WMHs is the most frequent type of CSVDs and a common incidental finding in MRI films of up to 70% of MRI images in individuals > 60 years, and 90% in those > 70 years. Meticulous assessment of asymptomatic WMHs subjects reveals the presence of subtler cognitive, gait, balance and psychiatric disturbances.

4. ◘ MAS is a 67 year old male, not HTN, DM, IHD or
dyslipidemia.
◘ He was presented by acute right hemiparesis due
to left capsular infarction.
◘ MRI showed extensive CSVDs (WMHs, DPVs).
◘ Poststroke, the patient suffered marked delay in
gait rehabilitation and repeated falls compared
to his age matched counterparts.
(1)Whatis therelationbetweenWMHsanddelayedfunctionalrecovery?
(2)CouldWMHsbe considereda strokerisk?

5. ◘ CSVD is an umbrella term that describes a Group of Neuroimaging and Neuropathological Changes in the white matter and subcortical grey
matterresultsfromstructuraland/orfunctionalabnormalitiesoftheperforating arteries,capillaries and venules.
◘ CSVDinoldconsistsof 2 maintype;CAAandhypertensivearteriopathy.

7. ◘ Visual rating assessment revealed non-significant differences in topographic distribution of WMHs related to CAA or hypertensive
arteriopathy.
◘ AutomatedWMHsanalysisshowedthat:
(1)MultiplesubcorticalspotpatternandmoreparietalWMHsdistributionis goingwithCAA.
(2)Peri-basalgangliaWMHspatternis stronglylinkedto hypertensivearteriopathy.

8. ◘ WMHs of presumed vascular origin are defined as areas of
aberrant white matter appearance with increased
intensity in T2WI and FLAIR images:
(1) Away from areas of cortical lesions or ventricular
enlargement.
(2) Not related to demyelinating disease, leukodystrophy or
other nonvascular causes.
◘ WMHs is the most frequent type of CSVDs and a common
incidental finding in MRI films of up to 70% of MRI
images in individuals > 60 years, and 90% in those > 70
years.

9. ◘ More than 50 terms are used in literatures to describe WMHs including Binswanger disease, leukoaraiosis, age related white matter changes,
incidentalwhitematterlesions,leukoencephalopathy,subcorticalhyperintensitiesandsmallvesselischemicdisease.

10. ◘ Till a recent time, WMHs are considered as
incidental age-related imaging findings with little
attention paid to their clinical implications and
spectrum of their benign range.
◘ Meticulous assessment of asymptomatic WMHs
subjects reveals the presence of subtler cognitive,
gait, balance and psychiatric disturbances.

11. ◘ Thetimeoflifeat whicha personbeginstoreceivepensionbenefits.
◘ > 65yearsindevelopedcountries.
◘ > 60 yearsindevelopingcountries.
◘ Racialandindividualgeneticpredispositionforacceleratedaging.
◘ Precedingbraininsult; trauma,vascular,inflammation.
◘ Agingassociateddisorders;CSVDs,AD,PD.

13. (1) Periventricular WMHs:
(i) grade 0: no WMHs.
(ii) grade 1: caps or pencil-thin lining.
(iii) grade 2: smooth halo.
(iv) grade 3: irregular periventricular WMH
extending into the deep white matter.
(2) Deep Subcortical WMHs:
(i) grade 0: no WMHs.
(ii) grade 1: punctuate foci.
(iii) grade 2: beginning confluence of foci.
(iv) grade 3: large confluent areas.
◘ Visual rating scales as the Fazekas, CREDOS or the ARWMC provide semi-quantitative assessments of WMHs burden but subjected to high inter-
ratervariabilities.

14. ◘ Several automated WMHs quantification have been proposed e.g. Medical Imaging Processing, Analysis, and Visualization, UBO, fully automated
WMHsdetector.
◘ ThesemethodsallowintegratedWMHsvolumelesionsinstrategictracts.(34)
UBO, fully automated WMHs
detector

16. ◘ The pathogenesis of WMHs is a combination of endothelial dysfunction, inflammation, increased vascular permeability, BBB disruption and
venousinsufficiency.
◘ Thenet resultsareperivascularischemicinjury,demyelinationandglialscarring.

17. ◘ Endothelial dysfunction is one of the leading
etiological causes of WMHs through variable
mechanisms;
(1) Cerebral hypoperfusion secondary to reduction of
nitric oxide signaling.
(2) Leakage of inflammatory mediators into the blood
vessel wall and perivascular spaces.
(3) Blockage of oligodendrocyte precursor cell
maturation, to mature oligodendrocyte with
consecutive impairment in axonal myelin repair.

18. ◘ Many studies revealed increased vascular resistance is a
major contributor of WMHs pathogenesis.
◘ Perforating arterial wall stiffness is could be identified
by luminal stenosis, tortuosity, focal dilatation and
increased intracranial pulsatility.
◘ Microangiopathy results in impaired cerebral
autoregulation with consecutive sluggish vascular
reactivity in response to increased neuronal activity
or breathing of 6% CO2 in inspired air.
◘ 7–T MRA showing (a) normal
perforators, (b) highly tortuous
lenticulostriate arteries in a patient
with WMHs.

19. ◘ Astrocytic dysfunction results in perivascular leakage of CSF and inflammatory mediators to the blood vessel wall and perivascular
interstitial space.(14)

20. ◘ Immuneresponseshaverecentlyemergedasa majorcontributorofWMHspathogenesis.
◘ The triggered responses include activation of microglia, provocation of cytokine secretion, leukocyte recruitment and lymphocytes migration to
theCNS.

21. ◘ Some studies proposed some roles of gut microbiota and persistent systemic inflammation in middle-to late-life with the development of WMHs in
olderages.(14)

22. ◘ Significant increase in periventricular WMHs volume
was noticed in astronauts after long-duration
spaceflight but no changes were denoted regarding
deep WMHs.
◘ WMHs burden was significantly increased in high-
altitude U-2 pilots compared to age-matched healthy
controls with associated wide range of cognitive
impairments.
◘ This observation points to the role of CSF weightlessness
in the pathogenesis of periventricular WMHs.
(a) pre-flight and (b) post- flight
periventricular WMHs

23. ◘ The relation of WMHs and extra- or intra- cranial large arteries atherosclerosis is not well established, but most researchers consider it as an
associationratherthanconsequence.

25. ◘ WMHs is a dynamic whole brain disorder with pathological changes not only in the WMHs lesions but also in the NAWM as well as the grey
matter.(3)

26. ◘ ProgressionofWMHsis therulewhichfollowsnon-lineartemporaldynamicswithquadraticaccelerationcourse.
◘ Progressionis higheramongAPOEε4 allelesubjects,elderly,smokersandin thepresenceof lacunarcavitieswithinthevicinityof WMHs.

27. ◘ TheRUNDMCstudyshowedregressionofWMHslesionloadin 10%ofcasesin firstfollow-upbut unfortunately,progressionoccurredlater.
◘ WMHsvolumeregressioncouldbe attributedto atrophyofthetissueandabsorptionof edemaratherthanregenerationof theaffectedaxons.(12,21)

28. ◘ Decreased perfusion, BBB disruption as well as impaired micro-structural integrity of the NAWM surrounding WMHs in multimodal imaging
approaches(PET,xenon-CT,perfusionMRI)arepredictorsof theirfuturetransitionto WMHs.(15)

29. ◘ Refers to brainvolume lossadjacent to WMHsdue to cortical thinningandwhitematter shrinkageby gliosis.
◘ Periventricular
WMHs are
associated with
cortical thinning
than deep WMHs
with consecutive
more cognitive
dysfunction.(40)

30. ◘ 55-year-old patient with WMHs at baseline assessment with follow-up T1 scan shows clear sulcal widening, and ventricular enlargement.
(13)

32. ◘ The human brain is the most complex network in the real
word which is composed of about 100 billion neurons
connected by 100 trillion synapses permitting highly
efficient and rapid information transmission.
◘ The graph theory is based on the connectome is the
structural as well as functional unit of the brain web
system.
◘ Each network is composed of nodes and edges where the
nodes represent functionally uniform neurons grouped
together while the edges represent meaningful
connections between pairs of nodes.

33. ◘ Represents anatomical associations among
different neuronal elements, based on white
matter fiber tracts' integrity
◘ Corresponds to the magnitudes of temporal
correlations in activity between pairs of
anatomically unconnected regions.
◘ The brain network strength is referred as the
minimum number of edges linking the nodes.

34. ◘ The tinny WMHs lesions disrupt the traversing axons
with a resultant die back of their neuronal cell bodies
and secondary disruption of brain network integrity
progressing to disconnection syndrome. (20)
◘ The brain undergoes several neuro-modulatory processes
resulting in paradoxical functional hyper-connectivity
by reorganizing the resting-state and default mode
networks to reduce the cost of wiring.(39)
◘ These brain organizational changes result in delayed
clinical implications of WMHs, but unfortunately on
the expense of network reserve. (4)

35. Normally activated areas
Additionally activated areas in
WMHs
◘ This study showed the compensatory mechanisms of brain networks in response to cognitive as well as motor tasks in patients with high WMHs
burdenbyrecruitmentofsecondarynetworkstoperformequivalenttasks(reorganizationof defaultnetworks).

37. ◘ WMHs are among the strongest radiological predictors of
cognitive functions and both the severity and
distribution may alter the risk and progression of
cognitive impairment.
◘ Extensive WMHs greater than expected for age are
associated with double risk of VCI. (33)
◘ Increasing parietal lobe WMHs volume is associated with
AD and is a biomarker of its rapid progression. (39)
MixedVascularand AlzheimerDementia

38. ◘ Extensive WMHs is associated with
triple risk of stroke as well as poor
functional outcome after stroke.
◘ Stroke is a major risk of dementia and
cognitive decline predict upcoming
stroke.
◘ Like an ink drop falling into a glass of
water, an occult or a manifest stroke
may start neuropathological changes
disrupting white matter tracts and end
in post-stroke cognitive impairment.

40. ◘ Onesizetreatment will not fit for all:-
(1) Management of patients at risk of WMHs
development may differ from those with already
established lesions where the aim is to slowdown the
disease progression.
(2) Preventive measures for development of acute stroke
are quite different from protocols done to protect
against gradually progressing VCI.
(3) Treatment protocols for the chronic WMHs must be
designed for long-term use.

41. ◘ Many observational studies concluded that, prevention and/or slowing down of WMHs progression should be started very early in the
presymptomaticphasebeforeirreversibleneuronaldamagetakesplace.

43. ◘ Vascular risk reduction strategies may offer some
value for prevention and treatment of WMHs.
◘ However, some studies assumed that, WMHs is
highly heritable (e.g. PLEKHG1 gene that encodes
a Rho guanyl-nucleotide exchange factor) while
risk factors control has very limited values in
striking disease progression.

44. ◘ Hypertension is the most important independent risk
factor for WMHs development.
◘ However, the relation of blood pressure control as well
as the targeted blood pressure level is obscured.
◘ In the PROGRESS MRI sub-study as well as ACCORD
MIND study, higher systolic blood pressure was
associated with WMHs progression while intensive
blood pressure control reduced this progression in 3-
years MRI follow-up.

45. ◘ The SPS3 study showed non-significant decrease in the
risk of new occult LBIs or WMHs progression by
lowering systolic blood pressure to 130 mmHg,
possibly due to inclusion of patients after symptomatic
stroke. (19)
◘ Excess blood pressure reduction (systolic <125 mmHg) is
not indicated in severe WMHs due to impaired
autoregulation and increased risk of falls by the
associated subtler gait and balance disturbances. (21)

46. ◘ Therelationof DM controlandWNHsprogressionpreventionis controversial.
◘ Inthe ACCORDMINDstudy,intensiveglucose-loweringtherapyin patientswithtype-IIDM didnotsignificantlyaffectWMHsprogression.(22)

47. ◘ For statin treatment-based trials, conflicting results were
attained.
◘ Some RCTs showed evidences of valuable roles of statins
in reduction of WMHs disease load progression and
consequent stroke and cognitive decline risks
explained by the statin induced antiplatelet, anti-
inflammatory and pro-endothelial activity (increase
NO production). (23)
◘ On the other hand, some studies showed non-beneficial
effects of statins with a superadded increased risk of
ICH in patients with extensive WMHs .

49. (1)NitricOxideDonors:-
- Sodium nitroprusside, isosorbide mononitrate and
glyceryl trinitrate.
(2)Phosphodiesterase(PDE)3 and5: -
(a) Non-selective as pentoxifylline.
(b) Selective PDE–5 inhibitors (e.g. dipyridamole, tadalafil
or Cialis).
(c) Selective PDE–3 inhibitors (e.g. cilostazol or triflusal).
(3)Endothelin-1antagonists:-
- Clazosentan and TAK-044.
(4)Pioglitazone:-
- A peroxisome proliferator-activated receptor gamma
(PPAR-γ) agonist.
Tract-definedregionalWMHs(30)

50. ◘ Such drugs are theoretically beneficial, but there is a
paucity of studies regarding their values:
(1) Matrix metalloproteinases–9 inhibitors (minocycline).
(2) Antioxidants.
(3) Topiramate.
(4) Vascular endothelial growth factors antibodies.
(5) Cyclic AMP modulators (cilostazol, pentoxifylline).
(6) Fasudil is a selective rho-kinase inhibitor used in
management of vasospasm following SAH, however
its use in WMHs is still unevidenced.

51. (1) NSAIDs inhibit cyclooxygenase-2 with consecutive
decrease in prostaglandins formation, but the
serious GIT bleeding makes the drawbacks
outweigh the benefits.
(2) Fingolimod and natalizumab have been tried with
limited success.
(3) Allopurinol increases NO availability and has anti-
inflammatory effects, however, its value in
reduction of WMHs progression is doubtful.

52. ◘ Obesity is associated with more microstructural changes
within the WMHs (lower fractional anisotropy DTI).
(23, 25)
◘ Lifestyle modifications including weight control,
smoking cessation, salt reduction, increased dietary
nitrates, dietary flavanones and regular exercises have
their potential to reduce the risk of WMHs
cerebrovascular and cognitive complications. (36)

53. ◘ Trials used multiple classes of vitamins failed to
prevent stroke risk in WMHs.
◘ The VITATOPS trial (Vitamins to Prevent Stroke),
MRI sub-study suggested that Mediterranean diet
with daily vitamin B6, B12 and folate
supplementation for 2 years might be associated
with less WMHs progression in non-stroke
patients.
◘ On the other hand, stroke patients showed non-
significant effect of daily vitamin B
supplementation on WMHs progression.

55. ◘ Warfarin use is associated with increased ICH
risk in patients with extensive WMHs.
◘ A single antiplatelet agent may be beneficial
for secondary stroke prevention with lower
risk of hemorrhage.
◘ The SPS-3 (Small Subcortical Strokes) trial
revealed that, long-term dual
aspirin/clopidogrel therapy double the risk
of major ICH and mortality in WMHs
patients which out-weight the benefits of
secondary stroke prevention. (27)

56. ◘ The benefits of cholinesterase inhibitors (tacrine,
rivastigmine, galantamine and donepezil) as well as
NMDA receptor antagonist (memantine) in
management of VCI associating WMHs were very
minimal.
◘ The NICE guidelines as well as the FDA do not
recommend the use of antidementia drugs for VCI
except in mixed dementia with predominant
Alzheimer’s component.

58. ◘ AccidentlydiscoveredWMHs are neithersilent norinnocent.
◘ Avoid the use of dual antiplatelets or antidementia drugs in WMHs without
reasonableindication.
◘ Lifestylemodificationis effective, has no sideeffectsandfreeof charge.
◘ The introduction of non-invasive, sensitive, inexpensive biomarkers is crucial, but
the costs/benefits of screening high risk healthy individuals need to be
estimated.

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