Chapter 576

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 ...

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