Cerebral Amyloid Angiopathy Without and with Cerebral Hemorrhages: A Comparative Histological Study Jean Paul G. Vonsattel, MD,"§ Richard H. Myers, PhD,$ E. Tessa Hedley-Whyte, MD,* Allan H. Ropper, MD,? Edward D. Bird, MD,T§ and Edward P. Richardson, Jr, MD"?
TO identify those factors associated with cerebral hemorrhage among brains with cerebral amyloid angiopathy (CAA), we undertook a comparative postmortem histopathological study of amyloid-containing vessels in the brains of patients with and without hemorrhage. Those without hemorrhage were represented by the following two groups: (1) elderly patients from a large general hospital (n = 66; age range, 75-107 years) and (2) patients with various neuropsychiatric disorders (n = 70; age range, 27-96 years). CAA was found in 45% of the first group and in 54% of the second group. The findings in these patients were compared with those in 17 brains in which both CAA and cerebral hemorrhage were present. We found that CAA was more severe in the brains with cerebral hemorrhage than in those without, and that fibrinoid necrosis was seen only in the brains with cerebral hemorrhage (12 of the 17 brains). Microaneurysms occurred only in the presence of severe, rather than moderate or mild, CAA. Serial sections in 2 brains of patients with cerebral hemorrhage showed fibrinoid necrosis, microaneurysms, and vascular rupture in close association with the hemorrhage. In 2 patients, hemorrhage was precipitated by trauma, and in 1, it was secondary to metastatic carcinoma. The features of brains from patients with CAA that are most consistently related to cerebral hemorrhage are (1)a severe degree of CAA and (2) the presence of fibrinoid necrosis, with or without microaneurysms. Vonsattel JPG, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr. Cerebral amyloid angopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 1991;30:637-639
Cerebral amyloid angiopathy (CAA) is a disease that occurs frequently in elderly people, both in those who are demented and those who are not, and it preferentially involves the vessels of the leptomeninges and cerebral cortex [1-61. The majority of the brains from patients with CAA are free of hemorrhage; however, CAA and hemorrhage are often associated, especially when the hemorrhages are lobar or multiple 17-22}. Although in some patients, CAA clearly is the cause of bleeding into the brain [23-261, in others the relationship is less certain. When cerebral hemorrhage has been seen in the presence of CAA, it has occurred (1) spontaneously, with or without hypertension {7, 11, 271, (2) after trauma 19, 281, (3) in the setting of inflammatory vascular disease (vasculitis) {29-3 11, and (4) together with microaneurysms {lo, 1I, 32). To define better the factors that predispose to cerebral hemorrhage among brains from patients with CAA, we undertook a comparative neuropathological study of the following three sets of patients: (1) elderly
patients from a general hospital, with miscellaneous medical and surgical disorders but without cerebral hemorrhage, (2) patients with various neurological and psychiatric diseases, also without cerebral hemorrhage, and (3) patients with CAA and cerebral hemorrhages. Together with attempting to determine what morphological changes in the congophilic vessels might relate to hemorrhage, we also were interested in ascertaining the overall frequency of CAA in the general hospital and neuropsychiatric patients. Moreover, because a preliminary study had shown that fibrinoid necrosis of the vessel wall occurred at sites of rupture or aneurysm formation in amyloid-involved vessels 1331, we devoted particular attention to the presence or absence of this vascular lesion.
From the *C. S. Kubik Laboratory for Neuropathology, James Homer Wright Pathology Laboratories, the ?Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and the $Departmentof Neurology, Boston University School of Medicine, Boston, and the $Brain Tissue Resource Center, McLean Hospital and Harvard Medical School, Belmont, MA.
Received Jan 28, 1991, and in revised form Mar 21. Accepted for publication Apr 2 I , 1991.
Materials and Methods Tissue and Sources A total of 151 brains and 2 cerebral biopsies (153 specimens) were studied, including from the following three groups of
Address correspondence to Dr Vonsattel, Molecular Neurogenetics Laboratory, Neuroscience Center, Massachusetrs General Hospital, Charlestown, MA 02129.
Copyright 0 1991 by the American Neurological Association 637
patients: (1) A consecutive series of autopsies on patients aged 75 years or older (range, 75-107 years) who died without clinical or pathological evidence of cerebral hemorrhage during the time period from December 31, 1980 through June 8, 1787. This series, made up of 66 whole brain specimens, and hereafter referred to as “general hospital patients,” was taken to represent the elderly general population seen in a large medical center. (2) A consecutive series of 70 half brain specimens, obtained during the period from February 2, 1982 through September 1, 1984, with various neurological or psychiatric disorders but without cerebral hemorrhage (age range, 27-96 years). All of the specimens in this series (to be referred to as “neuropsychiatric patients”) were obtained from the Brain Tissue Resource Center (BTRC) at McLean Hospital (Belmont, MA), where they had been received from hospitals and institutions all over the united States. (3) A selected group of 17 specimens (15 brains, 2 biopsies) in which CAA and cerebral hemorrhage were combined. Of these, 14 were derived from the Massachusetts General Hospital (MGH) files (including 1 biopsy), 2 were referred from outside hospitals (U.S.A.) for evaluation, and 1 (previously published C12)) came from Lausanne, Switzerland. In all patients, the brain tissue material was fixed in 10% formalin solution. The cerebral hemispheres were sectioned coronally at 0.5- to 1.0-cm intervals, the brainstem and cerebellum transverseiy at 0.5-cm intervals. Hemorrhage was defined as any extravasation of blood within the brain or the leptomeriinges that was identifiable on gross examination. Representative blocks, taken from the cortex (frontal, parietal, temporal with hippocampus, and occipital regions), basal ganglia, cerebellum, and brainstem, were embedded in paraffin. Sections for general tissue stains (Lux01 fast blue, hematoxylin and eosin) and the Bodian method €or axons and neurofibrils were cut at 6 pm. In addition, when indicated, 6-pm sections were stained with phosphotungstic acid hematoxylin (FTAH) for fibrin and fibrinoid necrosis [34]. For amyloid, 12-pm sections were stained with Congo red and examined with and without polarized light [35, 36).
Serial Sections Two blocks from 1 brain with CAA and multiple hemorrhages had been previously sectioned serially, and the sections, stained with PTAH (Patient 8, see below), were kindly provided by D r C . Miller Fisher, from the Neurology Service, MGH. Step-sections stained with hematoxylin and eosin were also available from 1 patient with CAA, cerebral hemorrhage, and granulomatous angiitis (Patient 14, see below). Microscopic Evabation A brain was considered positive €or CAA when it showed at least one leptomeningeal or cortical congophilic vessel with yellow-green birefringency under polarized light. The severity of CAA was classified as follows: M I L D . Amyloid is restricted to a congophilic rim around normal or atrophic smooth muscle fibers (which might be absent, leaving an optically empty tiny vacuole-like zone surrounded by amyloid) in the media of otherwise normal vessels (Fig I A, B).
638 Annals of Neurology
Vol 30 No 5
Fig 1. Amyloid-containing leptomeningeal (A, B ) and cortical (C) vessel. Mild involvement (A, B); a thin rim of amyloid surrounds smooth muscle fibws that are, in places, absent leaving vacuole-like foci (arrows). Moderate involvement (C); there i s replacement of the media, which is thickened, and patent lumen. There is no evidence of blood leakage. (Congo red x 500, before 30% reduction.)
MODEKATE. Media is replaced by amyloid and is thicker than normal, with no evidence of remote or recent blood leakage (Fig 1C). SEVERE. There is extensive amyloid deposition with focal wall fragmentation (Fig 2) and at least one focus of paravascular leakage evidenced by the presence of erythrocytes or hemosiderin or both. Fibrinoid necrosis (defined as homogeneous discrete foci or segments of vascular wall with smudgy eosinophilic material that stains dark blue with FTAH and that obscures cytoarchitecture 134, 37)) was sought in each specimen with moderate or severe CAA with or without cerebral hemorrhage. Neuritic plaques and Alzheimer’s neurofibrillary tangles were looked for in Bodian-stained sections and recorded as present or absent.
Isohtion of Cortical Vessels To visualize the distribution and extent of amyloid deposits along the course of individual vessels, intact vessels isolated from the surrounding cerebral tissue were examined. The vessels were obtained from the occipital lobes of two previously fresh-frozen half brains. Evaluation of the severity of CAA as seen in the corresponding formalin-fixed half brains had shown moderate CAA and no hemorrhage in 1 patient, and severe CAA with multiple microhemorrhages in the other. The procedure for obtaining the vessels was as described by Selkoe and Abraham [38}. In brief, occipital cortex after removal of the leptomeninges (60.0gm) was minced and incubated at room temperature in sodium dodecyl sulfate (SDS) buffer, homogenized, and sieved first through 100-pm nylon mesh (residue discarded) and then 73-pm nylon mesh (residue kept). This residue was homogenized in SDS buffer and sieved through a 50-pm nylon mesh. The residue and filtrate were then centrifuged at 300 g, resuspended in SDS
November 1971
presence or absence of dementia and of infarction. In the combined group of 68 patients without hemorrhages but with CAA, congophilic vessels were found within the leptomeninges and in the cortex in 75.7%, in the leptomeninges alone in 18.6%, and in the cortex alone in 5.7%. These proportions were nearly the same in both the group of general hospital patients and in the group of neuropsychiatric patients. Table 3 indicates the severity of CAA, and the presence or absence of neuritic plaques and Alzheimer’s neurofibrillary tangles, in the general hospital patients and in the neuropsychiatric patients. Severe CAA was much more frequent in the neuropsychiatric patients (26.3%) than in the general hospital patients (3.3%) (x2= 13.5, p = 0.001). The presence of CAA was strongly associated with neuritic plaques (p = 0.0000 1) and less strongly with Alzheimer’s neurofibrillary tangles (p = 0.03) in a logistic regression model controlling for age.
Isolated Cortical Vessels
Fig 2. Amyloid-containingparietal cortical artery (Patient 2) wzlb fDcal wall fragmentation and fibrznoid deposits. (Phosphotungstic acid hemtoxylin, x 200 before 11% reduction.)
buffer, and centrifuged on discontinuousgradients composed of layers of 1, 1.2, 1.4, and 2 M sucrose. The fractions with the vessels (211.4 and 1.4/1.2 M sucrose interfaces) were smeared o n slides, briefly fixed in 90% ethanol, stained with Congo red, and examined microscopically with and without polarized light.
In the brain from the patient with moderate CAA, the amyloid in most of the vessels was deposited in the wall in the form of discrete transverse bands, 10- to 25-pm wide, separated by 10- to 20-pm-wide m y loid-free segments (Fig 3A, B). The amyloid-containing bands became increasingly closer to one another as vascular bifurcations were approached, and only minimal residual spaces were left between them at the bifurcations themselves. In the presence of severe CAA, the isolated cortical vessels showed continuous dense deposits of amyloid that were especially thick near and at bifurcations (Fig 4A). About 10% of the vessels showed discrete aneurysmal dilatation (Fig 4B), in which the diameter of the vessel was 50 to 100% greater than elsewhere.
Clinical Features The medical records of all 153 patients were reviewed; age, sex, blood pressure, presence or absence of dementia, and clinical diagnoses were recorded.
Statistical Methods
The xL statistic was used to compare the frequency of CAA, of dementia, and of infarcts between groups. Comparisons of means were made by t test (two-tailed). For those data that are ordinal in nature, nonparametric correlations were performed with the Kendall tau B. Multivariate analyses were used to examine the relationship between CAA and age, age2, neuritic plaques, and Alzheimer’s neurofibrillary tangles. A logistic regression predicting the presence or absence of CAA was used for the multivariate analysis. Results The clinical diagnoses of the patients without hemorrhages are summarized in Table 1. The relative frequency of CAA in these patients is shown in Table 2, which also includes sex and age, blood pressure, and
C A A with Cerebral Hemorrhage The clinical history and the pathological findings of the 1 7 patients with CAA and cerebral hemorrhage are summarized in Tables 4 and 5. CAA was found within the leptomeninges and in the cerebral parenchyma of the 17 specimens. Discrete hemorrhages or portions of hematomas overlapping many cerebral lobes simultaneously were distributed as follows: frontal lobe, 19 times; parietal and occipital lobes, 18 times each; and temporal lobe, 12 times. The severity of CAA was slightly but not significantly more severe in both the parietal and occipital lobes than in the frontal lobe; it was much less severe in the temporal lobe. T o illustrate some of the various clinicopathological patterns that were seen in this group, the following 6 patients are presented in greater detail. PATIENT 2. This patient was a typical example of CAA with a fatal lobar hemorrhage and two old corticosub-
Vonsattel et al: Cerebral Amyloid Angiopathy 639
Table 1. Brains Without Hemorrhage: Diagnoses
General Hospital Patients (n = 66) With CAA Dementia Alzheimer’s disease (AD) Multiple infarcts Unclassified Down’s syndrome Huntington’s disease (HD) Grade 1‘ Grade ld Grade 2d Grade 3d Grade 4d HT> with AD Grade 2 Grade 3 Binswanger‘s disease Parkinson’s disease Multiple sclerosisd Tardive dyskinesiad Schizophrenia Bipolar depression Alcoholism Myasthenia gravis Malignancies Collagen diseases Coronary artery disease Trauma Clinically normal Miscellaneous‘ Total
Without CAA
6
Neuropsychiatric Patients With CAA
14
2
6
Without CAA 1 3
lb
la
Combined (n
(n = 70)
1
2
4
1 1 2 10
With CAA 20 6 2 1
2
4
2
1
Without CAA
3 3
1 1 2 10 2
3
2 1 1 1
1 1
3
3
3
30
136)
1 2 1
1 2
5 4 5 3 4 1
=
1
1 8 1
1
12 5
1
5 36
2
38
3 32
6 4 5 4
8 1 12 5
4 3 68
8 68
aHyperthyroidism. bDiabetes mellitus and hypoglycemic episodes. ‘Four grades of neuropathological severity 1-4: dwith dementia; ‘suicides, postoperative death, diabetes mellitus, and infections.
CAA
=
cerebral amyloid angiopathy.
cortical hemorrhages 1261. Leptomeningeal and cortical CAA was severe in the frontal and occipital lobes, moderate in the temporal and parietal lobes, and slight in the cerebellar leptomeninges. Four foci of fibrinoid necrosis involving congophilic vessels were identified in the occipital cortex. PATIENT 8. This patient had severe CAA and more than 100 cortical and corticosubcortical hemorrhages, 1 to 5 mm, mostly in the cerebral hemispheres but some in the cerebellum and brainstem (this is the only patient of the entire series showing CAA in the pons) 1231. There were foci of fibrinoid necrosis in congophilic vessels in the cerebral leptomeninges and cortex. Serial sections of a small (30 p m in diameter) intracortical congophilic vessel showed rupture of the wall, with acute hemorrhage, at the site of a focus of
640 Annals of Neurology Vol 30 No 5
fibrinoid necrosis (Fig 5). Another cortical vessel, 70 pm in diameter, showed two foci of rupture of the wall at the site of fibrinoid necrosis; however, in this instance, there was adherent fibrin clot in the vessel at the points of rupture and no hemorrhage. Serial sectioning of another vessel showed a fusiform aneurysm, 750 pm in length and 350 pm in maximum width. In the necks of this aneurysm, there was fibrinoid necrosis. The aneurysm contained fibrin clot; there was no evidence of hemorrhage.
14. This patient was remarkable for the presence of both CAA and granulomatous angiitis 139,401. There were punctate hemorrhages in the cerebral cortex and a few hemorrhages in the central gray nuclei and in the white matter. CAA was severe in the cerebral leptomeninges and cortex, and moderate in the PATIENT
November 1991
Table 2. Brains Witboat Hemowbage: Sex, Age, Presence or Absence of CAA, Hypertension, Dementia and Infarcts
Number of brains (%) Sex: MIF (unknown) Known age {n) Mean (yr) (SD) Range (yr)
Blood pressure 135195 mm Hg Unknown With dementia Without dementia Cerebral infarcts (% of brains of each category) Total with infarcts Total without infarcts CAA
=
General Hospital Patients
Neuropsychiatric Patients
(n = 6 6 )
(n = 7 0 )
Combined (n = 136)
With CAA
Without CAA
With CAA
Without CAA
With CAA
Without CAA
30 (45.5) 11/19 30 82.2 (4.8) 75-94
36 (54.5) 22114 36 82.4 (7.5) 75-107
38 (54.3) 27110 (1) 34 75.1 (14.4) 34-96
32 (45.7) 20111 (1) 30 62.1 (13.6) 27-92
68 (30.0) 38129 (1) 64 78.4 (11.5) 34-76
68 (50.0) 42125 (1) 66 73.9 (14.5) 27-107
15 1 14 8 22
17 2 17 2
12 7 19 32
6
21 11
23 10 35 23
34
27 8 33 40 28
45
16 (53.3) 14 (46.7)
25 (67.4) 1 1 (30.6)
5 (15.6) 27 (84.4)
25 (36.8) 43 (63.2)
30 (44.1) 38 (55.9)
6 8
-Y)
9 (23.7) 29 (76.3)
cerebral amyloid angiopathy.
Table 3. Cerebral Amyloid Angiopathy Without Hemorrhage: Severity, Association with Neuritic Plaques, and Tangles Severity ofCAA
Mild Moderate Severe Total
n(%)
NP Alone
Both NT NPand Alone NT
Neither NPor "I
n (%)
NP Alone
NT Alone
Both NPand NT
Neither N P or NT
General Hospital Patients with CAA (n = 30)
Neuropsychiatric Patients with CAA (n = 38)
13 ( 4 3 . 3 ) 2 16 (53.3) 4 1 (3.3) 0
22 (57.9) 2
6
5 2 0 7
2 8 1 11
4 2 0
6
6(15.8) 0 10 (26.3) 1 3
7
7
CAA = cerebral amyloid angiopathy; N P
6 =
1
15
6 9 30
4 0 0 4
Neuropsychiatric Patients Without CAA ( n = 3 2 )
General Hospital Patients 36) Without CAA (n
6
1 0 0
1
17
neuritic plaques; NT
=
3
3
n (%)
NP Alone
NT Alone
Both NPand NT
Neither NPor NT
Combined with CAA (n = 68)
35 (51.5) 4 22 (32.3) 4 11 (16.2) I 9
6
17
8
2 0 8
14
2 0 10
10
41
Combined Without CAA (n = 68)
25
7
10
9
42
Alzheimer's neurofibrillary tangles.
cerebellar leptomeninges. Granulomatous inflammation with lymphocytic infiltration and multinucleated giant cells involved the walls of about 20% of the leptomeningeal and cerebral cortical vessels. Some of the giant cells contained intracytoplasmic fragments of amyloid. Fibrinoid necrosis was present in 596 of the congophilic cerebral cortical vessels with and without inflammation (Fig 6). In the cerebellum, 80% of the leptomeningeal vessels showed pronounced amyloid deposits, with inflammation in about 3%. The following 2 patients had craniocerebral injuries in association with CAA and cerebral hemorrhage.
to some of the congophilic frontal intracortical vessels were clusters of macrophages containing hemosiderin, indicating that hemorrhages had occurred, probably as a result of falls to which Huntington's disease predisposed him.
15. This man with Huntington's disease struck his head in a fall and died 2 days later with a temporo-occipital hemorrhage. There was moderate CAA in the frontal, temporal, and occipital leptomeninges and cortex without fibrinoid necrosis. Adjacent
17. This hypertensive man had lobar hematomas, a putaminal hemorrhage, focal CAA, and foci of metastatic carcinoma, clinically unsuspected. One old corticosubcortical hemorrhage was present in the parieto-occipital region, and there was one recent corti-
PATIENT
16. Cerebral trauma was the cause of death in this patient who had Alzheimer's disease. In addition to the large hematoma (Table 5), there were punctate recent hemorrhages especially in the cerebral cortex. CAA without fibrinoid necrosis was focally severe in the fronto-occipital leptorneninges and cortex. PATIENT
PATIENT
Vonsattel et al: Cerebral Arnyloid Angiopathy
641
A
B
Fig 3. Isolated cortical vessels from frozen occipital cortex of a brain with modwate cerebral amyloid angiopathy. The amyloid deposh form discrete bands with amyloid-free segments (see text). Near and at the bifurcation (centw of picture), the amyloid-containing bands are closer together than elsewhere. (Congo red, without (A) and with (Bj polarized light; x 256 before 48 and 45 % reductions, respectively.)
cosubcortical clot in the occipital lobe. These hemorrhages were closely associated with deposits of metastatic carcinoma. The putaminal hemorrhage, which extended focally into the temporal lobe, also appeared to be recent; it was not associated either with tumor or CAA. Scattered arterioles showing lipohyalinosis were present in the striatum. CAA without fibrinoid necrosis was severe in the occipital cortex and leptomeninges, and moderate in other lobes, but was absent in the central gray nuclei, brainstem, and cerebellum. With the exception of the putaminal hemorrhage, all the hemorrhages were in regions with moderate or severe CAA.
Fibrinoid Necrosis Fibrinoid necrosis was not found in any of the 136 brains without hemorrhage, but it was present in 12 of the 17 patients with CAA with hemorrhage (Table 5). There was a strong correlation between fibrinoid necrosis in congophilic vessels and cerebral hemorrhage (x2 = 94.9; p = 0.00001 with Yates correction). At the sites of fibrinoid necrosis with or without cerebral hemorrhage, fibrin clots causing luminal stenosis or occlusion were almost always present. Discussion Our findings show that the two major features of CAA most frequently associated with spontaneous lobar hemorrhage are as follows: (1) severe angiopathy, characterized by thick amyloid deposits with clefts, foci of fragmentation of the walls, presence of microaneu642 Annals of Neurology Vol 30 No 5
A
B
Fig 4. Isolated cortical vessels from frozen occipital cortex of a brain with severe cerebral amyloid angiopathy. In this patient, the amyloid forms continuous thick deposits that are especially dense near and at a vascular bifurcation (A).Discrete ball-like aneurysmal dilatations (B) involve other vascular segments (see text). (Congo red with polarized light; x 640 (A) and x 400 (BI before 33 and 2996 reductions. respectively.)
rysms, and evidence of leakage of blood in the cerebral tissue as shown by erythrocytes, hemosiderin-laden macrophages, and gliosis, and ( 2 ) foci of fibrinoid necrosis, in both normotensive and hypertensive patients. These observations are in agreement with earlier reports indicating that severe vascular amyloidosis is associated with structural changes in the walls that could result in hemorrhage C4 1-43]. Cerebral hemorrhage in the presence of only mild to moderate CAA, however, is less likely to be due to CAA than to other factors. For example, lobar hemorrhages without identifiable vascular disease may occur in elderly patients ll9, 447; alternatively, they may be due to some demonstrable cause other than CAA, such as leukemia, bleeding dyscrasia, anticoagulant medication, alcohol or alkaloidal cocaine use, vascular malformation 127, 45-52}, or neoplasm, particularly metastatic, as exemplified by our Patient 17 and by previously reported cases 150, 5 2 , 531. Our experience with cerebral hemorrhages resulting from CAA indicates that these are peripherally situated in the cortex, subcortex, or leptomeninges. We occasionally found CAA in the cerebellum, but we did not see it in vessels of the central gray nuclei in any of our brains, and saw it in the brainstem in only 1 patient (Patient 8). One patient, already mentioned as having had hemorrhages secondary to metastatic carcinoma
November 1991
Table 4. Cerebral Amyloid Angiopatby with Cerebral Hemorrhages: Clinical Summar), in
=
17)
Episodes of CH Age (yr)lSex
B>
1
80/F
No
2
73lM 74!M
Yes
3 4
~
2 or More
Time Between Onset and Death
Onset
1
No
Spontaneous
+
No No
Spontaneous Spontaneous
+
>
...
+
15 mo 52 days
82lM
?
Recent
Spontaneous
...
+
4 mo
5
64lM
Yes
No
Spontaneous
+
...
5 5 days
6
701F
No
No
Spontaneous
7
83lF
Yes
Recent
Spontaneous
+ ... + ...
6 days
8
57lF
No
No
Spontaneous
...
T
14 mo
9
81lM
No
No
Spontaneous
+
...
2 days
10"
62lM
No
No
Spontaneous
...
+
About 3 mo
11"
71lM
?
No
Spontaneous
...
+
18 mo
12
92lM
Yes
No
Minor trauma
+
...
About 5 wk
13
75lM
No
No
Minor trauma
...
+
7 mo
14
64lM
Yes
No
Convulsion
...
+
5 wk
15
70lM
Yes
Yes
Trauma
+
...
2 days
16
84lF
No
Yes
Trauma
+
...
2 days
17
711M
Yes
Yes
Spontaneous
... +
Total
12 MI5 F
Patient
Mean = 73.7 yr
1i519~mm Hg Dementia
(sn = 9.1 yr); range
=
...
3 days
About 20 days
4 days
Preceding Condition Good health until onset Hypertension (10 yr) Good health until onset Diabetes mellitus, otherwise in good health Headache and lung disease; on prednisone Good health until onset History of vertiginous episodes Migraines, often relieved by ergotamines Good health until onset Good health until onset Occasional headaches, otherwise good health Good health until onset Good health until 12 mo before death Good health until onset; episode of diplopia preceded convulsion Huntington's disease (15 yr); fall from bed Alzheimer's disease; struck by a vehicle Hypertension; Alzheimer's disease; unsuspected malignancy with cerebral metastases
57-92 yr
"Cerebral biopsy. CH = cerebral hemorrhage; ( + ) = presenc; (?) = unknown
Vonsattel et al: Cerebral Amyloid Angiopathy
643
Table 5. Cerebral Amyloid Angiopathy with Cerebral Hemorrhages: Neuropathology ( n = 17) Brain Weight Patient
(gm)
Number of Hemorrhages
1
1.500
1
2
1,340
3
1
1,380
4
4
5 6 7
8
9 10
11 12 13
1,400 1,850 1,350 1,320 1,350 1,140 (Biopsy)
>15
1 1
1
>lo0 18 4
(Biopsy) 2 1,250 1 1,430 2
14
1,790
Multiple
15
1,150
2
16 17
1,500 1,200
Multiple
2
Hemorrhage Location
F
L" L R R L
P
0
T
L"
L" L"
L"
La R
L"
L-R L R R" L" e R" L R L-R R R R L R R
Other Findings
Reference and Their Patient No. ( i
Severe
+
5-10
Duret's hemorrhage
..
5
Severe
+
5
...
26
Severe
+
20-30
L'
4.5 3 2.5
Thrombosis in superior sagittal and straight sinuses
L-R L-R R"
1.5 4.5
Severe
+
Severe
+
L"
6
Severe
+
5-10 10
R" R" L-R L-R R R R
4 0.5
Severe Severe
+
10
1.5
Severe Severe
+ +
10 5-10
-
5
R"
-
-
-
+ +
20
5
Moderate Severe Severe
1
Severe
+
-
3
Moderate
-
TO identify those factors associated with cerebral hemorrhage among brains with cerebral amyloid angiopathy (CAA), we undertook a comparative postmortem histopathological study of amyloid-containing vessels in the brains of patients with and without hemorrhage. Those without hemorrhage were represented by the following two groups: (1) elderly patients from a large general hospital (n = 66; age range, 75-107 years) and (2) patients with various neuropsychiatric disorders (n = 70; age range, 27-96 years). CAA was found in 45% of the first group and in 54% of the second group. The findings in these patients were compared with those in 17 brains in which both CAA and cerebral hemorrhage were present. We found that CAA was more severe in the brains with cerebral hemorrhage than in those without, and that fibrinoid necrosis was seen only in the brains with cerebral hemorrhage (12 of the 17 brains). Microaneurysms occurred only in the presence of severe, rather than moderate or mild, CAA. Serial sections in 2 brains of patients with cerebral hemorrhage showed fibrinoid necrosis, microaneurysms, and vascular rupture in close association with the hemorrhage. In 2 patients, hemorrhage was precipitated by trauma, and in 1, it was secondary to metastatic carcinoma. The features of brains from patients with CAA that are most consistently related to cerebral hemorrhage are (1)a severe degree of CAA and (2) the presence of fibrinoid necrosis, with or without microaneurysms. Vonsattel JPG, Myers RH, Hedley-Whyte ET, Ropper AH, Bird ED, Richardson EP Jr. Cerebral amyloid angopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol 1991;30:637-639
Cerebral amyloid angiopathy (CAA) is a disease that occurs frequently in elderly people, both in those who are demented and those who are not, and it preferentially involves the vessels of the leptomeninges and cerebral cortex [1-61. The majority of the brains from patients with CAA are free of hemorrhage; however, CAA and hemorrhage are often associated, especially when the hemorrhages are lobar or multiple 17-22}. Although in some patients, CAA clearly is the cause of bleeding into the brain [23-261, in others the relationship is less certain. When cerebral hemorrhage has been seen in the presence of CAA, it has occurred (1) spontaneously, with or without hypertension {7, 11, 271, (2) after trauma 19, 281, (3) in the setting of inflammatory vascular disease (vasculitis) {29-3 11, and (4) together with microaneurysms {lo, 1I, 32). To define better the factors that predispose to cerebral hemorrhage among brains from patients with CAA, we undertook a comparative neuropathological study of the following three sets of patients: (1) elderly
patients from a general hospital, with miscellaneous medical and surgical disorders but without cerebral hemorrhage, (2) patients with various neurological and psychiatric diseases, also without cerebral hemorrhage, and (3) patients with CAA and cerebral hemorrhages. Together with attempting to determine what morphological changes in the congophilic vessels might relate to hemorrhage, we also were interested in ascertaining the overall frequency of CAA in the general hospital and neuropsychiatric patients. Moreover, because a preliminary study had shown that fibrinoid necrosis of the vessel wall occurred at sites of rupture or aneurysm formation in amyloid-involved vessels 1331, we devoted particular attention to the presence or absence of this vascular lesion.
From the *C. S. Kubik Laboratory for Neuropathology, James Homer Wright Pathology Laboratories, the ?Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and the $Departmentof Neurology, Boston University School of Medicine, Boston, and the $Brain Tissue Resource Center, McLean Hospital and Harvard Medical School, Belmont, MA.
Received Jan 28, 1991, and in revised form Mar 21. Accepted for publication Apr 2 I , 1991.
Materials and Methods Tissue and Sources A total of 151 brains and 2 cerebral biopsies (153 specimens) were studied, including from the following three groups of
Address correspondence to Dr Vonsattel, Molecular Neurogenetics Laboratory, Neuroscience Center, Massachusetrs General Hospital, Charlestown, MA 02129.
Copyright 0 1991 by the American Neurological Association 637
patients: (1) A consecutive series of autopsies on patients aged 75 years or older (range, 75-107 years) who died without clinical or pathological evidence of cerebral hemorrhage during the time period from December 31, 1980 through June 8, 1787. This series, made up of 66 whole brain specimens, and hereafter referred to as “general hospital patients,” was taken to represent the elderly general population seen in a large medical center. (2) A consecutive series of 70 half brain specimens, obtained during the period from February 2, 1982 through September 1, 1984, with various neurological or psychiatric disorders but without cerebral hemorrhage (age range, 27-96 years). All of the specimens in this series (to be referred to as “neuropsychiatric patients”) were obtained from the Brain Tissue Resource Center (BTRC) at McLean Hospital (Belmont, MA), where they had been received from hospitals and institutions all over the united States. (3) A selected group of 17 specimens (15 brains, 2 biopsies) in which CAA and cerebral hemorrhage were combined. Of these, 14 were derived from the Massachusetts General Hospital (MGH) files (including 1 biopsy), 2 were referred from outside hospitals (U.S.A.) for evaluation, and 1 (previously published C12)) came from Lausanne, Switzerland. In all patients, the brain tissue material was fixed in 10% formalin solution. The cerebral hemispheres were sectioned coronally at 0.5- to 1.0-cm intervals, the brainstem and cerebellum transverseiy at 0.5-cm intervals. Hemorrhage was defined as any extravasation of blood within the brain or the leptomeriinges that was identifiable on gross examination. Representative blocks, taken from the cortex (frontal, parietal, temporal with hippocampus, and occipital regions), basal ganglia, cerebellum, and brainstem, were embedded in paraffin. Sections for general tissue stains (Lux01 fast blue, hematoxylin and eosin) and the Bodian method €or axons and neurofibrils were cut at 6 pm. In addition, when indicated, 6-pm sections were stained with phosphotungstic acid hematoxylin (FTAH) for fibrin and fibrinoid necrosis [34]. For amyloid, 12-pm sections were stained with Congo red and examined with and without polarized light [35, 36).
Serial Sections Two blocks from 1 brain with CAA and multiple hemorrhages had been previously sectioned serially, and the sections, stained with PTAH (Patient 8, see below), were kindly provided by D r C . Miller Fisher, from the Neurology Service, MGH. Step-sections stained with hematoxylin and eosin were also available from 1 patient with CAA, cerebral hemorrhage, and granulomatous angiitis (Patient 14, see below). Microscopic Evabation A brain was considered positive €or CAA when it showed at least one leptomeningeal or cortical congophilic vessel with yellow-green birefringency under polarized light. The severity of CAA was classified as follows: M I L D . Amyloid is restricted to a congophilic rim around normal or atrophic smooth muscle fibers (which might be absent, leaving an optically empty tiny vacuole-like zone surrounded by amyloid) in the media of otherwise normal vessels (Fig I A, B).
638 Annals of Neurology
Vol 30 No 5
Fig 1. Amyloid-containing leptomeningeal (A, B ) and cortical (C) vessel. Mild involvement (A, B); a thin rim of amyloid surrounds smooth muscle fibws that are, in places, absent leaving vacuole-like foci (arrows). Moderate involvement (C); there i s replacement of the media, which is thickened, and patent lumen. There is no evidence of blood leakage. (Congo red x 500, before 30% reduction.)
MODEKATE. Media is replaced by amyloid and is thicker than normal, with no evidence of remote or recent blood leakage (Fig 1C). SEVERE. There is extensive amyloid deposition with focal wall fragmentation (Fig 2) and at least one focus of paravascular leakage evidenced by the presence of erythrocytes or hemosiderin or both. Fibrinoid necrosis (defined as homogeneous discrete foci or segments of vascular wall with smudgy eosinophilic material that stains dark blue with FTAH and that obscures cytoarchitecture 134, 37)) was sought in each specimen with moderate or severe CAA with or without cerebral hemorrhage. Neuritic plaques and Alzheimer’s neurofibrillary tangles were looked for in Bodian-stained sections and recorded as present or absent.
Isohtion of Cortical Vessels To visualize the distribution and extent of amyloid deposits along the course of individual vessels, intact vessels isolated from the surrounding cerebral tissue were examined. The vessels were obtained from the occipital lobes of two previously fresh-frozen half brains. Evaluation of the severity of CAA as seen in the corresponding formalin-fixed half brains had shown moderate CAA and no hemorrhage in 1 patient, and severe CAA with multiple microhemorrhages in the other. The procedure for obtaining the vessels was as described by Selkoe and Abraham [38}. In brief, occipital cortex after removal of the leptomeninges (60.0gm) was minced and incubated at room temperature in sodium dodecyl sulfate (SDS) buffer, homogenized, and sieved first through 100-pm nylon mesh (residue discarded) and then 73-pm nylon mesh (residue kept). This residue was homogenized in SDS buffer and sieved through a 50-pm nylon mesh. The residue and filtrate were then centrifuged at 300 g, resuspended in SDS
November 1971
presence or absence of dementia and of infarction. In the combined group of 68 patients without hemorrhages but with CAA, congophilic vessels were found within the leptomeninges and in the cortex in 75.7%, in the leptomeninges alone in 18.6%, and in the cortex alone in 5.7%. These proportions were nearly the same in both the group of general hospital patients and in the group of neuropsychiatric patients. Table 3 indicates the severity of CAA, and the presence or absence of neuritic plaques and Alzheimer’s neurofibrillary tangles, in the general hospital patients and in the neuropsychiatric patients. Severe CAA was much more frequent in the neuropsychiatric patients (26.3%) than in the general hospital patients (3.3%) (x2= 13.5, p = 0.001). The presence of CAA was strongly associated with neuritic plaques (p = 0.0000 1) and less strongly with Alzheimer’s neurofibrillary tangles (p = 0.03) in a logistic regression model controlling for age.
Isolated Cortical Vessels
Fig 2. Amyloid-containingparietal cortical artery (Patient 2) wzlb fDcal wall fragmentation and fibrznoid deposits. (Phosphotungstic acid hemtoxylin, x 200 before 11% reduction.)
buffer, and centrifuged on discontinuousgradients composed of layers of 1, 1.2, 1.4, and 2 M sucrose. The fractions with the vessels (211.4 and 1.4/1.2 M sucrose interfaces) were smeared o n slides, briefly fixed in 90% ethanol, stained with Congo red, and examined microscopically with and without polarized light.
In the brain from the patient with moderate CAA, the amyloid in most of the vessels was deposited in the wall in the form of discrete transverse bands, 10- to 25-pm wide, separated by 10- to 20-pm-wide m y loid-free segments (Fig 3A, B). The amyloid-containing bands became increasingly closer to one another as vascular bifurcations were approached, and only minimal residual spaces were left between them at the bifurcations themselves. In the presence of severe CAA, the isolated cortical vessels showed continuous dense deposits of amyloid that were especially thick near and at bifurcations (Fig 4A). About 10% of the vessels showed discrete aneurysmal dilatation (Fig 4B), in which the diameter of the vessel was 50 to 100% greater than elsewhere.
Clinical Features The medical records of all 153 patients were reviewed; age, sex, blood pressure, presence or absence of dementia, and clinical diagnoses were recorded.
Statistical Methods
The xL statistic was used to compare the frequency of CAA, of dementia, and of infarcts between groups. Comparisons of means were made by t test (two-tailed). For those data that are ordinal in nature, nonparametric correlations were performed with the Kendall tau B. Multivariate analyses were used to examine the relationship between CAA and age, age2, neuritic plaques, and Alzheimer’s neurofibrillary tangles. A logistic regression predicting the presence or absence of CAA was used for the multivariate analysis. Results The clinical diagnoses of the patients without hemorrhages are summarized in Table 1. The relative frequency of CAA in these patients is shown in Table 2, which also includes sex and age, blood pressure, and
C A A with Cerebral Hemorrhage The clinical history and the pathological findings of the 1 7 patients with CAA and cerebral hemorrhage are summarized in Tables 4 and 5. CAA was found within the leptomeninges and in the cerebral parenchyma of the 17 specimens. Discrete hemorrhages or portions of hematomas overlapping many cerebral lobes simultaneously were distributed as follows: frontal lobe, 19 times; parietal and occipital lobes, 18 times each; and temporal lobe, 12 times. The severity of CAA was slightly but not significantly more severe in both the parietal and occipital lobes than in the frontal lobe; it was much less severe in the temporal lobe. T o illustrate some of the various clinicopathological patterns that were seen in this group, the following 6 patients are presented in greater detail. PATIENT 2. This patient was a typical example of CAA with a fatal lobar hemorrhage and two old corticosub-
Vonsattel et al: Cerebral Amyloid Angiopathy 639
Table 1. Brains Without Hemorrhage: Diagnoses
General Hospital Patients (n = 66) With CAA Dementia Alzheimer’s disease (AD) Multiple infarcts Unclassified Down’s syndrome Huntington’s disease (HD) Grade 1‘ Grade ld Grade 2d Grade 3d Grade 4d HT> with AD Grade 2 Grade 3 Binswanger‘s disease Parkinson’s disease Multiple sclerosisd Tardive dyskinesiad Schizophrenia Bipolar depression Alcoholism Myasthenia gravis Malignancies Collagen diseases Coronary artery disease Trauma Clinically normal Miscellaneous‘ Total
Without CAA
6
Neuropsychiatric Patients With CAA
14
2
6
Without CAA 1 3
lb
la
Combined (n
(n = 70)
1
2
4
1 1 2 10
With CAA 20 6 2 1
2
4
2
1
Without CAA
3 3
1 1 2 10 2
3
2 1 1 1
1 1
3
3
3
30
136)
1 2 1
1 2
5 4 5 3 4 1
=
1
1 8 1
1
12 5
1
5 36
2
38
3 32
6 4 5 4
8 1 12 5
4 3 68
8 68
aHyperthyroidism. bDiabetes mellitus and hypoglycemic episodes. ‘Four grades of neuropathological severity 1-4: dwith dementia; ‘suicides, postoperative death, diabetes mellitus, and infections.
CAA
=
cerebral amyloid angiopathy.
cortical hemorrhages 1261. Leptomeningeal and cortical CAA was severe in the frontal and occipital lobes, moderate in the temporal and parietal lobes, and slight in the cerebellar leptomeninges. Four foci of fibrinoid necrosis involving congophilic vessels were identified in the occipital cortex. PATIENT 8. This patient had severe CAA and more than 100 cortical and corticosubcortical hemorrhages, 1 to 5 mm, mostly in the cerebral hemispheres but some in the cerebellum and brainstem (this is the only patient of the entire series showing CAA in the pons) 1231. There were foci of fibrinoid necrosis in congophilic vessels in the cerebral leptomeninges and cortex. Serial sections of a small (30 p m in diameter) intracortical congophilic vessel showed rupture of the wall, with acute hemorrhage, at the site of a focus of
640 Annals of Neurology Vol 30 No 5
fibrinoid necrosis (Fig 5). Another cortical vessel, 70 pm in diameter, showed two foci of rupture of the wall at the site of fibrinoid necrosis; however, in this instance, there was adherent fibrin clot in the vessel at the points of rupture and no hemorrhage. Serial sectioning of another vessel showed a fusiform aneurysm, 750 pm in length and 350 pm in maximum width. In the necks of this aneurysm, there was fibrinoid necrosis. The aneurysm contained fibrin clot; there was no evidence of hemorrhage.
14. This patient was remarkable for the presence of both CAA and granulomatous angiitis 139,401. There were punctate hemorrhages in the cerebral cortex and a few hemorrhages in the central gray nuclei and in the white matter. CAA was severe in the cerebral leptomeninges and cortex, and moderate in the PATIENT
November 1991
Table 2. Brains Witboat Hemowbage: Sex, Age, Presence or Absence of CAA, Hypertension, Dementia and Infarcts
Number of brains (%) Sex: MIF (unknown) Known age {n) Mean (yr) (SD) Range (yr)
Blood pressure 135195 mm Hg Unknown With dementia Without dementia Cerebral infarcts (% of brains of each category) Total with infarcts Total without infarcts CAA
=
General Hospital Patients
Neuropsychiatric Patients
(n = 6 6 )
(n = 7 0 )
Combined (n = 136)
With CAA
Without CAA
With CAA
Without CAA
With CAA
Without CAA
30 (45.5) 11/19 30 82.2 (4.8) 75-94
36 (54.5) 22114 36 82.4 (7.5) 75-107
38 (54.3) 27110 (1) 34 75.1 (14.4) 34-96
32 (45.7) 20111 (1) 30 62.1 (13.6) 27-92
68 (30.0) 38129 (1) 64 78.4 (11.5) 34-76
68 (50.0) 42125 (1) 66 73.9 (14.5) 27-107
15 1 14 8 22
17 2 17 2
12 7 19 32
6
21 11
23 10 35 23
34
27 8 33 40 28
45
16 (53.3) 14 (46.7)
25 (67.4) 1 1 (30.6)
5 (15.6) 27 (84.4)
25 (36.8) 43 (63.2)
30 (44.1) 38 (55.9)
6 8
-Y)
9 (23.7) 29 (76.3)
cerebral amyloid angiopathy.
Table 3. Cerebral Amyloid Angiopathy Without Hemorrhage: Severity, Association with Neuritic Plaques, and Tangles Severity ofCAA
Mild Moderate Severe Total
n(%)
NP Alone
Both NT NPand Alone NT
Neither NPor "I
n (%)
NP Alone
NT Alone
Both NPand NT
Neither N P or NT
General Hospital Patients with CAA (n = 30)
Neuropsychiatric Patients with CAA (n = 38)
13 ( 4 3 . 3 ) 2 16 (53.3) 4 1 (3.3) 0
22 (57.9) 2
6
5 2 0 7
2 8 1 11
4 2 0
6
6(15.8) 0 10 (26.3) 1 3
7
7
CAA = cerebral amyloid angiopathy; N P
6 =
1
15
6 9 30
4 0 0 4
Neuropsychiatric Patients Without CAA ( n = 3 2 )
General Hospital Patients 36) Without CAA (n
6
1 0 0
1
17
neuritic plaques; NT
=
3
3
n (%)
NP Alone
NT Alone
Both NPand NT
Neither NPor NT
Combined with CAA (n = 68)
35 (51.5) 4 22 (32.3) 4 11 (16.2) I 9
6
17
8
2 0 8
14
2 0 10
10
41
Combined Without CAA (n = 68)
25
7
10
9
42
Alzheimer's neurofibrillary tangles.
cerebellar leptomeninges. Granulomatous inflammation with lymphocytic infiltration and multinucleated giant cells involved the walls of about 20% of the leptomeningeal and cerebral cortical vessels. Some of the giant cells contained intracytoplasmic fragments of amyloid. Fibrinoid necrosis was present in 596 of the congophilic cerebral cortical vessels with and without inflammation (Fig 6). In the cerebellum, 80% of the leptomeningeal vessels showed pronounced amyloid deposits, with inflammation in about 3%. The following 2 patients had craniocerebral injuries in association with CAA and cerebral hemorrhage.
to some of the congophilic frontal intracortical vessels were clusters of macrophages containing hemosiderin, indicating that hemorrhages had occurred, probably as a result of falls to which Huntington's disease predisposed him.
15. This man with Huntington's disease struck his head in a fall and died 2 days later with a temporo-occipital hemorrhage. There was moderate CAA in the frontal, temporal, and occipital leptomeninges and cortex without fibrinoid necrosis. Adjacent
17. This hypertensive man had lobar hematomas, a putaminal hemorrhage, focal CAA, and foci of metastatic carcinoma, clinically unsuspected. One old corticosubcortical hemorrhage was present in the parieto-occipital region, and there was one recent corti-
PATIENT
16. Cerebral trauma was the cause of death in this patient who had Alzheimer's disease. In addition to the large hematoma (Table 5), there were punctate recent hemorrhages especially in the cerebral cortex. CAA without fibrinoid necrosis was focally severe in the fronto-occipital leptorneninges and cortex. PATIENT
PATIENT
Vonsattel et al: Cerebral Arnyloid Angiopathy
641
A
B
Fig 3. Isolated cortical vessels from frozen occipital cortex of a brain with modwate cerebral amyloid angiopathy. The amyloid deposh form discrete bands with amyloid-free segments (see text). Near and at the bifurcation (centw of picture), the amyloid-containing bands are closer together than elsewhere. (Congo red, without (A) and with (Bj polarized light; x 256 before 48 and 45 % reductions, respectively.)
cosubcortical clot in the occipital lobe. These hemorrhages were closely associated with deposits of metastatic carcinoma. The putaminal hemorrhage, which extended focally into the temporal lobe, also appeared to be recent; it was not associated either with tumor or CAA. Scattered arterioles showing lipohyalinosis were present in the striatum. CAA without fibrinoid necrosis was severe in the occipital cortex and leptomeninges, and moderate in other lobes, but was absent in the central gray nuclei, brainstem, and cerebellum. With the exception of the putaminal hemorrhage, all the hemorrhages were in regions with moderate or severe CAA.
Fibrinoid Necrosis Fibrinoid necrosis was not found in any of the 136 brains without hemorrhage, but it was present in 12 of the 17 patients with CAA with hemorrhage (Table 5). There was a strong correlation between fibrinoid necrosis in congophilic vessels and cerebral hemorrhage (x2 = 94.9; p = 0.00001 with Yates correction). At the sites of fibrinoid necrosis with or without cerebral hemorrhage, fibrin clots causing luminal stenosis or occlusion were almost always present. Discussion Our findings show that the two major features of CAA most frequently associated with spontaneous lobar hemorrhage are as follows: (1) severe angiopathy, characterized by thick amyloid deposits with clefts, foci of fragmentation of the walls, presence of microaneu642 Annals of Neurology Vol 30 No 5
A
B
Fig 4. Isolated cortical vessels from frozen occipital cortex of a brain with severe cerebral amyloid angiopathy. In this patient, the amyloid forms continuous thick deposits that are especially dense near and at a vascular bifurcation (A).Discrete ball-like aneurysmal dilatations (B) involve other vascular segments (see text). (Congo red with polarized light; x 640 (A) and x 400 (BI before 33 and 2996 reductions. respectively.)
rysms, and evidence of leakage of blood in the cerebral tissue as shown by erythrocytes, hemosiderin-laden macrophages, and gliosis, and ( 2 ) foci of fibrinoid necrosis, in both normotensive and hypertensive patients. These observations are in agreement with earlier reports indicating that severe vascular amyloidosis is associated with structural changes in the walls that could result in hemorrhage C4 1-43]. Cerebral hemorrhage in the presence of only mild to moderate CAA, however, is less likely to be due to CAA than to other factors. For example, lobar hemorrhages without identifiable vascular disease may occur in elderly patients ll9, 447; alternatively, they may be due to some demonstrable cause other than CAA, such as leukemia, bleeding dyscrasia, anticoagulant medication, alcohol or alkaloidal cocaine use, vascular malformation 127, 45-52}, or neoplasm, particularly metastatic, as exemplified by our Patient 17 and by previously reported cases 150, 5 2 , 531. Our experience with cerebral hemorrhages resulting from CAA indicates that these are peripherally situated in the cortex, subcortex, or leptomeninges. We occasionally found CAA in the cerebellum, but we did not see it in vessels of the central gray nuclei in any of our brains, and saw it in the brainstem in only 1 patient (Patient 8). One patient, already mentioned as having had hemorrhages secondary to metastatic carcinoma
November 1991
Table 4. Cerebral Amyloid Angiopatby with Cerebral Hemorrhages: Clinical Summar), in
=
17)
Episodes of CH Age (yr)lSex
B>
1
80/F
No
2
73lM 74!M
Yes
3 4
~
2 or More
Time Between Onset and Death
Onset
1
No
Spontaneous
+
No No
Spontaneous Spontaneous
+
>
...
+
15 mo 52 days
82lM
?
Recent
Spontaneous
...
+
4 mo
5
64lM
Yes
No
Spontaneous
+
...
5 5 days
6
701F
No
No
Spontaneous
7
83lF
Yes
Recent
Spontaneous
+ ... + ...
6 days
8
57lF
No
No
Spontaneous
...
T
14 mo
9
81lM
No
No
Spontaneous
+
...
2 days
10"
62lM
No
No
Spontaneous
...
+
About 3 mo
11"
71lM
?
No
Spontaneous
...
+
18 mo
12
92lM
Yes
No
Minor trauma
+
...
About 5 wk
13
75lM
No
No
Minor trauma
...
+
7 mo
14
64lM
Yes
No
Convulsion
...
+
5 wk
15
70lM
Yes
Yes
Trauma
+
...
2 days
16
84lF
No
Yes
Trauma
+
...
2 days
17
711M
Yes
Yes
Spontaneous
... +
Total
12 MI5 F
Patient
Mean = 73.7 yr
1i519~mm Hg Dementia
(sn = 9.1 yr); range
=
...
3 days
About 20 days
4 days
Preceding Condition Good health until onset Hypertension (10 yr) Good health until onset Diabetes mellitus, otherwise in good health Headache and lung disease; on prednisone Good health until onset History of vertiginous episodes Migraines, often relieved by ergotamines Good health until onset Good health until onset Occasional headaches, otherwise good health Good health until onset Good health until 12 mo before death Good health until onset; episode of diplopia preceded convulsion Huntington's disease (15 yr); fall from bed Alzheimer's disease; struck by a vehicle Hypertension; Alzheimer's disease; unsuspected malignancy with cerebral metastases
57-92 yr
"Cerebral biopsy. CH = cerebral hemorrhage; ( + ) = presenc; (?) = unknown
Vonsattel et al: Cerebral Amyloid Angiopathy
643
Table 5. Cerebral Amyloid Angiopathy with Cerebral Hemorrhages: Neuropathology ( n = 17) Brain Weight Patient
(gm)
Number of Hemorrhages
1
1.500
1
2
1,340
3
1
1,380
4
4
5 6 7
8
9 10
11 12 13
1,400 1,850 1,350 1,320 1,350 1,140 (Biopsy)
>15
1 1
1
>lo0 18 4
(Biopsy) 2 1,250 1 1,430 2
14
1,790
Multiple
15
1,150
2
16 17
1,500 1,200
Multiple
2
Hemorrhage Location
F
L" L R R L
P
0
T
L"
L" L"
L"
La R
L"
L-R L R R" L" e R" L R L-R R R R L R R
Other Findings
Reference and Their Patient No. ( i
Severe
+
5-10
Duret's hemorrhage
..
5
Severe
+
5
...
26
Severe
+
20-30
L'
4.5 3 2.5
Thrombosis in superior sagittal and straight sinuses
L-R L-R R"
1.5 4.5
Severe
+
Severe
+
L"
6
Severe
+
5-10 10
R" R" L-R L-R R R R
4 0.5
Severe Severe
+
10
1.5
Severe Severe
+ +
10 5-10
-
5
R"
-
-
-
+ +
20
5
Moderate Severe Severe
1
Severe
+
-
3
Moderate
-
