is

characterized by the existence of cerebral ischemic events that

have a peculiar tendency for recurrence and progression to multi

infarct dementia. These ischaemic events are commonly

associated with increased incidence of depression, parkinsonian

manifestations, essential hypertension and blood hyperviscosity.

The associates of the microvascular brain disease are collectively

called the metabolic syndrome . However, misleadingly, the term

small vessel disease is used to describe only the pathologic

component of the ischemic process. Instead abroader view of

small vessel disease should be kept in mind, particularily for

therapeutic aspects, because patients of small vessel disease also

have arisk of hemorrhage (Metwally, 2001).

Pathology of ischemic cerebral parenchymal consequence of

microvascular diseases includes central and cortical atrophy

which is secondary to chronic global reduction of brain perfusion.

Leukoaraiosis is an ischaemic demyelination of the immediate

periventricular white matter with axonal loss, astrogliosis and

interstitial edema. Lacunar infarctions are secondary to the micro

vascular thromboocclusive episodes. They are most numerous in

the periventricular gray matter (thalamus and basal ganglia) and

the immediate periventricular white matter. Spasm of the fine

penetrating arterioles (secondary to increased vascular smooth

muscles (VSMCs) sensitivity) can also result in lacunar

infarctions. Initially lipohyalinosis was thought to be the



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predominant small vessel pathology of lacunes; however,

microatheroma now is thought to be the most common

mechanism of arterial occlusion or stenosis.Granular atrophy is

defined pathologically as infarctions localized to the cerebral

cortex and not extending to the subcortical white matter. Basal

ganglionic calcifications are calcification of the the arteriolar wall

of the microcirculation within the basal ganglia. Pathologic

dilatation of Virchow-Robin spaces is most commonly associated

with arteriolar abnormalities that arise due to aging, diabetes,

hypercholesterolemia, smoking, and hypertension and other

vascular risk factors and cerebral microbleeds are small brain

hemorrhages that are presumed to result from leakage of blood

cells from damaged small vessel walls. Concerning the pathology

of the haemorragic division of microvascular disease it's caused

by arteriosclerosis secondary to hypertension this leads to

formation of microaneuysms liable for rupture. Cerebral amyloid

angiopathy has significant role in lobar haemorrhage (Thomas et

al., 2002; Fisher, 1982; Ghatak et al., 1974; Lang, 2001).

Many risk factors are associated with microvascular disease of

the brain. These risk factors include diabetes mellitus,

hypertension, smoking, high low density lipoprotein.

Hypertriglycridemia, hyperuricemia, type 2 diabetes, insulin

resistance and truncal obesity (The metabolic syndrome) and

hyperhomocystenemia. There is also genetic factors like cerebral

autosomal dominant arteriopathy with subcortical infarction and

leukoencephalopathy (CADASIL) ,cerebral autosomal recessive

arteriopathy with subcortical infarction and leukoencephalopathy

(CARASIL) and hereditary endotheliolopathy with



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retinopathy,nephropathy and stroke (HERNS). Heamrheology

changes also plays an important role in microvascular disease of

the brain due to Increased whole blood viscosity and

hypercoagulability characterized by an increased plasminogen

activator inhibitor-1 (PAI-1) level. Non modifiable risk factors

like age, sex and race should also considered (khan et al., 2007;

Richard et al., 2007; Metwally, 2001).

There seems to be a complex interrelationship between

Alzheimer disease (AD) and cerebrovascular disease that extends

beyond the coexistence of these 2 disease processes. Imaging

features of small vessel disease are seen at higher frequency in

Alzheimer's disease than in healthy controls. Cerebrovascular

disease and Alzheimer disease often coexist, whereas stroke

often exacerbates preexisting, sometimes previously subclinical

disease. Furthermore, Alzheimer disease , Vascular dementia and

microvascular brain disease share common risk factors, such as

diabetes and hypertension, as well as genetic factors for brain

tissue vulnerability (presenilins, amyloid precursor protein,

APOE genes) (Small et al., 2008).

Management of microvascular disease of the brain depends on

early diagnosis clinically and on brain imaging . Clinical picture

may be Stroke, transient ischemic attacks (TIAs), multi-infarct

dementia, depression or parkinsonism. The diagnosis of lacunar

infarction relies upon finding clinical syndrome that is consistent

with the location small noncortical infarct seen on computerized

tomography (CT) or magnetic resonance imaging (MRI). CT

brain has low sensitivity for lacunar infarction and leukoariosis

but it is important for exclusion of cerebral haemorrhage.MRI



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Diffusion-weighted imaging help in rapid diagnosis and FLAIR

differentiate between acute and chronic lacunar infarction.

However; several recent studies have shown that GRE MRI (T2*)

sequences are accurate as CT for the detection of

intraparenchymal haemorrhge and far superior to CT for the

detection of chronic haemorrhage. MRI techniques have made a

significant contribution to our understanding of how structural

alterations in small vessel disease contribute to cognitive deficits.

The neuroanatomy of cognitive networks is complex and the

spatial distribution of lesions is an important factor to consider to

develop a richer understanding of the links between structure and

cognitive function (O’Sullivan, 2010; koch, 2011; Kidwell,

2002; Fiebach, 2002; Chalela, 2007).

Treatment of small vessel disease of the brain must be directed to

control risk factors like DM and hypertension and secondary

prevention to avoid progression and recurrence. Some data on

antiplatelet drugs in secondary prevention after stroke caused by

small vessel disease can be drived from afew trials: trial of asprin

plus dipyridamole versus placebo, trial of ticlopidine versus

placebo and trial of aspirin versus placebo in early prevention

after thirteen days. Results from all these studies suggested

efficacy of the drug study in the subgroup of patients with stroke

caused by small vessel disease but there was no evidence that one

drug, or combination, was better than another. More over there

was no data about the risk of haemorrhage.Patients with

microvascular disease also benefit from statin therapy (Bousser

et al., 1983; Gent et al., 1989; CAST, 1997).



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Aim of the work

To overview update in pathophysiology and new trends of

prophylaxis and treatment of microvascular disease of the brain.

And to provide clinicians with some concepts of the modern

overview of micovascular disease of the brain to enable

understanding of recent progress and future direction in this field.



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Definition of microvascular disease of the brain

The term small vessel disease encompasses all the pathological

processes that affect the small vessels of the brain, including

small arteries and arterioles but also capillaries and small veins.

However, the definition of a small vessel is not uniform: the

results from a survey showed that there was less than 50%

agreement among leading neuropathological centres on its

definition. Most often, small vessel disease is used to refer only

to the arterial vessels and little attention has been paid to the

venous compartment. This possible exclusive reference to the

arterial part of the vascular tree must be kept in mind when

dealing with small vessel disease (Pantoni et al., 2006).

Microcirculatory brain disease is acollective terminology that

comprises small arteries and arterioles vascular pathology but

also capillaries and small veins, metabolic endocrinal

abnormalities and haemorheological abnormalities. Clinically it is

characterized by the existence of cerebral ischemic events that

have a peculiar tendency for recurrence and progression to multi

infarct dementia. These ischaemic events are commonly

associated with increased incidence of depression, parkinsonian

manifestations, essential hypertension and blood hyperviscosity.

The associates of the microvascular brain disease are collectively

called the metabolic syndrome . However, misleadingly, the term

small vessel disease is used to describe only the pathologic

component of the ischemic process. Instead abroader view of

small vessel disease should be kept in mind, particularily for

therapeutic aspects, because patients of small vessel disease also

have arisk of haemorhage (Metwally, 2001).



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Anatomy of microvascular circulation of the

brain

There are two systems of microvascular circulation of the brain

The centrifugal subependymal system and centripetal pial system.

The centrifugal subependymal system originates from the

subependymal arteries which are terminal branches of choroidal

arteries, then extends cetrifugally into periventricular white and

grey matter especially basal ganglia and thalamus. The centripetal

pial system originates from pial arteries then extends centripetally

towards the ventricular system to supply the cortical grey matter

and immediate subcortical white matter. Most lacunes occurs in

the basal ganglia, pons and subcortical white matter

(internalcapsule and corona radiata). These small branches

originate directly from large arteries, making them particularly

vulnerable to the effects of hypertension, probably explaining this

peculiar distribution. A study using fluorescent and radiopaque

dye injection techniques has demonstrated that penetrating

vessels supply distinct microvascular territories of the basal

ganglia, with minimal overlap and sparse anastomoses between

the penetrating vessels. The ultimately terminal rather than

anastomotic nature of these vessels is another factor explaining

the predisposition of this region to lacunar infarction (Feekes,

2005).



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Figure 1 : Anatomic location of lentriculostriate, thalamoperforant and paramedian

pontine branches (Kistler et al., 1994).

Pathogenesis of cerebral damage in small vessel

disease

The mechanisms that link small vessel disease with parenchyma

damage are heterogeneous and not completely known. There is

little knowledge because animal models that convincingly reflect

the pathological changes in human small vessel disease are scarce

(Hainsworth and Marcus, 2008).



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The hypothesised cascade of pathophysiological events leading

from small vessel disease to brain damage is summarised in the

next figure. Pathological changes in the small vessels can lead to

both ischaemic and haemorrhagic consequences. The reason why

some vessel ruptures lead to major haemorrhage while others lead

to microhaemorrhage is unknown. In cerebral amyloid

angiopathy, differences in thickness of vessel walls are thought to

explain the differences in haemorrhage, with thicker walls

associated with more microhaemorrhages (Greenberg et al.,

2009), the pathogenesis (and even the aetiology) of some

ischaemic lesions such as white matter lesions is more

hypothetical ( Pantoni et al., 2002).

In ischaemic lesions caused by small vessel disease, the vessel

lumen restriction is thought to lead to a state of chronic

hypoperfusion of the white matter, eventually resulting in

degeneration of myelinated fibres as a consequence of repeated

selective oligodendrocyte death. This ischaemic mechanism has

been demonstrated in animals ( Petito et al, 1998).

This kind of white matter damage is thought to be a form of

incomplete infarct or selective necrosis similar to what has been

described for neurons. Alternatively, acute occlusion of a small

vessel is hypothesised to occur, leading to focal and acute

ischaemia and complete tissue necrosis (pannecrosis): this is the

putative mechanism of lacunar infarcts (Garcia et al., 1997).

Other mechanisms such as blood–brain barrier damage

(Wardlaw et al., 2003), local subclinical inflammation,

(Rosenberg, 2009) and oligodendrocytes apoptosis could be

involved in the so-called ischaemic forms of small vessel disease



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and contribute to the final pathological picture (Brown et al.,

2000).

Figure 2 : pathogenesis of cerebral damage as result of small vessel disease

(Pantoni, 2010).



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CEREBRAL PARENCHYMAL CONSEQUENCES

OF MICROVASCULAR BRAIN DISEASE

1- Leukoaraiosis

Pathophysiology of leukoaraiosis

Several pathophysiologic mechanisms have been proposed to

explain the histology of leukoaraiosis. In addition to ependymitis

granularis and Virchow-Robin space dilatation, more extensive

regions of leukoaraiosis have been attributed to the ischemic

effects of chronic oligemia and to perivascular edema and

retrograde axonal degeneration (Roman et al., 1987).

1-Chronic hypoperfusion

In the severe (Binswanger's disease) form of leukoaraiosis,

chronic microvascular oligemia and intermittent thrombotic

occlusion appear responsible for the observed pattern of multiple

lacunar infarcts with interspersed areas of edema, demyelination,

and gliosis. Unlike the richly collateralized cerebral cortex, the

leukoaraiosis vulnerable white matter is perfused by long

penetrating corticofugal endarteries with few side branches, a

vascular architecture that provides little protection from the

ischemic effects of microvascular stenosis (Roman et al., 1987).

The extent to which the more common and histologically milder

forms of leukoaraiosis can also be explained by ischemic

mechanisms is currently unclear. The term "incomplete white

matter infarction" has been proposed to designate regions of mild

demyelination, oligodendroglial loss, astrocytosis, and axonal

rarefaction that occur in proximity to cystic infarcts or in



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association with arteriolar hyaline vasculopathy (Englund et al.,

1987).

Direct evidence for hypoperfusion as an explanation of

leukoaraiosis pathogenesis is conflicting. Several studies have

demonstrated diminished cerebral blood flow (CBF) in white

matter regions affected by leukoaraiosis, but it is unclear whether

such hypoperfusion is itself causative or occurs as a secondary

response to reduced metabolic activity of the leukoaraiosis tissue

(Caplan et al., 1990).

Chronically inadequate hemispheric perfusion may not play a role

in leukoaraiosis pathogenesis. While this interpretation gains

support from the observation that hemodynamically significant

extracranial carotid stenosis does not correlate with the presence

of ipsilateral leukoaraiosis, others have seen leukoaraiosis to

progress in concert with a severely stenosed ipsilateral carotid

that advanced to complete occlusion (Ylikoski et al., 1993).

2- Fluid accumulation and edema

The subependymal accumulation of interstitial fluid has been

proposed as an alternative explanation for leukoaraiosis

Approximately 10% to 20% of cerebrospinal fluid may be

produced intraparenchymally and transependymally absorbed

into the lateral ventricles.Such a drain age pattern might increase

the water content of the periventricular region and result in

leukoaraiosis, particularly if exacerbated by the effects of age

related ependymal degeneration (ependymitis granularis). The

edema would then trigger cytotoxicity, gliosis, and demyelination

and potentiate the degenerative microvascular changes

(Rosenberg et al., 1980).



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3- Axonal degeneration

Ischemic axonopathy may also account for leukoaraiosis. Ball in

1988 described the presence of leukoaraiosis with cortical layer

III laminar necrosis in the postmortem brains of four elderly

patients who experienced episodic systemic hypotension during

life. Because the leukoaraiosis regions consisted of rarefied white

matter without necrosis or microvascular sclerosis, this author

proposed that distal axonopathy secondary to cortical neuronal

ischemia was the underlying process.

Histopathology of leukoaraiosis

In most cases, periventricular leukoaraiosis consists of variable

degrees of axonal loss, demyelination, astrocytosis, and finely

porous, spongy, or microcystic changes in the neuropil (Rezek,

1987). These changes are frequently associated with

arteriosclerotic vasculopathy and, in more severe cases, with

frank lacunae infarction (Kinkel et al., 1985).

On MR imaging the mild degree of leukoaraiosis almost always

present adjacent to the angles of the frontal horns is usually due

to focal gaps in the ependymal epithelium with mild underlying

gliosis (Sze et al, 1986).This change, known as ependymitis

granularis, increases in frequency with age and is believed to be

due to the wear and tear effects of ventricular CSF pulsations on

an ependymal lining incapable of self-repair (Salomon et al.,

1987).

Rarely, patients with extensive leukoaraiosis can be diagnosed as

having Binswanger's disease. This condition, sometimes referred

to as lacunar dementia, etat lacunaire, or subcortical



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arteriosclerotic encephalopathy, is characterized pathologically

by extensive athero and arteriosclerosis, multiple foci of white

matter infarction, diffuse white matter demyelination with sparing

of the subcortical "U" fibers, and variable evidence for cortical

infarction (Babikian and Ropper, 1987).

Figure 3: Postmortem specimen. Note the topographically extensive periventricular

white matter changes in a hypertensive case with evidence leukoaraiosis on MRI

study (www.yassermetwally.com, 2013)



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Figure 4.: Radiographic/histopathologic correlation for a case of diffuse and

extensive periventricular LE occurring in an 86-year-old patient. A, Antemortem

coronal MR image of left occipital lobe. Note extensive white matter hyperintensity

adjacent and superior to the occipital horn of the lateral ventricle sparing the

subcortical arcuate fibers. B,Postmortem coronal MR image of left occipital lobe.

Note topographically coextensive white matter changes compared with A. C,

Bielschowsky-stained postmortem specimen (2X) corresponding to A and B. D,

Photomicrograph (hematoxylin-eosin, original magnification x 140) from involved

white matter demonstrating perivascular parenchymal rarefaction and macrophage

infiltration. E, Photomicrograph (GFAP, original magnification x 660) from

involved white matter demonstrating reactive astrocytes. No regions of cystic

(lacunar) infarction could be identified in this case (www.yassermetwally.com,

2013).



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2- Lacunar infarctions

Pathophysiology of lacunar infarction

Several mechanisms for small vessel disease and lacunar

infarction have been described.

Lipohyalinosis of the penetrating arteries is considered the

usual cause, particularly of smaller infarcts (3 to 7 mm in

length).

Microatheroma of the origin of the penetrating arteries

coming off the middle cerebral artery stem, circle of Willis,

or distal basilar or vertebral arteries. This mechanism has

been proven pathologically by serial section for the basilar

artery.

In some cases, not proven pathologically, tiny emboli have

been suspected as the cause of these small infarcts.

Failure of the cerebral arteriolar and capillary endothelium

and the associated blood-brain barrier.

The first two mechanisms are proven pathologically and

generally regarded as a consequence of systemic hypertension

(Wardlaw et al., 2013).

The third mechanism (embolism) is supported both

experimentally and by case reports of lacunes in patients with

high-risk cardiac sources for emboli or following cardiac and

arch angiography (Macdonald et al., 1995).

Other mechanisms have been proposed to account for lacunar infarcts, but

none are pathologically proven. One alternate explanation is that failure of

the arteriolar and capillary endothelium and the blood-brain barrier leads to



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small vessel disease, lacunar stroke, and white matter lesions . This failure

allows extravasation of blood components into the vessel wall, which results

in perivascular edema and damage to the vessel wall, perivascular neurons,

and glia. However, one neuropathologic study found no compelling evidence

of a specific cerebral endothelial response in patients with small vessel

disease (Wardlaw et al., 2009).

.

Figure 5: lacunar infarctions are secondary to the microvascular thrombo-occlusive

episodes. They are most numerous in the periventricular gray matter (thalamus and

basal ganglia) and the immediate periventricular white matter

(www.yassermetwally.com, 2013).

Histologic Finding of lacunar infarction

Lacunes are not examined histologically except at necropsy.

Histologically, lacunes are no different from other brain infarcts.

Cells undergoing necrosis initially are pyknotic, then their plasma

and nuclear membranes break down. Polymorphonuclear cells

appear followed by macrophages, and the necrotic tissue is

removed by phagocytosis. A cavity surrounded by a zone of

gliosis is the end result. Careful examination may reveal the

underlying small vessel pathology.



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Markers of endothelial dysfunction in lacunar

infarction and ischaemic leukoaraiosis

Circulating levels of intercellular adhesion molecule 1 (ICAM1),

thrombomodulin (TM), tissue factor (TF) and tissue factor

pathway inhibitor (TFPI) are markers of endothelial activation

and damage and may provide insights into disease pathogenesis

or differences between phenotypes. Intercellular adhesion

molecule 1, thrombomodulin and tissue factor pathway inhibitor

were elevated in cerebral small vessel diseases subjects compared

with controls . The ischaemic leukoaraiosis group had a different

endothelial marker profile, with lower levels of tissue factor

pathway inhibitor and a higher tissue factor/ tissue factor pathway

inhibitor (TF/TFPI) ratio compared with the isolated lacunar

infarction group. thrombomodulin levels were associated with the

number of lacunes and the leukoaraiosis score , but tissue factor

levels and the tissue factor/ tissue factor pathway inhibitor ratio

were associated only with the extent of leukoaraiosis . These

results suggest that there is evidence of chronic endothelial

dysfunction in cerebral small vessel diseases, and endothelial

prothrombotic changes may be important in mediating the

ischaemic leukoaraiosis phenotype. Therapies which help to

stabilize the endothelium may have a role in this group of patients

(Hassan et al., 2003).

3- Granular atrophy (Cortical laminar necrosis)

Granular atrophy is defined pathologically as infarctions

localized to the cerebral cortex and not extending to the

subcortical white matter. It is characterized by the presence of

small punched- out foci of cavitated cicatricial softening situated



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entirely in the cortex and accompanied by focal glial scar and

thinning of the cortical ribbon. The lesions are bilateral and

situated along the crest of the gyri. The presence of arteriolar

pathology over the cerebral convexity points to its ischemic

etiology.It usually develops as a result of generalized hypoxia

rather than a local vascular abnormality. Depletion of oxygen or

glucose as in anoxia, hypoglycemia, status epilepticus and

ischemic stroke has been attributed as an underlying cause of

cortical laminar necrosis. Immunosuppressive therapy

(cyclosporin A and FK506) and polychemotherapy (vincristine

and methotrexate) have been observed to cause laminar necrosis

due to hypoxic-ischemic-insult. Hypoxic insult leads to death of

neurons, glia and blood vessels along with degradation of

proteins (Bargallo et al., 2000).

Figure 6.: Granular atrophy, notice laminar necrosis with early cavitation. Note

persistence of the outer most gray matter (www.yassermetwally.com, 2013).

4-Basal ganglionic calcifications

These are calcification of the the arteriolar walls within the basal

ganglia. Physiological intracranial calcification occurs in about

0,3-1,5% of cases. It is asymptomatic and is detected incidentally



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by neuroimaging. Pathological basal ganglia calcification is due

to various causes, such as: metabolic disorders, infectious and

genetic diseases and other. Hypoparathyroidism and

pseudohypoparathyroidism are the most common causes of

pathological basal ganglia calcification. Besides tetany and

seizures this condition is presented by parkinsonism and

dementia. Such parkinsonism does not respond to drugs

containing levodopha. Infections (toxoplasmosis, rubella,

cytomegalovirus, cysticercosis, AIDS) give multiple and

asymmetric intracranial calcification. Inherited and

neurodegenerative diseases cause symmetrical, bilateral basal

ganglia calcification which is not related to metabolic disorders

(blood calcium level and other), those are: Cockayne syndrome,

tuberous sclerosis, Fahr's syndrome, Down syndrome and other.

Some cases of basal ganglia calcification and studied clinical

manifestations and treatment tolerance of this pathological

condition are observed. Since adequate treatment of

hypoparathyroidism may lead to marked clinical improvement,

serum concentration of calcium, phosphorus and parathyreoid

hormone is suggested to be determined in all individuals with

calcification of the basal ganglia to rule out hypoparathyroidism.

Basal ganglia calcification in young patient with acute hepatitis

may be result of Wilson disease (Verulashvili et al., 2006).

5- Dilated Virchow-Robin spaces (VRSs)

Pathologic dilatation of Virchow-Robin Spaces is most

commonly associated with arteriolar abnormalities that arise due

to aging, diabetes, hypercholesterolemia, smoking and

hypertension and other vascular risk factors. This dilatation forms



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part of a histologic spectrum of abnormalities, which include old,

small infarcts (type 1 changes); scars from small hematomas

(type 2 changes); and dilatations of Virchow-Robin Spaces (type

3 changes) ( Hommel et al., 1995).

The presence of these abnormalities on histologic examination is

believed to result from moderate to severe microangiopathy

characterized by sclerosis, hyalinosis, and lipid deposits in the

walls of small perforating arteries 50 – 400 `im in diameter

(Furuta et al., 1991).

As the severity of the microangiopathy increases, microvessels

demonstrate increasingly severe changes, with arterial narrowing,

microaneurysms and pseudoaneurysms, onion skinning, mural

calcification, thrombotic and fibrotic luminal occlusions (Brun et

al., 1992).

Several mechanisms for abnormal dilatation of Virchow-Robin

Spaces have been suggested, These include mechanical trauma

due to CSF pulsation or vascular ectasia, fluid exudation due to

abnormalities of the vessel wall permeability and ischemic injury

to perivascular tissue causing a secondary ex vacuo effect

(Fayeye et al., 2010).

6- Cerebral Microbleeds

Cerebral microbleeds are small brain hemorrhages that are

presumed to result from leakage of blood cells from damaged

small vessel walls. Histologically, these small black dots on MR

imaging represent hemosiderin-laden macrophages that are

clustered around small vessels. The choice of field strength,

sequence parameters (particularly echo time), and postprocessing



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(eg, susceptibility-weighted imaging technique) have all been

found to have a major influence on the detection rate of cerebral

microbleeds (Vernooij et al., 2008).

With these advances in imaging, the prevalence of microbleeds

has been estimated to be more than 20% in persons aged 60 years

and older, increasing to nearly 40% in those older than 80 years.

Microbleeds are also commonly asscoiated with microvascular

brain disease (Poels et al., 2010).

Microbleed location is generally divided into deep (ie, basal

ganglia, thalamus) and infratentorial versus lobar brain regions .

In the aging population, microbleeds in lobar locations share

apolipoprotein E (APOE) e4 genotype as a common risk factor

with cerebral amyloid angiopathy (CAA) and Alzheimer's disease

(AD), suggestive of a potential link between vascular and

amyloid neuropathology. This link has further been corroborated

by the finding that topography of lobar microbleeds in

communitydwelling elderly individuals follows the same

posterior distribution as is known from amyloid disease in

cerebral amyloid angiopathy and Alzheimer's disease suggestive

of a potential link between vascular and amyloid neuropathology

(Mesker et al., 2011).



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Figure 7 : Radiologic-pathologic correlation of cerebral microbleeds on MR

imaging (3 T). Postmortem brain MR imaging shows on T2-weighted imaging a

hypointense focus on the gray-white matter interface (white arrow). MR image in

the middle of the isolated tissue block containing this hypointense focus. Pathologic

analysis of this tissue block (hematoxylin and eosin stain) shows macrophages

containing hemosiderin (black arrows), confirming that the hypointense lesion on

MR imaging is compatible with a microbleed (www.yassermetwally.com, 2013).

7- Cerebral haemorrhage

Many types of cerebral haemorrhge may occur due to

microvascular disease of the brain. The most common risk factors

associated with adult primary intracerebral haemorrhage are

hypertension and cerebral amyloid angiopathy and the probable

underlying pathophysiology varies by haemorrhage location

(Woo and Broderick, 2002).

Primary intracerebral haemorrhage associated with hypertension

most commonly occurs in deep brain structures (eg, putamen,

thalamus, cerebellum and pons). By contrast, primary

intracerebral haemorrhages that occur in lobar regions,

particularly in elderly patients, are most commonly related to

cerebral amyloid angiopathy but might also be associated with

hypertension (Lang et al., 2001).

Subarachnoid haemorrhage can be of traumatic or non-traumatic

origin, with trauma being the most common aetiology.



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Subarachnoid haemorrhage can occur in head injury, as a result

of laceration of the cortical veins or arteries that course through

the subarachnoid space but can also occur as a result of cortical

contusions and lacerations with extravasation of blood into the

subarachnoid space. Typical locations for subarachnoid

haemorrhage after head trauma are the interpeduncular cistern,

Sylvian fissure, or over the cerebral convexity (Stuckey et al.,

2007).

Spontaneous subarachnoid haemorrhage usually results from

ruptured aneursyms (older patients), arteriovenous vascular

malformations (younger patients) and can be less commonly due

to intracranial vessel dissection or vasculitis. Perimesencephalic

(or pretruncal) nonaneurysmal subarachnoid haemorrhage is a

benign variant of unknown (probably venous) cause with the

center of bleeding most commonly located in the prepontine

cistern. Subarachnoid haemorrhage can also be present in Call-

Fleming syndrome a generally benign and reversible condition

due to segmental cerebral vasoconstriction that presents with

severe recurrent headaches and transient or fluctuating

neurological abnormalities (Moustafa et al., 2007).

Vascular ectasia (fusiform aneurysm)

A dolichoectatic vessel is one that is both too long (elongated)

and too large (distended) usually secondary to hypertension. The

term ''fusiform aneurysm'' has, unfortunately, been used

interchangeably in the scientific literature with dolichoectatic

change and ectasia, all referring to diffuse tortuous enlargement

and elongation of an artery and they are associated with frequent

mural thrombosis and occasional wall calcification.



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Dolichoectasia occurs with greatest frequency in the

vertebrobasilar system but may also involve the intracranial

internal carotid and middle cerebral arteries. A contour deformity

of the pons resulting from basilar artery ectasia is a not

uncommon incidental finding on MRI in the elderly population.

Traction or displacement of cranial nerves can, however, lead to

symptoms. Depending on the segment of the basilar artery

involved, cranial nerve II, III, VI, VII, or VIII can be affected.

The lower cranial nerves can be affected with vertebral artery

involvement (Metwally, 2001).

Ectasia of the vertebro-basilar system is occasionally associated

with microvascular brain disease and rarely rupture to produce

subarachnoid hemorrhage unless associated with berry aneurysm.

Symptomatic vertebrobasilar dolichoectasia exists in two

different patient populations: those with isolated cranial nerve

involvement and those with multiple neurologic deficits. The

latter population includes patients with combinations of cranial

nerve deficits (resulting from compression) and central nervous

system deficits (resulting from compression or ischemia). A

tortuous, but normal-caliber, basilar artery is more likely to

produce isolated cranial nerve involvement, whereas ectasia is

more likely to cause multiple deficits of either compressive or

ischemic cause (Metwally, 2001).



28

Figure 8: Pathological features of small vessel disease

(A) Lipoyalinosis (basal ganglia ×100). (B) Microaneurysm in the right thalamus ina 70-year-old hypertensive patient who died 42 days after developing a massiveintracerebral haemorrhage in the left thalamus. Fibrinoid necrosis of the aneurysmalwall is almost ready to rupture. Phosphotungstic acid haematoxylin stain. Originalmagnifi cation ×25. (C) Microatheroma (basal ganglia ×20). (D) Fibrinoid necrosis(pons ×20) (Pantoni, 2010).



29

Classification and risk factors of microvascular

diseases of the brain

Classification of microvascular disease of the brain

Type 1: arteriolosclerosisArteriolosclerosis is also known as age-related and vascular risk-

factor-related small vessel disease.

From a pathological point of view, type 1 small vessel diseases

are mainly characterised by loss of smooth muscle cells from the

tunica media, deposits of fibrohyaline material, narrowing of the

lumen and thickening of the vessel wall. This form of the disease

is a common and systemic type that also affects the kidneys and

retinas and is strongly associated with ageing, diabetes and in

particular, hypertension. For this reason, type 1 diseases are also

named hypertensive small vessel diseases. Other possible

pathological features of this form of microangiopathy are distal

manifestations of atherosclerosis (microatheroma) and the

presence of elongated and dilated vessels (microaneurysms)

(Furuta et al., 1991).

Type 2: sporadic and hereditary cerebral amyloid

angiopathy

Cerebral amyloid angiopathy is characterised by the progressive

accumulation of congophilic, βA4 immunoreactive, amyloid

protein in the walls of small-to-medium sized arteries and

arterioles predominantly located in the leptomeningeal space, the

cortex and to a lesser extent, also in the capillaries and veins. In

the most severe form of cerebral amyloid angiopathy, the vessels



30

become dilated and disrupted with focal wall fragmentation and

blood extravasation, with or without microaneurysmal dilatation

and sometimes show luminal occlusion (Vonsattel et al., 1991).

Type 3: inherited or genetic small vessel diseases

distinct from cerebral amyloid angiopathy

A group of inherited cerebral small vessel diseases has been

reported recently and the number of these forms is increasing (

Hara et al., 2009), of these diseases, CADASIL (cerebral

autosomal dominant arteriopathy with subcortical ischaemic

strokes and leukoencephalopathy) and Fabry’s disease are among

the most prominent. These diseases are important because they

could be used as models for the understanding of the

pathogenesis of sporadic small vessel diseases (Dichgans, 2007).

Type 4: inflammatory and immunologically mediated

small vessel diseases

Inflammatory and immunologically mediated small vessel

diseases are a heterogeneous group of rare diseases characterised

by the presence of inflammatory cells in the vessel walls

(vasculitis) and are usually part of a systemic disease (Jennette

and Falk, 1997).

Type 5: venous collagenosis

Venous collagenosis is a pathological appearance of veins and

venules closely located to the lateral ventricles. These vessels

have an increased thickness of the walls that results in narrowed

lumen and, sometimes, occlusion. The material in the thickened

walls is mainly collagen (Moody et al., 1995).



31

Type 6: other small vessel diseases

Post-radiation angiopathy, a delayed side effect of cerebral

irradiation therapy (after months or years), is classified within a

miscellaneous group of small vessel diseases. This angiopathy

mainly affects the small vessels of the white matter that show

fibrinoid necrosis, thickening of the wall caused by deposition of

hyaline material, narrowing of the lumen and thrombotic

occlusion. The consequence is a diffuse leukoencephalopathy

with degeneration of the myelin sheaths that can be so severe in

some cases that a state of frank coagulative necrosis is reached (

Dropcho et al., 1991) .These parenchyma changes are thought to

be ischaemic in origin. Also included in the same group are the

non-amyloid changes seen in the capillaries and basal membrane

in patients with Alzheimer’s disease (Zipser et al., 2007).



32

Figure 9 : aetiopathogenic calassification of small vessel disease (Pantoni, 2010).



33

Risk factors of microvascular diseases of the brain

Age

In their recent review in the Lancet, in 2007 Vermeer and his

colleagues report the incidence of silent brain infarcts seen on

serial MRI scans to be 3% per year among elderly people. The

prevalence averaged over many studies increases with age: from

approximately 6% to 7% at age 60 to 28% at age 80.

The most recent contribution to the prevalence of small vessel

diseases in the brain indicated that 10.7% of participants in the

Framingham Offspring Study with a mean age of 62±9 years had

at least one brain infarct on MRI in the absence of any clinical

evidence for stroke. Cumulatively, these studies confirm not only

that covert brain infarcts are the most prevalent brain disorder

ever described, but that their prevalence increases dramatically

with age. Thus, age alone is a major risk factor for brain small

vessel diseases (Das et al., 2008).

Hypertension

An abrupt increase in pressure brings about a rapid and reversible

vasoconstriction of small resistance vessels due to their inherent

myogenic tone. Prolonged elevations of pressure can cause a

range of more lasting changes in the microcirculation, two of

which, remodeling of small arteries and arterioles and rarefaction

of arterioles and capillaries (Davis and Hill, 1999).

Small Artery and Arteriolar Remodeling: Small arteries and

arterioles, with pronounced myogenic responses, react to acutely

increased pressure with a reduction in luminal diameter produced

by smooth muscle contraction. If the high pressure is prolonged,



34

the luminal narrowing may be maintained by a form of

remodeling in which the vessel wall components are rearranged

without growth, known as eutrophic inward remodeling. These

more permanent structural changes, characterized by an increase

in wall:lumen ratio, displace the initial active vasoconstriction,

and myogenic responses return to normal (Feihl et al., 2006).

Microvascular Rarefaction : Microvascular rarefaction, the

reduced number or combined length of small vessels in a given

volume of tissue has been a consistent observation over many

years in hypertensive patients and animal models ( Debbabi et

al., 2006).

In most vascular beds, not all microvessels are perfused at any

one time; the fraction of nonperfused vessels constitutes a reserve

that may be called on under conditions of high metabolic

demand. Two forms of rarefaction can be distinguished:

functional rarefaction, in which the number of perfused vessels is

decreased without reduction of the number of vessels

anatomically present and structural rarefaction, in which the

number of vessels existing in the tissue is reduced. It has been

suggested, initially on the basis of work in genetic spontaneously

hypertensive rats (SHR), that functional rarefaction can progress

to structural rarefaction: Prolonged vessel closure or

nonperfusion can lead to its structural loss, analogous to the

progression of active vasoconstriction to structural remodeling of

resistance vessels described above (Prewitt et al., 1982).

Oxidative stress may be important in microvascular rarefaction.

Impaired endothelium-dependent vasodilation (endothelial

dysfunction) is a complex and multifaceted disorder, but



35

inactivation of nitric oxide (NO) by reactive oxygen

species(ROS) is a key component. Loss of nitric oxide mediated

vasodilation may contribute to functional rarefaction (DeLano et

al., 2006).

Apoptosis is also involved in microvascular rarefaction. Absence

of flow induces apoptosis in endothelial cells adjacent to

immobilized platelets and leukocytes which may represent a

mechanism linking functional and structural rarefaction(Tran et

al., 2007).

There is evidence that experimental elevation of blood pressure

causes an increase in generation of reactive oxygen species in

endothelial cells, which may trigger adverse functional and

structural changes in microvessels. Such changes would be

viewed as consequences of elevated pressure. However, there is

considerable evidence that microvascular changes can also be a

cause rather than a consequence of hypertension. In animal

models of hypertension, increased reactive oxygen species

generation and arteriolar rarefaction occur even in parts of the

vasculature not exposed to elevated blood pressure (Jacobson et

al., 2007).

Diabetes Mellitus

There is considerable evidence to suggest that insulin resistance

and hyperglycemia, acting via oxidative stress, inflammation and

advanced glycation end products can induce microvascular

abnormality. However, inflammation may also be important in

the development of insulin resistance and impaired microvascular

perfusion may itself play a role in the pathogenesis of diabetes.



36

Capillary recruitment is an important mechanism by which

insulin promotes uptake of glucose from the blood. Capillary

rarefaction and impaired recruitment may, therefore, reduce

glucose uptake and contribute to insulin resistance (Shoelson et

al., 2007).

Table 1: Microvascular brain disease associates (the metabolic syndrome)


ObesityIn humans, coronary flow reserve is significantly lower in obese

than in nonobese subjects,( Schindler et al., 2006) and capillary

recruitment is reduced in nondiabetic obese individuals compared

with lean control subjects Even in a sample of healthy children

(11 to 14 years of age), microvascular function was negatively

correlated with adiposity. Thus, obesity appears to have an

independent effect on microvascular function (Khan et al.,

2003).

Several mechanisms have been identified by which excessive

adiposity could cause microvascular abnormalities. First,

oxidative stress and reduced nitric oxide availability are

important mechanisms in the development of microvascular

rarefaction (Frisbee, 2005).



http://www.yasser/

37

Second, excess adiposity is associated with a chronic state of

vascular inflammation with increased levels of proinflammatory

cytokines. In particular, production of tumor necrosis factor-α

(TNF-α), largely from non fat cells in adipose tissue, is markedly

increased in obesity (Fain, 2006). Deposits of fat around

arterioles may be involved in local necrosis factor-α signaling

resulting in impaired perfusion and insulin resistance (Yudkin et

al., 2005).

Third, increased fat mass leads to prolonged elevation of free

fatty acid levels in the blood, which can impair capillary

recruitment (De Jongh et al., 2004).

In the human coronary microcirculation, endothelium-dependent

vasodilation is impaired in both overweight and obese

individuals, but endothelium-independent vasodilation is reduced

significantly only in obese subjects. Thus, in obesity as in

hypertension and diabetes it appears that an early functional

microvascular impairment can progress to involve more

permanent structural abnormality (Schindler et al., 2006).

Cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA), although usually

asymptomatic, is an important cause of primary lobar

intracerebral hemorrhage in the elderly. It can occur as a sporadic

disorder, sometimes in association with Alzheimer disease or as

a certain familial syndrome. Cerebral amyloid angiopathy is

characterized by the deposition of congophilic material in small

to medium-sized blood vessels of the brain and leptomeninges. In

its most severe stages, the amyloid deposits cause breakdown of



38

the blood vessel wall with resultant hemorrhage (Viswanathan

and Greenberg, 2011).

The incidence of cerebral amyloid angiopathy like Alzheimer

disease is strongly age dependent. There is no strong predilection

for gender. Although the association of cerebral amyloid

angiopathy with hypertension is debated, it is clear that many

patients with cerebral amyloid angiopathy related hemorrhage are

normotensive ( Arima et al., 2010).

Clinical and radiological features of cerebral amyloid angiopathy

includes spontaneous lobar haemorrhage limited to cortical and

subcortical area of the brain in contrast to hypertensive

haemorrhage that occures in deep structure like the the basal

ganglia. Despite extensive pathologic involvement of the

leptomeningeal vessels, primary subarachnoid hemorrhage

related to cerebral amyloid angiopathy is rare (Charidimou et

al., 2012).

A less common, but clinically important manifestation of cerebral

amyloid angiopathy is transient neurologic symptoms . Affected

patients complain of recurrent, brief (minutes), often stereotyped

spells of weakness, numbness, paresthesias, or other cortical

symptoms that can spread smoothly over contiguous body parts.

These episodes may reflect abnormal activity (either focal seizure

or spreading depression) of the surrounding cortex in response to

the small hemorrhages. The anecdotal observation that

anticonvulsants may stop the attacks is consistent with this

hypothesis (Greenberg et al., 1993).



39

Features that help distinguish these spells from true transient

ischemic attacks include the smooth spread of the symptoms, the

absence of hemodynamically significant stenosis in the relevant

vascular supply and the presence of small hemorrhage in the

corresponding region of cortex (best shown with gradient-echo

MRI). Avoiding misdiagnosis is critical since the administration

of anticoagulants for a presumed transient ischemic attack can

increase the risk of hemorrhagic stroke from cerebral amyloid

angiopathy (Eng et al., 2004).

cerebral amyloid angiopathy related perivascular inflammation

appears to represent a distinct subset of cerebral amyloid

angiopathy (Kinnecom et al., 2007). The clinical presentation is

that of acute or subacute cognitive decline rather than

hemorrhage. Seizures, headache and focal neurologic signs are

common. Neuroimaging shows a potentially reversible

leukoencephalopathy consisting of patchy or confluent white

matter hyperintensities on T2 weighted MRI sequences; multiple

microhemorrhages are seen on gradient echo sequences

(Greenberg et al., 2010).

Angiography or MRA does not show evidence of vasculitis.

Neuropathology shows perivascular inflammation with

multinucleated giant cells that is associated with amyloid laden

vessels. ESR and C-reactive protein are commonly normal.

Cerebrospinal fluid analysis may be normal, but often shows a

pleocytosis and/or mildly elevated protein (Chung et al., 2011).



40

Definite CAA Full postmortem examination demonstrating:

-Lobar, cortical, or corticosubcorticalhemorrhage

-Severe CAA with vasculopathy

-Absence of other diagnostic lesion

Probable CAAwithsupportingpathology

Clinical data and pathologic tissue (evacuatedhematoma or cortical biopsy) demonstrating:

-Lobar, cortical, or corticosubcorticalhemorrhage

-Some degree of CAA in specimen

-Absence of other diagnostic lesion

Probable CAA Clinical data and MRI or CT demonstrating:

-Multiple hemorrhages restricted to lobar,cortical, or corticosubcortical regions(cerebellar hemorrhage allowed)

-Age ≥55 y

-Absence of other cause of hemorrhage

Possible CAA Clinical data and MRI or CT demonstrating:

-Single lobar, cortical, or corticosubcorticalhemorrhage

-Age ≥55 y

-Absence of other cause of hemorrhageTable 2: Classic Boston criteria for CAA-related hemorrhage (Linn et al., 2010).

Cerebral autosomal dominant arteriopathy with

subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical

infarcts and leukoencephalopathy (CADASIL) is an autosomal

dominantly inherited angiopathy that, in the 1990s, was shown to

be caused by mutations in the NOTCH3 gene on chromosome 19.



41

CADASIL is now recognized as an important cause of stroke in

the young (Chabriat et al., 2009).

Dichgans and his colleagues in 1998 showed that Patients with

CADASIL usually present with one or more of the following

four manifestations :

Ischemic episodes

Cognitive deficits

Migraine with aura

Psychiatric disturbances

Magnetic resonance imaging ( MRI ) of the brain shows two

major types of abnormalities:

Small circumscribed regions that are isointense to

cerebrospinal fluid on T1- and T2-weighted images. Most

of these lesions are consistent with lacunar infarcts in terms

of their size, shape, and location.

Less well demarcated T2-hyperintensities of variable size

that may show different degrees of hypointensity on T1-

weighted images but are clearly distinct from CSF.

The majority of these lesions are located in the subcortical white

matter but similar lesions may be seen in other brain regions,

including the brainstem and subcortical gray matter ( Auer et al.,

2001).

The onset of MRI-visible lesions and the rate of lesion

progression are variable but by age 35 years all mutation carriers



42

have developed magnentic resonance imaging lesions. Small

irregular T2-hyperintensities involving the periventricular and

deep white matter are usually the first sign in younger individuals

(Liem et al., 2008).

Figure 10: flow chart for CADASIL diagnosis. (Federico et al., 2012)

Cerebral autosomal recessive arteriopathy with

subcortical infarcts and leukoencephalopathy

Cerebral autosomal recessive arteriopathy with subcortical

infarcts and leukoencephalopathy (CARASIL), also known as

Maeda Syndrome, is clinically similar to CADASIL but with

earlier onset and several extraneurological symptoms and other

differences shown in the next table (Fukutake, 2011).



43

CARASILCADASIL20-3040-50Onset (years)

Cerebrovasculardisturbances and strokes(gait and cognitive deficits)

Migraine, TIA/strokes,psychiatric disorders,cognitive impairment

Clinicalfeatures

Arthropathy, lumbago,spondylosis deformans,disc herniation and alopeciain some cases

-Additional

signs

Autosomal recessiveAutosomal dominantinheritanceWhite matter lesions in theperiventricular and deepwhite matter, with sparingof U-fibres

Involvement of temporallobe and/or externe capsules

Cerebral MRI

HTRA1 (chromosome10q26)

NOTCH3 (chromosome19q12)

Gene

-+GOMTable 3: Main clinical and biological findings in CADASIL and CARASIL(

Federico et al., 2012).

Apolipoprotein E

The role of apolipoprotein E (APOE) phenotypes in

cerebrovascular disease and ischemic stroke is unsettled. This

apolipoprotein is a ligand for hepatic chylomicron and VLDL

remnant receptors, leading to clearance of these lipoproteins from

the circulation, and for LDL receptors. The apolipoprotein E e4

allele has been reported to be a stroke risk factor in some studies

(Schneider et al., 2005).



44

Small vessel disease associated with COL4A1

mutation

The COL4A1 gene encodes the α1(IV)-chain of type IV collagen

and its mutations have been associated with autosomal dominant

porencephaly and infantile hemiparesis (Gould et al., 2005)

COL4A1 mutations have also been identified in adult patients

with small vessel diseases. Clinical features include ischemic

stroke and intracerebral haemorrhage with cerebral MRI features

of lacunar infarction, leukoaraiosis and microbleeds. Besides

haemorrhagic strokes, COL4A1 mutations may also cause

variable degrees of retinal arteriolar tortuosity, cataracts,

glaucoma and ocular anterior segment dysgenesis (Axenfeld-

Rieger anomaly). These features are part of widespread systemic

disease that may include large vessel involvement with

aneurysms of the intracranial segment of the internal carotid

artery, muscle cramps, Raynaud phenomena, kidney defects and

cardiac arrhythmia. ( Sibon et al., 2007).



45

Figure 11:Cerebral MRI in CADASIL: characteristic MRI finding in

CADASIL with involvement of the external capsule and anterior temporal

lobes ( Federico et al.,2012).

Vasculitus of small vessels of the brain

Vasculitis is a spectrum of clinicopathological disorders defined

by inflammation of the blood vessels, including arteries and veins

of varying caliber, which result in a variety of clinical

neurological manifestations related to ischemic injury of the

central nervous system and peripheral nervous system. The

presence of vasculitis should be considered in patients who

present with systemic symptoms in combination with evidence of

single and/or multiorgan dysfunction. Although neither sensitive

nor specific, common complaints and signs of vasculitis include

fatigue, weakness, fever, arthralgias, abdominal pain,

hypertension, renal insufficiency (with an active urine sediment



46

containing red and white cell and occasionally red cell casts) and

neurologic dysfunction (Younger et al., 2003).

1- Churg-strauss syndrome

In 1951, Churg and Strauss delineated a syndrome of asthma,

eosinophilia, extravascular granulomas and necrotizing arteritis,

involving arterioles, capillaries, and venules that was named in

their honor. The extravascular granulomas, epithelioid and giant

cell infiltrates distinguish Churg–Strauss syndrome from classic

polyarteritis nodosa and resemble microscopic polyangitis in the

tendency to involve the lung and kidney. Early suspected patients

present with allergic rhinitis, nasal polyposis, and asthma,

followed by tissue eosinophilia and systemic vasculitis, with

central nervous system involvement that includes confusion,

seizures, cranial nerve involvement, optic neuropathy, and less

common radicular and plexus peripheral nervous system

manifestations (Sinico and Bottero, 2009).

2- Henoch schenolin purpura

Henoch-Schönlein purpura (HSP) is a systemic vasculitis that is

characterized by the tissue deposition of IgA-containing immune

complexes. Biopsy of lesions reveals inflammation of the small

blood vessels (most prominent in the postcapillary venules). This

disorder is considered a form of hypersensitivity vasculitis but is

distinguished from other forms of hypersensitivity by the finding

of prominent deposits of IgA. Affected children present with

fever, urticaria, arthralgia, lymphadenopathy, and headache and

abdominal pain so severe as to suggest meningitis and acute

surgical abdomen, usually after injection with heterologous



47

antiserum. Single reports and case series document neurologic

manifestations including headaches, seizures, focal neurologic

deficits, ataxia, intracerebral hemorrhage and central and

peripheral neuropathy in children with Henoch-Schönlein

purpura. Most of the central nervous system findings are transient

except for occasional permanent sequelae associated with

hemorrhagic stroke (Misra et al., 2004).

3- Granulomatosis with polyangiitis (Wegener’s)

Granulomatosis with polyangiitis (Wegener’s), abbreviated as

GPA, is a systemic vasculitis of the medium and small arteries, as

well as the venules and arterioles. It typically produces

granulomatous inflammation of the upper and lower respiratory

tracts and necrotizing, pauci-immune glomerulonephritis in the

kidneys. Granulomatosis with polyangiitis is usually associated

with antineutrophil cytoplasmic antibodies (ANCA). Nervous

system (mononeuritis multiplex, cranial nerve abnormalities,

central nervous system mass lesions, external ophthalmoplegia,

hearing loss) . Meningeal disease is most commonly associated

with granulomatous inflammation of the central nervous system

(Garovic et al., 2001).

4-Microscopic polyarteritis

Microscopic polyarteritis or polyangiitis is a vasculitis that

primarily affects capillaries, venules, or arterioles. Involvement

of medium and small- sized arteries may also be present. This

disorder is thought by some investigators to represent part of a

clinical spectrum that includes Granulomatosis with polyangiitis,

since both are associated with the presence of antineutrophil



48

cytoplasmic antibodies and similar histologic changes outside the

respiratory tract (Hogan et al., 2005).

5-Essential cryoglobulinemic vasculitis

Essential cryoglobulinemic vasculitis is characterized by the

presence of cryoglobulins, which are serum proteins that

precipitate in the cold and dissolve upon rewarming.

Cryoglobulins typically are composed of a mixture of

immunoglobulins and complement components. In this disorder,

which is most often due to hepatitis C virus infection, immune

complexes are deposited in the walls of capillaries, venules or

arterioles, thereby resulting in small vessel inflammation.

Neuropathy affects a high percentage of mixed in contrast to

type I, cryoglbulinemic patients but clinically significant

neuropathy is uncommon. Electromyographic and nerve

conduction studies have demonstrated the presence of peripheral

neuropathy presumably due to vasculitis in over 70 to 80 percent

of patients with mixed cryoglbulinemic (Ferri et al., 1992).

6-Hypersensitivity vasculitis

The term "hypersensitivity vasculitis" has been used by some

authors to include several forms of vasculitis of small blood

vessels. These have included Henoch-Schönlein purpura, mixed

cryoglobulinemia, allergic vasculitis, and serum sickness.

However, the term "hypersensitivity vasculitis" is most properly

used to refer to vasculitis that occurs as a hypersensitivity

reaction to a known or suspected substance such as a vasculitic

drug reaction. In hypersensitivity vasculitis, the presence of skin

vasculitis with palpable petechiae or purpura is typically a major

finding. Biopsy of these lesions reveals inflammation of the small



49

blood vessels, called leukocytoclastic vasculitis, which is most

prominent in the postcapillary venules (Calabrese and Duna,

1996).

7- Vasculitis secondary to connective tissue disorders

A- Systemic Lupus Erythromatosus (SLE) Vasculopathy

Nervous system involvement in Systemic Lupus Erythromatosus

was initially thought to be due to vasculitis. This idea was

challenged, however, by investigators who found that true

vasculitis was a rare finding in patients with Systemic Lupus

Erythromatosus and neurologic symptoms. However, many

patients may have a vasculopathy that may cause direct injury

and can also affect the blood-brain barrier, thereby allowing

antibodies to enter the nervous system. This vasculopathy is

characterized by a small to moderate perivascular accumulation

of mononuclear cells, without destruction (eg, fibrinoid necrosis)

of the blood vessel. There may be small infarcts due to luminal

occlusion. Neurologic complications include cognitive defects,

organic brain syndromes, delirium, psychosis, seizures, headache

and/or peripheral neuropathies. Other less common problems are

movement disorders, cranial neuropathies, myelitis and

meningitis (Romero-Díaz et al., 2009).

B- Rheumatoid arthritis (RA)

Rheumatoid arthritis is associated with various nonarticular

manifestations, including severe neurologic abnormalities. A

variety of pathogenic mechanisms are responsible:

Rheumatoid synovitis and pannus may compress or invade

adjacent structures (including the spinal cord and



50

peripheral nerves), resulting in myelopathy, radiculopathy,

and entrapment neuropathies.

Rheumatoid vasculitis may cause ischemia, infarction or

bleeding; these may ultimately result in transient ischemic

attacks, stroke, quadriplegia or paraparesis. With peripheral

nervous system involvement due to vasculitis, there may be

multiple nerve dysfunction (mononeuritis multiplex) or a

more indolent polyneuropathy (Bacani et al., 2012).

C- Behçet’s disease

The triad of oral and genital ulceration and uveitis with variable

arthritis, retinal and cutaneous vasculitis, thrombophlebitis,

gastroenteritis and chondritis characterizes Behc¸et disease. The

essential pathological changes are foci of leukocytoclastic

vasculitis with or without fibrinoid necrosis, and perivascular

lymphocytic infiltration around small blood vessels of involved

tissues of the skin, mucosa and brain with varying gliosis. Focal

parenchymal lesions and complications of vascular thrombosis

are the most common abnormalities. Other manifestations include

epileptic seizures, aseptic meningitis, encephalitis and arterial

vasculitis. Progressive personality change, psychiatric disorders

and dementia may develop. Unlike many other systemic

vasculitic disorders, peripheral neuropathy is not a common

feature of Behçet’s disease, though it may develop in a subset of

patients (Akubult et al., 2007).

8- Vasculitis secondary to viral infection

A number of viral infections may cause a vasculitis of medium

and/or small vessels. This association is most commonly



51

observed with hepatitis B and C viruses but may also be seen

with HIV, cytomegalovirus, Epstein-Barr virus and Parvovirus

B19. The clinical presentation may be similar to that of

polyarteritis nodosa or microscopic polyangiitis. Although the

disorder is probably immune complex mediated, it must be

distinguished from nonviral associated vasculitides since

treatment consists of the administration of antiviral and not

antiinflamatory agents (Hoffman, 1998).

Radiotherapy

Head and neck radiotherapy for cancer treatment may lead to a

delayed vasculopathy of large and small vessels mediated by

endothelial damage, fibrosis and accelerated atherosclerosis.

Radiotherapy-related occlusive disease is often diffuse and occurs

in uncommon locations in contrast to the typical focal lesions that

develop at vessel bifurcations from atherosclerosis in the absence

of radiation. Depending on the site and dose of radiation the

involved vessels may include the extracranial carotid, vertebral

arteries and the intracranial circle of Willis vessels. This process

may lead to symptomatic carotid disease, moyamoya syndrome

and ischemic stroke (Plummer et al., 2011).

Hyperhomocystinemia

Homocysteine has primary atherogenic and prothrombotic

properties. Histopathologic hallmarks of homocysteine-induced

vascular injury include intimal thickening, elastic lamina

disruption, smooth muscle hypertrophy, marked platelet



52

accumulation and the formation of platelet-enriched occlusive

thrombi (Rolland et al., 1995).

There are multiple mechanisms by which homocysteine may

induce vascular injury:

Homocysteine promotes leukocyte recruitment by

upregulating monocyte chemoattractant protein-1 and

interleukin-8 expression and secretion (Poddar et al.,

2001).

The thiolactone metabolite of homocysteine can combine

with LDL-cholesterol to produce aggregates that are taken

up by vascular macrophages in the arterial intima; these

foam cells may then release the lipid into atherosclerotic

plaques (McCully, 1996).

Homocysteine increases smooth muscle cell proliferation

and enhances collagen production (Majors et al., 1997).

Prothrombotic effects of homocysteine which have been

demonstrated in patients with acute coronary syndromes

include attenuation of endothelial cell tissue plasminogen

activator binding sites, activation of factor VIIa and V,

inhibition of protein C and heparin sulfate, increased

fibrinopeptide A and prothrombin fragments 1 and 2,

increased blood viscosity and decreased endothelial

antithrombotic activity due to changes in thrombomodulin

function (Al-Obaidi et al., 2000).

Oxidative stress by free radicals formed during the

oxidation of reduced homocysteine may directly injure

endothelial cells (Mansoor et al., 1995).



53

Prolonged exposure of endothelial cells to homocysteine

reduces the activity of dimethylarginine

dimethylaminohydrolase, the enzyme that degrades

asymmetric dimethylarginine an endogenous inhibitor of

nitric oxide synthase; this impairs the production of nitric

oxide. This may contribute to impaired endothelium-

dependent vasodilation of both conduit and resistance

vessels ( Stühlinger et al., 2001).

Support for the role of homocysteine in endothelial dysfunction is

derived from studies that found that folic acid supplementation

both lowers the homocysteine concentration and improves

measures of endothelial dysfunction (Willems et al., 2002).

An alternate view is that hyperhomocysteinemia is not directly

harmful but that it indirectly inhibits methyl fluxes during

transmethylation of methionine; the resulting impairment of

DNA methylation could then affect many physiologic processes

(van Guldener and Stehouwer, 2003).

Rheological changes

The rheological changes associated with microvascular brain

disease include increase in the whole blood viscosity and

thrombotic tendency of the blood. In general a significant

increase of blood, plasma and serum viscosity and a decrease of

whole blood filterability significantly impair flow in the

microcirculation and contribute to the development of the

ischemic microvascular brain disease (Brun et al., 1996).



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A negative relationship is observed between directly measured

whole blood viscosity and insulin sensitivity as a part of the

insulin-resistance syndrome (The metabolic syndrome) and a

positive relationship is observed between insulin resistance and

whole blood viscosity. In general, obesity and insulin resistance

both impair blood rheology by acting on red cell rigidity and

plasma viscosity. Whole blood viscosity reflects rather obesity

than insulin resistance (Høieggen et al., 1998).

Whole blood viscosity is a collective terminology that include

blood viscosity and plasma viscosity. Blood viscosity is

determined by the haematocrit value and plasma viscosity is

determined by serum fibrinogen. Increase of the haematocrit

value and serum fibrinogen (even within the normal range)

increases the whole blood viscosity. Increase of the platelet

aggregation also increases whole blood viscosity. Reduced red

blood cells deformability and increased red blood cells

aggregability also increase whole blood viscosity. Normally the

red blood cells must be deformed (they usually become

parachuted) in order to pass through the microcirculation.

Reduction of the red blood cells deformability results in poor red

blood cells flow through the microcirculation and subsequently

poor tissue oxygenation ( Høieggen et al., 1998).

Plasma fibrinogen is associated with the risk of stroke and

cardiovascular disease and may act by several possible

mechanisms, including promotion of atherogenesis and

inflammation, elevation of blood and plasma viscosity, increased

platelet aggregability and increased tendency to form fibrin

within thrombus. Elevated fibrinogen levels appear to correlate



55

with vulnerable atherosclerotic plaque characteristics, including

thinning of the fibrous cap of atheroma predisposing to rupture,

and to increased plaque inflammation. However, it is not

established that elevated fibrinogen is an independent risk factor

for carotid atherosclerosis progression as some evidence suggests

it is rather a nonspecific marker of inflammatory activity

(Mauriello et al., 2000).

Increase of the blood viscosity results in global reduction of

brain perfusion, however, this is normally compensated for by the

physiological process of autoregulation. In response to critical

reduction of brain perfusion, the brain microvascular bed dilates

thus increasing brain perfusion. Normally the autoregulatory

process keeps the brain perfusion at a constant level despite the

normal daily fluctuation of the whole blood viscosity. Loss of the

autoregulatory physiological process secondary to microvascular

arteriolar pathology, will simply mean that brain perfusion will

fluctuate with fluctuation of the whole blood viscosity. The

microvascular brain disease is the end result of a vicious circle

that starts at one end of the circle with loss of the autoregulatory

process and restarts at the other end of the circle by increase of

the whole blood viscosity (Høieggen et al., 1998).

The antiphospholipid syndrome (APS) is a hypercoagulable state

characterized by recurrent arterial or venous thromboembolism or

pregnancy loss, in association with antibodies directed against

plasma proteins that may be bound to anionic phospholipids. The

presence of such antibodies may be detected as lupus

anticoagulants, anticardiolipin antibodies or anti-ß2 glycoprotein-

I antibodies. This disorder has been referred to as primary



56

antiphospholipid syndrome when it occurs alone; however, it can

also be seen in association with systemic lupus erythematosus,

other rheumatic disorders and autoimmune diseases. Warfarin

and antiplatelet agents have been employed to prevent stroke due

to antiphospholipid syndrome. For patients with cryptogenic

ischemic stroke or transient ischemic attack and positive

antiphospholipid antibodies with a target INR of 2 to 3 is

reasonable (Furie et al., 2011).

Inherited thrombophilias

Inherited thrombophilias are hypercoagulable states that include

a number of disorders:

Protein C deficiency.

Protein S deficiency.

Antithrombin III deficiency.

Activated protein C resistance.

Factor V Leiden as a cause of activated protein C

resistance.

Prothrombin G20210A mutation.

Methylenetetrahydrofolate reductase (MTHFR) mutations

associated with hyperhomocysteinemia.

These conditions are thought to be rare causes of ischemic stroke

in adults but may be more important causes of ischemic stroke in

children (Lansberg et al., 2012).



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Effect of small vessel disease on cognition and

age related disability

Effect of small vessel disease on cognition

Small vessel disease is thought to be among the main causes of

vascular cognitive impairment. Vascular cognitive impairment

itself is a broad term under which all forms of vascular disease

that possibly lead to cognitive consequences are grouped. Despite

repeated efforts we are far from having definite classification and

criteria for this type of cognitive impairment. This is due to

several reasons of which the heterogeneity of the pathological

and clinical aspects of vascular cognitive impairment and the

different underlying pathogenic mechanisms and neuroimaging

correlates are among the most important (Hachinski et al., 2006).

Vascular cognitive impairment associated with small vessel

disease has received particular attention because of the following

five factors. First, small vessel disease is reputed to be a common

and possibly the most frequent cause of vascular cognitive

impairment. Second, this type of cognitive impairment is thought

to be reasonably homogeneous in clinical and neuroimaging

terms (Roman et al., 2002) and, therefore, suitable as a target for

implementing studies and therapeutic trials (Inzitari et al.,

2000). Third, the neuroimaging correlates of small vessel disease

have been the object of many studies and thus, this type of

cognitive impairment could be appropriately studied in vivo.

Fourth, vascular cognitive impairment associated with small

vessel disease is thought to be a progressive condition from

normal cognitive status to frank dementia therefore, it is a



58

category that might benefit from prevention. Finally, because this

type of cognitive impairment has homogeneous clinical and

neuroimaging features and a progressive course, it is thought to

be a disease rather than a condition, by contrast with post-stroke

dementia (Pantoni et al., 2009).

As well as cognitive disorders, the clinical characteristics of

vascular cognitive impairment associated with small vessel

disease are gait, mood and behavioural and urinary disturbances.

In the early phases, these disturbances can be mild and loosely

associated. The final stage is one in which the patient fits the

criteria for dementia (ie, cognitive deficits have a clear and

relevant effect on the functional status), gait is very impaired with

many patients almost unable to walk and having frequent falls,

mood is altered with prominent depressive symptoms or apathy,

and urinary incontinence is present (Pantoni et al., 2009).

Table 4 :symptoms associated with cerebral small vessel disease (pantoni , 2010).



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Pathogenic factors of vascular dementia(VaD)

Important pathogenic factors of vascular dementia include the

volume of brain destruction, its location and the number of

cerebrovascular lesions although Pantoni in 2003 emphasized an

overlap between vascular and degenerative mechanisms and a

frequent lack of correlation between clinical and pathology

findings.

1. Volume of brain destruction

destruction of large parts of the cortex usually causes dementia

while small infarcts may or may not contribute to dementia,

probably depending on their location, suggesting the concept of

strategic sites of infarcts. Some studies in vascular dementiarevealed mean volumes of infarcted brain loss of 39–47 ml (range

1–229 ml) (Zekry et al., 2003), another suggestion that dementia

is not directly and consistently related to the volume of infarction

or found only a nonsignificant trend for lobar infarcts to occupy

more brain volume than in patients without dementia (Vinters et

al., 2000).

2. Location of vascular lesions

This is probably more important than the volume of tissue

destruction. Multiple brain areas have been implicated in

vascular dementia: infarction in the dominant hemisphere or

bilateral lesions with predominant involvement of the dominant

hemisphere; those in left angular gyrus, left or bilateral anterior

cerebral artery and posterior cerebral artery territories increase

the risk of dementia after stroke. Bilateral thalamic infarction and

lacunar lesions in basal ganglia, caudate head and inferior genu of



60

the anterior capsule, interrupting corticothalamic and

thalamocortical pathways, have been associated with “subcortical

dementia”(Van derWerf et al., 2003).

Hippocampal infarcts and sclerosis either alone or in combination

with other vascular lesions, have been related to dementia

(Bastos-Leite et al., 2007). A nother study showed

correspondence between focal subinsular vascular lesions, white

matter lesions and lacunes (Tomimoto et al., 2007).

3. Number of cerebrovascular lesions

Although a basic concept of vascular dementia suggests that

multiple small infarcts irrespective of their volume, can lead to

intellectual decline, only few studies have addressed this

problem. The mean number of infarcts in vascular dementiawas 5.8–6.7 compared to 3.2 in non-demented subjects but

additional factors, such as age, degree of aging changes, extent of

white matter lesions, medial temporal lobe atrophy, education,

etc., are involved in determining intellectual decline

(Pohjasvaara et al., 2000).

Correlations between dementia and microvascular

brain damage

Evaluation of the type and topographic pattern of cerebrovascular

lesions in a large autopsy series of demented subjects, in cases

with “pure” vascular dementia, i.e without essential

concomitant Alzheimer type or other pathologies, showed a

significantly higher frequency of small subcortical lesions

representing 70% than of large infarcts involving one or both

hemispheres (30%). This pattern differed considerably from that



61

in cases with mixed dementia (definite AD + vascular

encephalopathy), where 64% revealed large, often lobar infarcts

or multiple cortical and subcortical lesions larger than 10 cm in

diameter involving one or both hemispheres, whereas lacunes and

small subcortical microinfarcts were seen in only 36% . These

data suggest different pathogenic mechanisms between both types

of disorders (Jellinger, 2007).

In conclusion, subcortical lacunes and multiple disseminated

microinfarcts appear to represent the most common morphologic

features of vascular dementia, while large cystic infarcts are

less common. This has been confirmed in animal models of

vascular dementia due to chronic hypertension (Ince, 2005).

The Neurochemical studies in vascular dementia of Tomimoto

and his colleagues in 2005 showed abnormalities in key

neurotransmitter systems in particular in the basal forebrain

cholinergic system related to diffuse white matter lesions and

other vascular lesions involving the central radiation fields for

this projection pathway causing widespread disconnection of

cholinergic projections to the center. Since cholinergic

mechanisms play a role in the regulation of cerebral blood flow

dysfunction of the cholinergic system may cause decreased

cerebral blood flow and hypoperfusion as critical factors in the

pathogenesis of vascular dementia (Hamel, 2004).

Other neurotransmitter deficits in vascular dementia concern

reduction in vasopressin and histamine due to lesions in the

supraoptic and tuberomamillary nuclei (Ishunina et al., 2004).



62

The Hachinski criteria were developed using clinical criteria to

separate vascular disease from primary degenerative dementia. It

was developed at the time when CT scanning was being

introduced, and thus has no imaging component. A high score

(≥7) suggests vascular dementia, while a low score (≤4) suggests

Alzheimer disease (Hachinski et al., 1975).

ScoreFeature

1Stepwise deterioration

2Abrupt onset

2Fluctuating course

1Relative preservation of personality

1Depression

1Nocturnal confusion

1Somatic complaints

1Somatic complaints

1Emotional incontinence

1History of hypertension

2History of strokes

1Evidence of associated atherosclerosis

2Focal neurological symptoms

2Focal neurological signs

Table 5 : Hachinski Ischemia Score (Rosen et al, 1980).



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The criteria for the clinical diagnosis of probable vasculardementia include all of the following:DementiaDefined by cognitive decline from a previously higher level offunctioning and manifested by impairment of memory and of twoor more cognitive domains (orientation, attention, language,visuospatial functions, executive functions, motor control, andpraxis), preferably established by clinical examination anddocumented by neuropsychological testing; deficits should besevere enough to interfere with activities of daily living not dueto physical effects of stroke alone.Exclusion criteria: Cases with disturbance of consciousness,delirium, psychosis, severe aphasia, or major sensorimotorimpairment precluding neuropsychological testing. Also excludedare systemic disorders or other brain diseases (such as AD) that inand of themselves could account for deficits in memory andcognition.Cerebrovascular diseaseDefined by the presence of focal signs on neurologicexamination, such as hemiparesis, lower facial weakness,Babinski sign, sensory deficit, hemianopia, and dysarthriaconsistent with stroke (with or without history of stroke), andevidence of relevant CVD by brain imaging (CT or MRI)including multiple large vessel infarcts or a single strategicallyplaced infarct (angular gyrus, thalamus, basal forebrain, or PCAor ACA territories), as well as multiple basal ganglia and whitematter lacunes or extensive periventricular white matter lesions,or combinations.A relationship between the above two disordersManifested or inferred by the presence of one or more of thefollowing:(a) onset of dementia within three months following a recognizedstroke;(b) abrupt deterioration in cognitive functions; or fluctuating,stepwise progression of cognitive deficits.Table 6 : NINDS-AIREN criteria for probable vascular dementia(www.UpToDate.com, 2013) .



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Cerebrovascular lesions and Alzheimer disease

Recent emphasis on co-morbidity of Alzheimer disease and

cerebrovascular diseases. the link between Alzheimer diseaseand atherosclerosis cognitive impairment associated with cerebral

amyloid angiopathy, present in up to 100% in Alzheimer

disease brain (Attems, 2005), and in brains with

Cerebrovascular lesions significant cerebral microangiopathy

deficient clearance of amyloid cross the blood brain barrier in

Alzheimer disease and many other data indicate an association

between cerebrovascular diseases and Alzheimer diseasevascular disorders being important features in chronic

neurodegeneration in Alzheimer disease. Therefore,

neurovascular dysfunction could have a major role in the

pathogenesis and progression of Alzheimer disease (Mielke et

al., 2007) that, by some authors even, has been considered a

primary vascular disorder. Although there are close relationships

between Alzheimer disease and cerebrovascular lesions(Sheng et al., 2007).

A nother clinico-pathologic study showed that subcortical

infarcts increased the odds of dementia by almost 4-fold, their

interaction with Alzheimer disease pathology farther

worsening working memory (Schneider et al., 2007).

There are more vascular Aβ-42 deposits in vascular dementia

cases compared to Alzheimer disease with similar degree of

cerebral amyloid angiopathy and Aβ-40 deposition, suggesting

differential mechanisms (Haglund et al, 2006). The severity of β



65

amyloid load in the brain is not significantly influenced by

cerebrovascular diseases except for a shift from Aβ-40 to Aβ-42

in the thalamus of elderly subjects, the reason of which is

unknown while other authors found accumulation of brain Aβ

increasing with age in vascular dementia subjects more than in

elderly without cerebrovascular diseases (Lewis et al., 2006).

In general, there are no major differences in neurodegenerative

lesion load between Alzheimer disease and Alzheimer

disease + cerebrovascular lesions, except when these are

located in the temporal lobe and hippocampus, suggesting that

this location may be important in the pathophysiology of both

vascular dementia and mixed Alzheimer disease + vascular

dementia (Del Ser et al., 2005).

Effects of small vessel disease on age-related disability

Because white matter lesions are not only associated with

cognitive disorders but also with gait and mood disturbances and

urinary problems it has been hypothesised that they are a

neuroimaging correlate of age-associated disability (Baezner et

al., 2008).

Patients with severe white matter lesions had more than twice the

risk of transition to disability than patients with mild lesions,

independently of many other predictors of disability. The yearly

rate of transition or death was 10·5%, 15·1%, and 29·5% for

patients with mild, moderate or severe age-related white matter

lesions. A comparison of the groups with severe versus mild age-

related white matter lesions with adjustment for clinical factors of

functional decline, revealed a two-times higher risk of transition



66

to disability or death in the severe group. The effect of severe

white matter lesions remained significant after correction for

baseline degree of brain atrophy and infarct number (Inzitari et

al., 2009).

Vascular parkinsonism

Vascular parkinsonism (VP) is probably one of the most

frequently erroneous neurological diagnoses. The reason for this

misdiagnosis is that both cerebral vascular disease and

parkinsonism usually occur at the same age. Due to the high

incidence of cerebral vascular disease it is possible for cerebral

vascular disease and idiopathic Parkinson’s disease (IPD) to

coincide in some cases. Another reason for the misdiagnosis is

that the concept of vascular parkinsonism lacks clarity. The

clinical picture of vascular parkinsonism is heterogeneous. The

authors concluded that vascular parkinsonism is a distinct clinical

entity, and they suggest that there are two types of vascular

parkinsonism. The first type is characterised by an acute onset

probably related to infarction or other lesion affecting the basal

ganglia; the second type is characterized by slower progression

associated with a more diffuse ischaemic impairment of the

subcortical white matter (Winikates et al., 1999).

Nevertheless, according this study the clinical picture of vascular

parkinsonism is heterogeneous. There are no symptoms or groups

of symptoms that would be specific for vascular parkinsonism. In

1999 Sibon and his colleagues summarized that the diagnosis of

vascular parkinsonism should be based on a convergence of

clinical and imaging clues, but none of these clues taken alone



67

may be specific enough for diagnosis. They suggested the term

‘‘atypical parkinsonism’’.

Fe´nelon and Houe´to in 1998 following a study of recent

publications, and based on their own clinical experience,

proposed to sort vascular parkinsonism into four types according

to clinical manifestation:

1. Vascular parkinsonism manifesting itself in a manner identical

to Parkinson’s disease.

2. Unilateral parkinsonism following a contralateral vascular

lesion.

3. ‘‘Atypical’’ parkinsonian syndromes.

4. ‘‘Parkinsonian’’ gait disorders.

1. Vascular parkinsonism manifesting itself as IPD

In a clinico-anatomical study by Hughes et al in 1992 which

included a group of 100 patients who met the clinical criteria of

Parkinson’s disease, autopsy verified the diagnosis in 76 cases. In

21 patients, other pathological findings were present; the causal

relationship to the vascular lesions was confirmed in 3 patients .

It is possible for vascular lesions and idiopathic Parkinson’s

disease to coincide. In the 76 cases of verified idiopathic

Parkinson’s disease, the simultaneous occurrence of vascular

lesions (mostly of ischaemic aetiology) located in the striatal

region was proven in a quarter of the patients. However most

clinical information about the appearance of Parkinson’s disease

symptoms in patients with cerebral vascular lesions is based on

case reports. There are no data that would indicate a pathological

role of the cerebrovascular disease in the idiopathic Parkinson’s



68

disease. In a study by Inzelberg et al. in 1994. the only

symptomatic difference between 20 patients suffering from

parkinsonism with CT-verified lacunae in the striatal region and

the patients suffering from parkinsonism without the finding of

lacunae was the lower prevalence of tremor. The only practical

difference was the more advanced age and higher prevalence of

arterial hypertension in the first group. Therefore, the authors

suggested that the incidence of lacunae was consistent with that

of the normal population of corresponding age.

2. Unilateral parkinsonian syndromes caused by contralateral

vascular lesions

This category might support the validity of the whole vascular

parkinsonism concept. Patients that meet the following criteria

should be included: the appearance of unilateral parkinsonism

following an ischaemic or haemorrhagic stroke; neuroradiological

or anatomical evidence of a contralateral vascular lesion in the

striatopallidal, substantia nigra or thalamus region. Surprisingly,

ischaemic lesions in the substantia nigra region have only rarely

been identified as an etiopathogenetic factor in contralateral

parkinsonian syndromes. Striatal or striatopallidal ischaemic

lesions related to Vascular parkinsonism have been more

frequently observed (Marsden et al., 1996).

Fe´nelon and Houe´to in 1998 suggest the following reasons:

the basal ganglia lesions may also involve the motor cortex and

descending motor pathways; resulting in a central palsy, that

makes it difficult to distinguish slight parkinsonian symptoms

against a background of serious motor lesion.



69

Weiller et al. in 1990 emphasise the possible involvement of

compensatory mechanisms, e.g. the activation of contralateral

motor systems.

3. ‘‘Atypical’’ parkinsonian syndromes

Parkinsonism with various atypical features, compared with the

typical syndrome in the idiopathic Parkinson’s disease and

associated with cerebrovascular disease, is not rare. The clinical

manifestation is atypical in many aspects, e.g. in the absence of

rest tremor, in the axial predominance of signs and symptoms, in

the presence of associated symptoms, and/or in a low sensitivity

to l-dopa. Vascular lesions have been found most frequently in

the striatal region or in the hemisphereal white matter. Moreover,

minor striatal lesions are usually asymptomatic, while lesions that

are located in the region of the white matter and that can be seen

using imaging methods are very common, but non-specific

(Baloh and Vinters, 1995).

4. Parkinsonian Gait disorders

This category includes patients who suffer from a gait disorder of

a ‘‘parkinsonian’’ nature as an isolated or, more frequently, as a

dominant clinical sign. In 1987, Thompson and Marsden used

the term ‘‘lower half parkinsonism’’ to describe the symptoms of

a group of 12 patients suffering from arterial hypertension and

clinical gait and equilibrium disorders. CT images revealed

arteriosclerotic leukoencephalopathy in all these patients.

In 1989 Fitzgerald and Jankovic preferred the term ‘‘lower

body parkinsonism’’. In their study, they described 10 patients

with minimal parkinsonian signs and symptoms in the upper



70

limbs, and dominating gait disorders. MR revealed lesions in the

subcortical white matter in 7 of these patients. The incidence of

arterial hypertension in this group was higher than that of the

control group of patients with idiopathic Parkinson’s disease.

In 1995 Zijlmans et al. compared the MR images of 15 patients

suffering from vascular parkinsonism that manifested

predominantly as ‘‘lower body parkinsonism’’ with the MR

images of patients with idiopathic Parkinson’s disease and

hypertension, and concluded that the involvement of subcortical

white matter in the first group was significantly pronounced. Of

course, a gait disorder may be also a part of the broader vascular

parkinsonism syndrome.

However, it remains unclear how a white matter lesion can result

in a gait disturbance. It has been suggested that the gait disorder

was caused by ischaemic damage to the motor cortex–basal

ganglia connections. Other authors have attributed more

importance to the connections between the frontal cortex and the

basal ganglia, or to the brain stem. The frontal atrophy is related

to the postural signs and a gait disorder (Baloh and Vinters,

1995).

In 1993 Nutt et al. described ‘‘frontal gait’’ as the small step gait

(marche a´ petit pas) in patients who suffered from

cerebrovascular diseases. An impairment of long-loop reflexes

that leads to a disturbance of the sensory-motor integration has

also been suggested.

We conclude that a common pathophysiology of isolated or

predominant gait disorder in patients with cerebrovascular

diseases and gait disorder in Parkinson’s disease has not been



71

proven. In patients with predominant gait disorder, the other

parkinsonian symptoms are absent or rudimentary. A causal or

decisive influence of the extrapyramidal system malfunction in

the gait disorder could not be proven (Rector et al., 2006).

A constant finding in patients with isolated or dominant gait

disorder and cerebrovascular diseases is an extensive impairment

of the subcortical white matter. We suggest replacing the term

‘‘lower body parkinsonism’’ etc. with a more appropriate term

(not including the ‘‘parkinsonism’’). An alternative term could be

‘‘cerebrovascular gait disorder’’. In contrast with other types of

gait disorder, cerebrovascular gait disorder presents as a clearly

detectable entity, with a characteristic clinical picture and the

presence of cerebrovascular diseases manifesting itself in MRI

(Rector et al., 2006).

Microvascular disease of the brain and idiopathic

parkinsonism

Although the association between parkinsonian manifestations

(vascular parkinsonism) and microvascular brain disease can be

attributed to the pathologic findings of multiple basal ganglia

cavitations (etat crible) and infarcts (etat lacunaris) that are

encountered in the ischemic microvascular brain disease, The

association between type 2 diabetes and Parkinson disease is

independent of sex, smoking, alcohol and coffee intake, and body

weight. The demonstrated link between the idiopathic Parkinson

disease and type 2 diabetes could result in increased incidence of

the idiopathic Parkinson disease in the microvascular brain

disease that is independent of any structural ischemic cerebral

pathology (Hu et al., 2007).



72

Vascular parkinsonism and vascular dementia

There is a certain overlap in both clinical conditions. They share

the frequent occurrence of brain atrophy, white matter lesion and

a predominance of motor symptoms on the lower half of body,

specifically gait disturbance. The conditions occurred more

frequently in patients with multiple infarcts in several vascular

territories. The conditions may result from subcortical infarctions

that result in a global cerebral hypometabolism affecting mainly

the frontal lobes or from a small artery subcortical disease.

Cognitive disturbance is frequently associated with vascular

parkinsonism. In a comparative study, dementia occurred in 45%

of the patients with vascular parkinsonism, in contrast to only

10% in the idiopathic Parkinson disease group. It is possible that

a part of vascular parkinsonism and subcortical dementia are

manifestations of a common underlying disorder, namely of

subcortical vascular encephalopathy. The normal pressure

hydrocephalus in all patients should be excluded (Kwan et al.,

1999).

Lacunar infarction symndromes

Each of the 5 classical lacunar syndromes has a relatively distinct

symptom complex. Symptoms may occur suddenly,

progressively, or in a fluctuating (e.g., the capsular warning

syndrome) manner. Occasionally, cortical infarcts and

intracranial hemorrhages can mimic lacunar infarcts, but true

cortical infarct signs (such as aphasia, neglect, and visual field

defects) are always absent (Grau-Olivares et al., 2007). The 5

classic syndromes are as follows:



http://en.wikipedia.org/wiki/Intracranial_hemorrhage

73

Lacunarsyndrome

Location Clinical findings

Pure motorhemiparesis

Internal capsule,corona radiata, basalpons, medial medulla

Unilateral paralysis offace, arm and leg, nosensory signs,dysarthria anddysphagia may bepresent

Pure sensorysyndrome

Thalamus, pontinetegmentum, coronaradiata

Unilateral numbnessof face, arm and legwithout motor deficit

Ataxichemiparesis

Internal capsule-corona radiata, basalpons, thalamus

Unilateral weaknessand limb ataxia

Sensorimotorsyndrome

Thalamocapsular,maybe basal pons orlateral medulla

Hemiparesis orhemiplegia of face,arm and leg withipsilateral sensoryimpairment

Dysarthria-clumsy handsyndrome

Basal pons, internalcapsule, coronaradiata

Unilateral facialweakness, dysarthriaand dysphagia, withmild hand weaknessand clumsiness

Table 7 : Lacunar infarction syndromes (Grau-Olivares et al, 2007).

Silent lacunar infarction

A Silent lacunar infarction (SLI) is one type of silent stroke

which usually shows no identifiable outward symptoms thus the

term "silent". Individuals who suffer a Silent lacunar infarction

are often completely unaware they have suffered a stroke. This

type of stroke often causes lesions in the surrounding brain tissue

that are visibly detected via neuroimaging techniques such as

MRI and computerized axial tomography (CAT scan). Silent

strokes, including silent lacunar infarctions, have been shown to



http://en.wikipedia.org/wiki/Silent_stroke

http://en.wikipedia.org/wiki/MRI

http://en.wikipedia.org/wiki/Computerized_axial_tomography

74

be much more common than previously thought, with an

estimated prevalence rate of eleven million per year in the United

States. Approximately 10% of these silent strokes are silent

lacunar infarctions. While dubbed "silent" due to the immediate

lack of classic stroke symptoms, Silent lacunar infarctions can

cause damage to the surrounding brain tissue (lesions) and can

affect various aspects of a persons mood, personality, and

cognitive functioning. A Silent lacunar infarction or any type of

silent stroke places an individual at greater risk for future major

stroke (Longstreth et al , 1998).



http://en.wikipedia.org/wiki/Lesion

http://en.wikipedia.org/wiki/Cognitive_functions

75

Neuroimaging of microvascuolar disease of the

brain

Neuroimaging of leukoariosis

Appears as an area of hyperintense signal in the white matter on

magnetic resonance images it usually appears around the lateral

ventricles. Radiographic leukoariosis has been correlated with a

variety of neuropathological findings. Punctuate hyperintensities

are caused by perivascular demyelination and gliosis, dilated

Virchow-Robin spaces or small lacunae (Munoz et al., 1993).

Multiple lacunae and multiple sclerosis plaques have also been

found in areas of radiological leukoariosis. In cerebral

autosomal dominant arteriopathy with subcortical infarcts and

leukoencephalopathy electron-dense, eosinophilic deposits are

found in the media of small vessels; this leads to lumen

narrowing (Pantoni and Garcia, 1997).

Neuroimaging of lacunar infarction

Noncontrast head computed tomography (CT) is the initial

imaging modality for most patients presenting with an acute

stroke syndrome. CT has low sensitivity for detecting lacunes (30

to 44 percent). The sensitivity of CT for lacunes in the hyperacute

phase (<6 hours) has not been systematically studied, but is likely

to be even lower; thus, a lacune seen on CT in this time window

is more frequently chronic and not related to the clinical

symptoms. CT also is limited in identifying posterior fossa

infarcts and in defining the degree of cortical extension in

subcortical infarcts (Hommel et al., 1990).



76

Magnetic resonance imaging (MRI) has been extensively studied

in lacunar infarcts. It has a higher sensitivity and specificity than

CT and is better for defining the exact anatomical localization. In

one study, for example, MRI detected lacunar infarcts in 19 of 22

patients with compatible symptoms, compared with 11 found by

CT. A second report confirmed that MRI was superior to CT for

detecting lacunes; the sensitivity of MRI was greatest for patients

who presented with pure motor hemiparesis, detecting 85 percent

of lesions. MRI usually shows infarcts within 8 hours of

symptom onset (Brown et al., 1988).

Diffusion-weighted imaging (DWI) is a fast MRI technique that

demonstrates a hyperintense signal whenever there is an area of

restricted water diffusion, as occurs during acute ischemia. DWI

has the advantages of a higher sensitivity for acute lesions than

T2-weighted MRI or FLAIR, ability to differentiate between

acute and chronic lacunar infarcts, and ability to identify multiple

acute infarcts potentially linked to embolic sources . In one study,

25 percent of DWI-hyperintense lacunar infarcts were either not

seen or mistakenly called "chronic" on T2 or FLAIR imaging.

This finding suggests that patients require DWI to define the

clinically appropriate infarct when multiple subcortical infarcts of

various ages are present (Oliveira-Filho et al., 2000).

The size of acute lacunar infarction is overestimated on DWI by

approximately 40 percent when compared with final infarct size

at 30 days or more after stroke onset on conventional MRI (T2 or

FLAIR sequences) and CT (Koch et al., 2011).



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Figure 12 : Periventricular lacunar infarctions and calcifications


Vascular imaging (CTA or MRA) can be performed at the same

time as brain imaging (CT or MRI) to exclude occlusion of the

parent feeding artery, a condition that can mimic a lacunar

infarct. It is particularly important to perform intracranial

vascular imaging in blacks and persons of Asian descent, since

intracranial large artery occlusive disease is common in these

populations. An alternative diagnostic test to exclude intracranial

occlusive disease is transcranial Doppler (TCD), a technique that

measures the blood flow velocities in the large intracranial

arteries using an ultrasound probe placed over the orbit, temporal

bone and foramen magnum (Khan et al., 2012).

Neuroimaging of dilated Virchow-Robin spaces

These are enlargements of the spaces around the penetrating

vessels in the brain parenchyma which must be distinguished

from lacunr infarctions by MRI as they are typically located in

some areas (eg, anterior commissure, vertex) that are different

from those of lacunar infarcts. Other MRI characteristics that can

help to distinguish dilated perivascular spaces from lacunar

infarcts are that dilated perivascular spaces are usually smaller



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78

than 1×2 mm and have an isointense appearance with the CSF on

proton density sequences (Kobari M et al., 1990).

Figure 13: MRI T2 (A), MRI FLAIR (B) and precontrast MRI T1 (C) images

showing dilated Virchow-Robin Spaces associated with diffuse white matter

changes (leukoaraiosis) (www.yassermetwally.com, 2013).

Granular atrophy (Cortical laminar necrosis)

The laminar cortical necrosis, seen as a laminar high-signal lesion

on T1-weighted MR images, was first described by Swada et al.

in a patient of anoxic encephalopathy (Sawada et al., 1990).

Early cortical changes usually show low signal intensity on T1-

weighted, which could be due to acute ischemic changes (tissue

edema). Usually, cortical high intensity lesions on both T1-

weighted and FLAIR images appear 2 weeks after the ictus



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indicating short T1 and long T2 lesions. Proton-density images

are more sensitive than T1-weighted MR images. On proton-

density images, cortical laminar necrosis may be seen as high

intensity due to increased mobile protons in the reactive tissue.

To conclude, cortical laminar necrosis shows characteristic

chronological signal intensity changes, and T1-weighted, FLAIR

and proton-density MR images are especially helpful in depicting

these changes (Komiyama et al., 1997).

Figure 14 : Cortical laminar necrosis. Sagittal T1-weighted MR image depicts the

gyriform increased signal area in right temporal and parietal region. T2-weighted

MR and FLAIR images show these areas as dark signal




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Basal ganglionic calcifications

Appears as hyperdense signal of the basal ganglia in CT and MRI

(Smith et al., 2009).

Figure 15. Basal ganglionic calcification (Amogh et al, 2011) .

Neuroimaging of cerebral microbleeds

GRE MRI has the ability to not only detect acute and chronic

haematomas but also old, clinically silent cerebral microbleeds

that are not seen on CT. Microbleeds are generally defined as

punctate, homogeneous, rounded, hypointense lesions in the

parenchyma that are smaller than 5–10 mm . Pathological studies

have shown that microbleeds seen with GRE MRI usually

correspond to haemosiderin-laden macrophages adjacent to small

vessels and are indicative of previous extravasation of blood.

Microbleeds have been seen in up to 80% of patients with

primary intracerebral haemorrhage, 21–26% of patients with

ischaemic stroke, and 5–6% of asymptomatic or healthy elderly

individuals (Herholz et al., 1990).



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Figure 16 : Microbleed imaging. T1-weighted (left), T2-weighted (middle), and T2-

weighted (right) images. Cerebral microbleeds, depicted by arrows, are visualized

only on the T2- weighted image and not on the T1-weighted or T2-weighted

images. The T2-weighted image is susceptible to paramagnetic properties of

hemosiderin, causing the microbleeds to appear as black dots of signal loss


Neuroimaging of cerebral haemorrhage

Until recently, non-contrast CT was the gold standard for the

diagnosis of intracerebral haemorrhage, and at many centres it is

still the imaging modality of choice for the assessment of

intracerebral haemorrhage, owing to its widespread availability

and rapid acquistion time. Conventional T1-weighted and T2-

weighted MRI pulse sequences are not sensitive to blood in the

hyperacute stage; however, several recent studies have now

shown that GRE MRI sequences are as accurate as CT for the

detection of intraparenchymal haemorrhage and far superior to

CT for the detection of chronic haemorrhage (Chalela et al.,

2007).

In some cases, MRI might actually detect haemorrhages that are

missed on CT (Packard et al., 2003) and MRI is better than CT

at identifying underlying structural lesions and for quantifying

perihaematomal oedema. However, up to 20% of patients with

acute stroke are unsuitable for MRI (eg, they have pacemakers or



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metal implants or are unable to lie flat or still for the duration of

the scan) ( Singer et al., 2004). For both MRI and CT, baseline

and serial studies can be used to identify patients who might

benefit from acute interventions (eg, hydrocephalus that requires

cerebrospinal fluid drainage or large or expanding cerebellar

haematomas that require posterior fossa decompression). Both

modalities can include post contrast studies and vessel

angiography to rule out underlying structural lesions (eg,

arteriovenous malformation, aneurysm or tumour). In general,

contrast studies and catheter angiography are indicated in patients

without a clear underlying aetiology or in patients with

haemorrhages in unusual locations (Broderick et al., 2007). One

recent study suggested a high yield for angiography, even in

patients with putaminal haemorrhage, unless the patient is older

than 55 years and has hypertension (Park et al., 2007).

Neuroimaging provides considerable information with regard to

prognosis. Early CT studies in patients with intracerebral

haemorrhage have shown that more than a third of patients have

substantial (>33%) haematoma growth when imaged within 3

hours of onset. Haematoma expansion is associated with larger

baseline haematoma volumes (Broderick et al., 2007). In turn,

haematoma expansion and the presence of intraventricular

haemorrhage are predictors of poor outcome. Cortical

intracerebral haemorrhage can be associated with better

functional outcome; however, the rate of long-term recurrence is

increased by a factor of 3·8 (Castellanos et al., 2005). Several

recent studies have reported that contrast extravasation seen on

CT angiography might also be an early predictor of haematoma



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expansion and poor outcome. Therefore, CT angiography could

have important applications for the selection of patients for acute

therapies (eg, blood pressure management or haemostatic

therapy) (Wada et al., 2007).

Imaging techniques also provide insights into the underlying

pathophsyiology of intracerebral haemorrhage. Interest in these

imaging approaches is driven by the belief that poor outcome in

primary intracerebral haemorrhage results, in part, from ongoing

secondary neuronal injury in the perihaematomal region. Some of

the studies that use PET, single-photon emission computed

tomography (SPECT), and, more recently, perfusion MR and

perfusion CT have shown perihaematomal regions of

hypoperfusion and bioenergetic compromise. The results of MRI

studies have suggested that approximately a third of patients who

are imaged in the acute phase will have reduced perihaematomal

apparent diffusion coefficient abnormalities on diffusion-

weighted imaging, and further studies have characterised the

timecourse for early perihaematomal changes. Apparent diffusion

coeffcient values were low during the first day and then gradually

increased, which probably matches the development of

perihaematomal oedema (Herweh et al., 2007; Pascual et al.,

2007).



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Table 8 : Appearance of blood on CT and MRI (Chelsea et al., 2008)

Figure 17: Neuroimaging features of small vessel disease. (A)Multiple

microbleeds (small foci of hypointensity) in the cortex of a patient with possible

cerebral amyloid angiopathy as shown on a gradient-echo MRI sequence. (B) Acute

haematoma on a CT scan. (C) White matter lesions or hyperintensities on MRI

FLAIR. (D) A lacunar infarction in right thalamus on T1-weighted MRI (Pantoni,

2010).



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Figure 18 : Examples of primary intracerebral haemorrhage

(A) Appearance of acute hypertensive haemorrhage on CT (left) and GRE MRI

(right) both obtained within 12 h of symptom onset. GRE MRI shows a

classic rim of hypointense signal surrounding the core of the haematoma.

(B) Subacute left thalamic intracerebral haemorrhage (black arrow),

chronic haematoma with slit-lik appearance (white arrow), and large

microbleed (green arrow), all seen with GRE MRI. (C) GRE MRI that

shows a large number of lobar microbleeds in the setting of an acute left

frontal intracerebral haemorrhage. These are consistent with

underlyingcerebral amyloidangiopathy. A larger version of (C) can be

found online (Chelsea et al., 2008).



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Imging of intracranial aneurysms

Current neuroimaging techniques for intracranial aneurysms

include intra-arterial digital subtraction angiography, magnetic

resonance angiography, computed tomographic angiography and

transcranial Doppler ultrasonography. Although intra-arterial

digital subtraction angiography is the gold standard, it is an

invasive test with a 1 percent risk of transient neurologic

complications and a 0.5 percent risk of permanent neurologic

complications (Mayberg et al., 1994).Caution must be exercised

in using magnetic resonance imaging in a patient with a history of

surgery, because surgical clips may pose a threat to the patient

during the test. The sensitivity and specificity of imaging

modalities are presented in next table (Wardlaw and White,

2000).

ModalitySensitivity(%)

Specificity(%)

Magnetic resonance angiography 69 to 100 75 to 100Computed tomographicangiography

85 to 95 Not reported

Transcranial Dopplerultrasonography

50 to 91 87.5

Table 9: The sensitivity and specificity of imaging modalities (Wardlaw and

White, 2000).



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Figure 19Partially thrombosed giant intracranial aneurysm. A large low-signalintensity esion is noted on the spin echo scan with intermediate T2-weighting (A) inthe region of the eft cavernous sinus. A pulsation artifact (black arrows) is seenextending in the phase ncoding direction posteriorly from the lesion but originatingfrom only the more medial ortion. Comparison of pre(B) and postcontrast (C) T1-weighted scans reveals nhancement in only the more anterior and medial portionsof the lesion (white arrow). hree-dimensional time-of-flight magnetic resonanceangiography depicts a patent lumen wthin the mass corresponding in position tothat suggested by the pulsation artifact andcontrast enhancement. The majority ofthis giant aneurysm of the cavernous and distalpetrous carotid artery is thrombosed.Only a crescent of residual lumen remains. Theprecontrast scans are misleadingbecause the clotted portion of the aneurysm has very lowsignal intensity on the T2-weighted scan and intermediate to low signal intensity on the T1-weighted scan. butnormal-caliber, basilar artery is more likely to produce isolated cranialnerveinvolvement, whereas ectasia is more likely to cause multiple deficits ofeithercompressive or ischemic cause (www.yassermetwally.com, 2013).



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Treatment and prevention of microvascular

diseases of the brain

Acute treatment of lacunar infaction

The main goals in the initial phase of acute stroke management

are to ensure medical stability, begin to uncover the

pathophysiologic basis of the neurologic symptoms and to

determine whether patients with acute ischemic stroke are

candidates to receive treatment with thrombolysis.Randomized

controlled trials have shown that intravenous

alteplase (recombinant tissue-type plasminogen activator or rtPA)

improves functional outcome from ischemic stroke and that

benefits outweigh the risks for eligible patients who receive

treatment within 4.5 hours of symptom onset (or within 4.5 hours

of when the patient was last seen normal in cases when onset time

is unknown) (Hacke et al., 2008).

Subgroup analysis of trial data suggest that the benefit with

thrombolysis is sustained in patients with lacunar stroke.

However, until better data are available, patients with lacunar

syndromes should be selected for thrombolysis according to

current guidelines in the same way as patients with other subtypes

of ischemic stroke. Thrombolytic therapy is associated with a 6

percent risk of symptomatic brain hemorrhage. Thus, its benefits

must be viewed with caution in a condition with a relatively

benign natural history. This treatment option should be discussed

with the patient and family in each individual case (NINDS t-PA

Stroke Trial, 1997).



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Most patients with acute ischemic stroke who are not eligible for

thrombolytic therapy should be treated with aspirin.

Anticoagulation with heparin is generally not indicated for the

management of acute lacunar stroke. Eligibility criteria for the

treatment of acute ischemic stroke with recombinant tissue

plasminogen activator (alteplase) is summarized in the next table.



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Inclusion criteriaClinical diagnosis of ischemic stroke causing measurable neurologic deficit withthe onset of symptoms <4.5 hours before beginning treatment; if the exact time ofstroke onset is not known, it is defined as the last time the patient was known to benormal

Exclusion criteria

Historical

Stroke or head trauma in the previous 3 monthsAny history of intracranial hemorrhageMajor surgery in the previous 14 daysGastrointestinal or urinary tract bleeding in the previous 21 daysMyocardial infarction in the previous 3 monthsArterial puncture at a noncompressible site in the previous 7 daysThe use of dabigatran within 48 hours prior to stroke onset is a relativecontraindicationFor treatment from 3 to 4.5 hours, additional relative exclusions (where therisk/benefit ratio is less clear) are age >80 years and/or a combination of bothprevious stroke and diabetes mellitusClinical

Spontaneously clearing stroke symptomsOnly minor and isolated neurologic signsSeizure at the onset of stroke is an exclusion if the residual impairments are due topostictal phenomenon; seizure is not an exclusion if the clinician is convinced thatresidual impairments are due to stroke and not to postictal phenomenonSymptoms of stroke suggestive of subarachnoid hemorrhagePersistent blood pressure elevation (systolic ≥185 mmHg, diastolic ≥110 mmHg)Active bleeding or acute trauma (fracture) on examinationFor treatment from 3 to 4.5 hours, an additional relative exclusion (where therisk/benefit ratio is less clear) is an NIH Stroke Scale score of >25Laboratory

Platelets <100,000/mm3*Serum glucose <50 mg/dL (<2.8 mmol/L)International normalized ratio (INR) >1.7 if on warfarin*; the use of dabigatranwithin 48 hours of stroke onset is a relative contraindicationFor treatment from 3 to 4.5 hours, an additional relative exclusion (where therisk/benefit ratio is less clear) is oral anticoagulant use regardless of INRElevated partial thromboplastin time (aPTT) if on heparin*Head CT scan

Evidence of hemorrhageEvidence of a multilobar infarction with hypodensity involving >33 percent of thecerebral hemisphere

table 10 Eligibility criteria for the treatment of acute ischemic stroke with

recombinant tissue plasminogen activator (alteplase)( Jauch et al, 2013).



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Prevention of microvascular disease of the brain

The American Heart Association/American Stroke Association

(AHA/ASA) has published guidelines for the prevention of stroke

in patients with ischemic stroke risk factors . All patients with

atherosclerotic cerebrovascular disease should have risk factors

controlled. Most patients with an ischemic stroke or transient

ischemic attack should be treated with all available risk reduction

strategies. Currently viable strategies include blood pressure

reduction, statins and antiplatelet therapy ( Furie et al., 2011).

Antiplatelet therapy

Aspirin is effective for secondary stroke prevention in patients

with noncardioembolic transient ischemic attack and ischemic

stroke. However, clopidogrel treatment was better than aspirin as

measured by a composite outcome of stroke, myocardial

infarction or vascular death in the clopidogrel versus aspirin in

patients at risk of ischaemic events (CAPRIE) study(CAPRIE

Steering Committee, 1996), and the combination of aspirin-

extended-release dipyridamole had greater benefit for secondary

stroke risk reduction than aspirin alone in two clinical trials

(ESPS-2 and ESPRIT)(ESPRIT Study Group, 2006).

Current guidelines from the American Heart

Association/American Stroke Association (AHA/ASA) and the

American College of Chest Physicians (ACCP) recommend that

patients with a noncardioembolic (ie, atherothrombotic, lacunar,

or cryptogenic) stroke or transient ischemic attack and no

contraindication receive an antiplatelet agent to reduce the risk of




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recurrent stroke. These guidelines note that aspirin, clopidogrel

and the combination of aspirin-extended-release dipyridamole are

all acceptable options for preventing recurrent noncardioembolic

ischemic stroke or transient ischemic attack. The 2012 American

College of Chest Physicians guidelines include cilostazol in this

group of recommended antiplatelet agents, and further suggest

the use of the combination of aspirin-extended-release

dipyridamole or clopidogrel over aspirin or cilostazol (Lansberg

et al., 2012).

Aspirin and clopidogrel should not be used in combination for

stroke prevention, given the lack of greater efficacy compared

with either agent alone and given the substantially increased risk

of bleeding complication.The use of dual antiplatelet therapy with

aspirin plus clopidogrel has been studied in different subtypes of

ischemic stroke, including small vessel disease and large artery

atherosclerosis (Benavente et al., 2012).

In a randomized trial Secondary Prevention of Small Subcortical

Strokes (SPS3) evaluating over 3000 patients with subcortical (ie,

lacunar) stroke confirmed by MRI, the arm testing the

combination of aspirin plus clopidogrel versus aspirin alone was

terminated before completion because of a higher frequency of

bleeding events (mostly systemic) and a higher mortality rate in

patients assigned to dual antiplatelet therapy compared with those

assigned to aspirin only (Benavente et al., 2012).

The Warfarin-Aspirin in Recurrent Stroke Study (WARSS) was a

randomized, double-blind trial that investigated the benefits of

aspirin (325 mg/day) compared with warfarin (international






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93

normalized ratio 1.4 to 2.8) in 2206 patients who had an ischemic

stroke within the previous 30 days . Patients scheduled for carotid

endarterectomy or who had a presumed cardioembolic source of

stroke were not included. After two years of follow-up, there was

no difference between the two groups in the prevention of

recurrent ischemic stroke or death, or in the rate of major

hemorrhage. More than one-half of the cohort (1237 patients) had

a lacunar stroke as their initial event; this group also

demonstrated no difference in outcome between warfarin and

aspirin. Since warfarin does not appear to provide benefit over

aspirin, and is more expensive and more difficult to manage, it

does not appear to have a role in secondary prevention in patients

who have had a lacunar infarct, other than in patients with a

presumed embolic source. (Mohr et al., 2001)

Blood pressure reduction

The 2011 American Heart Association/American Stroke

Association guidelines recommend blood pressure reduction for

the prevention of recurrent stroke and other vascular events in

patients with an ischemic stroke and transient ischemic attack

who are beyond the hyperacute period (Furie et al., 2011).

It has been confirmed recently in hypertensive patients that

effective antihypertensive therapy can reverse both functional

and structural rarefaction of skin capillaries (Debbabi et al.,

2006). Several years ago, literature reviews concluded that

antihypertensive agents that act mainly by vasodilation are

effective in improving microvascular structure, whereas agents

that act mainly by reducing cardiac output are not effective.



94

Recent work has confirmed this view and highlighted the

antioxidative and antiinflammatory actions of some agents

(Christensen and Mulvany, 2001).

Β Blockers

β-Blockers act primarily by reducing cardiac output and are not

effective in improving microvascular structure and function in

spontaneously hypertensive rat or in hypertensive or hypertensive

and diabetic patients. (Savoia et al., 2006) Nebivolol, a β1-

blocker with a β3-adrenoceptor agonist effect and vasodilatory

properties, improved coronary flow reserve and maximal

coronary blood flow in hypertensive patients (Galderisi et al.,

2004).

Diuretics

Hydrochlorothiazide therapy has no beneficial effect, but

chlorthalidone improves minimal forearm vascular resistance (an

indirect measure of microvascular structure) in hypertensive

patients. Indapamide prevented hypertrophic remodeling of

cerebral arterioles in spontaneous hypertensive rat (Dell'Omo et

al., 2005).

Calcium Antagonists

Calcium antagonists inhibit vascular smooth muscle contraction

to produce vasodilation and generally improve microvascular

structure, including reducing the media:lumen ratio of resistance

arteries (Levy et al., 2001).



95

ACE Inhibitors and Angiotensin Receptor Blockers

Angiotensin II is not only a vasoconstrictor but also promotes the

generation of reactive oxygen species and inflammatory

mediators that are implicated in many of the adverse changes in

microvascular structure and function. There is a substantial body

of evidence showing that agents that inhibit the renin-angiotensin

system, particularly ACE inhibitors, improve microvascular

structure and function. ACE inhibition has been shown to

improve microvascular structure in hypertensive patients and

resistance arterial structure in hypertensive patients and in

hypertensive individuals with type 2 diabetes (Rizzoni et al.,

2005).

Combination Therapy

Many hypertensive patients require more than one drug to

achieve blood pressure targets. The combination whose effects on

tissue perfusion have been studied most extensively is a low-dose

combination of the ACE inhibitor perindopril and the diuretic

indapamide. This combination improves myocardial capillary

density in renovascular hypertensive rats (Levy et al., 2001),

and stroke-prone spontaneously hypertensive rat and enhances

neovascularization, capillary density and perfusion in response to

experimental hypoperfusion and ischemia in rat skeletal muscle.

In each of these studies, the beneficial effect of the combination

was greater than with either component alone. This combination

also increases insulin sensitivity allowing proper control of

diabetic hypertensive patients (Silvestre et al., 2002).



96

Control of diabetes mellitus

Strict glycemic control, if achieved before irreversible end-organ

damage has occurred, reduces the incidence of microvascular

disease, neurologic dysfunction and cardiovascular disease in

patients with type 1 and 2 diabetes. Thus, intensive insulin

therapy should be attempted in all appropriate patients with type

1 diabetes as early in the course of disease as is safely feasible.

Both patient and clinician education and support are required to

perform this task safely (Brownlee and Hirsch, 2006).

The optimal level of glycemic control is uncertain. In general, we

aim for an A1C value of 7 percent or lower in patients in whom

the benefits outweigh the risks. Specific glycemic targets should

be set for individual patients, weighing benefits related to life

expectancy and existing complications against the risk of

hypoglycemia. In general, A1C goals are set higher for children

and adolescents, especially in children with frequent

hypoglycemia or hypoglycemia unawareness. Increasing the

intensity of glycemic control to achieve A1C <7 percent is

indicated during pregnancy in type 1 and type 2 diabetic women,

since the A1C level in nondiabetic women falls during pregnancy

and the demonstrated benefits to the fetus and neonate drive the

therapeutic goals (Brownlee and Hirsch, 2006).

The effect of fluctuations in glucose levels as measured within or

between days on the risk of developing diabetic complications is

uncertain. This has theoretical clinical implications, as free

radicals have been implicated in endothelial damage and the

formation of atherosclerotic plaques. One may therefore



97

hypothesize that control of daily blood glucose fluctuations, in

addition to management of chronic hyperglycemia (as measured

by A1C) in diabetic patients, could be important in protection

against micro- and macrovascular disease (Kilpatrick et al.,

2006)

Statin therapy

In patients with hyperlipidemia, treatment with HMG CoA

reductase inhibitors (statins) decreases the risk of stroke, while

lipid lowering by other means (eg, fibrates, resins, diet) has no

significant impact on stroke incidence (Corvol et al., 2003).

Therefore, it seems plausible that the protective effects of statins

are not mediated by cholesterol lowering but by anti

atherothrombotic properties (Donnan and Davis, 2004).

Statins reduce the risk of both initial and recurrent stroke. This

conclusion is supported by a meta-analysis of randomized

controlled trials with more than 165,000 participants published

through December 2008 that evaluated statin treatment in

combination with other preventive strategies for all stroke

(ischemic and hemorrhagic), including both primary and

secondary prevention (Amarenco et al., 2009).

The following observations were made :

Compared with control assignment, statin treatment

reduced the risk of all stroke by 18 percent (95% CI

13-23 percent).



98

In 10 trials with over 83,000 patients, statins did

NOT increase the risk of hemorrhagic stroke .

However, in a subgroup of patients with prior

symptomatic cerebrovascular disease, most from the

SPARCL trial, there was an increased risk of

hemorrhagic stroke .

In the only trial (SPARCL) designed to evaluate

statins for secondary stroke prevention, intense

reduction of LDL significantly reduced the risk of

noncardioembolic recurrent stroke (RR 0.84).

The Stroke Prevention by Aggressive Reduction in Cholesterol

Levels (SPARCL) trial is the first to show that statin treatment

decreases the risk of recurrent ischemic stroke among patients

with a history of stroke or TIA (Amarenco et al., 2009).

The heart protection study (HPS) findings showed that statin

therapy is associated with a substantial reduction in ischemic

stroke, regardless of age, gender or blood lipid concentration

when treatment is initiated. Furthermore, statin therapy reduced

the risk of major vascular events among people who have had a

previous stroke (Collins et al., 2004).

Utility despite normal cholesterol

Even patients with "average" serum cholesterol concentrations

appear to benefit from statin therapy in terms of stroke reduction.

This was demonstrated in the SPARCL trial where the mean

baseline LDL-C and total cholesterol levels were 133 and 212

mg/dL (3.4 and 5.5 mmol/L), respectively, and in the The heart



99

protection study where the mean baseline LDL-C and total

cholesterol levels were 131 and 224 mg/dL (3.4 and 5.8 mmol/L),

respectively (Plehn et al., 1999).

Benefit with statin treatment was also seen in the Cholesterol and

Recurrent Events (CARE) trial, which included 4159 patients

with a history of a myocardial infarction in the previous two

years who had mean LDL-C and total cholesterol serum

concentrations of 139 and 209 mg/dL (3.6 and 5.4 mmol/L),

respectively. In addition to a reduction in coronary events,

therapy with pravastatin was associated with significant

reductions in the frequency of stroke (2.6 versus 3.8 percent) and

of stroke plus transient ischemic attacks (4.4 versus 6.0 percent)

(Plehn et al., 1999).

Potential mechanisms

The totality of evidence presents a paradox: long term treatment

with statins reduces the risk of stroke but hypercholesterolemia is

not a strong risk factor for stroke. An explanation for this

apparent paradox is becoming clear as we continue to learn more

about the mechanism of benefit of statins. In addition to their

cholesterol lowering properties, statins also have a role in plaque

stabilization, reducing inflammation, slowing carotid arterial

disease progression improving endothelial function and reducing

embolic stroke by prevention of myocardial infarction and left

ventricular dysfunction (Hegland et al., 2003).

As already noted, several meta-analyses have found that

treatment with statins decreases the risk of stroke in patients with



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hyperlipidemia, while lipid lowering by other means (eg, fibrates,

resins, diet) has no significant impact on stroke incidence

(Corvol et al., 2003).

Few stroke prevention studies have looked at the effectiveness of

agents other than statins for the treatment of dyslipidemia. In a

randomized controlled trial, niacin (nicotinic acid) reduced the

risk of cerebrovascular events . In the Veterans Affairs High-

Density Lipoprotein Intervention (VA-HIT) trial, Patients taking

gemfibrozil had a lower rate of stroke (4.6 versus 6 percent for

placebo), TIA (1.7 versus 4.2 percent), and carotid

endarterectomy (1.3 versus 3.5 percent). The reduction in stroke

risk was evident after 6 to 12 months of therapy. (Corvol et al.,

2003)

Alcohol intake

Alcohol affects the risk of stroke in contradictory directions

depending upon level of consumption, type of stroke and

possibly ethnicity. Light drinking (one to two drinks per day) is

associated with a reduced risk of stroke, while heavy drinking is

associated with an increased risk. National guidelines from the

American Heart Association and American Stroke Association

issued in 2011 recommend that patients with ischemic stroke or

transient ischemic attack who are heavy drinkers should

eliminate or reduce their alcohol consumption (Furie et al.,

2011).



101

Lowering homocysteine levels

Vitamin supplementation with folate lowers homocysteine levels.

In patients who are treated to lower homocysteine levels

treatment is suggested to be with folic acid (1 mg/day), vitamin

B6 (10 mg/day) and vitamin B12 (0.4 mg/day). All patients

should receive a B complex vitamin to mitigate against peripheral

neuropathy. Normalization of the homocysteine concentration has

been reported within two weeks, but further lowering of

homocysteine levels occurs by six weeks. The dose of folic acid

should be increased up to 5 mg/day as needed to lower the

homocysteine concentration below 15 µmol/L. In patients with a

homocysteine concentration >30 µmol/L or chronic renal failure

the initial dose of folic acid is 5 mg/day. Although the data are

limited, in refractory cases we begin therapy with

trimethylglycine (betaine) 750 mg twice daily and increase the

dose as necessary (Brattström et al., 1990).

The effect of dose and treatment duration was illustrated in a

study in which 37 otherwise normal subjects with persistent

hyperhomocysteinemia were treated with 0.2 mg/day of folic

acid . The plasma homocysteine concentration was reduced in

almost all within seven weeks and fell to the normal range in 21

by seven months; most of the remaining subjects attained normal

homocysteine concentrations on a higher folate dose of 5 mg/day

(Guttormsen et al., 1996).




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Treatment of vasculitis

No randomised clinical trials of medical management in primary

central nervous system vasculitis exist; therefore, treatment for

primary central nervous system vasculitis has been derived from

therapeutic strategies used in other vasculitides, from anecdotal

reports and from cohort studies. Earliest reports suggested a poor

outlook with fatal outcome in most patients and transient or

doubtful effectiveness of glucocorticoids. Studies, including those

by Cupps and his colleagues in 1983 reported the effectiveness

of cyclophosphamide in combination with corticosteroids.

Since these early reports, cohort studies have described a more

favourable course of primary central nervous system vasculitis. In

a cohort study of 101 patients, glucocorticoids alone or in

combination with cyclophosphamide achieved a favourable

response in most patients. Response rates were similar (81%) in

both treatment groups with improvement of Rankin scale scores

over time. Glucocorticoid therapy should be started as soon as

primary central nervous system vasculitis is diagnosed. An initial

dose of prednisone of 1 mg/kg per day (or equivalent) as a single

or divided dose is recommended. If a patient does not respond

promptly, cyclophosphamide should be started (Salvarani et al.,

2007).

In an approach to reduce the toxic effects of drugs, a 3–6 month

course of oral cyclophosphamide (2 mg/kg per day) might also be

beneficial to induce remission in primary central nervous system

vasculitis because it has proved effective in other vasculitides.

Intravenous pulses of cyclophosphamide (0,75 g/m2 per month

for 6 months) are probably safer than is daily oral therapy,



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although whether the two regimens differ in terms of

effectiveness is unclear. Infection, cancer (in particular

transitional cell carcinoma of the bladder), and infertility are the

most serious toxic effects of cyclophosphamide. Subsequently,

consideration of a low-risk immunosuppressant such as

azathioprine (1–2 mg/kg daily), methotrexate (20–25 mg/week),

or mycophenolate mofetil (1–2 g daily) for maintenance of

remission is advised. However, little direct evidence exists for the

effectiveness of these drugs. A treatment course of 12–18 months

is adequate in most patients (Salvarani et al., 2007).

In patients with severe or progressive primary central nervous

system vasculitis that is life-threatening, high-dose intravenous

methylprednisolone (1000 mg daily for 3 days) and

cyclophosphamide can be used immediately after diagnosis,

although no evidence exists that methylprednisolone pulses are

more effective than oral prednisone. Repeated pulses of

intravenous methylprednisolone can also be given for disease

flares. Tumour necrosis factor α (TNFα) blockers and

mycophenolate mofetil (2 g daily) can successfully treat patients

with primary central nervous system vasculitis that is resistant to

glucocorticoids and immuno suppressants.(Sen et al., 2010).

However, only two reported patients given TNF blockade for

primary central nervous system vasculitis exist, given to both as

adjunctive treatment. Infliximab (5 mg/kg) seemed to rapidly and

effectively improve the neurological status and MRI

abnormalities of one patient with a rapidly progressive course,

and longterm etanercept (50 mg/week) stopped relapse and led to

the discontinuation of prednisone in the second patient. Anti-



104

CD20 therapy with rituximab has been used successfully in

refractory Wegener’s granulomatosis with central nervous system

features, suggesting a possible therapeutic role for this drug in

primary central nervous system vasculitis (Holle and Gross,

2011).

All patients should receive prophylactic treatment for

osteoporosis and prophylaxis against Pneumocystis jirovecii

infection (co-trimoxazole [trimethoprim 80 mg and

sulfamethoxazole 400 mg, per day]). Evidence that all patients

with primary central nervous system vasculitis do not need the

same therapy is emerging . Those with several bilaterally affected

large vessels, rapidly progressive disease and many recurrent

cerebral infarctions should be started promptly on aggressive

therapy, although those with progressive disease usually have a

poor response to therapy with a fatal outcome. By contrast,

patients with affected small vessels, characterised by prominent

leptomeningeal enhancement on MRI or by negative cerebral

angiogram and a positive brain biopsy, typically have a rapid

response to treatment with a favourable neurological outcome

(Salvarani et al., 2008).

Trials in dementia and small vessel disease

Some indirect evidence about the cognitive effect of antidementia

drugs on patients with small vessel disease can be extrapolated

from trials done in unselected samples of patients with vascular

dementia. Memantine, an NMDA antagonist used in Alzheimer’s

disease, slightly improved cognition in a group of more than 500

patients with vascular dementia. The authors reported that the

largest clinical effect was seen in patients without



105

cerebrovascular macrolesions, who made up about four-fifths of

the group (Wilcock et al., 2002).

In another double-blind trial, the acetylcholinesterase inhibitor

galantamine was superior to placebo in the general population

with vascular dementia in terms of cognition and function but

was also superior to placebo in the vascular dementia subgroups;

two of these subgroups could possibly be defined as small vessel

disease groups (patients with multiple lacunar infarcts and

extensive white matter changes) (Auchus et al., 2007).

There have been many other negative trials in which the

populations affected by vascular dementia have not been

specified or well described. Small vessel disease dementia (also

named subcortical vascular dementia) has been proposed as an

appropriate target for therapeutic studies because it has been

deemed more homogeneous in clinical, neuroimaging and

pathological terms. After some preliminary experiences with this

target population (Roman et al., 2002), the first placebo-

controlled study specifically focused on small vessel disease

dementia was done. In this trial, which tested oral nimodipine for

up to 12 months, positive findings were reported only for

secondary outcome measures (lexical production and a

deterioration of three or more points on the mini-mental state

examination), whereas negative results were reported for the

main outcome (a measure of global cognitive status)( Pantoni et

al., 2005).

A second trial was done exploratively in patients with CADASIL

and cognitive impairment. The study enrolled 168 patients who

were followed up after randomisation to the cholinesterase



106

inhibitor donepezil or placebo for 18 weeks. Significance on the

primary outcome measure (a change in the score on the vascular

Alzheimer’s disease assessment scale cognitive subscale) was

again not met, but in the group treated with the active drug, the

investigators reported a reduced decline on two secondary

cognitive measures that were more specifically affected in

patients with small vessel disease dementia (Dichgans et al.,

2008).

These two studies confirm that patients with the small vessel

disease subtype of vascular cognitive dementia can be selected as

a target group for a trial. They also lend support to the view that

the cognitive measures to be implemented in this sort of study

should be different from the general cognitive measures used in

trials of other dementia types and should be focused on the

specific cognitive deficits seen in subcortical vascular dementia

(Jokinen et al., 2009).

Another cholinesterase inhibitor, rivastigmine, has been tested in

two preliminary open studies in small vessel disease dementia,

with some encouraging results that need to be tested in larger

double-blind studies (Moretti et al., 2003).

The Vascular Dementia trial studying Exelon (VANTAGE) was a

large international trial in which more than 700 patients with pure

vascular dementia were randomly assigned to receive

rivastigmine (3–12 mg per day) or placebo and were followed up

for 24 weeks and then for an open phase of a further 12 months.

The study had a pre-specified inclusion subgroup of patients with

small vessel disease defined on the basis of a combination of

clinical and neuroimaging criteria. These criteria were used



107

because the commonly used measures for vascular dementia are

not sensitive in detecting cognitive impairment caused by small

vessel disease. At the end of the study, the population with small

vessel disease proved to make up three-quarters of the entire

population, whereas only 18% had large vessel vascular dementia

and another 8% had a combination of the two forms.

Unfortunately, only the main results relating to the entire group

have been published and no analysis about the group with small

vessel disease has been released (Ballard et al., 2008).

The PROTECT program was designed to integrate proven

secondary stroke prevention measures into the standard stroke

care provided during acute hospital stay, with initiation and

maintenance of the following goals for all patients with ischemic

stroke :

Antithrombotic therapy.

Statin therapy.

Angiotensin converting enzyme inhibitor or angiotensin

receptor blocker therapy.

Thiazide diuretic therapy.

Smoking cessation advice and referral to a formal cessation

program.

American Heart Association diet.

Exercise counseling.

Stroke education, including knowledge of stroke warning

signs.



108

Awareness of individual's risk factors.

Implementation of this program was associated with a substantial

increase in treatment utilization at the time of hospital discharge

compared with conventional care . High rates of adherence were

maintained at 90 days after discharge (Ovbiagele et al., 2004).



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Discussion

Cerebral small vessel disease (SVD) is the term commonly used

to describe a syndrome of clinical, cognitive, neuroimaging and

neuropathological findings thought to arise from disease affecting

the perforating cerebral arterioles, capillaries and venules and the

resulting brain damage in the cerebral white and deep grey matter

(Pantoni, 2010). These perforating vessels are essential to

maintain optimum functioning of the brain’s most metabolically

active nuclei and complex white matter networks (Bullmore and

Sporns, 2012).

In the past years, small vessel disease has been recognised as a

serious problem. The disease is very common and causes

substantial cognitive, psychiatric and physical disabilities (De

Laat et al., 2011), is responsible for about afifth of all strokes

worldwide more than doubles the future risk of stroke and

contributes to up to 45% of dementias (Gorelick et al., 2011).

The cost to society is huge. Because the cause of disease is

unknown, prevention and treatment (still mostly empirical) are

probably suboptimum or even dangerous (Weber et al., 2012).

This unawareness could have resulted from attention being given

to other stroke mechanisms (ie, cortical atherothromboembolic

and cardioembolic stroke), the cognitive component being

overshadowed by Alzheimer’s disease and because most research

has focused on individual features of small vessel disease and did

not recognise the combined components as one disorder. Why is

so little known about such an important disease? Small vessels

are difficult to image and investigate in vivo. The clinical

manifestations are diverse and include: sudden-onset stroke



110

symptoms or syndromes; covert neurological symptoms that

include mild, largely ignored, neurological symptoms and signs

(Saini et al., 2012); self-reported cognitive difficulties;

progressive cognitive decline, dementia, depression and physical

disabilities (De Laat et al., 2011).

The mechanisms that link small vessel disease with parenchyma

damage are heterogeneous and not completely known. The

commonest abnormality described pathologically is a diffuse

intrinsic disease of the small arterioles (40–200 μm diameter),

referred to as arteriolosclerosis, lipohyalinosis or fibrinoid

necrosis (depending on severity of the abnormality) which

thought largely to result from hypertension. The vessel wall

changes include infiltration of plasma components and

inflammatory cells into the vessel wall and perivascular tissue

with resulting vessel wall and perivascular brain tissue damage

(Bailey et al., 2012).

Adiffuse process that started in the endothelium and consisted of

failure of the cerebral arteriolar and capillary endothelium to

function is suggested. In capillaries, which have no smooth

muscle layer the endothelial failure and leakage of plasma

components into the tissue would result more directly in oedema

and tissue damage. In arterioles, the endothelial disruption,

thickening of the vessel wall and luminal distortion would

eventually lead to secondary perforating arteriolar thrombosis,

luminal occlusion and traditional infarction. Loss of the normal

autoregulatory ability in the thickened, stiffened vessels would

contribute further to tissue damage through reduced ability to



111

vasodilate when needed leading to ischaemic changes

superimposed on the endothelial failure (Simpson et al., 2010).

Few studies have measured cerebral blood flow in patients with

small vessel disease and produced conflicting results. increased

brain tissue loss with advancing age and damage caused by

increased white matter hyperintensities result in decreased rate of

blood flow because less tissue needs to be supplied. Larger

longitudinal studies are needed to examine cerebrovascular

reactivity and not just resting cerebral blood flow (Wardlaw et

al., 2011).

Primary intracerebral hemorrhage occurs secondary to cerebral

amyloid anngiopathy and hypertension. In the most severe form

of cerebral amyloid angiopathy, the vessels become dilated and

disrupted with focal wall fragmentation and blood extravasation

with or without microaneurysmal dilatation. Cerebral

microbleeds occur due to leakage of blood from the vessels

(Vonsattel et al., 1991).

A nother paper suggested that elderly patients with increased

white matter hyperintensities had more jugular venous reflux

detected on Doppler ultrasound not accounted for by

hypertension, diabetes, hyperlipidaemia or smoking. However,

other factors that might be associated both with jugular venous

reflux and white matter hyper intensities, such as lung disease,

were not assessed. More studies of vascular dynamics and small

vessel disease are needed (Chung et al., 2011).

Two points can help to explain how small vessel disease might

produce different lesions in different locations of the brain and

vascular tree . First, the endothelial tight junctions are tightest in



112

capillaries, in which the barrier function is most important, and

looser in arteriolar and venular endothelium (Bechmann et al.,

2007). The second point relates to how the anatomy of the

perivascular spaces differs by location and how the basal ganglia

perforating arterioles have two leptomeningeal layers, where as

arterioles entering the deep white matter from the superficial

cortex only have one (Pollock et al., 1997).

Parenchymal changes associated with small vessel disease range

from visible perivascular spaces (virchow robin spaces) and

areas of subtle white matter rarefaction (leukoariosis) to cavitated

cystic lesions . Although changes in tissue pathology seen at post

mortem are frequently interpreted as ischaemic changes

supporting the endothelial dysfunction idea are seen too. Some

particularly large lacunar lesions with cystic degeneration might

be a consequence of end stage occlusive small vessel disease but

the pathophysiology of visible perivascular spaces and localized

changes in white matter are less well understood (wardlaw et al.,

2013).

Perivascular rarefaction is poorly studied. Damaged endothelium,

passage of plasma proteins into the vessel wall, damaged vessel

walls and leakage of fluid, albumin, other plasma proteins and

inflamatory cells into the perivascular tissue are established

observations. Loss of normal vascular integrity was the only

factor associated with an increased white matter hyperintensities

score on MRI in several potential components examined

neuropathologically: myelin degradation, microglial activation,

vascular density and vascular integrity (Black et al., 2009).



113

Additionally, the blood brain barrier was impaired in white matter

hyperintensities and increased astrocyte staining with

immunoglobulin G was seen suggesting blood brain barrier

failure in deep white matter. These observations support the idea

that although pathological changes seen at post mortem are

frequently interpreted as ischaemic on the basis of their

histological similarities to thromboembolic infarcts, changes that

support the idea of altered blood brain barrier permeability exist

(Young et al., 2008).

Increased expression of endothelial thrombomodulin is seen in

the arterioles of patients with small vessel disease; this raised

protein could be protective against local thrombosis, which is

attributable to changes in blood flow secondary to altered

arteriolar structure (Giwa et al., 2012). The presence of hypoxia

inducible factors in white matter hyperintensities at autopsy in

elderly patients might be secondary to impaired autoregulation

caused by small vessel disease because vessel walls were

thickened without luminal reduction; however, capillary

endothelial and microglial activation were also observed

(Fernando et al., 2006).

Visible perivascular spaces have been attributed to the pulsatile

effects of hypertensive arterioles or changes in the handling of

interstitial fluid among other explanations. The interstitial fluid

hypothesis is interesting in view of the growing published work

on fluid drainage in the perivascular spaces and the development

of cerebral amyloid angiopathy (Weller et al., 2009).

Virchow-Robin spaces or visible perivascular spaces surround the

small deep perforating arterioles as the arterioles pass through the



114

deep grey and white matter. These spaces are visible on T2-

weighted or T1-weighted MRI because they contain increased

fluid (in comparison with the surrounding tissue) of similar signal

to CSF. Although a few visible perivascular spaces can be normal

at any age, the presence of many is not normal. Although visible

perivascular spaces were observed histologically for many years

in older people (often in association with other SVD features), the

presence of these spaces around perforating arterioles was often

dismissed as an artifact of tissue processing . The relevance of

visible perivascular spaces to small vessel disease is shown by

their presence in increased numbers in patients with white matter

hyperintensities and with symptomatic lacunar ischaemic stroke.

A higher number of visible perivascular spaces also suggests

active inflammation eg, in multiple sclerosis in which diameter of

the spaces increases during active inflammation and in lacunar

stroke. Visible perivascular spaces are not simply a consequence

of global brain atrophy because they are often seen in patients

who have little atrophy, although they might be an alternative

manifestation of atrophy (Zhu et al., 2010).

Other features of small vessel disease include microbleeds, which

are small punctate areas of hypointensity on T2* or

susceptibility-weighted imaging that are up to 10 mm in diameter

and correspond to small collections of haemosiderin - laden

macrophages around small perforating vessels. Microbleeds are

associated with lacunar stroke and white matter hyperintensities

and are clearly part of the range of small vessel disease

(Shoamanesh et al., 2011).



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As mentioned earlier, the consequences of small vessel disease on

the brain parenchyma are heterogeneous, encompassing

ischaemic and haemorrhagic manifestations . However, in

neuroimaging, the term small vessel disease is often used

misleadingly to describe the ischaemic consequences (ie, white

matter lesions and lacunar lesions). Haemorrhagic lesions can be

further distinguished as macrolesions and microlesions. Although

major haemorrhages are easily recognised by conventional

neuroimaging, including CT, the detection of microbleeds

requires the use of appropriate magnetic resonance sequences

such as gradient-echo sequences (Greenberg et al., 2009).

White matter lesions on MRI are seen as more or less confluent

areas that are bilaterally and symmetrically sited in the

hemispheric white matter and that appear hyperintense on T2-

weighted and FLAIR images . The CT correlates are hypodense

periventricular or subcortical areas. By definition, these lesions

should not be adjacent to focal areas of cortical damage or

ventricular enlargement to distinguish them from the effects of

focal large infarcts on white matter. Despite the fact that white

matter lesions are typically supratentorial, they do frequently

occur in one infratentorial location (ie, the pons) and this has

been called pontine ischaemic rarefaction or pontine

leukoaraiosis. Many years after the introduction of the term

leukoaraiosis, the amount of data on the clinical and pathological

correlates of white matter lesions has enormously increased and

white matter lesions are currently generally thought to be a

consequence of small vessel disease. New magnetic resonance

techniques such as diffusion tension imaging and functional MRI



116

are expected to contribute to the understanding of the

pathophysiology of white matter lesions (and of small vessel

diseases in general) and their clinical correlates (Pantoni et al.,

2007)

Lacunar infarcts are defined as hypointense foci on MRI T1-

weighted sequences.There is no full consensus on the size of

lacunar infarcts; the maximum accepted diameter for the

definition of a lacunar infarct is usually 15 mm because this is the

size derived from the original pathological studies. A consensus

on the minimum diameter is more difficult to establish; an

ongoing multinational study has chosen a cut-off size of 3 mm

(van der Flier et al., 2005).

Some lacunar infarcts are located within areas of diffuse white

matter lesions. In these cases, it is difficult to determine whether

these lesions should be classified as pure lacunar infarcts or the

extreme consequences of chronic white matter rarefaction. In

fact, the most severe forms of white matter rarefaction are

visualised on neuroimaging as holes when focal and, therefore,

might be interpreted as lacunar infarcts. Lacunar infarcts are a

widely accepted sign of small vessel disease. However, this

classification might not apply to all the cavitated small infarcts.

For example, isolated lacunar infarcts, such as striatal infarcts,

might be caused by non-small vessel disease mechanisms such as

emboli from atherosclerotic plaques in the carotid arteries or

aortic arch. Some authors find it more appropriate to classify

patients with lacunar infarcts as having small vessel disease only

when the lacunar infarcts are multiple or associated with

moderate to severe white matter lesions (Wardlaw, 2005).



117

Another problem in the assessment of lacunar infarcts on MRI is

the need to distinguish these from dilated perivascular spaces.

These are enlargements of the spaces around the penetrating

vessels in the brain parenchyma (also called Virchow-Robin

spaces) and are typically located in some areas (eg, anterior

commissure, vertex) that are different from those of lacunar

infarcts. Other MRI characteristics that can help to distinguish

dilated perivascular spaces from lacunar infarcts are that dilated

perivascular spaces are usually smaller than 1×2 mm and have

an isointense appearance with the CSF on proton density

sequences. Lacunar infarcts and dilated perivascular spaces share

the same risk factor profile and in fact some investigators believe

that dilated perivascular spaces are another expression of small

vessel disease in the brain (Rouhl et al., 2008).

MRI techniques have made a significant contribution to our

understanding of how structural alterations in small vessel

disease contribute to cognitive deficits. The neuroanatomy of

cognitive networks is complex and the spatial distribution of

lesions is an important factor to consider to develop a richer

understanding of the links between structure and cognitive

function (O’Sullivan, 2010).

The associations between vascular risk factors and small vessel

diseases are still not completely understood. Hypertension,

diabetes mellitus, hypercholesterolaemia and smoking are equally

common in patients with cortical atherothromboembolism as

they are in patients with lacunar stroke. Many patients with small

vessel disease are not hypertensive. For example, in 70

consecutive autopsies in patients with pathologically verified



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small vessel disease vascular risk factors were mostly absent.

Many sporadic cases and the monogenetic variants of small

vessel disease arise in normotensive patients. Hypertension is a

key risk factor for white matter hyperintensities (Godin et al.,

2011), but the association between white matter hyperintensities

and blood pressure is complex. In some longitudinal studies,

raised blood pressure some years previously seems to be more

strongly associated with white matter hyperintensities than is

concurrent blood pressure, although whether diastolic or systolic

blood pressure is more important is unclear (Marcus et al.,

2011).

Both previous and concurrent systolic and diastolic blood

pressure have been shown to predict the progression of white

matter hyperintensities in some but not other studies. In

observational studies, effective treatment with antihypertensive

treatment was associated with reduced progression of white

matter hyperintensities. However, in randomised controlled trials,

antihypertensive treatment has shown little or no effectiveness in

slowing progression of white matter hyperintensities (Weber et

al., 2012). This finding might be related to the short intervention

period or youngish age range (mean age 60–65 years) of the

patients in the trial. Both white matter tract integrity (Kohannim

et al., 2012) and burden of white matter hyperintensities are

highly heritable. It is possible that the association between small

vessel disease and blood pressure is at the genetic locus level

rather than being directly causal. However, this finding in a study

of small vessel disease gene associations in families has not been

replicated (Kochunov et al., 2011).



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Nonetheless, hypertension is likely to add harm and is at least

modifiable. The point is not to devalue the role of blood pressure

in small vessel disease but rather not to overlook other

mechanisms. If the apparent association between white matter

hyperintensities and hypertension is partly explained by genetic

co-association, then antihypertensive treatment might not be as

effective in the prevention of small vessel disease as is hoped

even if it is very effective in the prevention of large artery

atheromatous disease. Conversely, risk factors like hypertension

and smoking might particularly exacerbate small vessel disease in

those with any predisposition. Therefore, the prevention of

exacerbating risk factors such as hypertension and smoking could

be particularly effective if small vessel disease vulnerability can

be identified (Schmidt et al., 2011).

The roles of homocysteine, B12, and folate in small vessel

disease are complex. Although homocysteine seems unrelated to

large artery atherothrombotic disease (eg, myocardial infarction),

the aminoacid might be associated with small vessel disease.

Some evidence exists of slowed progression of white matter

hyperintensities in patients with more severe white matter

hyperintensities given B12 and folate. Further data on

homocysteine, B12, and folate are needed (Cavalieri et al.,

2012).

Vascular dementia/vascular cognitive impairment is not a single

entity, but a large group of conditions characterized by various

clinical and morphological findings and variable

pathophysiology. Clinical diagnostic criteria show moderate

sensitivity (50–70%) and variable specificity (64–98%).



120

Epidemiological studies are hampered by the lack of clear and

validated diagnostic criteria, the complexity of brain pathologies,

ethnic and geographic variations. In Western clinic-based series

Vascular dementia is suggested in 8–15% of cognitively impaired

aged subjects, with age-standardized incidence ratios 0.42–2.6

and clinical prevalence at age 70+ of 6–15/1000 person/ year.

Prevalence in autopsy series ranges from 0.03 to 58% (real mean

8–15% in Western series, 22–35% in Japan). Both prevalence and

incidence increase with age. Neuropathology shows multifocal

and/or diffuse lesions, ranging from lacunes and microinfarcts,

white matter lesions, hippocampal sclerosis to multi-infarct

encephalopathy, mixed cortico-subcortical and diffuse post

ischemic lesions. They result from systemic, cardiac, local large

and small vessel disease. Pathogenesis is multifactorial and

cognitive decline is commonly associated with small

ischemic/vascular lesions, often involving subcortical and

strategically important brain areas (thalamus, frontobasal, limbic

system) (Jellinger, 2008).

Pathophysiology affects neuronal networks involved in cognition,

behavior, execution and memory. Vascular lesions often coexist

with Alzheimer disease (AD) and other lesions, multiple

pathologies greatly increasing the odds of dementia; 25–80% of

demented subjects show both Alzheimer disease and

cerebrovascular lesions. While both factors by synergistic

interaction contribute significantly to the risk of dementia,

Alzheimer disease pathology is often less severe in the presence

of vascular lesions. Due to the heterogeneity of cerebrovascular

pathology and its causative factors, no validated neuropathologic



121

criteria for Vascular dementia are currently available and a large

variability across laboratories still exists in morphologic

examination procedures and techniques. Harmonization of

neuropathologic procedures and evaluation criteria in future

prospective clinico-pathologic studies are needed to validate

diagnostic criteria for Vascular dementia and to clarify the impact

of vascular lesions on cognition (Jellinger, 2008).

Many aspects related to vascular parkinsonism continue to be a

source of confusion which may be documented by the extensive

heterogeneity of opinions presented in recent literature. There are

even problems related to the characterisation of vascular

parkinsonism as a clinical unit. Diagnostic criteria are not clearly

defined and consequently, patients with widely varied clinical

pictures may be diagnosed with parkinsonism. Another critical

stage is the interpretation of a finding of vascular lesions.

Consequently, doubt may be cast on the diagnosis of vascular

parkinsonism in most cases and vascular genesis may be

attributed to parkinsonism of different aetiology in some other

cases. The following types of simultaneous occurrence first, gait

disorders of the lower body parkinsonism type are caused mostly

by changes in frontal lobes; such disorders may require a

diagnosis of vascular origin when alternative causes are excluded.

We suggest replacing the term ‘‘lower body parkinsonism’’ with

a more appropriate term not including the word ‘‘parkinsonism’’:

an alternative term could be ‘‘cerebrovascular gait disorder’’,

second, if the signs and symptoms are typical for Parkinson

disease the coincidence of Parkinson disease and cerebrovascular

diseases should be considered third, if the symptoms of



122

parkinsonism are neither typical for Parkinson disease nor for

vascular parkinsonism and there are clinical and/or MR signs of

cerebrovascular diseases, the vascular parkinsonism should be

regarded as possible; fourth, if the symptoms of parkinsonism and

clinical and MR signs are typical for vascular parkinsonism, it

should be regarded as probable, fifth, if a stroke affecting the

contralateral basal ganglia is followed by the occurrence of

hemiparkinsonism, the diagnosis of vascular parkinsonism is

unambiguous(Rector et al., 2006).

No specific treatment for strokes caused by small vessel disease

in the acute phase has yet been proposed and there are no data to

support the suggestion that any of the three approaches with

recognised evidence based efficacy in the acute setting (aspirin,

thrombolysis, admission to a stroke unit) are not efficacious in

strokes caused by small vessel disease. The presence of small

vessel disease is instead a marker of apoor outcome in some

specific therapeutic settings, including acute phase thrombolysis

(Cocho et al., 2009).

Intravenous thrombolysis with recombinant tissue plasminogen

activator is an effective treatment for acute ischaemic stroke

within the first 3 h after onset. Intracranial bleeding is the most

serious side effect of this treatment, and efforts have been made

to identify predictors of this occurrence. In addition to advanced

age, hyperglycaemia and increased blood pressure levels

(Wahlgren et al., 2008), neuroimaging evidence in small vessel

disease indicates a risk of haemorrhagic transformation of brain

infarcts. In both these studies, the rate of symptomatic cerebral

haemorrhages was about 10% in the presence of moderate to



123

severe leukoaraiosis. In the Canadian Alteplase for Stroke

Effectiveness Study (CASES) (Palumbo et al., 2007), the

multivariable analysis showed that the increased risk of bleeding

determined by the presence of leukoaraiosis or multiple lacunes

was independent of age and other factors reported to increase this

risk. Recent data suggest that the time window of thrombolysis

could be extended up to 4,5 h with potential benefits. At present,

there are no data on whether the presence of small vessel disease

on neuroimaging confers an additional risk of bleeding in this

extended time window (Hacke et al., 2008).

In the North American Symptomatic Carotid Endarterectomy

Trial (NASCET) (Streifler et al., 2002), the presence of

leukoaraiosis on baseline CT scans conferred an increased risk of

stroke and death during the perioperative period (30 days), with a

three-times increased risk in patients with widespread

leukoaraiosis in comparison to those without leukoaraiosis. These

results suggest that the presence of leukoaraiosis predicts a

reduced benefit from the treatment but should not be taken as a

contraindication to surgical treatment. The role of concomitant

small vessel disease has also been investigated in other major

vascular surgery settings, such as thoracic aorta replacement and

is also a predictor of neurological injury. These data emphasise

the role of small vessel disease as a marker of adjunctive risk and

raise the question of whether preventive measures could be

specifically targeted in these patients (Lin et al., 2007).

As discussed earlier, one of the manifestations of small vessel

disease is cerebral haemorrhage. For this reason, the presence of

small vessel disease has been assessed as an additional risk for



124

bleeding in specific treatment conditions. In the Stroke

Prevention in Reversible Ischemia Trial (SPIRIT) (Gorter,

1999), leukoaraiosis was, together with an age older than 65

years, the only independent predictor of major bleeding during

anticoagulation started after cerebral ischaemia. These data were

confirmed by another group that reported leukoaraiosis to be

present on CT in 24 of 26 patients who were treated with warfarin

for secondary prevention of stroke and who developed

intracranial haemorrhage versus 27 of 56 controls without

intracranial haemorrhage; this difference resulted in an odds ratio

of 8,4 for leukoaraiosis as an independent risk factor for

warfarin-related intracranial haemorrhage in the multivariate

analysis (Smith et al., 2002).

Given the different pathogenetic mechanisms of strokes caused

by small vessel disease, one would ideally expect a distinct

therapeutic and preventive approach from that used for

atherosclerotic or cardioembolic strokes. However, stroke caused

by small vessel disease has rarely been the specific object of trials

and recent progress in treatment and prevention of stroke mainly

apply to large vessel pathology (Greenberg, 2006). Some data on

antiplatelet drugs in secondary stroke prevention after stroke

caused by small vessel disease can be derived from a few trials:

the Accidents, Ischemiques Cerebraux Lies a l’Atherosclerose

(AICLA) trial of aspirin plus dipyridamole versus

placebo(Bousser et al., 1983), the Canadian American

Ticlopidine Study (CATS) trial of ticlopidine versus placebo

(Gent et al., 1989), and the Chinese Acute Stroke Trial (CAST)

study of aspirin versus placebo for early prevention after 30 days;



125

(CAST, 1997) results from all these studies suggested efficacy of

the study drug in the subgroup of patients with stroke caused by

small vessel disease but there was no evidence that one drug or

combination was better than another. Moreover, there are no data

about a possible increased risk of haemorrhage. In the Cilostazol

Stroke Prevention Study, a placebo controlled, double blind,

multicentre study, 1095 patients were enrolled and about 75%

had a lacunar stroke. Treatment with cilostazol (100 mg per day)

was associated with a relative risk reduction of recurrence of

lacunar stroke of 43,4% which was on the border of statistical

significance (Gotoh et al., 2000).

The ongoing Secondary Prevention of Small Subcortical Strokes

(SPS3) trial has been designed to specifically focus on cerebral

small vessel disease. This trial is an interventional phase 3 study

for which 2500 patients are hoped to be enrolled (1500 have

already been randomly assigned). The study includes two trials:

in the first double-blind trial, treatment with aspirin will be

compared with treatment with aspirin plus clopidogrel; in the

second (open-arm) trial, the standard (130–149 mm Hg) control

of systolic blood pressure will be compared with intensive control

of blood pressure (target <130 mm Hg). The primary outcomes of

the study are the prevention of recurrent stroke and a reduction in

cognitive decline (Pergola et al., 2007). Patients with small

vessel disease are defined on the basis of criteria from the Trial of

ORG 10172 in Acute Stroke Treatment (TOAST) supplemented

by MRI data. The study is of particular interest because it is

specifically targeted at small vessel disease, compares two

antiplatelet regimens, assesses the control of the major risk factor



126

for small vessel disease and also takes into account a cognitive

outcome measure (Adams et al., 1993).

Given the available data, treatment with either clopidogrel 75 mg

daily as monotherapy or aspirin-extended-release

dipyridamole 25 mg/200 mg twice a day, rather than aspirin alone

is suggested. Some experts still prefer aspirin as the first-line

agent noting that the alternative antiplatelet regimens (clopidogrel

or aspirin-extended-release dipyridamole) have an apparent

modest advantage in benefit that is potentially offset by a

disadvantage in cost.

With regard to other pharmacological preventive measures,

results from the Stroke Prevention by Aggressive Reduction of

Cholesterol Levels (SPARCL) study have shown that patients

with small vessel disease and increased low-density lipoprotein

cholesterol have a similar risk of stroke recurrence as do patients

with large vessel strokes, and that treatment with atorvastatin 80

mg daily is equally effective in reducing this risk, implying that

patients with small vessel disease also benefit from statin therapy

(Amarenco et al., 2009).

The 2011 American Heart Association/American Stroke

Association guidelines recommend blood pressure reduction for

the prevention of recurrent stroke and other vascular events in

patients with an ischemic stroke and TIA who are beyond the

hyperacute period (Furie et al., 2011).

It has been confirmed recently in hypertensive patients that

effective antihypertensive therapy can reverse both functional and

structural rarefaction of skin capillaries (Debbabi et al., 2006).

Several years ago, literature reviews concluded that








127

antihypertensive agents that act mainly by vasodilation (ACEI

and ARBS) are effective in improving microvascular structure

whereas agents that act mainly by reducing cardiac output are not

effective. Recent work has confirmed this view and highlighted

the antioxidative and antiinflammatory actions of some agents

(Christensen and Mulvany, 2001).

Strict glycemic control, if achieved before irreversible end-organ

damage has occurred reduces the incidence of microvascular

disease, neurologic dysfunction and cardiovascular disease in

patients with type 1 and 2 diabetes. Thus, intensive insulin

therapy should be attempted in all appropriate patients with type

1 diabetes as early in the course of disease as is safely feasible.

Both patient and clinician education and support are required to

perform this task safely (Brownlee and Hirsch, 2006).

Control of vasculitis by glucocorticoid and other

immunosuppressant drugs showed great benefit. Prevention of

vascular parkinsonism and vascular dementia occurs by control of

risk factors like DM and hypertension. Many trials using classic

antiparkinsonian and antidementia drugs are done with modest

results.



128

Summary and conclusion

Microvascular diseases of the brain or cerebral small vessel

disease (SVD) is the term commonly used to describe a syndrome

of clinical, cognitive, neuroimaging and neuropathological

findings thought to arise from disease affecting the perforating

cerebral arterioles, capillaries and venules and the resulting brain

damage in the cerebral white and deep grey matter. Misleadingly

this term is used to describe ischemic consequences but these

patients are liable to hemorrhage.

The exact pathogenesis of microvascular diseases of the brain is

not known. But many mechanisms are suggested like

arteriosclerosis, lipohyalinosis, endothelial dysfunction and

failure of blood brain barrier to explain ischemic changes of

microvascular diseases of the brain. Cerebral amyloid angiopathy

and hypertension are the most common etiologies suggested to

explain the hemorrhagic changes.

Leukoaraiosis is an ischaemic demyelination of the immediate

periventricular white matter associated with astrogliosis, enlarged

extracellular spaces and white matter microcavitations. It is

secondary to chronic global reduction of brain perfusion.

Leukoaraiosis, which appears as an area of hyperintense signal in

the white matter on MR images, is an age-related

neurodegenerative condition that when severe correlates with

dementia. It is characterized histologically by demyelination, loss

of glial cells and spongiosis.

Lacunar infarction may be defined as small subcortical infarcts

(less than 15 mm in diameter) in the territory of the deep



129

penetrating arteries and may present with specific lacunar

syndromes or may be asymptomatic.It is secondary to

lipohyalinosis or microatheroma of the origin of the pentrating

artery. MRI is prefered in dignosis as it has more sensitivity to

lacunes especially infratentorial lacunes, DWI help in rapid

dignosis of new lacunes. They are most numerous in the

periventricular gray matter (thalamus and basal ganglia) and the

immediate periventricular white matter.

Granular atrophy is defined pathologically as infarctions

localized to the cerebral cortex and not extending to the

subcortical white matter. It is characterized by the presence of

small punched out foci of cavitated cicatricial softening situated

entirely in the cortex and accompanied by focal glial scar and

thinning of the cortical ribbon. The lesions are bilateral and

situated along the crest of the gyri. It is secondary to generalized

hypoxia rather than local vascular abnormality. It is seen as a

high signal lesion on T1-weighted MR images.

Pathologic dilatation of Virchow-Robin Spaces is most

commonly associated with arteriolar abnormalities believed to

result from moderate to severe microangiopathy. As the severity

of the microangiopathy increases, microvessels demonstrate

increasingly severe changes with arterial narrowing,

microaneurysms and pseudoaneurysms, onion skinning, mural

calcification, thrombotic and fibrotic luminal occlusions as

arseult of mechanical trauma due to CSF pulsation or vascular

ectasia, distinguished from lacunr infarctions by MRI as they are

typically located in some areas (eg, anterior commissure, vertex)

that are different from those of lacunar infarcts and are usually



130

smaller than 1×2 mm and have an isointense appearance with the

CSF on proton density sequences.

Basal ganglionic calcification are calcification of the the

arteriolar walls within the basal ganglia. Physiological

intracranial calcification occurs in about 0,3-1,5% of cases. It is

asymptomatic and is detected incidentally by neuroimaging as it

appears hyperdense in CT and hyperintense in MRI.

Pathological basal ganglia calcification is due to various causes,

such as: metabolic disorders, infectious and genetic diseases like

hyperparathyroidism, toxoplasmosis, AIDS and fahr syndrome.

Wilson disease should be suspected in young patient with hepatic

insult.

Microbleeds are small punctate areas of hypointensity on T2* or

susceptibility-weighted imaging that are up to 10 mm in diameter

and correspond to small collections of haemosiderin laden

macrophages around small perforating vessels. Microbleeds are

associated with lacunar stroke and white matter hyperintensities

and are clearly part of the range of small vessel disease. Many

types of hemorrhage result from small vessel disease either lobar

or subarachnoid hemorrhage. The most common cause are

cerebral amyloid angiopathy and hypertension. CT still the best in

diagnosis of cerebral hemorrhage due to its availability and rapid

acquisition time however, several recent studies have now shown

that GRE MRI sequences are as accurate as CT for the detection

of intraparenchymal haemorrhage and far superior to CT for the

detection of chronic haemorrhage.

Pathoetiologic classification of small vessel disease includes 6

types. Type 1 arteiosclerosis characterised by loss of smooth



131

muscle cells from the tunica media, deposits of fibrohyaline

material, narrowing of the lumen, and thickening of the vessel

wall this is thought to be secondary to hypertension. Type 2

sporadic and hereditary cerebral amyloid angiopathy characterized

by deposition of amyloid protein in vessel wall when severe the

vessels become dilated and disrupted with focal wall

fragmentation and blood extravasation. Type 3 inherited or genetic

small vessel diseases distinct from cerebral amyloid angiopathy

like CADASIL. Type 4 Inflammatory and immunologically

mediated small vessel diseases are a heterogeneous group of rare

diseases characterised by the presence of inflammatory cells in

the vessel walls (vasculitis) and are usually part of a systemic

disease. Type 5 venous collagenosis characterized by increased

thickness of the walls that results in narrowed lumen and,

sometimes, occlusion. Type 6 other small vessel disease like post

radiation angiopathy.

An abrupt increase in pressure brings about a rapid and reversible

vasoconstriction of small resistance vessels due to their inherent

myogenic tone. Prolonged elevations of pressure can cause a

range of more lasting changes in the microcirculation, two of

which remodeling of small arteries and arterioles and rarefaction

of arterioles and capillaries. Howevere the role of hypertension in

small vessel disease is conflicting. DM and insulin resistance

acting via oxidative stress, inflammation and advanced glycation

end products, can induce microvascular abnormality through

functional and structural microvascular rarefaction. Although

obesity through oxidative stress, chronic inflammation and

elevation free fatty acids causes microvascular abnormality.



132

Cerebral amyloid angiopathy , although usually asymptomatic, is

an important cause of primary lobar intracerebral hemorrhage

limited to cortical and subcortical area of the brain in contrast to

hypertensive haemorrhage that occures in deep structure like the

the basal ganglia. A less common, but clinically important

manifestation of cerebral amyloid angiopathy is transient

neurologic symptoms distinguished from true TIAs include the

smooth spread of the symptoms, the absence of hemodynamically

significant stenosis in the relevant vascular supply and the

presence of small hemorrhage in the corresponding region of

cortex best shown in GRE-MRI.

CADASIL is autosomal dominant disease caused by mutations in

the NOTCH3 gene on chromosome 19. CADASIL presnts by

Ischemic episodes, cognitive deficits, migraine with aura or

psychiatric disturbances. MRI signs of CADASIL Small

circumscribed regions that are isointense to cerebrospinal fluid

on T1- and T2-weighted images. CARASIL also known as

Maeda Syndrome, is clinically similar to CADASIL but with

earlier onset and several extraneurological symptoms like

arthropathy and disc herniation.

Vasculitis is a spectrum of clinicopathological disorders defined

by inflammation of the blood vessels including arteries and veins

of varying caliber which result in a variety of clinical

neurological manifestations related to ischemic injury of the

central nervous system and peripheral nervous system. It

includes churg-strauss, henoch schenolien purpura, Wegener’s,

hypersensitivity vasculitis and vasculitis secondary to connective

tissue disorder like SLE, RA and behcet disease.



133

Hyperhomocystinemia causes cerebral microvascular diseases as

homocysteine has primary atherogenic and prothrombotic

properties. Histopathologic hallmarks of homocysteine induced

vascular injury include intimal thickening, elastic lamina

disruption, smooth muscle hypertrophy, marked platelet

accumulation and the formation of platelet-enriched occlusive

thrombi.

The rheological changes associated with microvascular brain

disease include increase in the whole blood viscosity and

thrombotic tendency of the blood. In general a significant

increase of blood, plasma and serum viscosity and a decrease of

whole blood filterability significantly impair flow in the

microcirculation and contribute to the development of the

ischemic microvascular brain disease. Whole blood viscosity is a

collective terminology that include blood viscosity and plasma

viscosity. Blood viscosity is determined by the haematocrit value

and plasma viscosity is determined by serum fibrinogen. Plasma

fibrinogen is associated with the risk of stroke and and may act

by several possible mechanisms, including promotion of

atherogenesis and inflammation, elevation of blood and plasma

viscosity, increased platelet aggregability, and increased tendency

to form fibrin within thrombus. The microvascular brain disease

is the end result of a vicious circle that starts at one end of the

circle with loss of the autoregulatory process and restarts at the

other end of the circle by increase of the whole blood viscosity.

The antiphospholipid syndrome is a hypercoagulable state

characterized by recurrent arterial or venous thromboembolism or

pregnancy loss in association with antibodies directed against



134

plasma proteins that may be bound to anionic phospholipids. For

patients with cryptogenic ischemic stroke or TIA and positive

antiphospholipid antibodies with a target INR of 2 to 3 by

warfarin is reasonable. Inherited thrombophilias are

hypercoagulable states that include a number of disorders like

protein S and protein C defiency. These conditions are thought to

be rare causes of ischemic stroke in adults but may be more

important causes of ischemic stroke in children.

Vascular cognitive impairment associated with small vessel

disease has recently received particular attention because this

type of cognitive impairment has homogeneous clinical and

neuroimaging features and a progressive course. The clinical

characteristics of vascular cognitive impairment associated with

small vessel disease are gait, mood, behavioural and urinary

disturbances. In the early phases, these disturbances can be mild

and loosely associated. The final stage is one in which the patient

fits the criteria for dementia. Clinical diagnostic criteria show

moderate sensitivity (50–70%) and variable specificity (64–98%).

Epidemiological studies are hampered by the lack of clear and

validated diagnostic criteria, the complexity of brain pathologies,

ethnic and geographic variations

Important pathogenic factors of vascular dementia include the

volume of brain destruction, its location which is the most

important suggesting the concept of strategic sites of infarcts

(thalamus, frontobasal, limbic system) and the number of

cerebrovascular lesions. Abnormalities in key neurotransmitter

systems in particular in the basal forebrain cholinergic system

related to diffuse white matter lesions causing widespread



135

disconnection of cholinergic projections to the center Which

causes decreased cerebral blood flow and hypoperfusion as

critical factors in the pathogenesis of vascular dementia. Other

neurotransmitters are involved like vasopressin and histamine in

the pathogenesis of vascular dementia.

Many aspects related to vascular parkinsonism continue to be a

source of confusion. There are even problems related to the

characterisation of vascular parkinsonism as a clinical unit.

Diagnostic criteria are not clearly defined and consequently,

patients with widely varied clinical pictures may be diagnosed

with parkinsonism. Doubt may be cast on the diagnosis of

vascular parkinsonism in most cases and vascular genesis may be

attributed to parkinsonism of different aetiology in some other

cases. The following types of simultaneous occurrence first, gait

disorders of the lower body parkinsonism type are caused mostly

by changes in frontal lobes; such disorders may require a

diagnosis of vascular origin when alternative causes are excluded.

second, if the signs and symptoms are typical for Parkinson

disease the coincidence of Parkinson disease and cerebrovascular

diseases should be considered, third, if the symptoms of

parkinsonism are neither typical for Parkinson disease nor for

vascular parkinsonism and there are clinical and/or MR signs of

cerebrovascular diseases the vascular parkinsonism should be

regarded as possible; fourth, if the symptoms of parkinsonism and

clinical and MR signs are typical for vascular parkinsonism, it

should be regarded as probable, fifth, if a stroke affecting the

contralateral basal ganglia is followed by the occurrence of



136

hemiparkinsonism, the diagnosis of vascular parkinsonism is

unambiguous.

The classic lacunar infarction syndromes includes pure motor

hemiparesis, Pure sensory syndrome, Ataxic hemiparesis,

Sensorimotor syndrome and Dysarthria-clumsy hand syndrome.

They are diagnosed by clinical symptoms consistent with

radiological findings. Silent lacunar infarction has no clinical

symptoms usually discovered accidently by MRI or CT. It can

affect various aspects of a persons mood, personality, and

cognitive functioning. A silent lacunar infarction or any type of

silent stroke places an individual at greater risk for future major

stroke.

The main goals in the initial phase of acute stroke management

are to ensure medical stability, begin to uncover the

pathophysiologic basis of the neurologic symptoms, and to

determine whether patients with acute ischemic stroke are

candidates to receive treatment with thrombolysis. Subgroup

analysis of trial data suggest that the benefit with thrombolysis is

sustained in patients with lacunar stroke. However, until better

data are available we recommend that patients with lacunar

syndromes be selected for thrombolysis according to current

guidelines in the same way as patients with other subtypes of

ischemic stroke. Thrombolytic therapy is associated with a 6

percent risk of symptomatic brain hemorrhage but increase to 10

percent in presensce of radiological signs of small vessel disease.

Currently viable strategies of prevention of microvascular

diseases of the brain include blood pressure reduction, statins,



http://en.wikipedia.org/wiki/Cognitive_functions

137

and antiplatelet therapy. treatment with either clopidogrel 75 mg

daily as monotherapy, or aspirin-extended-release

dipyridamole 25 mg/200 mg twice a day, rather than aspirin alone

is recommended. Some experts still prefer aspirin as the first-line

agent, noting that the alternative antiplatelet regimens

(clopidogrel or aspirin-extended-release dipyridamole) have an

apparent modest advantage in benefit that is potentially offset by

a disadvantage in cost. Aspirin should not used in combination

with clopidogrel as risk of hemorrhage increases.

Statins help in prevention in primary and secondary stroke unlike

other drugs used in treatment of dyslipdemia like fibrates. Statins

is used even within normal lipid profile as In addition to their

cholesterol lowering properties, statins also have a role in plaque

stabilization, reducing inflammation, slowing carotid arterial

disease progression improving myocardial infarction and left

ventricular dysfunction.

Control of blood pressure is amain strategy in prevention of

microvascular diseases of the brain and helps in prevention of

microvascular rarefaction and arteriolar remodeling.

Recommended drugs to use are acting by vasodilation like ACEI,

ARBS and calcium agonist. Control of DM also is important in

prevention of microvascular diseases of the brain. This is guided

by HbA1c which should be around 7 percent but should

individualized to avoid risk of hypoglycemia. Daily fluctuation of

blood sugar level should be controlled to prevent release of free

radicals and subsequent endothelial dysfunction. Control of

vasculitis using steroids and immunosuppressant drugs is also

helpful in prevention but side effects of these drugs should be








138

avoided. Control of hyperhomocystinemia by using vitamin B

complex in adequate dose is helpful in prevention of

microvascular diseases of the brain.

Many trials are done in treatment of vascular dementia caused by

microvascular diseases of the brain using memantine, donepzil,

rivastagmine and nimodipine but all these trials produced modest

results. Results of trial of antiparkinsonian drugs in treatment of

vascular parkinsonism were also poor. So control of risk factors

still the main strategy to prevent vascular dementia and vascular

parkinsonism.



139

Recommendations

Standard terminology and definitions are needed for

vascular pathology on neuroimaging with standards for

image acquisition, analysis and reporting to help

interpretation and for meta-analyses.

Research into the contributions of largely ischaemic

microvascular diseases pathologies (eg, arteriolosclerosis)

versus largely haemorrhagic microvascular diseases

pathologies (eg, amyloid angiopathy) is needed. Other

mechanisms for the formation of ageing-related white

matter hyperintensities, such as jugular venous reflux or

abnormal vascular reactivity should be tested in replication

studies.

Until more is known about the mechanism of small vessel

disease, clinical management of vascular risk factors,

particularly hypertension is recommended.

Until more is known about the cause of white matter

hyperintensities, instead of being referred to as ischaemic,

perhaps these intensities should be called white matter

hyperintensities, ageing-related whitematter

hyperintensities or white matter hyperintensities of

presumed vascular origin.

The consideration of individual components of small vessel

disease as different disorders should be discontinued until

better evidence of their disparities is available; the presence

of a few lacunes might have a similar effect in terms of



140

cognition, stroke or dementia risk as the presence of some

white matter hyperintensities.

More information on the role of hypertension,

homocysteine, B vitamins, and inflammation in small

vessel disease is needed.

Most importantly, interventions targeting suspected

mechanisms should be tested. For example, ways to

improve endothelial function, prevent the effects of

oedema and inflammation on the brain, prevent increased

endothelial permeability and manage platelet activity

without increasing risks of haemorrhage should be

investigated.

Studies matching detailed pathology with individual small

vessel disease lesions on MRI, combined with detailed

vascular, cognitive, medication and other health related

data are needed.

Methods for improved assessment of subtle endothelial and

blood brain barrier function in vivo, preferably with

imaging which enables localisation of affected tissues can

be followed over time.

Better information is needed on how other aspects of

endothelial dysfunction might contribute and how failing

vasodilatation might contribute to disease pathogenesis and

whether this can be modified by specific drug or lifestyle

interventions.

specific preventive and therapeutic measures to reduce the

burden of functional loss caused by small vessel disease



141

need to be designed. Neuroimaging could be a major tool

to assess efficacy of these measures.

Attention to hemorrhagic and venous components of

microvascular diseases of the brain should be increased.



142

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