More than 100 neurologic diseases, injuries, and intoxications are known to prominently or exclusively involve the white matter of the brain.1,2 Without exception, these disorders have the potential to disrupt aspects of cognitive and emotional function and to lead to important syndromes related to white matter dysfunction. Although not as familiar as the diseases of gray matter that have dominated thinking in behavioral neurology, the white matter disorders are emerging as common problems that erode neurobehavioral function. These disorders highlight the concept that white matter tracts provide the neuroanatomic connectivity between gray matter areas; thus, disruption of tracts produces neurobehavioral syndromes by disturbing the function of distributed neural networks that subserve higher brain function. In the era of MRI, which enables detailed imaging of white matter disorders, the diagnosis of neurobehavioral syndromes associated with these disorders is increasingly feasible and will lead to improved patient care. White matter constitutes nearly half of brain volume.1,2 Consisting of billions of myelinated axons that travel within and between the hemispheres to connect gray matter regions with each other, white matter occupies a central position that is important in both brain structure and function (Figure 1). In traditional neurologic teaching, white matter has been regarded as a component of the brain that is primarily dedicated to elemental sensory and motor function; thus, the major problems produced by white matter lesions include visu-al field deficits, hemihypesthesia, and hemiparesis. However, more recent information is justifying the view that white matter has neurobehavioral affiliations of its own and that a behavioral neurology of white matter can now reasonably be considered.3-5 Recognizing the clinical effects of white matter lesions helps illuminate the role of white matter tracts in the normal connectivity of the brain and illustrates how white matter makes an essential contribution to the distributed neural networks that subserve all higher functions. WHITE MATTER DISORDERS White matter disorders that affect the brain make up a widely diverse group of diseases, injuries, and intoxications (Table 1). The range of these disorders encompasses all major categories of neurologic illness, and the variety of white matter neuropathology is impressively broad. This review focuses on disorders that prominently or exclusively involve brain white matter. Not surprisingly, many of these clinical entities display variable degrees of cortical or subcortical gray matter damage as well, and the combination of neuropathologic involvement often introduces additional complexity. Nevertheless, consideration of the disorders in which white matter is significantly affected serves to highlight both the frequency with which white matter lesions are encountered and the tendency of these lesions to produce patterns of neurobehavioral dysfunction similar to gray matter lesions. White matter disorders can be classified as genetic, demyelinative, infectious, inflammatory, toxic, metabolic, vascular, traumatic, neoplastic, or hydrocephalic (Table 1).1,2 Each category involves a distinct pathophysiologic basis. Further, the entities within these categories also vary considerably in many clinical and neuropathologic respects.2 A comprehensive account of all white matter disorders is beyond the scope of this article, but a brief survey can show the diversity of clinical and neuropathologic phenomena. White matter disorders can affect any age group; they may first come to the attention of neurologists, psychiatrists, pediatricians, internists, geriatricians, or psychologists. In infants and children, genetic diseases, such as metachromatic leukodystrophy (MLD), demonstrate how the failure of brain myelin to develop normally produces dysmyelination that leads to early disability and death-or rarely, in older individuals, to a common sequence of psychosis followed by dementia.6,7 In contrast, young adults are most vulnerable to demyelinative diseases such as multiple sclerosis (MS), in which inflammatory destruction of myelin-and sometimes axons-leads to neurobehavioral and neurologic disability.8 MS is an example of how a white matter disease that was formerly regarded as having little significance for behavioral neurology has proved, with the application of modern neuroimaging and clinical assessment, to have major neurobehavioral sequelae.1,2,8 Infectious diseases may produce cognitive decline by involving the white matter, as illustrated by the AIDS dementia complex9 and by progressive multifocal leukoencephalopathy.10 Similarly, noninfectious inflammatory diseases, such as systemic lupus erythematosus, can have an impact on the white matter. Both immune-related and vascular pathology may be central in generating the multiple manifestations of neuropsychiatric lupus.11 One of the most interesting observations with MRI is in the category of toxic disorders. Among the large and growing number of white matter toxins recently identified, the common industrial and household solvent toluene has been correlated with a disabling leukoencephalopathy in solvent abusers that correlates with the severity of dementia in the abusers.12-14 Metabolic white matter disorders have been recognized as well, including dementia of vitamin B12 (cobalamin) deficiency15 that is regularly evaluated in the routine dementia workup. Among the most common white matter disorders is the subtype of vascular dementia known as Binswanger disease (BD).16,17 Closely related to BD is the recently described cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,18,19 which may appear clinically identical to BD except for the absence of hypertension and other cerebrovascular risk factors. Traumatic brain injury (TBI) qualifies as a white matter disorder because of the ubiquitous lesion, known as diffuse axonal injury, in the white matter of TBI patients.20 A variety of primary brain neoplasms also primarily affect white matter. Gliomatosis cerebri serves especially well to illustrate the adverse neurobehavioral consequences of neoplastic white matter infiltration.21 Finally, hydrocephalus from any cause exerts major effects on periventricular white matter. In children who have early hydrocephalus and in adults who have normal-pressure hydrocephalus, white matter damage of this type can result in major neurobehavioral sequelae.22,23 NEUROBEHAVIORAL SYNDROMES White matter offers an excellent opportunity to study brain-behavior relationships.1-5 The key question is how myelinated systems participate in the networks on which all higher functions are thought to depend. The role of white matter tracts in human behavior can be directly addressed by evaluating individuals with white matter lesions who experience cognitive dysfunction, emotional distress, or both. For the neurologist, a thorough history taking and physical examination can be joined with neuroimaging and other tests to yield a powerful method of correlating the lesion with the behavioral alteration. In practice, a syndrome diagnosis is crucial, because it is important that syndromes such as dementia, amnesia, aphasia, agnosia, visuospatial dysfunction, neglect, and executive dysfunction be distinguished from one another before specific diagnostic tests and therapeutic modalities are recommended. The syndrome approach proves particularly helpful in considering the white matter disorders, in which a surprising number of neurobehavioral syndromes-in addition to well-known elemental neurologic deficits-may be encountered. Many patients with white matter disorders, in fact, present with neurobehavioral issues even before other neurologic features come to clinical attention. A thorough review of the white matter disorders reveals that these syndromes can be classified as involving cognitive impairment, focal neurobehavioral disturbances, or neuropsychiatric dysfunction (Table 2).1,2 COGNITIVE IMPAIRMENT Cognitive impairment, broadly defined as a deficit in intellectual function, is the most common neurobehavioral syndrome that can be related to white matter pathology. This syndrome may manifest as cognitive dysfunction that may be so subtle that distinguishing it from normal mentation may be difficult; in many cases, however, the disturbance is sufficiently florid to merit the term "dementia."1,2 Cognitive impairment results from diffuse white matter involvement, reflecting the typically scattered distribution of white matter neuropathology that produces widespread dysfunction. In contrast, focal syndromes are far less common.1,2 The relative rarity of focal neurobehavioral syndromes is apparent from studies of MS, in which cognitive dysfunction or dementia may afflict as many as 65% of patients,24 whereas aphasia occurs in fewer than 1%.25 Similarly, although neuropsychiatric syndromes, such as depression, are frequent in patients with white matter disorders, the prevalence of these syndromes remains uncertain. Also, because they may stem from many etiologies, there is a less secure association with white matter pathology. Thus, cognitive impairment, especially when it reaches the stage of dementia, is the most important source of clinical distress and functional disability that results from white matter damage. White matter dementia, as a term, was introduced in 1988 to call attention to the morbidity caused by disabling cognitive impairment in patients with white matter disorders.26 Although cognitive dysfunction is more common than dementia in early stages of white matter dementia-and may be the presenting feature27-its severity as the disease progresses may justify a diagnosis of dementia. For example, an estimated 10% to 20% of patients with MS-a disease that typically involves little or no overt cognitive impairment initially-will develop dementia at some point in the disease course.28 The implication of this observation is that among the many benefits of developing effective interventions at an early stage may be the prevention of dementia. Because understanding the origin of dementia and reducing its prevalence are such high priorities for neurologists, a justification for the concept of white matter dementia is to alert clinicians to the importance of early diagnosis and treatment. Despite the neuropathologic diversity of the white matter disorders, a remarkable similarity in the cognitive profiles of the many afflictions can be discerned.1,2 Only a general portrait of white matter disorders can be given currently; relevant clinical observations have been unsystematic and difficult to compare. However, a preliminary profile of deficits and strengths seen in patients with white matter disorders has emerged that may prove useful in diagnosis, counseling, rehabilitation, and research on new therapeutic strategies.1,2 This profile consists of the following: sustained attention deficit, executive dysfunction, memory-retrieval deficit, visuospatial impairment, psychiatric dysfunction, and normal language; extrapyramidal function; and procedural memory. Sustained attention deficits, executive dysfunction, and memory-retrieval deficits may be especially salient. These problems are typical in patients with white matter disorders and relate to a slowing of cognition-what is often referred to neuropsychologically as impaired speed of information processing.2 Neuroanatomically, these disturbances are all closely associated with frontal lobe dysfunction, and most white matter disorders show a predilection for the frontal white matter.2 Even when white matter lesions are located in more posterior sites of the cerebrum, frontal lobe functions are still affected.29 This probably reflects the dense connectivity between the frontal and other regions. In contrast, language is usually normal or only mildly affected because the language-related cortex is spared,1,2 which may lead the clinician to overlook cognitive dysfunction involving nonlinguistic domains. The validity of the concept of white matter dementia is supported by substantial neuropsycho-logical, neuroimaging, and neuropathologic evidence. Neuropsychological studies have suggested that white matter dementia differs clinically from both the cortical and the subcortical dementias. In contrast to cortical dementias, such as Alzheimer disease, white matter dementia shows a retrieval deficit, but not an encoding deficit, in declarative memory; more impaired sustained attention; and relatively spared language. Unlike subcortical dementias, such as Huntington disease, white matter dementia shows spared procedural memory and extrapyramidal function.1,2 Neuroimaging studies have established at least modest correlations between cerebral white matter abnormality and the degree of dementia in white matter disorders, and more advanced MRI techniques promise to refine these investigations.1,2 Finally, neuropathologic observations, when available, have typically demonstrated that the degree of cerebral white matter pathology-of any type-predicts the severity of dementia. FOCAL NEUROBEHAVIORAL SYNDROMES In addition to cognitive loss and dementia, a wide range of focal neurobehavioral syndromes has been described (Table 2).2 The unique feature of these syndromes is that they identify a restricted area of the brain that has been damaged, thus producing an isolated neurobehavioral deficit. Classic focal syndromes in behavioral neurology, such as aphasia, apraxia, agnosia, and amnesia, have formed the foundation of brain-behavior relationships as currently understood.3-5 Although these syndromes are considered to be more common with cortical lesions, recent findings have confirmed that they also may occur after white matter damage.2 For example, conduction aphasia related to an acute MS plaque in the left arcuate fasciculus has been reported,30 which confirms the classic teaching on the role of this tract in language repetition.3 The critical point is that focal syndromes are associated with discrete, isolated white matter lesions; in contrast, white matter dementia results from the more typical widespread pathology of white matter disorders. Although less common than syndromes caused by diffuse white matter damage, the focal neurobehavioral syndromes illustrate the importance of white matter tracts in all mental domains. NEUROPSYCHIATRIC SYNDROMES Structural changes of white matter also have been associated with a wide spectrum of emotional disturbances, constituting a group that can be referred to as the neuropsychiatric syndromes.2 Neuropsychiatric dysfunction is a broad category that defies precise characterization, but many patients manifest clinically significant emotional disorders that may have a neurologic basis. New information indicates that these problems may be associated with abnormal white matter. These disturbances are less clearly defined than the neurobehavioral syndromes, because the correlation of white matter pathology with clinical syndromes is less defined. Some suggestion exists that the burden of white matter pathology contributes to emotional dysfunction, but other factors play a role as well, and the origin of psychiatric impairment must be considered multifactorial. It is useful to divide the neuropsychiatric syndromes into 2 general groups: psychiatric problems that may occur in patients with known white matter disorders and psychiatric diseases in which white matter abnormalities have been identified (Table 2). Numerous reports have documented the presence of syndromes such as depression, mania, psychosis, and euphoria in patients with white matter disorders.2 In psychiatric diseases, typically considered idiopathic and unrelated to known structural brain damage, research with MRI techniques has disclosed subtle changes in the structure of white matter. In schizophrenia, for example, microstructural white matter abnormalities implying altered cerebral connectivity have been found.31 Evidence also is accumulating to support an association between white matter changes and geriatric depression.32 Detailed examination of the white matter may offer new insights into psychiatric disease by concentrating on disruption of the neural networks devoted to emotional function. MAGNETIC RESONANCE IMAGING Although the appearance of CT in the 1970s greatly improved the clinical imaging of the brain, it was the advent of MRI in the 1980s that first enabled the detailed visualization of white matter structure.2 In particular, the capacity of T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences to permit the viewing of myelinated regions led to MRI becoming the preferred method for imaging white matter and its disorders. Neurology has been changed as much by MRI as by its predecessor CT. MRI, for example, has become the most important diagnostic test for MS because of its excellent imaging of demyelinative lesions in the CNS. Old disorders became better understood with MRI, and new ones were soon discovered.2 The early use of MRI in patients presenting with neurobehavioral symptoms and signs suggesting white matter involvement often reveals these disorders when more effective intervention is still possible. After the detection of white matter lesions, the identification of individual white matter disorders can proceed using specific clinical features analysis, neuroimaging, selected blood and cerebrospinal fluid (CSF) studies, and other investigations as indicated by the neurologic picture. To illustrate, a strong family history, widespread dysmyelination, and genetic testing may point to MLD.2,7 A history of episodic neurologic events, periventricular demyelination, and oligoclonal bands in the CSF may confirm MS.2,8 Infectious, inflammatory, toxic, metabolic, vascular, traumatic, neoplastic, and hydrocephalic disorders can be similarly diagnosed using a standard neurologic approach.2 In some cases, specific neurobehavioral syndromes can be detected by neuropsychological testing, a highly sensitive-but not necessarily specific-procedure. Neuropsychology is most helpful in detection of early or subtle cases of white matter dysfunction, such as toxic leukoencephalopathies,13 when standard medical or neurologic evaluation is inconclusive. The testing may be equally helpful in concluding that the patient has no deficits or in identifying psychiatric disease such as conversion disorder or malingering. CLINICAL DECISION MAKING The recognition of neurobehavioral dysfunction in white matter disorders may not be straightforward. Many patients present with subtle cognitive symptoms and signs, frequently commingled with other neurologic or medical features of their disease; this challenges the clinician to interpret the relationship of white matter burden to cognitive status. The range of clinical features heralding the onset of white matter involvement is impressively broad and may include inattention, executive dysfunction, confusion, memory loss, personality change, depression, somnolence, lassitude, or fatigue. The nonspecific clinical profile of many affected patients often suggests a primary psychiatric disorder. Indeed, many patients with white matter dementia had psychiatric dysfunction that antedated measurable cognitive impairment. This interplay of cognitive and emotional features may prove particularly perplexing. An awareness of the potential for white matter disorders to lead to neurobehavioral dysfunction is essential, and the early use of MRI and other tests is often definitive. Also frequent is the detection of unexpected white matter changes on MRI that introduce new complexities in the clinical picture. Especially in older people, white matter hyperintensities on MRI are common but not always clinically relevant. Review of the history and physical examination in concert with specific features of the white matter abnormality can often reveal a likely etiology, and the evaluation can be directed accordingly. Clinicians should avoid the equally perilous pitfalls of ignoring potentially significant white matter abnormalities and, conversely, ascribing too much importance to trivial ones. FUTURE DIRECTIONS In recent years, the visualization of white matter has been improved by more sophisticated MRI techniques. Diffusion tensor imaging (DTI) is an ideal tool for this, because it can reveal the course and structural integrity of specific tracts and can permit investigation of their participation in cognitive and emotional operations.33-35 This technique is based on the principle of anisotropy, a term referring to the propensity for water to diffuse along the direction of white matter tracts. In contrast, damaged white matter is characterized by isotropic diffusion, which is correspondingly less directional and more random. DTI can thus better define the anatomy of normal white matter tracts, as well as the changes they undergo when subjected to various neuropathologic processes.33-35 The application of DTI to both normal and abnormal white matter may offer a major step forward for clinicians, who may soon be able to identify individual tracts with the same specificity with which clinicians identify cortical regions and basal ganglia today. By improving the understanding of the origin, course, and destination of white matter tracts, DTI may redefine the neuroanatomy of white matter. Paralleling advances in structural neuroimaging are technologies for the examination of brain function. The cerebral cortex has been the focus of these methods because of its high degree of metabolic activity. The 2 most familiar of these methods are positron emission tomography36 and single photon emission CT.37 More recently, functional MRI (fMRI) has been added to the armamentarium of functional neuroimag-ing methods. Although some technical issues remain problematic, fMRI potentially offers more refined analyses of brain-behavior relationships.38 Structural and functional neuroimaging are complementary in the pursuit of understanding the architecture of higher function. Gray matter, particularly of the cerebral cortex, is inextricably linked to white matter tracts in the distributed neural networks subserving all domains of mental activity.39 Functional neuroimaging can identify cortical regions involved in cognitive processing, while DTI and other related methods can establish the connectivity between these areas. A combination of techniques capable of characterizing gray and white matter components of distributed neural networks will help formulate a unifying picture,40 and in so doing, will advance the practice of neurology. CHRISTOPHER M. FILLEY, MD, is a professor in the departments of neurology and psychiatry, University of Colorado School of Medicine, and a neurologist at the Denver Veterans Affairs Medical Center. REFERENCES 1. Filley CM. The behavioral neurology of cerebral white matter. Neurology. 1998;50:1535-1540. 2. Filley CM. The Behavioral Neurology of White Matter. New York: Oxford University Press; 2001. 3. Geschwind N. 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