Hereditary cerebral haemorrhage with amyloidosis, Dutch type (HCHWA-D): clinicopathological studies.

Clinical and neuropathological findings are reported in 63 patients with hereditary cerebral haemorrhage with amyloid angiopathy. Patients had mostly recurrent strokes, and at least 80% of these were haemorrhages. Almost a third of the patients died within a year of their first and only recorded haemorrhage, half of them within two weeks. This angiopathy was restricted to the cerebral and cerebellar cortex and its covering leptomeninges. As the most important consequence, haemorrhagic infarcts and haemorrhages occurred in the subcortical white matter--that is, the region most vulnerable to impaired cortical circulation. Further development of these subcortical lesions gives rise to the fatal haemorrhages seen at necropsy. In so far as dementia occurs this is likely to result from multiple microinfarcts or haemorrhages. In most cases preamyloid lesions or diffuse plaques and early plaques were seen. No other type of plaque or neurofibrillary degeneration was found. The plaques occur in conjunction with the angiopathy, but may not occur even when the angiopathy is severe. In one patient plaques were totally absent. Angiopathy and plaques may be the result of the same mutation, the expression of which is governed by tissue factors or phenotypic differences between individual subjects.

Handedness and progressive hydrocephalus in spina bifida patients.

Hand preference and functional hand-dominance of 45 spina bifida patients (aged 13 to 25 years) were assessed by means of self-reports on an ordinal scale and a tapping task. Non-right-handedness was more frequent among patients with accompanying progressive hydrocephalus. Left-hand preference was significantly more frequent in this group than in patients without shunts. Non-right-handedness in hydrocephalic patients correlated positively with the estimated degree of pre-operative progress of the hydrocephalus. The apparent failure to establish right-handedness in these patients seemed to reflect a developmental disorder of lateralization, related to a more advanced degree of progressive hydrocephalus at an early age. It is suggested that the disorder may be attributable to dysfunction of the corpus callosum, caused by delay in the development of callosal white matter when the hydrocephalus is in a progressive state.

The smile in anencephalic infants.

During the period 1947-1959 twelve new-born mero-anencephalics were observed, who survived for more than 1 day after birth. Two even lived for 20 and 237 days, respectively. In 4 of the 12 children studied touching or slight pressure, and also faradic stimulation of various spots of the cerebro-vascular area were invariably followed by a facial expression which was very similar to smiling. Movies of it were shown to groups of impartial observers. In 78% the facial expression was judged to be a smile, a laugh or a grin. The neuroanatomical finding of a largely intact pontine tegmentum as being the most rostrally situated identifiable structure of the brainstem, has led to the hypothesis that the neural mechanisms underlying the smile are localized in the pontine tegmentum.

Expression of a normal and variant Alzheimer's beta-protein gene in amyloid of hereditary cerebral hemorrhage, Dutch type: DNA and protein diagnostic assays.

Amyloid fibrils deposited in cerebral vessel walls in Dutch patients with hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) are formed by polymerization of a 39-residue peptide similar to the beta-protein of Alzheimer's disease, Down syndrome, sporadic cerebral amyloid angiopathy and normal aging. Sequence analysis of genomic DNA in HCHWA-D patients demonstrated a point mutation, cytosine for guanine at position 1852 of the precursor beta-protein gene, which causes a single amino acid substitution (glutamine for glutamic acid) corresponding to position 22 of the amyloid protein. The normal allele was also present in these patients. To examine the expression of normal and variant beta-protein alleles in HCHWA-D we analyzed all the tryptic peptides obtained from several amyloid fractions from leptomeningeal vascular walls. Amino acid sequence of two peptides (T3a and T3b) with identical amino acid composition revealed that T3a had glutamine and T3b had glutamic acid at position 22. Thus both the normal and variant Alzheimer's beta-protein alleles are expressed in vascular amyloid in HCHWA-D and may be detected by tryptic peptide mapping. Moreover, we have developed a diagnostic assay for high risk populations and prenatal evaluation that is based on the existence of the mutation.

Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.

An amyloid protein that precipitates in the cerebral vessel walls of Dutch patients with hereditary cerebral hemorrhage with amyloidosis is similar to the amyloid protein in vessel walls and senile plaques in brains of patients with Alzheimer's disease, Down syndrome, and sporadic cerebral amyloid angiopathy. Cloning and sequencing of the two exons that encode the amyloid protein from two patients with this amyloidosis revealed a cytosine-to-guanine transversion, a mutation that caused a single amino acid substitution (glutamine instead of glutamic acid) at position 22 of the amyloid protein. The mutation may account for the deposition of this amyloid protein in the cerebral vessel walls of these patients, leading to cerebral hemorrhages and premature death.

Does the artery of Adamkiewicz exist in the albino rat?

The arterial supply of the spinal cord of the rat in the thoracolumbar region was studied in 26 Wistar albino rats. Contrary to the situation in man, and in variance with earlier reports for the rat, we did not observe a single large artery at the thoracolumbar level supplying a large part of the spinal cord. The anterior spinal artery at this level seemed to be adequately supplied by three to five principal arteries. A considerable variation in the distribution and size of these feeding arteries was observed. It is concluded that the equivalent of the artery of Adamkiewicz is not invariably present in the rat and it would appear that the vascular anatomy of the rat spinal cord is not as similar to that of man as has previously been reported.

Beta-protein deposition: a pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies.

Cerebral amyloid angiopathy (CAA) refers to a group of hereditary (hereditary cerebral hemorrhage with amyloidosis, HCHWA and sporadic (SCAA) disorders characterized by amyloid fibril deposition restricted to the leptomeningeal and cortical vasculature leading to recurrent hemorrhagic and/or ischemic accidents. On clinical and biochemical grounds, two forms of HCHWA can be distinguished. The amyloid subunit of the HCHWA of Icelandic origin is related to Cystatin C, while amyloid from patients of Dutch origin (HCHWA-D) is related to the beta-protein (or A4), the main component of vascular and plaque core amyloid in Alzheimer's disease (AD) and Down's syndrome (DS) [corrected]. SCAA is an increasingly recognized cause of stroke in normotensive individual amounting to 5-10% of all cerebrovascular accidents. We now report the isolation and partial amino acid sequence of the amyloid subunit from a case of SCAA and a new case of HCHWA-D. The recognition that a heterogeneous group of diseases are linked by similar pathological and chemical features suggests that diversity of etiological factors may promote a common pathogenetic mechanism leading to amyloid-beta (A beta) deposition, and open new ways of research in AD and CAA as they are related to dementia and stroke.

Hereditary cerebral haemorrhage caused by cortical amyloid angiopathy.

This article describes 136 patients with hereditary cerebral haemorrhages; all patients belonged to families (originally) resident in Katwijk (The Netherlands). Cases of hereditary cerebral haemorrhage have also been reported in NW-Iceland, and in the Dutch coastal village of Scheveningen. Katwijk is a Dutch fishing-village, located 20 miles north of Scheveningen. These 136 cases were encompassed in three large pedigrees, and the disorder followed an autosomal dominant mode of inheritance. No connection between the pedigrees from Iceland, Scheveningen and Katwijk has as yet been established. In our series, sclerosis with amyloid deposits could be observed in roughly a quarter of the small arteries and arterioles in the cerebral cortex and the covering arachnoid. The pathological vessels were irregularly distributed in areas and clusters, possibly leading to superficial cerebral infarcts and, secondarily, to haemorrhages. Our findings are identical with those described in patients from Scheveningen, but different from the Icelandic group. In addition to some differences in the age at onset and in the distribution of the angiopathy, it has recently been demonstrated that the amyloid in our patients is constituted by a microprotein which shows a homology to the beta-protein in Alzheimer's disease and Down's syndrome, while the amyloid in Icelandic cases is formed by an aggregation of cystatin C (gamma trace). An unexpected finding in most of our patients is the accumulation of senile plaque-like lesions in the cerebral cortex. We did not observe Alzheimer's fibrillary tangles in any of our cases.

Different processing of Alzheimer's beta-protein precursor in the vessel wall of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type.

Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is an autosomal-dominant type of amyloidosis restricted to the small vasculature of the brain and clinically characterized by recurrent strokes. Amyloid fibrils from the leptomeninges of two patients were isolated and the primary structure determined. The complete sequence of the amyloid protein shows homology to the vascular (beta-protein) and plaque amyloid (A4-protein) obtained from Alzheimer's Disease. However, it is three residues shorter (39 instead of 42) than that reported for the plaque amyloid. The difference at the carboxy terminal may reflect specific degradation that occurs in the vessel wall and not in the brain parenchyma.

The great radicular artery of Adamkiewicz in man. Demonstration of a possibility to predict its functional territory.

A women in her early sixties suffered from a malignant intramedullary astrocytoma. It had caused a nearly complete neurological deficit extending from the 12th thoracic segment downward. Since progressive tumour growth caused excruciating pain it was decided to remove the tumorous non-functional part of the spinal cord. As the great radicular artery was located in the region of the tumour it was feared that it might have to be sacrificed during surgery. In order to be informed as to its vascularization and the clinical consequence of interrupting it, an anaesthetic agent (Etomidate) was injected through this vessel. This resulted in a temporary increase in the neurological deficit by two dermatomes. Fortunately during surgery the Adamkiewicz artery was preserved. This intervention completely abolished the patient's complaints.

Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease.

Hereditary cerebral hemorrhage with amyloidosis in Dutch patients is an autosomal dominant form of vascular amyloidosis restricted to the leptomeninges and cerebral cortex. Clinically the disease is characterized by cerebral hemorrhages leading to an early death. Immunohistochemical studies of five patients revealed that the vascular amyloid deposits reacted intensely with an antiserum raised against a synthetic peptide homologous to the Alzheimer disease-related beta-protein. Silver stain-positive, "senile plaque-like" structures were also labeled by the antiserum, yet these lesions lacked the dense amyloid cores present in typical plaques of Alzheimer disease. No neurofibrillary tangles were present. Amyloid fibrils were purified from the leptomeningeal vessels of one patient who clinically had no signs of dementia. The protein had a molecular weight of approximately equal to 4000 and its partial amino acid sequence to position 21 showed homology to the beta-protein of Alzheimer disease and Down syndrome. These results suggest that hereditary cerebral hemorrhage with amyloidosis of Dutch origin is pathogenetically related to Alzheimer disease and support the concept that the initial amyloid deposition in this disorder occurs in the vessel walls before damaging the brain parenchyma. Thus, deposition of beta-protein in brain tissue seems to be related to a spectrum of diseases involving vascular syndromes, progressive dementia, or both.

The localization of protruded lumbar discs in advancing age.

The Leiden case material of 6,565 protruded/herniated discs is analyzed with regard to age and localization. It appears that a positive correlation exists between these two parameters: in advancing age the protruded disc shows an apparent shift in localization to higher lumbar levels, the incidence of its localization at the L5-S1 level decreasing markedly at the same time.

The carpal tunnel syndrome. The role of a persistent median artery.

After the first description by Paget (1854) and later on by Mohr (1890) and Schultze (1892), more than 100 years have passed by before it was generally recognized that compression of the median nerve in the carpal tunnel could be related to the majority of cases with nocturnal acroparaesthesiae in the hand and fingers. A short survey is given on 914 surgically treated patients (1117 operations). In one of them a bilateral carpal tunnel syndrome is related to a large persistent median artery. Although persistent median arteries have a low incidence (2.2-4.4%), this anomaly is rarely the cause of a carpal tunnel syndrome. In our case material this amounts to 1.1% of our patients and to 1.8% of all operations. In order to avert unexpected findings at surgery, it is suggested that patients should be asked whether their complaints have a pulsating character.

The future role of neurosurgery in medicine.

Illustrated by several examples from the past it is demonstrated how difficult it is to predict future developments in neurosurgery. Several determinants can be recognized as exerting a positive or a negative influence in this respect. Careful observation of unexpected events and consequent consideration in combination with a spiritual independency, are aspects which will contribute in a positive way. The reverse will unavoidably lead to abolition of new ideas and concepts. Authority in a personal as well as in an impersonal way, may act as a negative determinant. This aspect is illustrated by some examples regarding the phenomenon of the "medical mandarin" as a personal authority, and the irrational adherence to paradigms as an impersonal one. Based upon recent experiments new ways for neurosurgical activities are indicated, concerning 1st transplantation of fetal central nervous tissue and of adrenal medullary tissue, and 2nd deep long-term stimulation of the beta endorphin-serotonin system for the control of chronic pain.