Medical

Medical treatment of white matter disorders is the area of therapy most commonly employed with patients with WMD or MCD. At least until other modalities become available, some of which will be considered in Chapter 13, most of the available treatments for these patients will involve pharmacotherapy as well as other noninvasive modalities.

In the vascular category, the primary approach remains preventive, and a considerable portion of the neurologist’s daily work is dedicated to primary and secondary stroke prevention (Grossman and Broderick, 2013). While these efforts often prove effective, less can be expected once the damage is done and dementia has set in. However, medical therapy with the cholinesterase inhibitors and memantine has been studied to a considerable extent in vascular dementia and vascular cognitive impairment (Demaerschalk and Wingerchuk, 2007). Among these agents, the most evidence exists for the cholinesterase inhibitors, providing some basis for the treatment of patients with ischemic white matter disease. Autopsy studies of patients with Binswanger’s Disease (BD) have shown damage to ascending cholinergic neurons similar to that seen in Alzheimer’s Disease (AD) (Tomimoto et al., 2005), helping justify efforts to treat dementia in BD with drugs such as donepezil and galantamine. No study of this kind of treatment in BD as a well-defined entity has appeared, and while the use of donepezil in vascular dementia (Román et al., 2010) and galantamine in vascular cognitive impairment (Birks and Craig, 2006) has some experimental support, whether white matter dysfunction is specifically addressed by these medications remains conjectural.

Toxic leukoencephalopathy is by definition a disorder caused by exogenous white matter toxins, and an increasing number of leukotoxic agents have been identified by clinical observation combined with magnetic resonance imaging (MRI) (Filley and Kleinschmidt-DeMasters, 2001; Rimkus et al., 2014). Removal of the toxin and appropriate supportive care can often lead to partial or complete recovery (Rimkus et al., 2014), implying that many of these disorders involve myelin injury but preservation of axons. The clinical recovery is often evident in parallel with steady resolution of neuroimaging changes (Rimkus et al., 2014). With the increasing recognition of toxic leukoencephalopathy as MRI is more widely used, attention has been called to the syndrome of acute toxic leukoencephalopathy, and the treatment of this disorder is generally thought to be more successful than that of more chronic forms of intoxication (Rimkus et al., 2014). Dementia from long-standing toluene abuse, for example, may be irreversible, as will be considered further later.

Medical therapy has also been investigated for individuals with traumatic brain injury (TBI), in whom white matter is damaged by diffuse axonal injury (DAI). As discussed later, the first line treatment for cognitive impairment after TBI is considered to be rehabilitative, and, in general, the use of medications is regarded as adjunctive (Arciniegas, Wortzel, and Frey, 2013). However, several medications may find utility in selected cases (Wortzel and Arciniegas, 2012). The best-studied agents that can be considered in TBI are amantadine, methylphenidate, bromocriptine, donepezil, and rivastigmine (Wortzel and Arciniegas, 2012). Amantadine has been found to improve cognitive recovery in patients with severe TBI (Meythaler et al., 2002), and was recently found effective in hastening functional recovery in patients with TBI of sufficient severity to produce the vegetative or minimally conscious state (Giacino et al., 2012). Methylphenidate was observed in several studies of adult and childhood TBI patients to be helpful for memory and attentional problems, although larger studies are needed (Siddall, 2005). Bromocriptine has been found efficacious for executive dysfunction following mild to severe TBI (McDowell, Whyte, and D’Esposito, 1998). The cholinesterase inhibitors donepezil (Zhang et al., 2004) and rivastigmine (Tenovuo, Alin, and Helenius, 2009) have been observed in some studies to improve attention and memory after TBI. All of these treatments are based on augmentation of neurotransmitter systems – principally dopaminergic or cholinergic – and it is of interest that DAI is associated with a reduction in dopamine turnover in the brain (Meythaler et al., 2002) and has also been implicated in the pathogenesis of cholinergic dysfunction after TBI (Arciniegas et al., 1999). Further study is warranted on whether the cognitive benefit of these medications observed after TBI signifies a specific effect on damaged white matter and, if so, what fiber systems are involved.

Perhaps the most thoroughly studied white matter disorder – with the necessary caveat that gray matter is also involved to a variable extent – is multiple sclerosis (MS). Among many questions in MS is whether immunosuppressive and immunomodulatory treatment in MS can effect cognitive improvement (Tumani and Uttner, 2007). Treatment of cognitive dysfunction in MS has been explored in recent years, as it has been recognized that cognitive dysfunction is a major source of disability, and some treatment trials have included cognitive measures among the study outcomes. For acute exacerbations, corticosteroids remain the mainstay of conventional treatment, and it is plausible, although not established, that cognitive decline in the context of an acute exacerbation responds to this intervention.

More pertinent for this account is the use of immunomodulatory drugs, four of which – interferon β-1-a, interferon β-1-b, glatiramer, and natalizumab – have assumed a prominent position in MS therapeutics. The rationale for these drugs in relapsing-remitting MS is persuasive: This form of the disease, if untreated, can be associated with progressive brain atrophy (Simon, 1999), and treatment can reduce relapse rate as well as lessen MRI white matter disease burden (Rudick et al., 1997). An early study of interferon β-1-b in MS did find improvement in a visual reproduction test after 4 years of therapy (Pliskin et al., 1996), while the use of glatiramer in MS patients did not affect cognitive function compared to those treated with a placebo (Weinstein et al., 1999). A comprehensive study of this kind was a prospective placebo-controlled trial of interferon β-1-a in MS that showed significant benefit in information processing, memory, visuospatial ability, and executive function (Fischer et al., 2000). More recently, an open-label study of natalizumab in MS showed promise for improving both cognition and mood (Lang, Reiss, and Mäurer, 2012). One important implication of these studies is that they may justify the use of immunomodulatory drugs in MS for cognitive dysfunction alone. Therapy with these agents could thus plausibly improve or stabilize cognitive function because of a disease-modifying effect.

Post-marketing studies of four standard immunomodulatory drugs have revealed evidence of a positive effect on MS cognition (Comi, 2010). Despite the need for more study, these agents are generally thought to show promise for improving cognition by reducing the accumulation of white matter lesions and brain atrophy (Comi, 2010). Inclusion of cognitive measures in future clinical trials has been advocated (Comi, 2010), and an underappreciated benefit of immunomodulatory drugs in MS may be a positive effect on cognitive dysfunction.

Another intriguing possibility for the pharmacological treatment of cognitive loss in MS is 4-aminopyridine, a potent inhibitor of voltage-gated potassium channels that improves impulse conduction through demyelinative lesions and is now used to treat gait disorder (Jensen et al., 2014). Whereas evidence for an improvement in cognition has thus far not appeared, there is ample rationale for presuming a benefit might be found (Jensen et al., 2014).

In the inflammatory disorders, preliminary evidence for the cognitive benefit of treating white matter dysfunction can be found in the literature. The treatment of cognitive impairment in these diseases remains empirical, with corticosteroids the mainstay of therapy, and provocative clues can be found regarding the idea that treatment directed against white matter disease could be effective. In systemic lupus erythematosus (SLE), evidence that inflammatory microstructural involvement is related to MCD (Filley et al., 2009; Kozora et al., 2013) raises the possibility that anti-inflammatory therapy may address this form of neuropathology early in the disease. Consistent with this idea, a volumetric MRI study of early SLE patients showed that those who received immunosuppressive medications had greater white matter volume in several brain regions (Xu et al., 2010). While cognitive evaluation showed no association of white matter volumes with cognition, the only measure used was the Mini-Mental State Examination (MMSE; Folstein, Folstein, and McHugh, 1975), and more sensitive cognitive assessment might be more revealing. The data from this study (Xu et al., 2010) thus imply that the putative inflammatory myelinopathy of early SLE (Filley et al., 2009) may be a target of immunosuppressive treatment, and that MCD or WMD could be addressed with this approach. In this regard, a recent case report found that a young woman with neuropsychiatric SLE who was treated with corticosteroids and azathioprine improved her MMSE (Folstein, Folstein, and McHugh, 1975) score from 16 to 30 while diffusion tensor imaging (DTI) demonstrated higher fractional anisotropy (FA) of the corpus callosum (Lee et al., 2014).

In the infectious category, investigation of white matter changes associated with human immunodeficiency virus (HIV) infection has been pursued since the first reports of dementia related to the acquired immunodeficiency syndrome (AIDS) in the 1980s (Navia, Jordan, and Price, 1986; Navia et al., 1986). White matter changes were noted to be prominent both on neuroimaging and at postmortem in the AIDS dementia complex (ADC), now known as HIV-associated dementia (HAD), and whereas other regions such as the basal ganglia also sustain damage from HIV infection, initial reports supported the idea that improvement in cognition with antiretroviral therapy may relate to restoration of normal white matter. One of the first studies to show this effect was that of Tozzi and colleagues (1993), which found improvement of MRI white matter burden and on cognition as measured by the Wisconsin Card Sorting Test in some ADC patients treated with zidovudine. Soon therafter, protease inhibitors were found to have a similar effect on cognition in HIV patients (Filippi et al., 1998). Highly active antiretroviral therapy also proved helpful for both cognition and white matter lesions in ADC (Thurnher et al., 2000).

However, a cure for dementia in AIDS has not been found, and white matter injury has been shown to continue even among HIV patients receiving antiretroviral treatment (Cardenas et al., 2009). Indeed, while gains have undeniably been made in enhancing longevity and quality of life, the main impact of antiretroviral therapy seems to have been prevention of HIV complications such as opportunistic infections and neoplasms, and both white and gray matter injury continues to impair cognition even as patients rarely progress to dementia (Gongvatana et al., 2013). Data now suggest that HIV exerts damage to many brain regions through a complex pathogenesis, but the role of white matter injury continues to merit attention. An instructive recent case report documented that, in an HIV patient with HAD who was on antiretroviral therapy and had extensive MRI white matter hyperintensity, the dementia was completely reversed within 2 months of the addition of zidovudine to the treatment regimen, in concert with dramatic improvement of the MRI white matter changes (Hoogland and Portegies, 2014).

A disorder of white matter for which evidence of reversible leukoencephalopathy has often been presented is cobalamin deficiency. Several case studies using MRI have supported this claim, noting that clinical and neuroradiological improvement of leukoencephalopathy may occur in parallel with cobalamin replacement (Chatterjee et al., 1996; Stojsavljević et al., 1997; Su et al., 2000; Graber et al., 2010). Most cases of cobalamin deficiency are related to insufficient dietary vitamin B₁₂, but genetic causes are also recognized, and these too have been observed to respond to cobalamin replacement (Biotti et al., 2014). Recent findings from community-based studies that vitamin B₁₂ supplementation can decrease the conversion from mild cognitive impairment to dementia while simultaneously reducing MRI white matter lesion burden (Blasko et al., 2012) offer solid support for the classification of cobalamin deficiency as a WMD. Although questions remain about the pathophysiological relationship between leukoencephalopathy and deficiency of this vitamin (Stabler, 2013), very low levels of cobalamin are associated with WMD, reversibility of cognitive and neuroimaging abnormalities can be seen with B₁₂ treatment, and routine use of cobalamin appears to help prevent both dementia and white matter lesions.

Brain neoplasia has been little studied with respect to whether treatment can bring about cognitive improvement because of an effect on white matter involvement, but a report of patients with lymphomatosis cerebri is instructive (Deutsch and Mendez, 2015). In this series, among 6 of the 12 patients who had cognitive assessment, treatment with regimens including corticosteroids, radiation, and chemotherapy produced cognitive improvement (Deutsch and Mendez, 2015). In a study of patients with recurrent glioblastoma multiforme, the anti-angiogenic drug bevacizumab was found to reduce the volume of abnormal fluid-attenuated inversion recovery (FLAIR) signal and the volume of contrast enhancement (Ellingson et al., 2011), implying that chemotherapy may reduce white matter disease burden. These reports suggest that investigation is warranted in the assessment of the extent to which treatment of brain neoplasia may improve cognition in conjunction with regression of white matter disease.

Hydrocephalus is traditionally considered a surgical condition (see next section), but pharmacotherapy may have a role in certain cases. In a small study of patients with normal pressure hydrocephalus (NPH), the carbonic anhydrase inhibitor acetazolamide was recently shown to significantly reduce the volume of periventricular white matter hyperintensities and, in some patients, improve gait (Alperin et al., 2014). Given that acetazolamide acts by reducing the formation of cerebrospinal fluid (CSF) from the choroid plexi, it may be that the periventricular lesions of NPH can be reversed by a reduction in CSF volume. NPH remains a vexing disease with many unanswered dilemmas to be resolved, but evidence is mounting that the cognitive dysfunction that develops and sometimes can be improved may originate in damage to periventricular white matter (Akai et al., 1987; Del Bigio, 1993; Del Bigio et al., 1994; Leinonen et al., 2012). Acetazolamide has also been used successfully to control progressive hydrocephalus in a preterm infant with intraventricular hemorrhage (Miner, 1986).

The genetic white matter disorders have proven very difficult to treat, and early demise is still the unfortunate expectation in many individuals, most of whom are infants or children. The leukodystrophies have attracted the most interest in terms of treatment, as the possibility of hematopoietic stem cell transplantation (HSCT) became available in recent decades (Krivit, Peters, and Shapiro, 1999). This procedure remains the most promising therapeutic approach to these diseases. Currently, the use of HSCT is thought to be appropriate for individuals early in the course of metachromatic leukodystrophy (MLD), adrenoleukodystrophy, and Krabbe’s Disease, and referral to a specialized clinical research center is recommended (Vanderver et al., 2014). Results of this procedure have often been disappointing because the treated patients had disease that was too far advanced for the restored enzyme activity to be effective (Biffi et al., 2008; Orchard and Tolar, 2010). The efficacy of prompt treatment, however, was recently shown in a 5-year-old girl with MLD in whom early treatment with HSCT led to stable cognitive function and normal school performance at age 15 (Krägeloh-Mann et al., 2013). Of special interest in this case, MRI white matter lesions regressed over 10 years, while on magnetic resonance spectroscopy (MRS), choline declined and N-acetyl aspartate (NAA) increased (Krägeloh-Mann et al., 2013). Thus both macrostructural and microstructural markers of leukodystrophy improved as cognition stabilized, implying that the direct treatment of the white matter disease enhanced cognitive function.

Most recently, a small controlled study of young adults with MLD showed that HSCT led to sustained neuropsychological and MRI stability, suggesting that adults with this disease may also benefit from this treatment modality (Solders et al., 2014). While the small numbers of patients in these reports highlight the need for more investigation, these studies offer support both for the early treatment of MLD and related disorders and for the restoration of white matter as important for normal cognition.

Surgical

In everyday neurologic practice, the surgical treatment of WMD and MCD is currently limited to patients with hydrocephalus, and the problem of NPH in older people brings up this issue in all its complexity. The selection of patients who may have NPH and could benefit from surgical insertion of a diversionary shunt is fraught with uncertainties (Graff-Radford, 2007; Wilson and Williams, 2010). Many patients, for example, are referred for neurologic evaluation on the basis of MRI scans that have been read as suggestive of possible NPH, when in fact the clinical picture is not consistent with this diagnosis. Moreover, whereas favorable shunting response rates exceeding 50% have been reported (Gustafson and Hagberg, 1978), further study has suggested that the gait disorder responds better to shunting than does the dementia, and that improvement in many patients may not be sustained (Klassen and Ahlskog, 2011). However, clinicians recognize that meaningful clinical improvement can occur in this disease with surgical treatment, and NPH remains an important concern in clinical neurology. As reviewed in Chapter 6, the neuropathology of hydrocephalus is characterized by a predominance of injury in the periventricular white matter (Akai et al., 1987; Del Bigio, 1993; Del Bigio et al., 1994; Leinonen et al., 2012). In NPH, this injury may be accompanied by cortical changes of AD, the white matter lesions of BD, or both, complicating not only patient selection but the assessment of shunt response. However, some studies have demonstrated that NPH patients who respond to shunting have reduced white matter disease burden that correlates with improved cognition (Tullberg et al., 2002; Akiguchi et al., 2008). In the study of Akiguchi and colleagues, shunted NPH patients who had reductions of white matter lesion ratings also had improved scores on cognitive measures, including the MMSE (Folstein, Folstein, and McHugh, 1975), the Frontal Assessment Battery (Dubois et al., 2000), and Form A of the Trail Making Test (Ehrenstein, Heister, and Cohen, 1982).

Other potential surgical avenues include applications of gene therapy (Leone et al., 2000) and stem cell therapeutics (Goldman, 2007; Tran, Ho, and Jandial, 2010). While these appear to have some promise, much more fundamental research is needed before modalities involving this kind of intervention can be routinely applied to brain white matter disorders. This topic will be further explored in Chapter 13.

Any enthusiasm for the surgical treatment of WMD, however, should be viewed in light of experience gained from the era of surgery for psychiatric illness in the mid-twentieth century (Anderson and Arciniegas, 2004). Before the introduction of major tranquilizers beginning with chlorpromazine in the 1950s, severe forms of schizophrenia and other psychiatric diseases were often treated with psychosurgical procedures that mainly targeted the frontal lobe white matter. In general, the idea motivating these procedures was that psychosis originated in the frontal lobes, and disconnecting these regions from other brain areas by lobotomy or leucotomy could reduce the severity of psychotic ideation. Whereas some patients may have had amelioration of severe psychosis by these procedures, many were not helped or were clearly worsened, and the operations were typically performed in a shockingly inappropriate – even barbaric – manner (Anderson and Arciniegas, 2004). Moreover, a paucity of useful information was gathered on long-term outcome because of little attention to proper follow-up and data acquisition.

The surgical targeting of white matter is thus burdened by a tarnished history in the recent past, and any approach of this kind must be undertaken with the utmost care and strictest adherence to ethical guidelines. Psychosurgery does appear to have a role in the treatment of selected, intractable neuropsychiatric conditions (Anderson and Arciniegas, 2004), but it is difficult at present to envision a scenario in which a patient with dementia – related to white matter or any neuropathology – could be helped by such intervention. Surgical options for the treatment of WMD (existing and theoretical) are not intended to involve the ablation of tracts, but rather their protection or restoration.

Rehabilitative

The rehabilitation of neurobehavioral disorders generally falls under the heading of cognitive rehabilitation, also known as cognitive neurorehabilitation (Stuss, Winocur, and Robertson, 2008). Much uncertainty has surrounded this field since its inception, with abundant enthusiasm unmatched by solid data supporting efficacy, and often considerable cost. Indeed, many patients are drawn to this form of treatment by overly optimistic predictions of successful recovery. Recent evidence, however, has offered more compelling support for this type of intervention. Most of the work has been done on TBI and stroke, and in selected patients cognitive rehabilitation has been shown effective for the remediation of attention, memory, executive function, social cognition, aphasia, apraxia, and visuospatial skills (Cicerone et al., 2011). Cognitive rehabilitation typically involves a variety of individual, group, and computer-based sessions targeted to specific cognitive deficits, and the goal is to produce improvement on therapeutic measures and achieve real-world functional gains (Arciniegas, Wortzel, and Frey, 2013).

Cognitive rehabilitation targeted specifically to individuals with WMD and MCD has not been formally addressed. One inherent advantage of attempting to treat cognitive impairments in white matter disorders is that treatment does not encounter the major obstacle of many gray matter diseases in which neurodegeneration produces inexorable loss of neurons and synapses. Static, relapsing, or slowly progressive deficits are more typical of white matter disorders, and thus the opportunity for substantial restoration of white matter tracts is not illusory. Very little is known about whether the repair of damaged white matter tracts relevant to neurobehavioral competence can be enhanced by cognitive rehabilitation, but the question is an important one given the substantial morbidity produced by white matter disorders.

One of the appealing possibilities in this area is the exploitation of new understanding regarding the response of cerebral white matter to neuropathological insult. As discussed in Chapter 10, evidence has been presented that white matter may be reparable by intrinsic plasticity that can remyelinate axonal segments through activity-dependent myelination (Wake, Lee, and Fields, 2011). One of the mechanisms by which this phenomenon is thought to occur is via glutamatergic transmission at axo-oligodendroglial synapses, present within white matter, which leads to increased production of myelin basic protein and enhanced myelination of the distal axon. In essence, the greater the electrical activity through a given tract, the more extensive will be its myelination. If this process is found to be sufficiently common and widespread after neuropathological insult, a rationale could be established for procedures intended to engage and stimulate the brain’s natural recovery system for the restoration of normal myelination and axonal function.

Studies in normal adults are beginning to shed light on the possibility of white matter repair as a result of behavioral interventions (Wang and Young, 2014). Box 11.1 lists some methods by which aspects of white matter structure have been suggested to be modifiable by environmental influences (Wang and Young, 2014). These methods will be familiar from the section on plasticity in Chapter 10, in which activities such as playing a musical instrument or speaking two languages were presented as capable of altering the structure of white matter. Such interventions have yet to be studied in the setting of rehabilitation after white matter pathology has been sustained, but they offer an intriguing new way to think about how brain repair might be accomplished, complementing emerging knowledge more relevant to gray matter such as synaptic plasticity and neurogenesis (Wang and Young, 2014).

Box 11.1 Behavioral interventions with the potential to alter white matter structure

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