Binswanger’s disease, leukoaraiosis and dementia

Review: Binswanger’s disease, leukoaraiosis and dementia

J. Santamaria Ortiz

Introduction

In 1894, Otto Binswanger described Encephalitis Subcorticalis Chronica Progressiva [1], a form of dimentia characterized by slowly progressive intellectual deterioration starting in the sixth decade, with intercurrent stroke-like events and seizures. Macroscopic examination of the brain of one of his eight patients revealed enlarged ventricles, symmetrical white matter softening of a periventricular and temporal-occipital distribution, and a relatively intact cortex. He attributed these changes to a deficiency in the blood supply, resulting from arteriosclerosis.

Alzheimer provided the first histological description in 1902 [2], and named the entity Binswanger’s disease (BD). The changes included axonal loss, demyelination and sclerosis of the deep penetrating arteries to the white matter. The presence of numerous lacunae in the white matter, inernal capsule, lenticular nucleus, thalamus and pons were also noted. The cortex appeared quite well preserved.

In his review of the literature in 1962, Olszewski [3] stressed the presence of lacunae and cortical infarcts, and suggested the term Subcortical Arteriosclerotic Encephalopathy (SAE). Two comprehensive reviews of the literature on BD have been published inrecent years. Babikian and Ropper [4], in 1987, studied the clinical pathological correlations in 47 reported cases with verified pathology and reatively complete clinical descriptions. Fisher [5], in 1989, also analysed in detail the significance of the typical CT and MRI changes, and their correlatioan with the clinical presentation and the pathological changes. For several decades, dementia in elderly patients was believed to be caused by ‘cerebral arteriosclerosis’. In 1974, Hachinski et al [6] defined Multi-infarct Dementia (MID) as a form of dementia due to multiple cerebral infarcts which were secondary to diseases of the extracranial arteries and the heart. Since then, Alzheimer’s disease (AD) and MID were considered to be the main aetiological types of dementia, with a proportion of cases having a mixed degenerative and vascular aetiology.

The main clinical features of MID were considered to be stepwise deterioration, presence of focal neurological signs, and, commonly, an association with hypertension. On the other hand, senile dementia of Alzhemier’s type (SDAT) was identified by an insidious and slowly progressive course. The clinical diagnosis of the type of dementia is usually based on an ischaemia score [7] which can accurately identify vascular dementia in cases with clinically evident stroke. However, this classification tool has some limitations. It may miss a number of patients with vascular dementia and without clinically evident strokes who would probably be included in the Alzheimer group [8]. On the other hand, patients who have a stroke early in the course of Alzheimer’s disease would be included in the vascular dementia group [9].

Clinical features

In the papers reviewed by Babikian and Ropper [4] and Fisher [5], more than 80% of the affected patients were in their sixth or seven decade, confirming that BD is predominantly a disease of elderly people. Men and women were equally affected. Mental impairment was present in all cases, and was the main feature at onset in nearly 30%. It was present early in the illness in at least 65%. The intellectual deterioration was usually insidious, but mental changes sometimes appeared suddenly after an ictus. Similarly, neurological deficits often start perniciously and progress gradually [10]. The evolution of the 50 pathological confirmed cases of BD reviewed by Fisher was as follows:

Thirty-four per cent presented as slowly progressive dementia plus stroke, TIAs or subacute evolving deficits.

Twenty-two per cent presented as slowly progressive dementia with subacute evolving neurological deficits, without evidence of stroke or TIA.

Twenty-eight per cent presented as demential without stroke or TIAs, with neurological signs of underdetermined time on onset and evolution.

Sixteen per cent presented as dementia late after stroke. TIA or subacute evolving neurological signs.

A gait disorder appeared in 60% of the cases in Babikian and Ropper’s review [4], and urinary incontinence was frequent in the more advanced cases. Clumsiness of the hands, hyperreflexia, bilaterial Babinski’s signs, grasping and sucking reflexes, and cerebellar limb ataxia were common amongs the cases reviewed by Fisher [5]. Frontal lobe symptoms, mainly apathy and emotional lability, and pseudobulbar palsy have often been reported [10-14]. Most patients with BD are hypertensive, but normotensive patients have also been reported [4, 13, 15].

It has been suggested that diffuse periventricular white matter lesions such as those seen in BD, may be an important cause, not only of cognitive impairment but also of oter psychiatric disturbances [16]. Depression has been commonly reported in BD patients (4). Fisher suggested that it may have been coincidental or mistaken for the abulia of the frontal lobe syndrome [5]. However, more recently, periventricular white matter hyperintensites on MRI have been found to be significantly more frequent and severe in elderly patients with severe depression, than in healthy matched controls [17].

Binswanger’s disease is therefore a type of vascular dementia that can present with a clinical course similar to MID or with a slowly progressive course, clinically difficult to differentiate from dementia of the Alzheimer’s type. The clinical picture can also closely resemble that of normal pressure hydrocephalus (NPH), with the triad of gait disturbances, urinary incontinence, and mental impairment. Patients with NPH seem to be older and have more frequent giat disturbance at the onset, shorter duration of illness, rarer signs of vascular disturbances, and more frequent severe mental deterioration [18].

Pathology

The pathological findings in the brains of patients with BD in the series reviewed by Babikian and Ropper [4] and Fisher [5] were highly consistent. There were macroscopic and microscopic vascular and parenchymal changes.

On macroscopic examination, the brains had normal external appearance and weight. There were patchy and fairly symmetrical confluent aeas of periventricular white matter discoloration. The lateral ventricles were moderately to greatly enlarged in more than 80% of cases, and this has been attributed to shrinkage of the white matter [19]. Large vessels at the base of the brain showed atheromatous changes of various degrees in 93%, but in most cases they were unlikely to cause significant distal haemodynamic effect.

In 93% of the cases there were zones of white matter rarefaction and scattered microcystic areas of infarction in the internal capsule, centrum semiovale, basal ganglia, and occasionally the cerebellum. In view of these findings, BD and the lacunar state could be the same entitye [20, 21]. However, Babikan and Ropper [14] suggested that the multiple lacunae present in the lacunar state are not associated with the typical white matter changes of BD, and that the mental changes in lacunar state are not as pronounced nor appear as early as in BD.

Microscopic vascular changes in the form of lipohyalinosis and thickened walls of the white matter arterioles were invariably present but they were seldom totally occluded. In most instances, similar changes were also eivdent in the basal ganglia, thalamus and pons [22, 23]. Cortical vessesl were usually better preserved.

Microscopic examination of the white matter revealed several degrees of los of myelin and oligodendrocytes, and astrocytic gliosis. Because of their similarity to the transitional area surrounding complete infarctions in MID, Brun and Englund [24] suggested that these changes could represent incomplete infarction. The subcortical association fibres were, as a rule, spared.

In summary, the pathological features of BD are, sclerosis of the white matter arterioles, demyelination, gliosis, and scattered small infarctions symmetrically affecting the periventricular areas.

Prevalence

For many years, BD was thought to be an uncommon cause of dementia, probably because of its pathological features were undetected owing to the rarity of whole brain sectioning and staining for myelin [20]. The same reason may account for the previous lack of association of white matter periventricular lesions with Alzheimer’s disease [24, 25].

The prevalence of BD is not known. Interpretation of the available data has to be cautious, as most of the studies have been retrospective and in selected populations [11, 15, 22, 26]. The largest pathological studies are those of Tomonaga [22] and Tohgi [26]. The first found, in a series of 1000 autopsied brains of elderly people that cerebrovascular disease was present in 6.7%, and pathological changes in BD in 3.8%. In the second, the prevalence of cerebrovascular disease in a series of 2000 autopsies of demented patients was 53%, with 35% showing pathological changes of BD. Only 18% had changes of MID. It seems that BD may account for a considerable proportion of the vascular dementias.

Imaging

Radiological white matter periventricular changes on CT and MRI became a common finding with the increasing availability of these techniques. Patients with the clinico-pathological diagnosis of BD consistently show diffuse periventricular hypodensity on CT, which does not enhance with contrast agents [11, 13, 19]. However, it soon became obvious that the same picture was also a common finding in patients with other conditions, and in a number of healthy subjects. In 1987, Hachinski et al. [27] suggested the term leukoaraiosis (LA) (from Greek, meaning white matter rarefaction), to name this CT pattern, independently of the underlying pathology [Figure].

The prevalence of LA in CT studies of elderly patients has ranged from 1.7% [19] to 5% [15]. LA is strongly associated with stroke disease [28, 29], and it has been found by CT in more than 32% of patients with dementia of the Alzheimer’s type [25, 28], and in around 8% of asymptomatic controls [28, 30, 31].

MRI is significantly more sensitive than CT in detecting white matter lesions [19, 32]. Areas of periventricular hypodensity on CT appear as bright areas of increased intensity on T2 MRI images. Furthermore, MRI commonly reveals small discrete bright foci of T2 activity not detected by CT, which are not only in the vicinity of the ventricles, but also in the peripheral white matter [5]. Zimmerman et al. [33] found some degree of periventricular hyperintensity on MRI in 93.56% of 365 patients aged 6 to 82 years. Awad et al. [34] found incidental white matter lesions on MRI (not explained by the patient’s clinical diagnosis, neurological examination or CT scan) in 92% of 50 patients aged between 60 and 82. The lesions were multiple in 80% of the cases, and they were multiple and confluent in 30% of the cases. Hunt et al. [35] found moderate to severe white matter hyperintensities in 30% of 46 healthy elderly people, and in 69% of patients with cerebrovascular disease.

Clinical-radiological correlations

The prevalence and severity of the white matter CT and MRI changes increase with age [15, 19, 29, 30, 36], and these changes are significantly more frequent in patients with neurological signs [11, 19, 22, 29]. Hypertension has been commonly reported in association with periventricular white matter radiological changes [13, 15, 19, 36]. In the prospective controlled study by Inzitari et at. [28], LA was associated with increaing age and systolic blood pressue on univariate analysis. However, these associations did not reach statistical significance when each of the variables (age and systolic blood pressure) were analysed in a multivariate model, controlling for the effects of other variables. The only significant independent contributor to the presence of LA was a history of stroke. No association was found between LA nad diastolic blood pressure, myocardial infarction, angina, diabetes or carotid bruits.

In a retrospective CT study [37], the severity of LA was strongly correlated with blood pressure instability (hypertension, labile systolic blood pressure, orthostatic hypotension, or a combination of these factors). Previous episodes of hypotension were also noted to be a frequent feature in demented patietns with pathological [24] and radiological [38] periventricular white matter changes.

Steigart et al. demonstrated an association of LA with mental impairment in their prospective study of LA in healthy elderly subjects [30]. Dementia scores were significantly lower in asymptomatic individuals with LA compared with control individuals without LA. The presence of abnormal gait, limb power, and plantar responses was also significantly more common in the subjects with LA. However, Rao et al. [39] did not find a significant difference on neuropsychological testing between healthy subjects with and without LA. No correlation was found between the extent of LA [11] or equivalent MRI white matter changes [40] and the presence of dementia. Inzitari et al. [28] found that the association between LA and dementia did not reach statistical significance when the influence of other variables (mainly age and stroke) was taken into account in a multivariate analysis. They thought that the association shown in the univariate analysis was explained by the confounding effect of stroke. Hunt et al. [35] found that cognitive performance tended to decline and the severity of white matter perinventricular changes on MRI tended to increase with age. However, cognitive performance failed to correlate with MRI changes when controlling for age. They suggested that the correlation of CT white matter hypodensities and intellectual deterioration in Steingart’s study probably represented a group of patients with more severe lesions.

From all these data we can conclude that the increase in prevalence of LA and equivalent MRI changes with increasing age is not attributable to age itself, but mainly to cerebrovascular disease. There seems to be a tendency for LA to be associated with hypertension and mental impairment, however this assertion remains controversial.

Pathological-radiological correlations

Histological changes of BD (demyelination, axonal loss and thickening of the arteriolar walls) were present in all patients with LA on CT. However, they were also present in a milder degree in seven out of ten control subjects without LA [11]. This suggests a false negative CT diagnosis at the mild end of the disease, despite which the authors estimated that the diagnosis of BD could be made with an accuracy of 90% by CT. These patients were not studied by MRI.

The pathological changes found underlying all white matter areas of increased MRI signals consisted of tortuous small arteries with sclerotic thickened walls and enlarged perivascular spaces [14-43], strongly supporting a vascular mechanism. These changes, which had been described in 1843 by Durland-Fardel as etat crible [44], result in an extensive network of tunnels filled with extracellular water producing a pattern of diffuse increased proton signals. However, MRI did not differentiate between the milder forms of histological change (enlarged perivascular spaces and vascular ectasia) and the more severe (gliosis and fibre loss) [41]. Etat crible has been considered as the most likely explanation of LA on CT [45]. It is usually asymptomatic and associated with advancing age and hypertension [46].

The presence of patchy areas of pallor to myelin stains and associated gliosis, although occasionally coexistent with etat crible, was not present in all the areas of increased MRI signal [41]. Similar changes were observed by Brun and Englund in the brains of patients with AD [24] in whom LA is also a common finding [25]. These changes, considered as areas of incomplete infarctin, are unlikely to be due to wallerian degeneration as there was no regional association between them and the cortical changes of AD.

CT and MRI changes reflect a change in the texture of the white matter periventricular tissue, with increased water content [41, 42] that occurs in etat crible. Demyelination, gliosis and infarction may also be present. Therefore, the radiological changes may represent different degrees of underlying pathological changes with different clinical features, ranging from asymptomatic to advanced dementia.

Pathophsiology

The arteriolar and perivascular changes of etat crible, associated with hypertension and perhaps other unknown factors, may cause chronic impairment of the oxygen and nutrients exchange, with subsequent demyelination and gliosis [42]. The periventricular region is particularly susceptible to these lesions, being an end zone or watershed area for the long medullary arteries [47]. The arteriolar wall changes may also cause impairment of the autoregulation of the cerebral blood flow [20, 24, 48], and vasomotor cerebral reactivity has been shown to be impaired in elderly hypertensive subjects [49]. Other factors that may play a role in this ischaemic process could be increased plasma viscosity [50], stenosis of the cortical arteries due to atheroma [13] or amyloid deposition [24, 51, 52]. The latter is closely related to AD and it may play a role in the origin of the white matter lesions commonly seen in these patients. In these circumstances, situations of low cardiac output as in heart failure, arrhythmias, or a drop in blood pressure due to automatic dysfunction or excessive antihypertensive therapy may result in a reduction of the blood supply to the brain, leading to further ischaemic damage and complete infarction. In fact, a history of previous hypotensive episodes was a frequent feature in demented patients with pathological changes of the periventricular white matter [24]. Situations of low cardiac output were also found to be common in patients with pathological [15, 22] and radiological [37, 38] white matter periventricular changes.

Kinkel et al. [19] suggested that the ventricular enlargement in BD is due to shrinkage of the periventricular white matter, and that BD may be the underlying problem in patients diagnosed as normal-pressure hydrocephalus who do not respond to shunting procedures. Apart from enlarged ventricles, patients with normal-pressure hydrocephalus may present white matter periventricular changes on CT and MRI similar to those of BD [53-55). However, both entities may coexist, accounting for the transient clinical improvement after ventricular shunting or withdrawal of CSF reported in two BD patients [56, 57]. CSF pressure has not been assessed in most reported patients with BD, and the possible role of normal-pressure hydrocephalus in the pathogenesis or progression of BD remains uncertain.

Perinventricular white matter lesions and dementia

The mechanisms of vascular dementia are not clear. Initially, MID was thought to cause dementia by the additive effect of large and small strokes, producing loss of brain tissue of 50-100 m [6]. However, patients with considerable volumes of infarction may not be demented while patients with only small volumes of infarction may be demented [58]. Rather than the total volume of infarction, it seems that the most important factors determining the presence of dementia are the specific location of the lesions (higher frequency of lesions in the corpus callosum and hypocampus) and the presence of bilateral lesions [9, 58]. It has been suggested that the pathophysiological mechanism of dementia in patients with subcortical white matter lesions may be the interruption of the subcortical association pathways connecting different cortical areas [20]. Tatemichi [59] suggested that progressive dementia following a single clinically obvious stroke may be explained by the cumulative effects of subsequent strategically located white matter infarctions, especially those that disrupt the association pathways in the periventricular zones, including the thalamocortical and corticostriate pathways. These infarctions may occur unnoticed over time, since they may not produce obvious motor or sensory signs.

Course of the disease

This pathophysiological hypothesis suggests a progression from the mild changes of the etat crible that becomes more common with advancing age and hypertension, to more severe changes with demyelination and gliosis that could correspond to the incomplete infarction already described, and finally to the lacunar infarctions present in patients with BD. All these pathological changes were present in the BD patients of Babikian’s review, suggesting that BD may be the end-stage of the above proposed sequence of events.

There is a lack of prospective studies of asymptomatic subjects with periventricular white matter changes, who are follow up for long enough to determine whether they are predisposed to develop BD or other forms of cerebrovascular disease. A recent prospective and controlled MRI study of a small group of healthy elderly subject over a perood of 18 months [60], revealed a mild but significant decline in learning capacity and memory in those with periventricular hyperintensities. None of the subjects in the studu presented any signs or symptoms of cerebrovascular incidents.

There is some evidence that control of vascular risk factors such as hypertension and cigarette smoking improves cognition in patients with MID[61]. Interestingly, hypertensive patients with MID deteriorated when their systolic blood pressure was reduced below 135 mmHg. It seems reasonable that the control of possible risk factors influencing the development of BD may prevent or slow the course of the disease. However, in one study [10], antihypertensive treatment in patients with symptomatic BD did not prevent further neurological deterioration, and might have even accelerated the course of the disease.

Alzheimer’s disease

Radiological and pathological changes of the perioventricular white matter are significantly more common in patients with AD than in controls [24-26], and may play a role in the progression of the disease. The effect of LA on mental impairment is most evident at the moderately severe stage of AD, rather than at the more advanced stages of the disease [25]. It has been suggested that white matter lesions that would be asymptomatic in normal individuals may have a dementing effect in patients with subclinical AD [62], or may accelerate the progressive course in patients with clinically apparent AD [59]. Therefore, there may be an added vascular component to at least a proportion of patients with AD. It is not known whether the coexistence of amyloid angiopathy and white matter periventricular changes in AD is coincidental, or the common presence of cerebral amyloid angiopathy in AD [63] may play a role in the pathogenesis of these changes.

Conclusions

Initially described nearly a century ago, Binswanger’s disease remains an elusive entity. Its aetiology is not clear and its clinical features overlap with multi-infarct dementia, demetia of the Alzheimer’s type, and normal-pressure hydrocephalus making the differential diagnossi difficult. CT and MRI white matter periventricular changes are not specific to Binswagner’s disease, and their interpretation must be made in the context of the clinical findings. The clinical significance of these radiological pictures is unclear. They seem to be associated with some degree of metnal impairment, but we do not know whether they are an indicator of future dementia. Prospective studies of asymptomatic subjects with CT and MRI changes would be required to clarify this issue and assess the importance of the possible risk factors for the development of Binswanger’s disease.

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