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Familial cerebral amyloid angiopathy presenting as recurrent cerebral haemorrhage
Journal of the Neurological Sciences, 1982, 55 : 121-135
121
Elsevier Biomedical Press
FAMILIAL CEREBRAL AMYLOID ANGIOPATHY PRESENTING AS RECURRENT CEREBRAL HAEMORRHAGE
A. R. W A T T E N D O R F F 1, G. Th. A. M. BOTS 2, L. N. WENT 3 and L.J. ENDTZ l
JDepartment of Neurology, Municipal Hospital of The Hague, The Hague and Departments of 2pathology and 3 Human Genetics, University of Leiden, Leiden (The Netherlands) (Received 25 November, 1981) (Accepted 12 January, 1982)
SUMMARY
Eleven patients belonging to two generations of a Dutch family with cerebral and cerebellar haemorrhage, haemorrhagic infarction and infarction are described. Their ages varied from 44 to 58 years. The principal clinical characteristic was recurring cerebral haemorrhages, sometimes preceded by a history of migrainous headaches or mental changes. In 4 of the 6 autopsied cases, old and new multiple cerebral haemorrhagic infarcts and infarcts were found, in one case a single cerebral haemorrhage and in another a cerebellar haemorrhage. In 5 cases this resulted in secondary subarachnoid haemorrhage. In one case the infarcts were only slightly haemorrhagic and did not result in subarachnoid haemorrhage. This patient presented as dementia. Microscopically, in these 6 cases and in one biopsy specimen hyaline thickening of the walls of cortical arterioles was found. The arteries of the arachnoid showed marked tortuosity, concentric proliferation, and focal hyalinization of the walls. Amyloid was found in the hyalinized vessels in 5 cases, but not outside the central nervous system. We believe that we are dealing with an inherited disorder with an autosomal dominant mode of inheritance, in which microangiopathy leads to cerebral haemorrhage and (haemorrhagic) infarction. It seems likely that amyloidosis underlies the angiopathy, and that this family suffers from a condition similar to the one described by Gudmundsson in 1972.
INTRODUCTION
In 1972, Gudmundsson et al. described an Icelandic family in which members belonging to four generations suffered from familial cerebral haemorrhage (FCH) 0022-510X/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press
122 and cerebral infarction at an early age. These authors reported 8 patients with proven cerebral haemorrhage (CH). At autopsy, which was performed in 5 of these cases, the brains showed deposition of amyloid in cerebral and meningeal artery walls, but no signs of amyloidosis were found outside the central nervous system. In this paper we report 11 patients with proven CH, belonging to two generations of one family from Scheveningen, The Netherlands. Histological investigation was possible in one surgically treated patient and in 6 cases with autopsy material. Pathological changes were found in small meningeal and cortical arteries and in the arterioles, which showed hyaline thickening of the walls. In 5 cases amyloid was present in these hyalinized meningeal and cortical vessels. We therefore believe the underlying pathological condition in our patients to be identical with that in the Icelandic cases. Only one patient is still alive. Other cases of FCH with a similar arteriopathy have been reported by Luyendijk and Bots (1980). Familial occurrence of intracranial arteriovenous malformations (Carter Snead et al. 1979; Aberfeld et al. 1981) and of intracranial aneurysms (Endtz 1968; Fairburn 1973) is, to our knowledge, the only known other cause of FCH. MATERIAL
Of the 11 patients, 9 were seen in the Municipal Hospital of The Hague. The other two had been admitted to and died in other hospitals, one of them, the most recent case, in Stockholm in 1980. One patient is still alive. An autopsy was performed in 6 cases, and in a 7th material obtained during craniotomy was available for microscopical examination. The patients are descendants of a couple who married in 1871 (Fig. 1). They belong to a family from Scheveningen, which was once a rather isolated fishing village but now forms part of The Hague. According to information obtained from the family, 3 other members died from CH and 6 developed mental deterioration in the 6th and 7th decades. We were able to obtain the medical histories of 5 of the patients with dementia; they will be presented in a separate group after the cases with CH. Some further family members have been seen in the out-patient department.
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Fig. 1. Pedigree of family.
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123 The first member seen in the Municipal Hospital (pedigree Ill-33) did not present as CH at the time (1951) but was diagnosed as a case of migraine complicated by hemiparesis. Later, he deteriorated mentally, and until his death in 1962 was regarded as a case of Alzheimer's disease. In 1953 another member, a 58-year-old woman, died from CH in the Municipal Hospital, but an autopsy was not performed. In 1956, a 45-year-old woman was admitted to our hospital after the sudden onset of confusion and headache (111-36, see case report below). Her relatives said that two sisters were known to have died of CH in their mid-forties. Since this patient was the first proven case of CH with angiopathy, she can be regarded as the index case. CASE REPORTS Index case (H1-36) A 45-year-old woman, born on March 2nd, 1911. In 1956, while at home, she suddenly became confused and incontinent, and at that time complained of headache. Since 1953 she had suffered from attacks of headache, located occipitally and preceded by scotomata. Also, her character seemed to have altered. During the 6 months before admission the headache attacks were accompanied by a sensation of numbness and stiffness on the right side o f her mouth and in her right arm, which felt weak. On admission in 1956, she was drowsy and incontinent for faeces and urine. She was aphasic. Blood pressure 200/100. Gaze paresis towards the right ; homonymous hemianopia on the right; paralysis of right arm and leg; extensor plantar response on the right. CSF : xanthochromic with 500 red cells/ram 3. She improved somewhat, but after a week developed papilloedema ; a carotid angiogram was suggestive of a left frontal space-occupying lesion. A left-sided craniotomy showed a subcortical haematoma frontally and two yellowish spots on the cortex which yielded old blood when punctured. Biopsy specimens were taken at several places, because the possibility of a tumour was considered. Microscopical examination showed numerous arterioles and small-calibre arteries with thickened walls usually showing distinct signs of hyaline degeneration. Post-operatively, she made a substantial recovery and after discharge was able to return to her home. In 1957, she suddenly began to have more difficulty in speaking, and had 4 presumably epileptic fits. Her behaviour became more disturbed and she was often depressed. In 1958, after being found unconscious and incontinent she was readmitted to the Municipal Hospital. She was in deep coma, with widened non-reacting pupils. Blood pressure 150/90. CSF: blood-stained. She died after a few hours. Autopsy was refused. Case 11 (Hl-33) A 46-year-old man, born on August 27th, 1905. He completed primary school without difficulty and before the Second World War served as a sailor in the merchant marine and Royal Navy. After the war he became an employee of the municipal energy department. Since 1942 he had been troubled by attacks of headache accompanied by paraesthesiae in his left hand. In 1951, a severe attack resulted in confusion and loss of power in the extremities on the left side. On admission, the blood pressure was 135/90. Left-sided hemiparesis and hemihypaesthesia were observed. The CSF was clear and colourless, with a total protein content of 71 mg/100 ml. An EEG showed slow waves over the right hemisphere and spikes over the left parieto-occipital region. Carotid angiography disclosed no abnormalities and an air encephalogram only widened lateral ventricles. He made a good recovery and was discharged after 2½ months under the diagnosis complicated migraine. Alter that, he showed progressive mental deterioration. In 1954, he again became very confused after a severe headache attack, and was admitted to another hospital, where no focal neurological signs were found, but instead a profound dementia (I.Q. 67 on the Wechsler test). The EEG showed widened ventricles, the right wider than the left. The CSF contained no blood, and the total protein content was 80 rag/100 ml. He was discharged after a month. His condition gradually deteriorated, with occasional epileptic seizures, and at times he became aggressive. In June, 1961, he was confined to a mental hospital in Leiden; at admission, no internal abnormalities were found. Blood pressure: 150/85. Neurological findings: generalized hyperreflexia, plantar reflexes flexor; no paresis. He lacked insight about his illness, and was inclined to spontaneous excessive speech. There was a slight receptive aphasia, dyslexia,
124 finger agnosia, and apraxia. The diagnosis was Alzheimer's disease. In March of 1962 he developed generalized seizures which began in his left face and arm and increased in frequency. Eventually hc became soporific, and in April, 1962, he died of bronchopneumonia. Autopsy findings: bronchopneumonia, lung oedema, tracheobronchitis, and splenitis. Hearl: weight 450 g, slight hypertrophy and dilatation. Little atherosclerosis. The brain weighed 1405 g. There were several areas of softening, and a cavity right frontally and left occipitally. Microscopy: fresh, somewhat haemorrhagic infarct in right internal and external capsule and neighbouring insular cortex. Infarcts of differing age in white matter and parietal cortex and cerebellum, most of them being slightly haemorrhagic. Oedema, demyelinization, and loss of perivascular substance in the hemispheral and cerebellar white matter. Diffuse loss of ganglion cells with proliferation of astroglia and satellitosis in the cortex. Excessive hyalinization of arterioles in frontal, parietal, occipital, and, locally, in insular and cerebellar cortex, with thrombosis and obliteration of the lumen by hyalinization. Tortuosity of small arteries in the leptomeninges of cerebrum and cerebellum with local hyalinization. Congo-red staining showed both hyalinosis and amyloidosis of small meningeal and cortical arteries. No amyloidosis of extracranial vessels could be demonstrated. There were no plaques or neurofibrillary tangles. There were no large haemorrhages in the parenchyma or subarachnoid spaces. Case III (III-1) A 58-year-old married woman, born 23 August, 1895. For the past year she had suffered from non-migrainous headaches. Ten days prior to admission in 1953 she was suddenly unable to speak and had weakness of one side of the face; these symptoms lasted one day. On the day before admission she had a severe headache accompanied by nausea, after which she became progressively drowsier. On admission she was soporous; there was neck stiffness. Blood pressure 180/100. Non-reacting left pupil, tendon reflexes more active on the right than on the left, and extensor plantar response on the right. CSF: blood-stained, after centrifugation xanthochromic. She became progressively comatose and died after three days. Autopsy was not performed. Case 1V (111-37) A 43-year-old married woman, born 3 February, 1913. In 1957. while working in her home. she suddenly developed a severe headache and vomited. She did not lose consciousness. On admission she was drowsy. There was some meningeal irritation; blood pressure 130/75: conjugate gaze paresis to the right; total aphasia. CSF: blood-stained. Left-sided carotid angiography: space-occupying lesion in the left hemisphere. On operation, a left parietal intra-cerebral and overlying subdural haematoma were found. Eventually she was discharged, her condition being described as dementia with psychopathic traits. In 1958, she suffered a short focal epileptic fit with convulsions of the fight arm and leg. In 1964, she again suffered an acute headache, and when readmitted to the Municipal Hospital exhibited the same clinical picture although the aphasia was less severe and mostly expressive. Blood pressure 120/80. No internal abnormality. Haematologieal status: normal. CSF: blood-stained. A left-sided carotid angiogram was again suggestive of a space-occupying lesion, now in the left fronto-temporal region, but because her level of consciousness improved, surgery was withheld. She had another right-sided focal epileptic fit but otherwise continued to improve, although on discharge she was still dysphasic. In 1965, she had to be taken to the hospital for the 3rd time, after a severe attack of headache; she said she was blind; she was unable to walk, was incontinent, and became progressively drowsier. On admission, she appeared to be unconscious; blood pressure 150/95: left pupil moderately dilated, both pupils reacted to light; central facial paresis on the right; increased tonus of the right extremities, plantar response extensor bilaterally; incontinence for urine and faeces. The CSF was blood-stained under high pressure. An echo-encephalogram revealed a 4-ram shift to the left, and a right carotid angiogram showed displacement of the anterior cerebral artery to the left; there was poor filling of the middle cerebral artery circulation but the picture was suggestive of a pericerebral haematoma over the parietal region. At right-sided craniotomy an extensive but rather thin (½ cm maximally) subdural haematoma was found. The cortical surface showed haemorrhagic discoloration in many spots and bulged after the dura was opened. On puncture, old blood was obtained from several sites. On exploration, however, extensive haemorrhagic infarction was a more prominent feature. She died in 1966 in a nursing home. Case V (111-34) A 51-year-old man, born 5 September, 1907. He was the father of two other patients, described below. In May and August of 1958 he was admitted to the Municipal Hospital under the diagnosis
125 cerebral haemorrhage in the right hemisphere. In 1960, he suddenly developed a headache, followed after 3 days by difficulty in speaking and loss of power in his left upper and lower extremity. On the next day he was admitted and was found to be in coma, with a left-sided hemiparesis, generalized hyperreflexia, and bilateral extensor plantar response. CSF: blood-stained. He died 5 days after admission. Autopsy findings: left-sided pneumonia; heart weight 410 g; thickness of left ventricle wall 14 mm. Otherwise, no morbid changes were found extracranially, there was no conspicuous atherosclerosis, and microscopical examination of heart, liver, spleen, and kidneys gave normal results. The brain showed flattening of the right frontal gyri, which felt soft on palpation. The subarachnoid space contained blood, especially on the right, frontally. There was no atherosclerosis of the large arteries at the base of the skull. On sectioning, a haemorrhagic area was found, extending from right frontally to parietally with a maximum diameter of 4.5 cm and containing a 2-cm wide cavity filled with a thrombus. The right temporal lobe contained a cleft with yellowish-brown walls, and in the right parietal lobe there was a 1-cm diameter cavity with the same discoloration of its w~tlls. In the left parietal lobe there was a cavity measuring 2½ x 1 cm and filled with a light-browni~ soft mass. Microscopically, the left parietal and right temporal morbid changes were compatible with old haemorrhagic infarctions, these areas containing accumulations of iron pigment. In the meninges over the parietal and temporal regions an extensive haemorrhage was found. The arteries showed concentric sclerosis. There was conspicuous hyalinosis of the smaller intracerebral arteries and arterioles. Congo-red staining showed amyloid in the walls of these vessels.
Case VI (III-7) A 53-year-old married woman, born 20 January, 1909. In 1962, she was admitted to another hospital under the diagnosis apoplexy, exhibiting aphasia, from which she recovered. In August, 1963, she had another epidose of being unable to speak; she also was drowsy at that time. Her condition improved somewhat, but in October, 1963, she suddenly became paralyzed on the right side. She was then on a salt-restricted diet. She was admitted to the Municipal Hospital, where she was found to be comatose. Blood pressure 140/85, internal examination normal. The left pupil was larger than the right, both reacting to light; right-sided hemiplegia with extensor plantar response. CSF: blood-stained.
Fig. 2. Case VI. Large haemorrhage in the left hemisphere extending via corpus callosum to the fight.
126 She developed pneumonia and died after 6 days. Autopsy findings: purulent bronchopneumonia and lung oedema ; apart from a large bilestone, there were no other morbid changes outside the brain. The heart weight was 380 g; there was little arteriosclerosis, and the kidneys did not show evidence ol secondary hypertensive changes. Microscopical examination of heart, adrenals, liver, and spleen gave normal results. There was blood in the subarachnoid space. The arteries at the base of the skull were normal. There was conspicuous yellow discoloration of the surface of the brain in certain areas. The sections showed a large haemorrhage in the left hemisphere which had ruptured into the lateral ventricle and extended via the corpus callosum towards the right hemisphere (Fig. 2). In both the left and right frontal lobes there were signs of old haemorrhages. Microscopical examination of the region of the most recent haemorrhage revealed cells loaded with haemosiderin, indicating an older haemorrhage in this area. The cortical tissue adjacent to the haemorrhage contained small arteries and arterioles whose walls showed hyaline changes. Congo-red staining showed amyloid in these vessel walls. There was some intimal thickening in the meningeal arteries. Signs of a recent haemorrhage were found in the meninges; here, the adventitial cells of the meningeal vessels contained iron pigment.
Case VII (111-14) A 50-year-old married woman, born 21 July, 1912. In March, 1962, she developed an acute headache right frontally. On admission, she was drowsy and exhibited some meningeal irritation. Blood pressure 115/75; there were no internal or neurological abnormalities. CSF: xanthochromic. Right carotid angiography: possible space-occupying lesion temporally, otherwise normal. She recovered and was discharged after a month, when the CSF had become clear and colourless. In August, 1962, she again had an acute attack of headache, accompanied by drowsiness, and this time a right-sided extensor plantar response was found after admission. After her consciousness had cleared she seemed to be blind, although she could walk around without bumping into objects. On closer examination she exhibited a slight expressive aphasia, agraphia, tactile agnosia, slight acoustic agnosia, optic agnosia, and constructive apraxia. A vertebral angiogram was normal. Six weeks later, the neurological picture showed marked amelioration and she was discharged. In 1965, she was admitted for the 3rd time to the Municipal Hospital after a right-sided headache attack accompanied by vomiting, and after having become unconscious a couple of hours later. Until then, she was reported to have been able to cope with her housekeeping. She appeared to be deeply comatose; blood pressure 135/85; both pupils moderately dilated and unresponsive. No spontaneous movement. Bilateral extensor plantar responses. CSF: blood-stained. She died after a few hours. Permission for autopsy was not given. Case VIII (111-39) A 53-year-old married woman, born 9 October, 1918. She had a history of chronic pyelonephritis. but no hypertension since 1969. In that year she had been hospitalized elsewhere after an epileptic fit. No neurological abnormalities were found on physical examination: the EEG showed moderately generalized abnormality without focal signs; the CSF, left-sided carotid angiogram, and air encephalogram were normal. She was put on anti-epileptic medication. In September, 1972, she suddenly developed paraesthesiae in the right arm. which felt powerless. After a week she suddenly lost consciousness, vomited, and was incontinent of urine. On admission. she was found to be comatose; there was some neck rigidity; blood pressure 160/90; otherwise no internal abnormality. Funduscopy was compatible with grade I hypertensive retinopathy. Left pupillary reaction sluggish; hemiparesis with hyperreflexia on the right. CSF: blo0d-stained. Blood urea and creatinine: normal. Left-sided carotid angiography was suggestive of a deeply situated space-occupying lesion frontoparietally; the arteries seemed spastic. In a week she improved and could speak a little. After another 4 days her level of consciousness declined and she became hemiplegic. A week later there was bilateral papilloedema and vomiting. On the next day she died. Autopsy findings: purulent bronchopneumonia with a lung abscess on the right, a septic spleen, pyelitis, and ureteritis cystica on the right. The kidneys showed marked arteriosclerotic changes: the renal artery on both sides was normal, as were the aorta and other large vessels. Heart weight 315 g, left ventricle wall 12 mm thick. Microscopical examination revealed hyalinosis of small renal artery branches; the arteries of the lungs, heart, spleen, liver, pancreas, adrenals, and thyroid were normal. There was a small amount of subdural blood overlying a ruptured left frontal cerebral haemorrhage. Left-sided uncal herniation. Brain weight 1270 g. No atherosclerosis of the large vessels. On sectioning, haemorrhages of different ages were found left frontally and extending into the basal ganglia. Both frontal lobes also showed several scars.
127 Microscopy: recent haemorrhagic infarct in the left frontal lobe, and signs of old haemorrhagic infarcts in cortex and white matter, those in the cortex generally being small, whereas the larger ones were in the white matter. Focally in the cortex of cerebrum, cerebellum, and overlying arachnoid, there was extreme thickening and hyalinization of small arteries and arterioles. With Congo-red staining these vessels were positive for amyloid. There were no plaques or neurofibrillary tangles.
Case I X (generation 1V) A 45-year-old married woman, born 7 December, 1932. Her father (111-34) and sister died of proven CH. She was known to have suffered from migrainous headaches, and a severe attack in 1974 had been temporarily accompanied by slight weakness of one arm. In January, 1978, she had an acute attack of severe headache; after an hour and a half she started to vomit and then became gradually drowsier and eventually comatose. She was taken to another hospital, where she was found to be in deep coma. Blood pressure 140/80. Right retinal haemorrhage; pupils reacting; no oculo-cephalic reflexes; corneal reflexes almost absent. No spontaneous movem~'lat of the extremities; on strong painful stimuli, abnormal extension on the right and abnormal flexion on the left. Bilaterally, exaggerated tendon reflexes and extensor plantar responses. CSF: blood-stained. She died shortly after admission. Autopsy findings: the internal organs showed no abnormalities on macroscopic and microscopic examination; no arteriosclerosis; heart weight 290 g, left ventricle wall 16-11 mm thick. The brain weighed 1300 g and appeared oedematous. The leptomeninges were oedematous and haemorrhagic, especially over the dorsal surface of the cerebellum. Below the tentorium, there was some subdural blood. Marked tonsillar herniation. The arteries at the base of the skull showed no abnormality. Large (4 cm in diameter) haemorrhage in the left cerebellar hemisphere, extending through the vermis to the right, principally located in the cerebellar medulla. The cerebral hemispheres and brain-stem did not show changes on macroscopic examination. Microscopy: the small leptomeningeal arteries surrounding cerebellum, brain-stem and cerebrum exhibited tortuosity and marked hyaline thickening of the walls without narrowing of the lumen. The same hyaline changes were found widespread in the small arteries and arterioles of the cerebral and cerebellar cortex. There were subarachnoid haemorrhages over the cerebellar surface, extending between the convolutions. Case X (generation IV) A 46-year-old woman, born 8 April, 1932. Her mother (111-35) died suddenly at the age of 45 after a severe headache, reportedly caused by a CH. The patient herself had suffered from left-sided migrainous headaches since she was 14. Because of her family history, she sought a neurological examination in 1973. At that time no abnormalities were found on physical examination, but an EEG showed an irritative focus right temporally. In August, 1978, she had a headache attack "which was different"; she had difficulty in speaking and vomited. When admitted, her consciousness was undisturbed. Blood pressure 130/90; internal examination normal. There was a slight dysarthria and upper neuron type left-sided facial paresis. Otherwise, the neurological examination was unremarkable. CSF: (on the 4th day) yellowish-orange. CT-scan : compatible with a right-sided intratemporal haematoma (Fig. 3). Ophthalmoscopy and retinal fluorescent angiography gave normal results; in particular, there was no sign of amyloidosis. Biopsy specimens of the temporal artery, skin, and subcutaneous tissue were normal, as was the haematological status. She made a quick recovery and until September, 1979, was doing well except for attacks of migraine. Then, after a severe attack of headache accompanied by vomiting, she again experienced left-sided weakness. On admission, in addition to this weakness there was some stiffness of the neck. CSF: 700 red cells/mm3, protein content 69 mg/100 ml. Cytology showed erythrophages. This time, a CT scan showed a paramedian haematoma in the right frontal lobe (Fig. 4). Again, she recovered completely. Lately, she has complained of some slowing of mentation, and at one time she could not speak for several minutes (she is right-handed). Case X I (generation IV) A 44-year-old married woman, born 9 February, 1936. She was the daughter of patient 111-34. Both her father and a sister died from proven CH. Since 1958 she has lived in Sweden. One night in June, 1980, she developed a headache and lost consciousness. She died in a hospital in Stockholm from a CH in the right parietal region. A carotid angiogram had revealed no vascular abnormalities. We have received microscopical preparations of brain tissue, which show arterioles with thickened hyalinized wails. Furthermore, in the material stained with Congo-red some of the vessels are positive for amyloid.
128
Fig. 3. Case X. CT scan showing right-sided intratemporal haematoma.
FIVE CASES WITH DEMENTIA. WITH OR WITHOUT STROKE (MEDICAL HISTORIES AVAILABLE)
Case I (11-1) Male, born 26 January, 1872. According to relatives he had a stroke at the age of 60, resulting in a right-sided hemiplegia. He made a partial recovery, but did not work since then. He was admitted to a mental institution at the age of 76. He appeared to be demented and there was a right-sided hemiparesis. He died after one month, presumably because of heart disease. Case H (11-2) Male, born 10 February, 1874. He was a barge hand. According to his wife he had a stroke at the age of 61. He recovered but did not work any more. His m e m o r y was somewhat impaired. In 1941, at the age o f 67, a carcinoma of the rectum was diagnosed and a colostomy was performed. After this, he was admitted to a mental institution. On physical examination, no neurological abnormality was found. He was confused, spoke incoherently, and sometimes misnamed objects. He developed fever and died two m o n t h s after admission.
129
Fig. 4. Case X. CT scan. H a e m a t o m a in the right frontal lobe, one year later.
Case 111 (11-4) Male, born 31 October, 1879. Until the age of 70 he worked as a hand on a ship of the inland waterways. Thereafter, he deteriorated mentally, and in 1952, at the age of 72, was admitted to a mental institution. Neurological examination showed increased tone in the extremities, an extensor plantar response on the right, and senile tremor o f the hands. He was confused and doubly incontinent. He became progressively more demented and died at the age of 74. Case I V (111-2) Male, born 21 August, 1897. He was a surveyor in the municipal cleansing department. According to his wife, he had a stroke at the age o f 57, resulting in a paresis of the left half o f his face and of his left arm. Thereafter, his m e m o r y became faulty, he was often depressed, and easily irritated. In 1957, at the age of 59, he became very confused after a prostatectomy and was temporarily treated in a mental institution. On examination there were facial paresis a n d slight paresis o f the arm on the left. His m e m o r y was seriously defective, he confabulated and misnamed objects. His mental condition improved a n d he was discharged after 3 weeks. Since 1961 he developed epileptic fits, and in 1963 he was readmitted because of confusion and aggressiveness. Expressive and eceptive dysphasia and apraxia were found. An E E G showed generalized abnormality, the CSF was clear and colourless with a protein content of 55 rag/100 ml. He was discharged to a nursing home, to be readmitted temporarily to the
130 mental institution in 1964 because of aggressive behaviour. Otherwise, his neurological and mental condition were the same; the CSF protein content now was 60 rag/100 ml. He died in 1964, at the age of 67, in a nursing home. Case V (111-3)
Male, born 3 December, 1900. This fisherman was seen in our department in 1951 for the first time at the age of 50, because of generalized epileptic attacks. Neurological examination gave normal results; the protein content of the CSF was 63 mg/100 ml; the EEG showed too much slow activity; air encephalography showed more widening of the left than of the right ventricle. In the following years he deteriorated mentally and in 1955 he appeared severely demented. A diagnosis of presenile dementia was made. He died at the age of 58.
DISCUSSION All but one of the 11 patients with C H had clinical manifestations of repeated cerebro-vascular accidents at intervals of days to years. In 6 the signs pointed to recurrences in the same hemisphere. Although the recurrence of stroke is certainly not exceptional, the pattern in this group of patients is most unusual. Only one case (Ili-33) did not present as CH. Instead, this patient showed progressive mental deterioration with epileptic fits and was for some time regarded as suffering from Alzheimer's disease. In this patient infarcts were only slightly haemorrhagic and did not result in secondary subarachnoid haemorrhage. Three more members died from CH, according to relatives. 111-2 in the pedigree, a man, died at the age of 67 after having been mentally disturbed for years. Ill-32 and Ili-35, both females, reportedly died from C H at the age of 43 and 45, respectively, in both cases shortly after the onset of a severe headache: In the second generation four of the 7 sibs (Nos. 1, 2, 4 and 7) stayed in a mental institution. The medical histories of Nos. 1, 2 and 4 were available. All 3 became demented in their 7th or 8th decade, and two had had a stroke at the beginning of their sixties. In generation III No. 2, who allegedly died from a C H at the age of 67, deteriorated mentally over the course of m a n y years; while No. 3 became demented in his early fifties. An inspection of the pedigree shows that the 11 clinically proven cases of C H (of w h o m 7 were pathologically examined) occur in 5 sibships over two generations. Three of these sibships are offspring of brothers, who became severely mentally defective; two of them in addition had a stroke. In two of the sibships (III-1 to 111-9 and 1II-31 to 111-42) in which 7 of the 21 sibs were proven affected, a further 3 (111-2, II1-32 and 111-35) died allegedly from a C H ; one of these (III-2) developed severe dementia, while a further Sib who died (111-3) was clinically diagnosed at that time as suffering from presenile dementia. Since the autopsy results of the case with the clinical appearance of presenile dementia (III-33), suggest that the recurrent infarcts without secondary subarachnoid haemorrhage resulted in dementia as a clinical expression of the angiopathy, it seems justified on the basis o f the foregoing and a study of the pedigree to suggest that an autosomal dominant gene with high penetranee is responsible for the angiopathy, in 7 instances the clinical expres-
131 sion of such a gene could be pathologically proven, while in others there was proof of a CH and in some further patients only the presence of dementia developing in the 6th-7th decade was certain. In view of the late onset of clinical symptoms in this disorder it is astonishing that such a high degree of penetrance (10 affected out of 21) is observed; probably because the family members are otherwise very healthy and reach an old enough age to be subject to the adverse effects of the angiopathy. Further evidence comes from the 3 proven patients in generation IV. The father of two of these patients was proven affected, the mother of one probably died from a CH. Thus we seem to have proven transmission over 3 generations. A point of interest is the occurrence in this family of migraine, from which 4 of the patients with CH suffered. Three of them had complicated migraine, in two with the neurological signs on the same side as during the CH. A daughter of III-36, two daughters of III-35 and a son of III-34 are under treatment by one of us for this condition. CT scans of two of these patients show evidence of a small infarct. One could speculate about a possible relationship between CH and migraine in this family. The macroscopic findings in the brains available after autopsy (III-7, 33, 34, 39, and two cases of generation IV) or seen during craniotomy (III-36 and 37) were those of subdural, subarachnoid, and intracerebral (cerebellar) haemorrhages, and infarcts, both recent and old. The haemorrhages and infarcts were multiple in all cases but two. Microscopically, small arteries and arterioles with hyaline thickening of the walls were found in the frontal, parietal, temporal, and occipital cortex, in the hippocampus and cerebellar cortex, as well as in the overlying arachnoid. The abnormal vessels in the arachnoid often showed marked tortuosity (Fig. 5). In the arachnoid small arteries were concerned rather than arterioles, and obliteration of their lumen by the hyalinization process seemed to have led to infarction of the underlying subcortical white matter (III-33). Both thrombosis and rupture of abnormal vessels were found. No abnormal vessels occurred in the basal ganglia or brain-stem, or in the one spinal cord that was examined (III-33). Since there was no history or evidence of long-standing severe hypertension, except possibly in one case, and no aneurysms or arterio-venous malformations were found angiographically or at autopsy, it seems plausible that the microangiopathy bore a close relationship to the CH and infarction. In 5 cases amyloid was demonstrated by Congo-red staining in the walls of the abnormal vessels (Figs. 6 and 7). The staining pattern and the green birefringence during exposure of the preparations to polarized light were compared with those of a control liver and a liver with known amyloidosis. Furthermore, electron microscopy of abnormal vessels showed fascicular, parallel, and radial formation of filaments (Figs. 8 and 9) as described for amyloid by Schlote (Schlote 1965) in congophilic angiopathy. In none of the patients investigated by us could amyloidosis be demonstrated outside the brain. Bielschowsky staining, done in patients III-33 and III-39, showed no plaques or neurofibrillary
Fig. 5. Abnormal vessels in arachnoid showing tortuosity: hyalinization of cortical arterioles.
Fig. 6. Arteriosclerosis of cortical arterioles. At the cross-section of l he left arteriole a deposit of amytoid is recognizable. Congo-red. x 150.
Fig. 7. Several cortical arterioles demonstrate hyalinization by amyloid deposit. Congo-red,
x 150.
Fig. 8. Electron microscopy of cross-section of abnormal vessel showing arrangement of amyloid filaments m different layers of the vessel wall. EM, x 4500.
134
Fig. 9. Fascicular arrangement o f amyloid filaments in vessel wall. EM, x 12,720.
tangles. In the patient of generation IV who is still alive, biopsy specimens of skin, fascia, and muscle were negative for amyloid, and there were no signs of ocular amyloidosis. We are of the opinion that this family suffers from a condition closely resembling the one described by Gudmundsson and his colleagues. In their family and the one described here, the patients suffered from repeated cerebrovascular accidents due to multiple haemorrhages and infarcts. However. the Icelandic patients, all in their twenties, were considerably younger than ours. As far as the microscopical aspects are concerned, Gudmundsson does not state the size of the abnormal arteries in 3 of his 5 autopsied cases: for the other two, mention is made o f the smaller arteries, as seen in our cases. Furthermore, m the Icelandic cases amyloidosis was sometimes present without thickening of the arterial walls. Lastly, in contrast to our cases, abnormal vessels were also found in the brain-stem. Familial occurrence of amyloid angiopathy leading to demenua and spastic paresis has been described (Worster-Drought et al. 1933, 1940, 1944: van Bogaert et al. 1940; Lfiers 1947; Corsellis and Brierley,1954). All of these cases showed plaque formation and neurofibrillary changes as well. There are indications that in the Dutch family dementia is, in addition to CH, a clinical expression of the angiopathy. Isolated cases of amyloid angiopathy, plaques, and tangles associated with CH also have been reported (Neumann 1960; Torack 1975; Jellinger 1977). In our
135 two cases investigated in this respect, plaques and neurofibrillary tangles were absent. Gudmundsson did not find plaques either. In some ways, the histopathological observations in our patients are compatible with those of congophilic angiopathy described in old age. However, the angiopathy in our cases was more extensive, and the severity was related to the localization of the haemorrhages and infarcts. Congophilic angiopathy in Alzheimer's disease (Mandybur 1975), as in old age, is accompanied by plaque formation, which was lacking in our cases. ACKNOWLEDGEMENTS
We thank Dr. C. H. Terpstra (Bethlehem Hospital, The Hague) and Dr. Goran Edner (Karolinska Hospital, Stockholm) for putting case history and microscopical preparations at our disposal. REFERENCES Aberfeld, D.C. and K.R. Rao (1981) Familial arteriovenous malformation of the brain, Neurology (Minneap.), 31 : 184-186. Carter Snead, O., J.C. Acker and R. Morawetz (1979) Familial arteriovenous malformation, Ann. Neurol., 5:585 587. Corsellis, J. A. N. and J. B. Brierley (1954) An unusual type of pre-senile dementia (atypical Alzheimer's disease with amyloid vascular change), Brain, 77: 571-587. Endtz, L.J. (1968) Familial incidence of intracranial aneurysms, Acta neurochir., 19: 297-305. Fairburn, B. (1937) "Twin" intracranial aneurysms causing subarachnoid haemorrhage in identical twins, Brit. med. J., I: 210-211. Gudmundsson, G., J. Hallgrimsson, T.A. Jonasson and O. Bjarnason (1972) Hereditary cerebral haemorrhage with amyloidosis, Brain, 95: 387404. Jellinger, K. (1977) Cerebrovascular amyloidosis with cerebral haemorrhage, J. Neurol., 214:195 206. Liiers, Th. (1947) 13ber die famili/ire juvenile Form der Alzheimerschen Krankheit mit neurologischen Herderscheinungen, Arch. Psychiat. Nervenkr., 179: 132-145. Luyendijk, W. and G. Th. A. M. Bots (1980) In: H. W. Pia, C. Langmaid and J. Zierski (Eds.), Advances in Diagnosis and Therapy, Springer-Verlag, Berlin, pp. 50-56. Mandybur, T. I. (1975) The incidence of cerebral amyloid angiopathy in Alzheimer's disease, Neurology (Minneap.), 25: 120-126. Neumann, M.A. (1960) Combined amyloid vascular changes and argyrophilic plaques in the central nervous system, J. Neuropath. exp. Neurol., 19: 370-382. Schlote, W. (1964) Die Amyloidnatur der kongophilen, drtisigen Entartung der Hirnarterien (Scholtz) im Senium, Acta neuropath. (Berl.), 4: 449468. Torack, R. M. (1975) Congophilic angiopathy complicated by surgery and massive haemorrhage, Amer. J. Path., 81 : 349-366. Bogaert, L. van, M. Maere and E. De Smedt (1940) Sur les formes familiales pr~coces de la maladie d'Alzheimer, Mschr. Psychiat. Neurol., 102: 24%301. Worster-Drought, C., T. R. Hill and W. H. McMenemey (1933) Familial presenile dementia with spastic paralysis, J. Neurol. Psychopath., 14: 27-34. Worster-Drought, C., J.G. Greenfield and W.H. McMenemey (1940) A form of familial presenile dementia with spastic paralysis (including the pathological examination of a case), Brain, 63: 237 254. Worster-Drought, C., J.G. Greenfield and W.H. McMenemey (1944) A form of familial presenile dementia with spastic paralysis, Brain, 67: 38-43.
121
Elsevier Biomedical Press
FAMILIAL CEREBRAL AMYLOID ANGIOPATHY PRESENTING AS RECURRENT CEREBRAL HAEMORRHAGE
A. R. W A T T E N D O R F F 1, G. Th. A. M. BOTS 2, L. N. WENT 3 and L.J. ENDTZ l
JDepartment of Neurology, Municipal Hospital of The Hague, The Hague and Departments of 2pathology and 3 Human Genetics, University of Leiden, Leiden (The Netherlands) (Received 25 November, 1981) (Accepted 12 January, 1982)
SUMMARY
Eleven patients belonging to two generations of a Dutch family with cerebral and cerebellar haemorrhage, haemorrhagic infarction and infarction are described. Their ages varied from 44 to 58 years. The principal clinical characteristic was recurring cerebral haemorrhages, sometimes preceded by a history of migrainous headaches or mental changes. In 4 of the 6 autopsied cases, old and new multiple cerebral haemorrhagic infarcts and infarcts were found, in one case a single cerebral haemorrhage and in another a cerebellar haemorrhage. In 5 cases this resulted in secondary subarachnoid haemorrhage. In one case the infarcts were only slightly haemorrhagic and did not result in subarachnoid haemorrhage. This patient presented as dementia. Microscopically, in these 6 cases and in one biopsy specimen hyaline thickening of the walls of cortical arterioles was found. The arteries of the arachnoid showed marked tortuosity, concentric proliferation, and focal hyalinization of the walls. Amyloid was found in the hyalinized vessels in 5 cases, but not outside the central nervous system. We believe that we are dealing with an inherited disorder with an autosomal dominant mode of inheritance, in which microangiopathy leads to cerebral haemorrhage and (haemorrhagic) infarction. It seems likely that amyloidosis underlies the angiopathy, and that this family suffers from a condition similar to the one described by Gudmundsson in 1972.
INTRODUCTION
In 1972, Gudmundsson et al. described an Icelandic family in which members belonging to four generations suffered from familial cerebral haemorrhage (FCH) 0022-510X/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press
122 and cerebral infarction at an early age. These authors reported 8 patients with proven cerebral haemorrhage (CH). At autopsy, which was performed in 5 of these cases, the brains showed deposition of amyloid in cerebral and meningeal artery walls, but no signs of amyloidosis were found outside the central nervous system. In this paper we report 11 patients with proven CH, belonging to two generations of one family from Scheveningen, The Netherlands. Histological investigation was possible in one surgically treated patient and in 6 cases with autopsy material. Pathological changes were found in small meningeal and cortical arteries and in the arterioles, which showed hyaline thickening of the walls. In 5 cases amyloid was present in these hyalinized meningeal and cortical vessels. We therefore believe the underlying pathological condition in our patients to be identical with that in the Icelandic cases. Only one patient is still alive. Other cases of FCH with a similar arteriopathy have been reported by Luyendijk and Bots (1980). Familial occurrence of intracranial arteriovenous malformations (Carter Snead et al. 1979; Aberfeld et al. 1981) and of intracranial aneurysms (Endtz 1968; Fairburn 1973) is, to our knowledge, the only known other cause of FCH. MATERIAL
Of the 11 patients, 9 were seen in the Municipal Hospital of The Hague. The other two had been admitted to and died in other hospitals, one of them, the most recent case, in Stockholm in 1980. One patient is still alive. An autopsy was performed in 6 cases, and in a 7th material obtained during craniotomy was available for microscopical examination. The patients are descendants of a couple who married in 1871 (Fig. 1). They belong to a family from Scheveningen, which was once a rather isolated fishing village but now forms part of The Hague. According to information obtained from the family, 3 other members died from CH and 6 developed mental deterioration in the 6th and 7th decades. We were able to obtain the medical histories of 5 of the patients with dementia; they will be presented in a separate group after the cases with CH. Some further family members have been seen in the out-patient department.
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Fig. 1. Pedigree of family.
no
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123 The first member seen in the Municipal Hospital (pedigree Ill-33) did not present as CH at the time (1951) but was diagnosed as a case of migraine complicated by hemiparesis. Later, he deteriorated mentally, and until his death in 1962 was regarded as a case of Alzheimer's disease. In 1953 another member, a 58-year-old woman, died from CH in the Municipal Hospital, but an autopsy was not performed. In 1956, a 45-year-old woman was admitted to our hospital after the sudden onset of confusion and headache (111-36, see case report below). Her relatives said that two sisters were known to have died of CH in their mid-forties. Since this patient was the first proven case of CH with angiopathy, she can be regarded as the index case. CASE REPORTS Index case (H1-36) A 45-year-old woman, born on March 2nd, 1911. In 1956, while at home, she suddenly became confused and incontinent, and at that time complained of headache. Since 1953 she had suffered from attacks of headache, located occipitally and preceded by scotomata. Also, her character seemed to have altered. During the 6 months before admission the headache attacks were accompanied by a sensation of numbness and stiffness on the right side o f her mouth and in her right arm, which felt weak. On admission in 1956, she was drowsy and incontinent for faeces and urine. She was aphasic. Blood pressure 200/100. Gaze paresis towards the right ; homonymous hemianopia on the right; paralysis of right arm and leg; extensor plantar response on the right. CSF : xanthochromic with 500 red cells/ram 3. She improved somewhat, but after a week developed papilloedema ; a carotid angiogram was suggestive of a left frontal space-occupying lesion. A left-sided craniotomy showed a subcortical haematoma frontally and two yellowish spots on the cortex which yielded old blood when punctured. Biopsy specimens were taken at several places, because the possibility of a tumour was considered. Microscopical examination showed numerous arterioles and small-calibre arteries with thickened walls usually showing distinct signs of hyaline degeneration. Post-operatively, she made a substantial recovery and after discharge was able to return to her home. In 1957, she suddenly began to have more difficulty in speaking, and had 4 presumably epileptic fits. Her behaviour became more disturbed and she was often depressed. In 1958, after being found unconscious and incontinent she was readmitted to the Municipal Hospital. She was in deep coma, with widened non-reacting pupils. Blood pressure 150/90. CSF: blood-stained. She died after a few hours. Autopsy was refused. Case 11 (Hl-33) A 46-year-old man, born on August 27th, 1905. He completed primary school without difficulty and before the Second World War served as a sailor in the merchant marine and Royal Navy. After the war he became an employee of the municipal energy department. Since 1942 he had been troubled by attacks of headache accompanied by paraesthesiae in his left hand. In 1951, a severe attack resulted in confusion and loss of power in the extremities on the left side. On admission, the blood pressure was 135/90. Left-sided hemiparesis and hemihypaesthesia were observed. The CSF was clear and colourless, with a total protein content of 71 mg/100 ml. An EEG showed slow waves over the right hemisphere and spikes over the left parieto-occipital region. Carotid angiography disclosed no abnormalities and an air encephalogram only widened lateral ventricles. He made a good recovery and was discharged after 2½ months under the diagnosis complicated migraine. Alter that, he showed progressive mental deterioration. In 1954, he again became very confused after a severe headache attack, and was admitted to another hospital, where no focal neurological signs were found, but instead a profound dementia (I.Q. 67 on the Wechsler test). The EEG showed widened ventricles, the right wider than the left. The CSF contained no blood, and the total protein content was 80 rag/100 ml. He was discharged after a month. His condition gradually deteriorated, with occasional epileptic seizures, and at times he became aggressive. In June, 1961, he was confined to a mental hospital in Leiden; at admission, no internal abnormalities were found. Blood pressure: 150/85. Neurological findings: generalized hyperreflexia, plantar reflexes flexor; no paresis. He lacked insight about his illness, and was inclined to spontaneous excessive speech. There was a slight receptive aphasia, dyslexia,
124 finger agnosia, and apraxia. The diagnosis was Alzheimer's disease. In March of 1962 he developed generalized seizures which began in his left face and arm and increased in frequency. Eventually hc became soporific, and in April, 1962, he died of bronchopneumonia. Autopsy findings: bronchopneumonia, lung oedema, tracheobronchitis, and splenitis. Hearl: weight 450 g, slight hypertrophy and dilatation. Little atherosclerosis. The brain weighed 1405 g. There were several areas of softening, and a cavity right frontally and left occipitally. Microscopy: fresh, somewhat haemorrhagic infarct in right internal and external capsule and neighbouring insular cortex. Infarcts of differing age in white matter and parietal cortex and cerebellum, most of them being slightly haemorrhagic. Oedema, demyelinization, and loss of perivascular substance in the hemispheral and cerebellar white matter. Diffuse loss of ganglion cells with proliferation of astroglia and satellitosis in the cortex. Excessive hyalinization of arterioles in frontal, parietal, occipital, and, locally, in insular and cerebellar cortex, with thrombosis and obliteration of the lumen by hyalinization. Tortuosity of small arteries in the leptomeninges of cerebrum and cerebellum with local hyalinization. Congo-red staining showed both hyalinosis and amyloidosis of small meningeal and cortical arteries. No amyloidosis of extracranial vessels could be demonstrated. There were no plaques or neurofibrillary tangles. There were no large haemorrhages in the parenchyma or subarachnoid spaces. Case III (III-1) A 58-year-old married woman, born 23 August, 1895. For the past year she had suffered from non-migrainous headaches. Ten days prior to admission in 1953 she was suddenly unable to speak and had weakness of one side of the face; these symptoms lasted one day. On the day before admission she had a severe headache accompanied by nausea, after which she became progressively drowsier. On admission she was soporous; there was neck stiffness. Blood pressure 180/100. Non-reacting left pupil, tendon reflexes more active on the right than on the left, and extensor plantar response on the right. CSF: blood-stained, after centrifugation xanthochromic. She became progressively comatose and died after three days. Autopsy was not performed. Case 1V (111-37) A 43-year-old married woman, born 3 February, 1913. In 1957. while working in her home. she suddenly developed a severe headache and vomited. She did not lose consciousness. On admission she was drowsy. There was some meningeal irritation; blood pressure 130/75: conjugate gaze paresis to the right; total aphasia. CSF: blood-stained. Left-sided carotid angiography: space-occupying lesion in the left hemisphere. On operation, a left parietal intra-cerebral and overlying subdural haematoma were found. Eventually she was discharged, her condition being described as dementia with psychopathic traits. In 1958, she suffered a short focal epileptic fit with convulsions of the fight arm and leg. In 1964, she again suffered an acute headache, and when readmitted to the Municipal Hospital exhibited the same clinical picture although the aphasia was less severe and mostly expressive. Blood pressure 120/80. No internal abnormality. Haematologieal status: normal. CSF: blood-stained. A left-sided carotid angiogram was again suggestive of a space-occupying lesion, now in the left fronto-temporal region, but because her level of consciousness improved, surgery was withheld. She had another right-sided focal epileptic fit but otherwise continued to improve, although on discharge she was still dysphasic. In 1965, she had to be taken to the hospital for the 3rd time, after a severe attack of headache; she said she was blind; she was unable to walk, was incontinent, and became progressively drowsier. On admission, she appeared to be unconscious; blood pressure 150/95: left pupil moderately dilated, both pupils reacted to light; central facial paresis on the right; increased tonus of the right extremities, plantar response extensor bilaterally; incontinence for urine and faeces. The CSF was blood-stained under high pressure. An echo-encephalogram revealed a 4-ram shift to the left, and a right carotid angiogram showed displacement of the anterior cerebral artery to the left; there was poor filling of the middle cerebral artery circulation but the picture was suggestive of a pericerebral haematoma over the parietal region. At right-sided craniotomy an extensive but rather thin (½ cm maximally) subdural haematoma was found. The cortical surface showed haemorrhagic discoloration in many spots and bulged after the dura was opened. On puncture, old blood was obtained from several sites. On exploration, however, extensive haemorrhagic infarction was a more prominent feature. She died in 1966 in a nursing home. Case V (111-34) A 51-year-old man, born 5 September, 1907. He was the father of two other patients, described below. In May and August of 1958 he was admitted to the Municipal Hospital under the diagnosis
125 cerebral haemorrhage in the right hemisphere. In 1960, he suddenly developed a headache, followed after 3 days by difficulty in speaking and loss of power in his left upper and lower extremity. On the next day he was admitted and was found to be in coma, with a left-sided hemiparesis, generalized hyperreflexia, and bilateral extensor plantar response. CSF: blood-stained. He died 5 days after admission. Autopsy findings: left-sided pneumonia; heart weight 410 g; thickness of left ventricle wall 14 mm. Otherwise, no morbid changes were found extracranially, there was no conspicuous atherosclerosis, and microscopical examination of heart, liver, spleen, and kidneys gave normal results. The brain showed flattening of the right frontal gyri, which felt soft on palpation. The subarachnoid space contained blood, especially on the right, frontally. There was no atherosclerosis of the large arteries at the base of the skull. On sectioning, a haemorrhagic area was found, extending from right frontally to parietally with a maximum diameter of 4.5 cm and containing a 2-cm wide cavity filled with a thrombus. The right temporal lobe contained a cleft with yellowish-brown walls, and in the right parietal lobe there was a 1-cm diameter cavity with the same discoloration of its w~tlls. In the left parietal lobe there was a cavity measuring 2½ x 1 cm and filled with a light-browni~ soft mass. Microscopically, the left parietal and right temporal morbid changes were compatible with old haemorrhagic infarctions, these areas containing accumulations of iron pigment. In the meninges over the parietal and temporal regions an extensive haemorrhage was found. The arteries showed concentric sclerosis. There was conspicuous hyalinosis of the smaller intracerebral arteries and arterioles. Congo-red staining showed amyloid in the walls of these vessels.
Case VI (III-7) A 53-year-old married woman, born 20 January, 1909. In 1962, she was admitted to another hospital under the diagnosis apoplexy, exhibiting aphasia, from which she recovered. In August, 1963, she had another epidose of being unable to speak; she also was drowsy at that time. Her condition improved somewhat, but in October, 1963, she suddenly became paralyzed on the right side. She was then on a salt-restricted diet. She was admitted to the Municipal Hospital, where she was found to be comatose. Blood pressure 140/85, internal examination normal. The left pupil was larger than the right, both reacting to light; right-sided hemiplegia with extensor plantar response. CSF: blood-stained.
Fig. 2. Case VI. Large haemorrhage in the left hemisphere extending via corpus callosum to the fight.
126 She developed pneumonia and died after 6 days. Autopsy findings: purulent bronchopneumonia and lung oedema ; apart from a large bilestone, there were no other morbid changes outside the brain. The heart weight was 380 g; there was little arteriosclerosis, and the kidneys did not show evidence ol secondary hypertensive changes. Microscopical examination of heart, adrenals, liver, and spleen gave normal results. There was blood in the subarachnoid space. The arteries at the base of the skull were normal. There was conspicuous yellow discoloration of the surface of the brain in certain areas. The sections showed a large haemorrhage in the left hemisphere which had ruptured into the lateral ventricle and extended via the corpus callosum towards the right hemisphere (Fig. 2). In both the left and right frontal lobes there were signs of old haemorrhages. Microscopical examination of the region of the most recent haemorrhage revealed cells loaded with haemosiderin, indicating an older haemorrhage in this area. The cortical tissue adjacent to the haemorrhage contained small arteries and arterioles whose walls showed hyaline changes. Congo-red staining showed amyloid in these vessel walls. There was some intimal thickening in the meningeal arteries. Signs of a recent haemorrhage were found in the meninges; here, the adventitial cells of the meningeal vessels contained iron pigment.
Case VII (111-14) A 50-year-old married woman, born 21 July, 1912. In March, 1962, she developed an acute headache right frontally. On admission, she was drowsy and exhibited some meningeal irritation. Blood pressure 115/75; there were no internal or neurological abnormalities. CSF: xanthochromic. Right carotid angiography: possible space-occupying lesion temporally, otherwise normal. She recovered and was discharged after a month, when the CSF had become clear and colourless. In August, 1962, she again had an acute attack of headache, accompanied by drowsiness, and this time a right-sided extensor plantar response was found after admission. After her consciousness had cleared she seemed to be blind, although she could walk around without bumping into objects. On closer examination she exhibited a slight expressive aphasia, agraphia, tactile agnosia, slight acoustic agnosia, optic agnosia, and constructive apraxia. A vertebral angiogram was normal. Six weeks later, the neurological picture showed marked amelioration and she was discharged. In 1965, she was admitted for the 3rd time to the Municipal Hospital after a right-sided headache attack accompanied by vomiting, and after having become unconscious a couple of hours later. Until then, she was reported to have been able to cope with her housekeeping. She appeared to be deeply comatose; blood pressure 135/85; both pupils moderately dilated and unresponsive. No spontaneous movement. Bilateral extensor plantar responses. CSF: blood-stained. She died after a few hours. Permission for autopsy was not given. Case VIII (111-39) A 53-year-old married woman, born 9 October, 1918. She had a history of chronic pyelonephritis. but no hypertension since 1969. In that year she had been hospitalized elsewhere after an epileptic fit. No neurological abnormalities were found on physical examination: the EEG showed moderately generalized abnormality without focal signs; the CSF, left-sided carotid angiogram, and air encephalogram were normal. She was put on anti-epileptic medication. In September, 1972, she suddenly developed paraesthesiae in the right arm. which felt powerless. After a week she suddenly lost consciousness, vomited, and was incontinent of urine. On admission. she was found to be comatose; there was some neck rigidity; blood pressure 160/90; otherwise no internal abnormality. Funduscopy was compatible with grade I hypertensive retinopathy. Left pupillary reaction sluggish; hemiparesis with hyperreflexia on the right. CSF: blo0d-stained. Blood urea and creatinine: normal. Left-sided carotid angiography was suggestive of a deeply situated space-occupying lesion frontoparietally; the arteries seemed spastic. In a week she improved and could speak a little. After another 4 days her level of consciousness declined and she became hemiplegic. A week later there was bilateral papilloedema and vomiting. On the next day she died. Autopsy findings: purulent bronchopneumonia with a lung abscess on the right, a septic spleen, pyelitis, and ureteritis cystica on the right. The kidneys showed marked arteriosclerotic changes: the renal artery on both sides was normal, as were the aorta and other large vessels. Heart weight 315 g, left ventricle wall 12 mm thick. Microscopical examination revealed hyalinosis of small renal artery branches; the arteries of the lungs, heart, spleen, liver, pancreas, adrenals, and thyroid were normal. There was a small amount of subdural blood overlying a ruptured left frontal cerebral haemorrhage. Left-sided uncal herniation. Brain weight 1270 g. No atherosclerosis of the large vessels. On sectioning, haemorrhages of different ages were found left frontally and extending into the basal ganglia. Both frontal lobes also showed several scars.
127 Microscopy: recent haemorrhagic infarct in the left frontal lobe, and signs of old haemorrhagic infarcts in cortex and white matter, those in the cortex generally being small, whereas the larger ones were in the white matter. Focally in the cortex of cerebrum, cerebellum, and overlying arachnoid, there was extreme thickening and hyalinization of small arteries and arterioles. With Congo-red staining these vessels were positive for amyloid. There were no plaques or neurofibrillary tangles.
Case I X (generation 1V) A 45-year-old married woman, born 7 December, 1932. Her father (111-34) and sister died of proven CH. She was known to have suffered from migrainous headaches, and a severe attack in 1974 had been temporarily accompanied by slight weakness of one arm. In January, 1978, she had an acute attack of severe headache; after an hour and a half she started to vomit and then became gradually drowsier and eventually comatose. She was taken to another hospital, where she was found to be in deep coma. Blood pressure 140/80. Right retinal haemorrhage; pupils reacting; no oculo-cephalic reflexes; corneal reflexes almost absent. No spontaneous movem~'lat of the extremities; on strong painful stimuli, abnormal extension on the right and abnormal flexion on the left. Bilaterally, exaggerated tendon reflexes and extensor plantar responses. CSF: blood-stained. She died shortly after admission. Autopsy findings: the internal organs showed no abnormalities on macroscopic and microscopic examination; no arteriosclerosis; heart weight 290 g, left ventricle wall 16-11 mm thick. The brain weighed 1300 g and appeared oedematous. The leptomeninges were oedematous and haemorrhagic, especially over the dorsal surface of the cerebellum. Below the tentorium, there was some subdural blood. Marked tonsillar herniation. The arteries at the base of the skull showed no abnormality. Large (4 cm in diameter) haemorrhage in the left cerebellar hemisphere, extending through the vermis to the right, principally located in the cerebellar medulla. The cerebral hemispheres and brain-stem did not show changes on macroscopic examination. Microscopy: the small leptomeningeal arteries surrounding cerebellum, brain-stem and cerebrum exhibited tortuosity and marked hyaline thickening of the walls without narrowing of the lumen. The same hyaline changes were found widespread in the small arteries and arterioles of the cerebral and cerebellar cortex. There were subarachnoid haemorrhages over the cerebellar surface, extending between the convolutions. Case X (generation IV) A 46-year-old woman, born 8 April, 1932. Her mother (111-35) died suddenly at the age of 45 after a severe headache, reportedly caused by a CH. The patient herself had suffered from left-sided migrainous headaches since she was 14. Because of her family history, she sought a neurological examination in 1973. At that time no abnormalities were found on physical examination, but an EEG showed an irritative focus right temporally. In August, 1978, she had a headache attack "which was different"; she had difficulty in speaking and vomited. When admitted, her consciousness was undisturbed. Blood pressure 130/90; internal examination normal. There was a slight dysarthria and upper neuron type left-sided facial paresis. Otherwise, the neurological examination was unremarkable. CSF: (on the 4th day) yellowish-orange. CT-scan : compatible with a right-sided intratemporal haematoma (Fig. 3). Ophthalmoscopy and retinal fluorescent angiography gave normal results; in particular, there was no sign of amyloidosis. Biopsy specimens of the temporal artery, skin, and subcutaneous tissue were normal, as was the haematological status. She made a quick recovery and until September, 1979, was doing well except for attacks of migraine. Then, after a severe attack of headache accompanied by vomiting, she again experienced left-sided weakness. On admission, in addition to this weakness there was some stiffness of the neck. CSF: 700 red cells/mm3, protein content 69 mg/100 ml. Cytology showed erythrophages. This time, a CT scan showed a paramedian haematoma in the right frontal lobe (Fig. 4). Again, she recovered completely. Lately, she has complained of some slowing of mentation, and at one time she could not speak for several minutes (she is right-handed). Case X I (generation IV) A 44-year-old married woman, born 9 February, 1936. She was the daughter of patient 111-34. Both her father and a sister died from proven CH. Since 1958 she has lived in Sweden. One night in June, 1980, she developed a headache and lost consciousness. She died in a hospital in Stockholm from a CH in the right parietal region. A carotid angiogram had revealed no vascular abnormalities. We have received microscopical preparations of brain tissue, which show arterioles with thickened hyalinized wails. Furthermore, in the material stained with Congo-red some of the vessels are positive for amyloid.
128
Fig. 3. Case X. CT scan showing right-sided intratemporal haematoma.
FIVE CASES WITH DEMENTIA. WITH OR WITHOUT STROKE (MEDICAL HISTORIES AVAILABLE)
Case I (11-1) Male, born 26 January, 1872. According to relatives he had a stroke at the age of 60, resulting in a right-sided hemiplegia. He made a partial recovery, but did not work since then. He was admitted to a mental institution at the age of 76. He appeared to be demented and there was a right-sided hemiparesis. He died after one month, presumably because of heart disease. Case H (11-2) Male, born 10 February, 1874. He was a barge hand. According to his wife he had a stroke at the age of 61. He recovered but did not work any more. His m e m o r y was somewhat impaired. In 1941, at the age o f 67, a carcinoma of the rectum was diagnosed and a colostomy was performed. After this, he was admitted to a mental institution. On physical examination, no neurological abnormality was found. He was confused, spoke incoherently, and sometimes misnamed objects. He developed fever and died two m o n t h s after admission.
129
Fig. 4. Case X. CT scan. H a e m a t o m a in the right frontal lobe, one year later.
Case 111 (11-4) Male, born 31 October, 1879. Until the age of 70 he worked as a hand on a ship of the inland waterways. Thereafter, he deteriorated mentally, and in 1952, at the age of 72, was admitted to a mental institution. Neurological examination showed increased tone in the extremities, an extensor plantar response on the right, and senile tremor o f the hands. He was confused and doubly incontinent. He became progressively more demented and died at the age of 74. Case I V (111-2) Male, born 21 August, 1897. He was a surveyor in the municipal cleansing department. According to his wife, he had a stroke at the age o f 57, resulting in a paresis of the left half o f his face and of his left arm. Thereafter, his m e m o r y became faulty, he was often depressed, and easily irritated. In 1957, at the age of 59, he became very confused after a prostatectomy and was temporarily treated in a mental institution. On examination there were facial paresis a n d slight paresis o f the arm on the left. His m e m o r y was seriously defective, he confabulated and misnamed objects. His mental condition improved a n d he was discharged after 3 weeks. Since 1961 he developed epileptic fits, and in 1963 he was readmitted because of confusion and aggressiveness. Expressive and eceptive dysphasia and apraxia were found. An E E G showed generalized abnormality, the CSF was clear and colourless with a protein content of 55 rag/100 ml. He was discharged to a nursing home, to be readmitted temporarily to the
130 mental institution in 1964 because of aggressive behaviour. Otherwise, his neurological and mental condition were the same; the CSF protein content now was 60 rag/100 ml. He died in 1964, at the age of 67, in a nursing home. Case V (111-3)
Male, born 3 December, 1900. This fisherman was seen in our department in 1951 for the first time at the age of 50, because of generalized epileptic attacks. Neurological examination gave normal results; the protein content of the CSF was 63 mg/100 ml; the EEG showed too much slow activity; air encephalography showed more widening of the left than of the right ventricle. In the following years he deteriorated mentally and in 1955 he appeared severely demented. A diagnosis of presenile dementia was made. He died at the age of 58.
DISCUSSION All but one of the 11 patients with C H had clinical manifestations of repeated cerebro-vascular accidents at intervals of days to years. In 6 the signs pointed to recurrences in the same hemisphere. Although the recurrence of stroke is certainly not exceptional, the pattern in this group of patients is most unusual. Only one case (Ili-33) did not present as CH. Instead, this patient showed progressive mental deterioration with epileptic fits and was for some time regarded as suffering from Alzheimer's disease. In this patient infarcts were only slightly haemorrhagic and did not result in secondary subarachnoid haemorrhage. Three more members died from CH, according to relatives. 111-2 in the pedigree, a man, died at the age of 67 after having been mentally disturbed for years. Ill-32 and Ili-35, both females, reportedly died from C H at the age of 43 and 45, respectively, in both cases shortly after the onset of a severe headache: In the second generation four of the 7 sibs (Nos. 1, 2, 4 and 7) stayed in a mental institution. The medical histories of Nos. 1, 2 and 4 were available. All 3 became demented in their 7th or 8th decade, and two had had a stroke at the beginning of their sixties. In generation III No. 2, who allegedly died from a C H at the age of 67, deteriorated mentally over the course of m a n y years; while No. 3 became demented in his early fifties. An inspection of the pedigree shows that the 11 clinically proven cases of C H (of w h o m 7 were pathologically examined) occur in 5 sibships over two generations. Three of these sibships are offspring of brothers, who became severely mentally defective; two of them in addition had a stroke. In two of the sibships (III-1 to 111-9 and 1II-31 to 111-42) in which 7 of the 21 sibs were proven affected, a further 3 (111-2, II1-32 and 111-35) died allegedly from a C H ; one of these (III-2) developed severe dementia, while a further Sib who died (111-3) was clinically diagnosed at that time as suffering from presenile dementia. Since the autopsy results of the case with the clinical appearance of presenile dementia (III-33), suggest that the recurrent infarcts without secondary subarachnoid haemorrhage resulted in dementia as a clinical expression of the angiopathy, it seems justified on the basis o f the foregoing and a study of the pedigree to suggest that an autosomal dominant gene with high penetranee is responsible for the angiopathy, in 7 instances the clinical expres-
131 sion of such a gene could be pathologically proven, while in others there was proof of a CH and in some further patients only the presence of dementia developing in the 6th-7th decade was certain. In view of the late onset of clinical symptoms in this disorder it is astonishing that such a high degree of penetrance (10 affected out of 21) is observed; probably because the family members are otherwise very healthy and reach an old enough age to be subject to the adverse effects of the angiopathy. Further evidence comes from the 3 proven patients in generation IV. The father of two of these patients was proven affected, the mother of one probably died from a CH. Thus we seem to have proven transmission over 3 generations. A point of interest is the occurrence in this family of migraine, from which 4 of the patients with CH suffered. Three of them had complicated migraine, in two with the neurological signs on the same side as during the CH. A daughter of III-36, two daughters of III-35 and a son of III-34 are under treatment by one of us for this condition. CT scans of two of these patients show evidence of a small infarct. One could speculate about a possible relationship between CH and migraine in this family. The macroscopic findings in the brains available after autopsy (III-7, 33, 34, 39, and two cases of generation IV) or seen during craniotomy (III-36 and 37) were those of subdural, subarachnoid, and intracerebral (cerebellar) haemorrhages, and infarcts, both recent and old. The haemorrhages and infarcts were multiple in all cases but two. Microscopically, small arteries and arterioles with hyaline thickening of the walls were found in the frontal, parietal, temporal, and occipital cortex, in the hippocampus and cerebellar cortex, as well as in the overlying arachnoid. The abnormal vessels in the arachnoid often showed marked tortuosity (Fig. 5). In the arachnoid small arteries were concerned rather than arterioles, and obliteration of their lumen by the hyalinization process seemed to have led to infarction of the underlying subcortical white matter (III-33). Both thrombosis and rupture of abnormal vessels were found. No abnormal vessels occurred in the basal ganglia or brain-stem, or in the one spinal cord that was examined (III-33). Since there was no history or evidence of long-standing severe hypertension, except possibly in one case, and no aneurysms or arterio-venous malformations were found angiographically or at autopsy, it seems plausible that the microangiopathy bore a close relationship to the CH and infarction. In 5 cases amyloid was demonstrated by Congo-red staining in the walls of the abnormal vessels (Figs. 6 and 7). The staining pattern and the green birefringence during exposure of the preparations to polarized light were compared with those of a control liver and a liver with known amyloidosis. Furthermore, electron microscopy of abnormal vessels showed fascicular, parallel, and radial formation of filaments (Figs. 8 and 9) as described for amyloid by Schlote (Schlote 1965) in congophilic angiopathy. In none of the patients investigated by us could amyloidosis be demonstrated outside the brain. Bielschowsky staining, done in patients III-33 and III-39, showed no plaques or neurofibrillary
Fig. 5. Abnormal vessels in arachnoid showing tortuosity: hyalinization of cortical arterioles.
Fig. 6. Arteriosclerosis of cortical arterioles. At the cross-section of l he left arteriole a deposit of amytoid is recognizable. Congo-red. x 150.
Fig. 7. Several cortical arterioles demonstrate hyalinization by amyloid deposit. Congo-red,
x 150.
Fig. 8. Electron microscopy of cross-section of abnormal vessel showing arrangement of amyloid filaments m different layers of the vessel wall. EM, x 4500.
134
Fig. 9. Fascicular arrangement o f amyloid filaments in vessel wall. EM, x 12,720.
tangles. In the patient of generation IV who is still alive, biopsy specimens of skin, fascia, and muscle were negative for amyloid, and there were no signs of ocular amyloidosis. We are of the opinion that this family suffers from a condition closely resembling the one described by Gudmundsson and his colleagues. In their family and the one described here, the patients suffered from repeated cerebrovascular accidents due to multiple haemorrhages and infarcts. However. the Icelandic patients, all in their twenties, were considerably younger than ours. As far as the microscopical aspects are concerned, Gudmundsson does not state the size of the abnormal arteries in 3 of his 5 autopsied cases: for the other two, mention is made o f the smaller arteries, as seen in our cases. Furthermore, m the Icelandic cases amyloidosis was sometimes present without thickening of the arterial walls. Lastly, in contrast to our cases, abnormal vessels were also found in the brain-stem. Familial occurrence of amyloid angiopathy leading to demenua and spastic paresis has been described (Worster-Drought et al. 1933, 1940, 1944: van Bogaert et al. 1940; Lfiers 1947; Corsellis and Brierley,1954). All of these cases showed plaque formation and neurofibrillary changes as well. There are indications that in the Dutch family dementia is, in addition to CH, a clinical expression of the angiopathy. Isolated cases of amyloid angiopathy, plaques, and tangles associated with CH also have been reported (Neumann 1960; Torack 1975; Jellinger 1977). In our
135 two cases investigated in this respect, plaques and neurofibrillary tangles were absent. Gudmundsson did not find plaques either. In some ways, the histopathological observations in our patients are compatible with those of congophilic angiopathy described in old age. However, the angiopathy in our cases was more extensive, and the severity was related to the localization of the haemorrhages and infarcts. Congophilic angiopathy in Alzheimer's disease (Mandybur 1975), as in old age, is accompanied by plaque formation, which was lacking in our cases. ACKNOWLEDGEMENTS
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