Binswanger's Disease: An Ongoing Controversy

A. Transaxial slice of a single-photon emission computed tomography (SPECT; 25 mCi of [^99mTc]HMPAO ) brain perfusion scan from a 57-year-old African-American male diagnosed with Binswanger's disease. Note the clearly increased uptake in the basal ganglia (arrow), consistent with the patient's long-standing history of torticollis. Cortical uptake is nearly normal except for a mild decrease in the parietal cortex bilaterally (not shown). The fluid-attenuated inversion recovery (FLAIR) magnetic resonance scan (see cover) showed multiple deep white matter and periventricular hyperintensities, particularly in the posterior areas. There was no lesion enhancement following contrast agent administration and no evidence of iron deposition or cerebral, cerebellar, or caudate atrophy. The patient presented for a first psychiatric hospitalization after wandering in the streets wearing his pajamas claiming that he was dying of AIDS, that his family was trying to kill him, and that if he raised his hands, the police would shoot him. Medical history indicated uncontrolled hypertension, idiopathic torticollis, and borderline hyper-thyroidism. Investigative studies included negative rapid plasma reagin test, drug screen, and HIV serostatus. Thyroid function, B₁₂, folate, sedimentation rate, liver function, electrolytes, CBC and CSF studies were normal. He was also negative for oligoclonal bands, ceruloplasmin, and genetic markers of Huntington's disease. Neuropsychological testing revealed decreased cognitive tone, impaired concentration, slowed information processing, executive dysfunction, and visuoperceptual impairment (with normal verbal and visual memory)—suggesting cortical disconnection.B. Photomicrographs of Klüver-Barrera staining in the frontal deep white matter from a nondiseased control brain (left) and one with Binswanger's disease (right). Note a marked proliferation of collagen fibrils (blue) in the adventitia and narrowing of the lumen in Binswanger's disease.C. Photomicrographs of the immunohistochemistry for GFAP (glial fibrillary acidic protein) staining in the frontal deep white matter from a nondiseased control brain (left) and one with Binswanger's disease (right). Note that the astroglia (brown) show regressive changes such as swelling, vacuolation of the cell bodies, and disintegration of processes (recognizable as brown granules in the neuropil) in Binswanger's disease.As the 19th century came to a close, Otto Binswanger, Alois Alzheimer, and Emil Kraepelin were defining the concept that dementia was a group of cognitive disorders with many underlying subtypes and pathophysiological causes. As the 20th century has ended, the descriptive criteria, incidence, and prevalence for many of these dementias continue to remain a controversy.¹ One subtype, labeled Binswanger's disease by Alzheimer in 1902, referred to arteriosclerotic subcortical white matter changes.² As time progressed, it became clear that subcortical white matter dementias varied in both pathology and clinical features. Recent authors propose differentiating patients with specific subcortical lacunar infarcts from those with only leukoaraiosis (LA; white matter rarefaction). Indeed, Pantoni and Garcia² state that the term Binswanger's disease “lacks medical significance or relevance,” since Otto Binswanger's original case was probably neurosyphilis. Because this controversy is still unsettled, we have chosen to use here the historical term Binswanger's disease (BD).

Binswanger-type leukoencephalopathy (BD; LA; ischemic vascular leukoencephalopathy; progressive subcortical vascular encephalopathy; subcortical arteriosclerotic encephalopathy; periventricular leukoencephalopathy) is a slowly progressing vascular dementia with average onset by age 60. Approximately 4% of the general population and 35% of dementia patients show the characteristic lesions of BD on autopsy.³ Clinical symptoms include frontal executive dysfunction, mild memory loss, psychosis, slowed thought processing, mood disorders, apathy, urinary incontinence, parkinsonian gait disturbance, and pseudobulbar palsy.^1,3,4 There may be signs of brain atrophy, including dilation of the ventricles and increased sulcal width (see cover and Figure A). The lesions characteristic of BD are located in the periventricular and deep cerebral white matter. They may be large and confluent with smooth margins and be contiguous with the lateral ventricles, or they can occur in other subcortical locations as patchy or punctate lesions. The subcortical arcuate fibers (U fibers) are usually spared.⁵

These lesions are believed to be due to repeated hypoxic-ischemic events in the long, thin end arterioles of the penetrating medullary arteries that supply the deep white matter.^5–7 The more superficial white matter interconnecting cortical areas (the U fibers) is spared because of collateral supply. Vascular disease is present, including thickening of the walls (due to fibrohyalinosis) of these small arteries as well as fibroid necrosis and segmental arterial disorganization of large cerebral arteries and atherosclerosis (see Figure B).⁸ There is a strong association between the degree of wall thickening and the magnitude of white matter lesions.⁹ There is evidence that changes in blood viscosity and coagulation state may be a factor in the development of lesions in BD. Thus, several intermediaries on the coagulation-fibrinolysis pathway have been shown to be elevated—including fibrinogen (which increases plasma viscosity), thrombin-antithrombin complex, prothrombin fragment F1+2, and D-dimer levels—in BD patients whose neurologic status had deteriorated within the previous 3 months, but not in stable BD patients.¹⁰ Activation of this pathway can cause formation of microthrombi as well as microcirculatory disturbance, perhaps exacerbating development of lesions. Pathological changes within lesions include a reduction in the density of nerve fibers in the deep subcortical white matter, associated with rarefaction and astrocytic changes.^8,9 Axonal damage is present within BD lesions, as is decreased myelin. Activated microglia are present, perhaps as a response to chronic ischemia or to presence of damaged axons. Some astroglial cells may be swollen, with disintegration of processes, possibly in response to edema (see Figure C).¹¹

Diagnostic imaging using clinical magnetic resonance (MR) or computed tomography (CT) provides clear visualization of white matter lesions and areas of infarction. These areas have decreased density on CT and increased signal intensity on T₂-weighted MR images.⁵ However, the appearance of these lesions is quite nonspecific with both of these techniques. Thus, areas of increased signal intensity on T₂-weighted MR images (sometimes referred to as “unidentified bright objects” or UBOs) are associated with a wide range of pathological conditions that can cause dilation of the perivascular spaces (état criblé), small areas of subcortical infarction (lacunae), or demyelination and gliosis.² Some studies have concluded that there is not a good correlation between lesion load and general cognitive measures, suggesting that the majority of these lesions may be clinically silent.¹² However, several studies suggest a close association between the extent and location of lesions and specific deficits related to the types of executive dysfunction commonly found in subcortical dementias, such as slowed thought processing.¹³ It is likely that the disconcordant results arise from differences in patient populations, image analysis methods, and cognitive tests utilized. More extensive studies are needed to resolve this issue.

Alternative types of MR imaging show promise of being able to distinguish among some of these pathological conditions. One method is sensitive to interactions between free protons (unbound water in tissue) and bound protons (water bound to macromolecules such as those in myelin membranes).^14,15 This type of MR image, called a magnetization transfer (MT) image, may be able to differentiate white matter lesions of BD from those not accompanied by cognitive changes or due to other causes such as infarction.^14,15 Another method of MR imaging is sensitive to the speed of water diffusion. Diffusion-weighted MR imaging may be able to differentiate the white matter lesions in BD from those in Alzheimer's disease.¹⁶ It may be that in future a combination of some of these newer methods of MR imaging will provide important information for differential diagnosis.

Functional brain imaging may provide more insight into the disease process in BD. Positron emission tomography studies indicate that cerebral blood flow and cerebral metabolic rate can be reduced in both cortex and white matter in BD patients compared with both normal control subjects and patients with white matter lesions but without dementia.^17–19 Oxygen extraction fraction is not elevated in either gray matter or white matter in these BD patients, suggesting that the areas are not at high risk for ischemia.^17,18 There are no histopathological abnormalities in the cortical areas with reduced blood flow and metabolic rate, so it is likely that these changes are secondary to damage to deep white matter and/or subcortical structures. In contrast, nondemented patients with white matter lesions have both decreased cerebral blood flow and increased oxygen extraction fraction in their deep white matter.¹⁸ This suggests that these areas are maintaining a normal metabolic rate in the face of diminished blood supply, and thus might be at risk for ischemic damage. Thus, one might speculate that asymptomatic individuals are in an earlier stage of the process that will eventually be called BD when areas that affect cortical function (white matter or subcortical gray matter) are damaged. Although most of these studies have not reported a high correlation between degree of dementia and measures of cerebral blood flow, the most frequently used global screening measures are insensitive to deficits in executive function.

Only a few studies have used single-photon emission computed tomography (SPECT) to assess blood flow changes in vascular dementia, and even fewer to examine BD specifically. SPECT would not be expected to be more informative than standard diagnostic imaging (CT or MR) at directly demonstrating white matter lesions typical of BD because white matter normally takes up very little radiotracer and is barely visible on a SPECT scan. However, SPECT is sensitive to the functional consequences of white matter and subcortical lesions. The most common finding early in BD is decreased perfusion in frontal cortex and basal ganglia (see Figure A). As clinical symptoms increase in severity, more widespread perfusion deficits are found.^20,21 These results are consistent with evidence of subcortical infarcts on MR and CT imaging and loss of frontal lobe executive function on neuropsychological testing.¹ These SPECT studies used gamma cameras built prior to 1990. The higher resolution of the modern triple-headed cameras (as was used to collect the images shown here) may yield somewhat different results.

The poor correlation that has been found between several measures of pathology (lesion load, decreased cerebral blood flow) and degree of dementia indicates that the etiology of BD is still not clear. As pathological processes become better understood, they may provide insight into new potential treatments. At the present time the most promising treatment is the vasoactive drug nimodipine (a calcium channel blocker that inhibits contraction of vascular smooth muscle). Initial clinical trials have reported stable or improved cognitive function over periods of treatment as long as 1 year.^22,23 A different cerebral vasodilator, fasudil hydrochloride (a calcium antagonist that acts intracellularly), decreased dementia and returned cerebral metabolic measures (as monitored by phosphorus MR spectroscopy) to normal values in a patient with BD. Cerebral blood flow (as monitored by xenon CT) was not increased toward normal by the treatment.¹⁸ The authors of the study suggest that the treatment was effective because of a direct effect on intracellular energy metabolism. A different approach targets the elevation in the levels of intermediaries on the coagulation-fibrinolysis pathway in BD. A recent study of a patient with BD and antiphospholipid syndrome reported improvement in gait disturbance and mental dysfunction with antithrombin (argatroban, a selective competitive inhibitor of thrombin) treatment.²⁴ An earlier study using a defibrinating agent (ancrod) was not successful.²⁵ Thus, although there is no clear treatment strategy for BD at the present time, the future looks promising.