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(Stroke. 1997;28:2222-2229.)
© 1997 American Heart Association, Inc.

Articles

Nonhypertensive Cerebral Small-Vessel Disease

An Autopsy Study

G. Alistair Lammie, MD, MRCPath; Frances Brannan; Jim Slattery; Charles Warlow, MD, FRCP

From the Neuropathology Laboratory, University Department of Pathology (G.A.L., F.B.), Department of Clinical Neurosciences (J.S., C.W.), Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.

	Abstract

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Background and Purpose Cerebral small-vessel disease (SVD) is a common aging phenomenon that is exacerbated by hypertension and diabetes mellitus. It is regarded as an important cause of lacunar infarction and intracerebral hemorrhage. The present study was performed to highlight the existence and to some extent the frequency of pathologically verified SVD lacking in classic risk factors and to extend the scope of risk factor analysis.

Methods The study group comprised 70 consecutively referred autopsy brains with microscopic evidence of SVD. In each case clinical records, autopsy reports, and central nervous system and systemic autopsy histology were reviewed. SVD was graded as mild, moderate, or severe in six standardized brain regions, and the results analyzed in relation to the presence or absence of classic SVD risk factors.

Results SVD was manifest largely as concentric hyaline wall thickening; lipohyalinosis and fibrinoid necrosis were rarely observed. Thirty-one percent of cases failed to meet stringent clinicopathological criteria for significant prior hypertension. In 9% of cases, patients had been nonelderly, nondiabetic, and normotensive. Five of six cases lacking classic risk factors had systemic conditions known to enhance small-vessel permeability.

Conclusions The nature of SVD appears to have been modified by effective treatment of hypertension. Classic risk factors are often absent. The hypothesis that a variety of conditions that enhance small-vessel permeability may contribute to the pathogenesis of SVD merits consideration.

Key Words: hypertension • lacunar infarction • risk factors • autopsy • small-vessel disease

	Introduction

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The term "hyaline arteriolosclerosis" describes a common structural alteration in small penetrating arteries and arterioles of the brain in which medial smooth muscle first hypertrophies and is then replaced by extracellular matrix and plasma proteins.^{1 2 3 4} It appears to be an aging phenomenon,⁵ but is said to be exacerbated by chronic HT and diabetes mellitus.² Enhanced small-vessel permeability is generally considered a key pathogenetic feature, with mural deposition of serum protein detectable specifically in areas of blood-brain barrier breakdown.^{3 4 6 7} The cerebral SVD literature is confused by a variety of terms for the same or closely related lesions, of which "lipohyalinosis" is perhaps the most commonly used.⁸ Hypertensive SVD, by whatever name, is regarded as an important cause of ICH and lacunar infarction, largely because the distribution of each in the brain is strikingly similar.^{9 10 11} So, it is generally postulated that in its early stages, the vascular lesion engenders vessel wall fragility and ICH but if rupture does not occur, segmental vessel occlusion evolves, producing small, deep (lacunar) infarcts.¹²

However, the importance of HT in both lacunar infarction and ICH is disputed because both may be seen in NT patients. To further explore this issue, we have reviewed 70 consecutive cases of autopsy verified cerebral SVD, prompted by our observation of occasional examples of severe SVD in patients without any conventional risk factors, in other words with no evidence of raised BP or diabetes. The aim of the study was to document the existence and frequency of such cases and to extend the scope of risk factor analysis. Our study raises the possibility that a number of systemic diseases with well-recognized effects on cerebrovascular permeability may contribute to the pathogenesis of SVD and its associated cerebral lesions.

	Methods

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The study group was derived from 110 brains examined consecutively by one of the authors (G.A.L.) during a 12-month period, beginning in October 1994, at the Neuropathology Laboratory of the University of Edinburgh. The 70 study cases were selected as those showing histological evidence of significant concentric hyaline thickening of deep small-vessel walls (SVD), in which adequate brain, kidney, and heart histology results and patient height, heart weight, and clinical data were all available. They included 28 cases (40%) who were known to have had a clinically evident stroke, a rather high proportion, reflecting the clinical interests of, and so the referral pattern to, the authors. The principal autopsy diagnoses in the remaining cases were neurological or neuropsychiatric in 10 (14%) and nonneurological in 32 (46%) (see Table 1). In 22 of the 42 cases in which stroke was not the principal autopsy diagnosis, there was neuropathological evidence of either lacunar infarction (12 cases) or other small ischemic lesions, usually small cortical infarcts (10 cases).

View this table: [in this window] [in a new window]   Table 1. Principal Autopsy Diagnoses in the 70 Study Cases

In each case the clinical records, autopsy report, and central nervous system and systemic autopsy histology were reviewed. Hospital notes were retrieved and reviewed when available. Family medical records were not available for review. Cerebral SVD was recorded as mild (+), moderate (++), or severe (+++) in each standardized hematoxylin and eosin–stained block from the basal ganglia, thalamus, frontal, parietal, temporal, and occipital lobe deep white matter. Mild SVD was defined as unequivocal concentric vessel wall thickening in small arteries (less than approximately 300 µm diameter) and arterioles but with mild or minimal luminal narrowing. The so-called "sclerotic index" (SI) in such vessels [defined as 1–(internal diameter/external diameter)], taking into consideration the effects of vascular remodeling, approximated to that of normal vessels (SI, 0.2 to 0.3). Moderate SVD implied significant luminal narrowing, but with the lumen spanning more than half the total external diameter (SI, 0.3 to 0.5). In severe SVD the internal vessel diameter was less than half of the external diameter (SI, >0.5). Measurements in arteries with elliptical profiles were taken perpendicular to the long axis of the ellipse. Any complex vessel lesion in which the normal architecture of the wall was destroyed or disorganized, resembling what Fisher termed "segmental arteriolar disorganisation,"⁸ was classified as severe SVD. Examples of each of these lesions are illustrated in the Figure. Specific brain regions showed a reasonably even distribution of affected vessels, and therefore the number/density of affected vessels was not used in the assessment of SVD severity. The single SVD grade applied to each case was the highest of the grades allocated in the six brain regions analyzed. The morphological characteristics of SVD were recorded in each case, as was the presence or absence of any lacunar infarcts. Type I lacunes were defined histologically as small, deep, irregular cavities consistent with small, old ischemic infarcts.

View larger version (77K): [in this window] [in a new window]   Figure 1. Grading of SVD. a, A small penetrating thalamic artery with mild hyaline SVD. Sclerotic index, as defined in the "Methods," is 0.30. (Hematoxylin and eosin [H & E]; bar=40 µm.) b, Moderate SVD in a small putaminal artery. SI =0.41. (H & E; bar=40 µm.) c, Severe concentric SVD in a small putaminal artery. SI =0.61. (H & E; bar=40 µm.) d, A complex, disorganized arterial lesion in the putamen of a 62-year-old NT woman with hepatic failure (case 17; Table 1). Autopsy revealed only mild ipsilateral cervicocranial atheroma and no risk factors or sources for cerebral embolism. (H & E; bar=80 µm.)

Patients were defined as having had significant systemic HT during life if one or more of the following criteria were met: a documented clinical label of "hypertensive" whether treated or untreated; macroscopic autopsy evidence of left ventricular hypertrophy (LVH) or a fresh heart weight of more than 400 g, each without other cause; or BP readings of more than 160 mm Hg systolic and/or 90 mm Hg diastolic, on at least two different occasions before or at least 1 week after a stroke. In each case, heart weight was also compared with a published reference normal value matched for body length and sex plus 2 SDs.¹³ Two authors reviewed independently postmortem heart and kidney histology, noting features characteristic of HT, namely cardiac myocyte hypertrophy and nuclear enlargement, renal afferent arteriolosclerosis, and glomerulosclerosis.

Statistically significant relationships between variables were sought using multiple and ordered logistic regression analyses.

	Results

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The study group of 70 patients (35 men, 35 women) with SVD had an age range of 45 to 96 years (mean, 75 years). In 48 cases (69%; 24 men, 24 women), there was evidence of prior HT, as previously defined. In many cases, interpretation of heart and kidney histology was hindered by postmortem autolysis or by other pathology, particularly myocardial ischemia/infarction, and diabetic and arteriosclerotic ischemic glomeruloscleroses. In addition, variable numbers of enlarged cardiac myocytes and subtly thickened glomerular arterioles were a common finding in aged, nonhypertensive patients. Such features lent an unacceptably high degree of subjectivity and interobserver variability to the histological assessment of HT. Comparison of heart weights with sex- and body length–matched standards identified 2 patients from the NT group (cases 17 and 20, Table 2), with heart weights that, although less than 400 g, were significantly greater than the reference norm. In these and other cases with conflicting heart weight data, the referring clinician was consulted directly to ascertain the patient's BP status. During their intensive, long-term medical supervision for liver and renal disease, respectively, patients 17 and 20 were consistently NT and significantly overweight, a factor known to be associated with increased heart weight.¹³

View this table: [in this window] [in a new window]   Table 2. Characteristics of the 22 "Normotensive" Patients With Cerebral SVD

In 22 cases (31%; 11 men, 11 women) there was no evidence of prior HT, as defined. The patient characteristics of this group (age range, 45 to 92 years; mean age, 73 years) are detailed in Table 2. Sixteen were aged 65 years or older, leaving a small but significant number of 6 (9%) nonelderly, nondiabetic, NT individuals with cerebral SVD (cases 17 to 22, Table 2). In 5 of these 6 cases (cases 17 to 21) there was evidence of liver failure, renal failure, or both. Two of these 5 were also alcoholics, and 1 had pancreatitis. The remaining patient (case 22) was a 45-year-old schizophrenic man with a terminal catatonic illness in whom postmortem disclosed extensive, predominantly perivascular cerebral edema of uncertain cause.

Liver, kidney, and pancreatic failure, as well as alcoholism, all have a well-documented association with increased cerebral small-vessel permeability. Therefore, significant relationships were sought between maximal severity of SVD and each of these variables (Table 3), as well as with actual and adjusted heart weights. No statistically significant relationships emerged when all variables were adjusted for (ie, multiple regression with all variables included). When the three-level categorization of SVD was used as the outcome variable in ordered logistic regressions with each potential explanatory variable, no significant associations were revealed between the explanatory variables and SVD: the smallest probability value was .052 for age. However, the test of the proportional odds assumption suggested that the ordered logistic regression model was not appropriate for age, adjusted heart weight, or HT. Exploratory analyses using these variables as outcomes suggested that they did vary between levels of SVD but possibly in a U-shaped fashion; in other words there appeared to be less HT in the brains with the least severe SVD (which is not surprising) and with the most severe SVD (which is surprising). The adjusted heart weight and HT in the moderate SVD group remained statistically significantly higher than in the other two groups, even when adjusted for age (P=.02 for adjusted heart weight; P=.009 for HT).

View this table: [in this window] [in a new window]   Table 3. Frequency of Conventional and Putative Risk Factors in Relation to Severity of SVD and Pathologically Verified Lacunar Infarction

The severity of SVD was evenly distributed in white matter, basal ganglia, and thalami (30 cases) or was slightly more severe in white than deep grey matter (31 cases). Less commonly deep grey structures were preferentially involved (nine cases). The distribution of disease severity was not obviously related to BP status or age. Similarly, the morphology of affected vessels was similar in all cases; concentric hyaline small-vessel thickening and concomitant luminal narrowing (Figure). Mural foam cells, a cardinal feature of lipohyalinosis, were seen only occasionally in very small vessels, and these were often seen in relation to areas of relatively recent infarction. No unequivocal miliary (Charcot-Bouchard) aneurysms were seen, although "focal segmental disorganisation" of small vessels occasionally resembled such lesions. Fibrinoid necrosis was seen only occasionally, and only in close proximity to acute ICH.

Of the 15 cases in whom the principal autopsy diagnosis was cerebral infarction, all were of large-vessel type; none presented with a typical lacunar syndrome. However, type I lacunar infarcts were present in 19 of the 48 HT brains (40%) and in 8 of the 22 NT brains (36%), including 3 of the 6 nonelderly NT cases (cases 17, 18, and 20; Table 2). In 6 of these 27 cases, one or more lacunes had definitely been symptomatic during life. Another 6 were possibly symptomatic, the uncertainty due to imprecision of remote clinical histories and the presence at autopsy of multiple old infarcts, both lacunar and nonlacunar (Table 3). In no case was any lacunar infarct the cause of final hospital admission or the cause of death, directly or indirectly. ICH was verified in 10 brains, all in patients with HT. Although each case of ICH had been diagnosed clinically as a solitary spontaneous hypertensive bleed, detailed neuropathology disclosed cerebral amyloid angiopathy with multiple lobar ICH in 3 cases, and an underlying cerebellar arteriovenous malformation in another. The remaining ICHs were located in the basal ganglia (3 cases), thalamus (1 case), and cerebellum (2 cases), and in each case structural lesions other than hypertensive SVD were excluded, as far as was possible histologically.

	Discussion

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The main conclusions from this retrospective autopsy study are that (1) the nature of cerebral SVD is likely to have changed since Fisher's original description⁸ based on hypertensive brains and (2) a significant proportion of cases of pathologically verified SVD have no classic risk factors. The data also allow speculation that factors other than HT that enhance SV permeability may contribute to the pathogenesis of SVD and related lesions. These issues will be discussed in turn, after first considering the difficulties of defining HT in a retrospective autopsy study.

Definition of HT
Increasing BP is the most important risk factor for stroke, at any age and in either sex.^{12 14} However, the definition of HT remains arbitrary and often its documentation, as illustrated in this report, can be difficult. Indeed, no single clinical or pathological definition of HT is entirely satisfactory. Hospital autopsy based studies, such as the present one, often include a significant number of cases for which adequate BP recordings are not available. A significant proportion of stroke cases in this series, for example, died within a week of admission, precluding useful inpatient BP data, because stroke can cause a rise in BP. LVH, with various definitions and in the absence of other causes, is a sensitive marker of HT, as established in the Framingham Study in which it was shown to be caused by even mild HT, if sufficiently prolonged.¹⁵ Increased heart weight is a reasonable index of LVH and a useful adjunct to its subjective assessment, although sex, body length, and state of nourishment all affect cardiac mass.¹³ The most quoted normal heart weight standards adjusted for sex and body length¹³ were derived from only "normally nourished" individuals. Values adjusted, alternatively or additionally, for body mass may be more reliable, but body weight was known for only a small proportion of the cases in this series. We found that autopsy histology indices of HT, merged with age-related and other pathologies, were frequently technically difficult to assess, and were usually not helpful in categorizing borderline cases. A combination of clinical history, macroscopic LVH assessment, and heart weight was therefore used to assign cases to HT or NT groups. This is a deliberately stringent definition which likely overestimates the frequency of clinically significant HT, but it strengthens the validity of the term "normotensive." Future large-scale studies might usefully involve general practitioner case-note retrieval and a single clinically based definition of HT.

Morphology of SVD
The small-vessel morphology was similar in all cases in this study, both HT and NT, and corresponded to published descriptions of hyaline arteriolosclerosis.^{2 3 4} Fisher has claimed⁸ that only three vascular lesions are relatively specific for HT: fibrinoid necrosis, miliary (Charcot-Bouchard) aneurysms, and lipohyalinosis. However, our study, while not primarily addressing this issue, suggests that these lesions are not at all common in HT brains, at least not in our patient population. Fibrinoid necrosis was seen only at the periphery of acute ICH, in which location it is probably a reactive phenomenon, despite claims that it is the leading cause of hypertensive ICH.^{16 17} In our experience, fibrinoid necrosis is not seen distant from the hematoma in cases of acute ICH, suggesting a reactive rather than a causal relationship. Furthermore, striking fibrinoid necrosis may be seen around stereotaxically injected clots in rodent brains, in which context it is clearly a reactive change (unpublished authors' personal observations). No convincing miliary aneurysms were seen, reinforcing recent claims that either they represent an effect rather than a cause of ICH¹⁸ or indeed that most are artifactual.¹⁹ The third lesion, lipohyalinosis, is a term coined to describe a small penetrating artery pathology characterized by loss of normal vessel wall architecture, subintimal hyaline deposition and foamy macrophage infiltration.⁸ Conspicuous lipid or foam cells were seen only in occasional small vessels in this study, in keeping with the suggestion²⁰ that lipohyalinosis may be less common than Fisher implied some 25 years ago.⁸ This impression, however, requires confirmation in larger series or in brains selected for symptomatic lacunar infarction that may be more analogous to Fisher's patient groups. However, recent large autopsy surveys would appear to agree that "angionecrosis" and lipohyalinosis are less common than previously.²¹ This subject warrants further study, but the term arteriolosclerosis is therefore preferred to lipohyalinosis, despite the fact that the pathology often prevents identification of the injured vessel as strictly arteriolar. The pathologically neutral term small-vessel disease or descriptive term "fibrohyalinosis" may be more accurate and in the present state of knowledge the most satisfactory. It seems likely that the relative rarity of fibrinoid necrosis and lipohyalinosis in contemporary brains is due largely to effective control of HT since Fisher's original series.

Nonhypertensive SVD
Although it is generally accepted that HT, aging, and diabetes mellitus are risk factors for SVD, the same arteriopathy was seen in NT, nonelderly, nondiabetic individuals in a small but significant proportion (9%) of our cases. Moreover, as discussed, this likely represents a significant underestimate. This must suggest that other factors cause or accentuate age-related SVD, in these six patients perhaps combinations of liver and renal failure, pancreatitis, and alcoholism. The failure to demonstrate statistically significant relationships between any of these putative SVD risk factors and SVD severity in this series is perhaps not surprising in view of the small number of patients. Indeed, a relatively small number of patients had any one of the "new" potential risk factors, making it difficult to detect anything but a very large association. The variation in adjusted heart weight and HT with SVD suggested by this study is interesting but difficult to evaluate formally since its form is derived from the data. In presenting it here we hope that further studies will be able to evaluate it on independent data and hence confirm or refute its existence.

Interestingly, each of the associated conditions in the younger normotensive group is documented as enhancing cerebral small-vessel permeability, which is a mechanism assumed to underlie hypertensive SVD. The predominant neuropathological change in acute hepatic failure in humans, and experimental animals, is cerebral edema,^{22 23 24} and ammonia may cause blood-brain barrier disruption.²⁵ An encephalopathic syndrome may be seen in alcoholic and nonalcoholic pancreatitis,^{26 27} in which the autopsy brains showed focal hemorrhage and perivascular edema.^{26 27 28} Increased vascular permeability in the uremic brain has been demonstrated in an experimental rat model.²⁹ Furthermore, arteriolar thickening is described following haemodialysis³⁰ and the dialysis "disequilibrium syndrome" is attributed to cerebral edema.³¹ Documented neuropathology of uremic brains^{32 33} includes vessel degeneration, perivascular demyelination, and edema as well as small (lacunar) infarcts and hemorrhages, although these are commonly attributed to HT. Alcohol, although a common cause of liver and pancreatic diseases, has an uncertain status as an independent stroke risk factor.³⁴ However, some studies suggest a role in stroke,^{35 36} particularly ICH.³⁷ Cerebral edema is often the only finding following fatal alcohol intoxication, and is pivotal in the pathogenesis of central pontine myelinolysis³⁸ now thought to be mediated by electrolyte and osmolality disturbances.

SVD-Related Stroke
Controversy surrounds the pathogenesis of the two stroke syndromes commonly attributed to hypertensive SVD, namely lacunar infarction and ICH. The strict pathological definition of a lacune is a small, fluid-filled cavity representing the healed stage of a small deep infarct.^{9 39} The original lacunar hypothesis attributes cause to a combination of HT and occlusive lesions of single perforating branch arteries.^{8 40 41} Implicit in this hypothesis is a central role for hypertensive narrowing of small vessels. A high frequency of HT in patients with lacunes was first reported by Fisher⁹ and subsequently supported by others.^{21 42 43 44} That aging⁴⁵ and diabetes^{42 44 46 47} are also implicated appeared to reinforce the lacunar hypothesis. However, dissenters suggest that the risk factors for lacunes are the same as for any other type of ischemic stroke.⁴⁸ More specifically, a recent epidemiological study⁴⁹ denies that HT is any more important for the development of lacunes than for atherosclerotic thromboembolic large vessel stroke, whereas others have also failed to confirm the importance of HT.⁵⁰ As a result, it has been suggested that "other causes of small-vessel arteriopathy" be considered as a cause of lacunar infarction.⁴⁹ In the present study, lacunes were almost as prevalent in NT (36%) as in HT (40%) brains, confirming that other factors must indeed be operative. An association with conditions known to affect small-vessel permeability, such as renal failure, is in keeping not only with the postulated pathogenesis of SVD but also with recent suggestions that some small deep brain lesions may be caused by increased permeability of arterioles. Observations in hypertensive rats,^{4 6 51 52} and more recently in humans,⁵³ invoke edema rather than ischemia in the formation of such lesions, which may mimic conventional lacunes radiologically.

In the same way, although up to 90% of spontaneous ICH cases were previously assumed to be directly related to HT, more recent studies have shown a much lower prevalence of HT.^{54 55 56 57} One explanation is illustrated by the four cases of "hypertensive" ICH in this study in which detailed pathology uncovered other structural causes. It is also possible, as Caplan has advanced,⁵⁸ that structurally normal arterioles may rupture following acute changes in BP or cerebral blood flow. A further possible explanation is the existence of different non-HT causes of SVD. However, as for lacunes, the complex interrelations between liver disease, pancreatitis, alcohol, hemostasis, renal failure, and HT complicate their status as independent risk factors, causal or otherwise.

Cerebral SVD is a vasculopathy of considerable importance, and may be implicated in up to one third of all strokes. This study suggests that modern control of HT has modified SVD pathology. Larger-scale studies of autopsy verified SVD are required to reassess the importance of classic risk factors and to investigate the possibility that a number of conditions that cause enhanced SVD permeability may play a role in SVD development. The lack of standardized terminology for pathological types of SVD and related brain lesions, as well as reproducible, quantitative methods of assessing SVD severity, is a significant obstacle to progress in this field.

	Selected Abbreviations and Acronyms

 

BP = blood pressure HT = hypertension ICH = intracerebral hemorrhage LVH = left ventricular hypertrophy NT = normotensive SI = sclerotic index SVD = small-vessel disease

	Acknowledgments

 
Dr Lammie, Francis Brannan, and Jim Slattery are funded by the Medical Research Council. The authors are grateful to Ann Mackenzie for the preparation of the manuscript and to Dr Jeanne Bell for her helpful comments.

Received April 11, 1997; revision received June 26, 1997; accepted July 19, 1997.

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