White matter abnormalities (MR).

Forms of white matter lesions (WML); small caps (A), large caps (B), extending caps (C), thin lining (D), smooth halo (E), irregular periventricular WML (F), punctuate deep WML (G), deep WML beginning confluence (H), confluent deep WML (I)

Sub-classification of white matter lesions (WMLs): juxtaventricular WMLs (blue), periventricular WMLs (red), deep WMLs (yellow), juxtacortical WMLs (green)

Proposed Sub-classification of white matter lesions

	Juxtaventricular	Periventricular	Deep	Juxtacortical
Locations	Within 3mm from ventricular surface	Periventricular watershed zone 3–13mm from ventricular surface	Between periventricular white matter and juxtacortical white matter	Within 4mm from corticomedullary junction
Etiologies	CSF leakage	Hypoperfusion	Small vessel disease	Small vessel disease
Pathologies	Non-ischemic	Ischemic	Ischemic	Ischemic
Functions	-	Disruption of long WM tracts	Disruption of long WM tracts	Disruption of U fibers

Between a third and 80% of MRI scans done in persons over the age of 65 have changes in their cerebral white matter (Wong et al, 2002). MRI studies of older persons with disequilibrium and gait disturbances of unknown cause often show frontal atrophy and subcortical white matter T2 hyperintense foci. (Kerber et al, 1998). Pathological studies, though scanty, suggest frontal atrophy, ventriculomegaly, reactive astrocytes in the frontal periventricular white matter, and increased arteriolar wall thickness (Whitman et al, 1999).

Causes of periventricular white matter lesions:

Casues of periventricular white matter (PWM) lesions include normal senescent changes (then they are called UBO's, for "unidentified bright objects), small strokes, and disorders related to multiple sclerosis (MS). PWM are correlated with vitamen B6 (pyridoxine) deficiency.

Getting older: Age is certainly the single most common cause of PWM. This is presumably a "wear and tear" phenomenon.

Small strokes: A period of hypertension is a common cause. In the authors experience, just a few days of extreme hypertension may be enough. This might suggest that small bleeds are the cause in some. Clinical studies also show association with diabetes, but not consistently with atherosclerosis. PWM are often an accompaniment ofmigraine, and occur in roughly 20% of persons with migraine. As about 10% of the population has migraine, this means that about 2% of the population has white matter lesions due to migraine. PWM are also more common in persons with frequent syncope and orthostatic intolerance (Kruit et al, 2013)

WM lesions are associated with retinal microvascular abnormalities. Persons with both WM lesions and retinopathy have a much higher risk of clinical stroke (20% vs 1.4%), (Wong et al, 2002).

MS and related conditions: Demyelinating disorders such as multiple sclerosis and relatives can cause PWM. There is an incredibly rare familial variant, called CADASIL. Testing for the notch-3 mutation that causes CADASIL is done by Athena, among other laboratories.

Serious consequences of periventricular white matter lesions

White matter lesions strongly correlate with reduced gait speed as well as reduced mental ability (Starr et al, 2003; Guttman et al, 2000; Whitman et al, 2001; Bazner et al, 2008). In other words, they slow you down and make you dumber ! Periventricular location of white matter lesions seem to cause the most serious consequences. Individuals with PVM lesions perform nearly 1 standard deviation below average on tasks involving psychomotor speed.

Acceleration in white matter hyperintensity burden, is a pathologic change that occurs early in the presymptomatic phase leading to mild cognitive impairment. In fact, on average, acceleration occurs 10 years prior to onset of mild cognitive impairment. (Silbert et al, 2012). Only a 3% burden of leukoaraiosis (white matter lesion percent of brain) is enough to reduce working memory scores 2 standard deviations (Price et al, 2012). A 3% burden on MRI, is the amount of PVM usually called "mild" on MRI reports.

If we consider gait and balance, according to a recent study of Bazner, the slow-down in walking is not extreme -- older people are about 20% slower with a large # of PVM than a small #. It would seem to us that people may simply be more cautious and walk more slowly when they are more prone to fall.

Pathologically, PWM correspond to areas of myelin thinning and gliosis, and are often accompanied by lacunar (small holes) infarctions and small vessel atherosclerotic disease. Lacunes are also associated with cognitive disturbances (Jokinen et al, 2011).

Treatment:

• Control vascular risk factors -- especially labile (variable) hypertension
• Pyridoxine (vitamin) supplement
• Migraine prevention treatment -- especially "vascular" agents such as verapamil and beta-blockers
• Physical therapy -- especially fall counseling
• Adjustment of medications

Practically, PVM seem to be associated with severe consequences. As once you have them, they are there for life, prevention is the main goal of treatment.

We advocate attention to reducing vascular risk factors, and especially controlling labile hypertension. Reducing elevated cholesteral, and strict control diabetes is probably helpful too. Small amounts of vitamin b6 (pyridoxine) supplementation also seem reasonable (i.e. 2 mg/day). It is not clear if daily aspirin intake is useful or harmful in persons with PVM, and in our opinion, the decision should be made on an individual basis. Beta blockers such as propranolol and related medications may be especially suitable to prevention of spikes in blood pressure. These drugs are also cardioprotective.

In persons with migraine, we generally suggest a prophylactic regimen such as a combination of low-dose aspirin and a migraine prevention agent such as verapamil. It is not known whether this treatment regimen is effective. Beta blockers would also seem very reasonable.

Treatment of the demyelinating diseases may be possible, but is outside the scope of this brief review.

With respect to the common symptom of unsteadiness, empirical treatment including physical therapy. While generally medications are not helpful in situations where fiber tracts or neurons have died, in some occasional cases, trials of medications such as antidepressants or anti-parkinsonian drugs are helpful.

We think it is unlikely that any treatment will be successful in reversing the mental slowing associated with PVM. However, there may be some room to readjust medications that are slowing down thinking independently -- such as antivertigo medications (e.g. meclizine or clonazepam), and replacing them with medications that do not impair thinking (such as betahistine) 


Reference.

Reference for three last images