Leukoencephalopathies comprise a
clinical and radiographic heterogeneous group of disorders. All these
disorders share the common features of neurologic dysfunction and
preferential involvement of CNS white matter. Although white matter
can be affected by many different processes, the term leukodystrophy is
generally reserved for those with an identified or presumed genetic
basis that is associated with a loss of previously formed myelin.
Acquired causes of white matter dysfunction include infectious (such
as encephalitis), inflammatory (such as acute disseminated encephalomyelitis and
multiple sclerosis; see Chapter 556, nutritional (such as vitamin
B12 deficiency), and neoplastic (such as astrocytoma) etiologies.
When evaluating a patient with a suspected leukoencephalopathy, these
acquired disorders should be considered and excluded with specific
testing when clinically indicated.
MRI can help to distinguish genetic from acquired white matter
disorders. Normal myelination starts prenatally and continues for decades,
generally proceeding in a caudal-to-rostral and central-to-peripheral
pattern.1 Depending on a patient’s age,
specific areas are expected to be myelinated, and others are unmyelinated.
With myelination, the brain MRI appearance changes, with increasing
T1 signal and decreasing T2 signal in the myelinated areas. In general,
brain MRI in acquired white matter disorders shows asymmetric disturbances
in this process, whereas the leukodystrophies produce a symmetric pattern
of abnormalities (see Fig. 556-2).
In the past, treatment of genetic leukoencephalopathies was largely
restricted to supportive measures. However, hematopoietic stem cell
transplantation (HSCT) has been increasingly used for some of these
leukoencephalopathies. For most of these disorders, replacement
of the deficient enzyme from donor cells, especially monocytes that
can cross the blood-brain barrier, serves as the underlying therapeutic
mechanism. This process is slow and inefficient, typically leading
to an approximate 6- to 12-month period before CNS symptoms stabilize,
and does not typically reverse existing deficits.2 Therefore,
although useful in certain disorders, HSCT has also been disappointingly
ineffective for patients with advanced symptoms and/or
one of the more rapidly progressing leukoencephalopathies. In addition,
HSCT is associated with significant potential morbidity and mortality.
Thus, as the genetic and molecular bases for the leukoencephalopathy
become increasingly delineated, it is hoped that more specific treatments,
such as enzyme replacement therapy or gene therapy, will become
available. At the time of the writing of this chapter, such therapies
have been implemented on a small scale for few of the disorders.
There is a very long list of leukoencephalopathies, which can
be broadly divided into disorders in which there is a permanent
deficit in myelin deposition (hypomyelinating), disturbances of
myelin formation (dysmyelinating), or loss of existing white matter (demyelinating).1 Although
useful for defining disease mechanisms, these categories do not
readily translate clinically. Therefore, this chapter will use a clinical
approach, dividing the leukoencephalopathies primarily based on
age of onset, associated symptoms, and MRI appearance (Figs.
576-1, 576-2). Given the frequent heterogeneity
within some of the leukoencephalopathies and the ever-expanding
list of disorders, this algorithm is an oversimplification, but
can nonetheless be ...