Subacute sclerosing panencephalitis (SSPE), a disease related to measles (rubeola) infection, was... more Subacute sclerosing panencephalitis (SSPE), a disease related to measles (rubeola) infection, was more common in Arabs and Sephardi Jews than in Ashkenazi Jews in Israel. There were no familial aggregates and it is unlikely that genetic differences account for this selectivity. Among several non-genetic factors which might explain the selectivity, family size emerged as a possible risk factor. Family size has not previously been suspected as influencing the risk of SSPE. Preponderance of SSPE in rural areas and among the poor would also be compatible with this idea as family size tends to be larger in rural and lower socioeconomic groups. In large families, there may be a greater change that older siblings will transmit measles to very young siblings. In small families, measles may be acquired from peers at about school age when risk of SSPE may be lower.
The relative frequency of aseptic meningoencephalitis (AME) was compared in populations of divers... more The relative frequency of aseptic meningoencephalitis (AME) was compared in populations of diverse origin, A countrywide search of Israel during 1969-1970 disclosed 1350 cases who fit strict diagnostic criteria. The average annual incidence was 21.6 per 100000 population. The total incidence was similar in Afro-Asian, Euro-American and Israeli Jewish groups but among Israeli Arabs, the incidence was apparently lower. Age-specific incidence showed a peak in infants under one year of age among Arabs and Afro-Asian Jews whereas Euro-Americans and Israeli Jews had a peak incidence at 5-9 years. Larger family size among Arabs and Afro-Asian Jews might account for the higher incidence in infants. Age-specific incidence may be a better index than total incidence of important differences in AME among various ethnic groups.
Cerebral amyloid angiopathy is characterized by deposition of amyloid in the walls of leptomening... more Cerebral amyloid angiopathy is characterized by deposition of amyloid in the walls of leptomeninged and cerebral blood vessels. Its most common form, sporadic CAA that results from deposition of beta-amyloid peptide, which is the subject of this short review, is present in virtually all cases of Alzheimer disease and is also common among non-demented subjects where its prevalence increases with age. Stroke due to massive cerebral lobar hemorrhage is the main clinical presentation of CAA, but transient neurologic symptoms due to microhemorrhages may also occur. CAA is also a risk factor for cerebral infarction and there is increasing evidence that CAA contributes to cognitive impairment in the elderly, usually in association with white matter abnormalities on imaging. Although the definitive diagnosis of CAA is neuropathologic, reliable diagnosis can be reached clinically, based on the occurrence of strictly lobar hemorrhages, particularly in the cortico-subcortical area when using g...
Early infantile Krabbe disease is relatively frequent in the Muslim-Arab population in Israel. It... more Early infantile Krabbe disease is relatively frequent in the Muslim-Arab population in Israel. It can be easily diagnosed when it presents with the classic clinical picture characterized by central nervous system manifestations of spasticity, irritability, motor regression and seizures associated with a positive family history. We studied eight children diagnosed with Krabbe disease. In two of these children (25%), peripheral neuropathy was the single initial symptom and the only neurologic finding noted for a period of months. In these patients, diagnosis of Krabbe's disease was delayed and established only 9-11 months after the initial symptoms. In two other children with "classical picture" Krabbe disease, areflexia was noted on admission. The occurrence of peripheral neuropathy as an initial symptom in early infantile Krabbe disease may be underestimated. Krabbe disease should be considered in the differential diagnosis of early infantile peripheral neuropathy. Ear...
Morphine was injected into a catheter implanted chronically into the intrathecal space of rats. T... more Morphine was injected into a catheter implanted chronically into the intrathecal space of rats. Three to eight minutes after drug administration, 80% of the rats developed arrhythmic stimulus-sensitive jerks that lasted up to 1 hr. The morphine-induced myoclonic activity was markedly reduced by naloxone. Methadone, pethidine, and etorphine failed to produce the syndrome. In spinally transected rats, morphine injected below the level of transection did not produce the syndrome. No significant changes in PaCO2 and PaO2 were produced by morphine before and throughout the period of myoclonic activity. Neither did induced hypoxia augment the effect of morphine. However, irreversible hypoxic-ischemic cell changes were noticed in some brain regions. The phenomenon described here resembles the human syndrome of action myoclonus and may serve as an animal model for studying the mechanism of that neurological disorder.
Molecular and chemical neuropathology / sponsored by the International Society for Neurochemistry and the World Federation of Neurology and research groups on neurochemistry and cerebrospinal fluid, 1991
The number and functional reactivity of peritoneal mast cells (MCs) were evaluated in rats with e... more The number and functional reactivity of peritoneal mast cells (MCs) were evaluated in rats with experimental allergic encephalomyelitis (EAE). Cells were counted following staining with toluidine blue and activation was measured by B-hexosaminidase (B-hex) release. The number of detectable MCs and their capacity to release B-hex decreased significantly by 40 and 65%, respectively, as compared with normal controls just prior to the onset of clinical signs. These values returned to normal on clinical recovery. Preliminary data on MC counts performed on histological sections of rat brains with EAE suggested a similar pattern of response, i.e., an early decrease prior to disease onset with subsequent normalization on recovery. In an attempt to modify the course of EAE, rats were treated with the MC stabilizing agent nedocromil or with the MC activating agent, compound 48/80. Nedocromil induced a slight delay in the onset of EAE, but only when administered at the time of EAE induction. C...
Although arachnoid granulations (AGs) were already described by Antonio Pacchioni more than 300 y... more Although arachnoid granulations (AGs) were already described by Antonio Pacchioni more than 300 years ago, two issues draw particular attention: first, the radiological features and differential diagnosis of the so-called giant AGs (GAGs) and second, their possible association with various disease processes. In order to evaluate the frequency, size and normal distribution of GAGs, an anatomical study of the dural sinuses was carried out. It involved all the autopsies performed during the period August 2002-February 2005 and included 651 cases: 306 females and 345 males, aged 13-99 years (mean 69 years). Grossly visible GAGs were identified in 24 cases: 7 females and 17 males, aged 45-92 years (mean 69 years). This is the largest population-based anatomical study on GAGs. It shows that GAGs, in general a rare finding (3.68%), are rather common in the adult population, especially in the elderly (aged >65 years) and that they can reach remarkable size (up to 2.5 cm and more in diameter). Giant AGs should be considered in the radiological differential diagnosis of intradural lesions, particularly those occurring in the transverse sinus of the elderly.
We report a patient who was referred to our department because of generalized status epilepticus.... more We report a patient who was referred to our department because of generalized status epilepticus. His condition deteriorated rapidly and he died 1 month after admission. Autopsy confirmed the clinical diagnosis of Creutzfeldt-Jakob disease (CJD). CJD should be added to the list of rare but possible causes of generalized status epilepticus.
We report a new neurocutaneous syndrome of apparent autosomal recessive inheritance consisting of... more We report a new neurocutaneous syndrome of apparent autosomal recessive inheritance consisting of early-childhood-onset palmoplantar keratoderma followed in adulthood by progressive tetrapyramidal syndrome and cognitive impairment. Of the four affected siblings, two were available for evaluation. Investigation disclosed cerebral white-matter involvement on MRI and arylsulfatase A pseudodeficiency carrier state, which was also identified in clinically unaffected family members. Since skin biopsies showed dermal connective tissue abnormalities, we studied collagens I, III, and VI biosynthesis. Northern blotting of RNA extracted from cultured skin fibroblasts revealed an increased steady-state messenger RNA (mRNA) level of alpha 1(VI) collagen, whereas no differences were detected for pro alpha 1(I), pro alpha 1(III), and tropoelastin mRNAs. The skin content of collagen and total protein was higher in the patients than in controls. We suggest that an extracellular matrix abnormality may be involved in the pathogenesis of this disorder.
Dementia with ubiquitinated neuronal inclusions has been described only with frontotemporal demen... more Dementia with ubiquitinated neuronal inclusions has been described only with frontotemporal dementia (FTD). The authors report a patient with progressive FTD accompanied by prominent impairments in visuospatial cognitive functions. Pathology was characterized by ubiquitin-positive intranuclear and cytoplasmic neuronal inclusions. Cortical pathology was widespread and posteriorly accentuated but spared the hippocampal dentate gyrus.
Inefficient vascular supply and the resultant reduction in tissue oxygen tension often lead to ne... more Inefficient vascular supply and the resultant reduction in tissue oxygen tension often lead to neovascularization in order to satisfy the needs of the tissue. Examples include the compensatory development of collateral blood vessels in ischaemic tissues that are otherwise quiescent for angiogenesis and angiogenesis associated with the healing of hypoxic wounds. But the presumptive hypoxia-induced angiogenic factors that mediate this feedback response have not been identified. Here we show that vascular endothelial growth factor (VEGF; also known as vascular permeability factor) probably functions as a hypoxia-inducible angiogenic factor. VEGF messenger RNA levels are dramatically increased within a few hours of exposing different cell cultures to hypoxia and return to background when normal oxygen supply is resumed. In situ analysis of tumour specimens undergoing neovascularization show that the production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions) and the clustering of capillaries alongside VEGF-producing cells.
A new method that can dramatically improve the sensitivity and especially the specificity of skin... more A new method that can dramatically improve the sensitivity and especially the specificity of skin naevi screening for melanoma by physicians is introduced. The method is based on measuring the similarity to previously classified naevi images. As more naevi are being classified, the power of the method is enhanced. Thus physicians can benefit from experience accumulated by others and the screening can be performed effectively by physicians with less experience.
We have compared the clinical signs, brain pathology and visually evoked responses (VEP) of guine... more We have compared the clinical signs, brain pathology and visually evoked responses (VEP) of guinea pigs with experimental allergic encephalomyelitis (EAE). Animals immunized with myelin basic protein had a milder disease, both from the clinical and histological points of views, compared to those immunized with crude white matter extract. However, VEP findings were quite similar in both groups. The VEP of the majority of animals from both groups showed changes before or at the same time that neurological signs appeared. Electrophysiological responses were usually characterized by abnormal wave shapes and prolonged latencies. Recovery of the VEP usually preceded the recovery from clinical signs. In contrast, the severity and incidence of brain tissue pathology was not correlated to either clinical signs or VEP changes. Possible explanations of the electrophysiological, clinical and histopathological changes and their time-course are discussed.
Mast cells (MC) have been implicated in the pathogenesis of experimental allergic encephalomyelit... more Mast cells (MC) have been implicated in the pathogenesis of experimental allergic encephalomyelitis (EAE). In order to further evaluate their role, several morphological and functional studies were performed. Semiquantitative counts of histological sections showed a significant reduction in MC numbers in EAE brains. In addition, a higher proportion of EAE MC (about 50-70%) appeared degranulated compared with about 20% degranulation in controls. Central nervous system (CNS) MC exhibited staining properties of connective tissue MC and about 98% of them, both in diseased and control rats, were located in the thalamus. They were not present in the spinal cord and did not relate to EAE lesions. In vitro incubation of peritoneal MC (of connective tissue phenotype) with either MBP, or with neuropeptides such as substance P or bradykinin resulted in release of beta-hexosaminidase and histamine. The latter responses were similar in both EAE and control rats. It is suggested that the decrease in number and in granular content of CNS MC in EAE may reflect prior in vivo activation. The fact that MC were activated by MBP and by neuropeptides in vitro suggests a possible mechanism of MC activation in EAE.
The combination of progressive dystonia and optic atrophy is extremely rare and its morphological... more The combination of progressive dystonia and optic atrophy is extremely rare and its morphological, metabolic and genetic basis is unknown. In a family of 9 children (8 males) born to consanguineous Israeli-Jewish-Iraqi parents, we identified four brothers who developed the syndrome at the end of the first decade. Patients had hemi or bilateral dystonia associated with striatal, mainly putaminal, atrophy on CT and MRI, various degrees of optic atrophy, minimal corticospinal tract involvement, normal intelligence and no peripheral nervous system or systemic abnormalities. No causative metabolic defect was identified. None of the several known mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy (LHON) or with LHON with dystonia were detected. Likewise, linkage to the idiopathic torsion dystonia region on chromosome 9q34 was excluded. It is suggested that this in our patients might be due to a yet unidentified genomic, autosomal recessive mutation.
Subacute sclerosing panencephalitis (SSPE), a disease related to measles (rubeola) infection, was... more Subacute sclerosing panencephalitis (SSPE), a disease related to measles (rubeola) infection, was more common in Arabs and Sephardi Jews than in Ashkenazi Jews in Israel. There were no familial aggregates and it is unlikely that genetic differences account for this selectivity. Among several non-genetic factors which might explain the selectivity, family size emerged as a possible risk factor. Family size has not previously been suspected as influencing the risk of SSPE. Preponderance of SSPE in rural areas and among the poor would also be compatible with this idea as family size tends to be larger in rural and lower socioeconomic groups. In large families, there may be a greater change that older siblings will transmit measles to very young siblings. In small families, measles may be acquired from peers at about school age when risk of SSPE may be lower.
The relative frequency of aseptic meningoencephalitis (AME) was compared in populations of divers... more The relative frequency of aseptic meningoencephalitis (AME) was compared in populations of diverse origin, A countrywide search of Israel during 1969-1970 disclosed 1350 cases who fit strict diagnostic criteria. The average annual incidence was 21.6 per 100000 population. The total incidence was similar in Afro-Asian, Euro-American and Israeli Jewish groups but among Israeli Arabs, the incidence was apparently lower. Age-specific incidence showed a peak in infants under one year of age among Arabs and Afro-Asian Jews whereas Euro-Americans and Israeli Jews had a peak incidence at 5-9 years. Larger family size among Arabs and Afro-Asian Jews might account for the higher incidence in infants. Age-specific incidence may be a better index than total incidence of important differences in AME among various ethnic groups.
Cerebral amyloid angiopathy is characterized by deposition of amyloid in the walls of leptomening... more Cerebral amyloid angiopathy is characterized by deposition of amyloid in the walls of leptomeninged and cerebral blood vessels. Its most common form, sporadic CAA that results from deposition of beta-amyloid peptide, which is the subject of this short review, is present in virtually all cases of Alzheimer disease and is also common among non-demented subjects where its prevalence increases with age. Stroke due to massive cerebral lobar hemorrhage is the main clinical presentation of CAA, but transient neurologic symptoms due to microhemorrhages may also occur. CAA is also a risk factor for cerebral infarction and there is increasing evidence that CAA contributes to cognitive impairment in the elderly, usually in association with white matter abnormalities on imaging. Although the definitive diagnosis of CAA is neuropathologic, reliable diagnosis can be reached clinically, based on the occurrence of strictly lobar hemorrhages, particularly in the cortico-subcortical area when using g...
Early infantile Krabbe disease is relatively frequent in the Muslim-Arab population in Israel. It... more Early infantile Krabbe disease is relatively frequent in the Muslim-Arab population in Israel. It can be easily diagnosed when it presents with the classic clinical picture characterized by central nervous system manifestations of spasticity, irritability, motor regression and seizures associated with a positive family history. We studied eight children diagnosed with Krabbe disease. In two of these children (25%), peripheral neuropathy was the single initial symptom and the only neurologic finding noted for a period of months. In these patients, diagnosis of Krabbe's disease was delayed and established only 9-11 months after the initial symptoms. In two other children with "classical picture" Krabbe disease, areflexia was noted on admission. The occurrence of peripheral neuropathy as an initial symptom in early infantile Krabbe disease may be underestimated. Krabbe disease should be considered in the differential diagnosis of early infantile peripheral neuropathy. Ear...
Morphine was injected into a catheter implanted chronically into the intrathecal space of rats. T... more Morphine was injected into a catheter implanted chronically into the intrathecal space of rats. Three to eight minutes after drug administration, 80% of the rats developed arrhythmic stimulus-sensitive jerks that lasted up to 1 hr. The morphine-induced myoclonic activity was markedly reduced by naloxone. Methadone, pethidine, and etorphine failed to produce the syndrome. In spinally transected rats, morphine injected below the level of transection did not produce the syndrome. No significant changes in PaCO2 and PaO2 were produced by morphine before and throughout the period of myoclonic activity. Neither did induced hypoxia augment the effect of morphine. However, irreversible hypoxic-ischemic cell changes were noticed in some brain regions. The phenomenon described here resembles the human syndrome of action myoclonus and may serve as an animal model for studying the mechanism of that neurological disorder.
Molecular and chemical neuropathology / sponsored by the International Society for Neurochemistry and the World Federation of Neurology and research groups on neurochemistry and cerebrospinal fluid, 1991
The number and functional reactivity of peritoneal mast cells (MCs) were evaluated in rats with e... more The number and functional reactivity of peritoneal mast cells (MCs) were evaluated in rats with experimental allergic encephalomyelitis (EAE). Cells were counted following staining with toluidine blue and activation was measured by B-hexosaminidase (B-hex) release. The number of detectable MCs and their capacity to release B-hex decreased significantly by 40 and 65%, respectively, as compared with normal controls just prior to the onset of clinical signs. These values returned to normal on clinical recovery. Preliminary data on MC counts performed on histological sections of rat brains with EAE suggested a similar pattern of response, i.e., an early decrease prior to disease onset with subsequent normalization on recovery. In an attempt to modify the course of EAE, rats were treated with the MC stabilizing agent nedocromil or with the MC activating agent, compound 48/80. Nedocromil induced a slight delay in the onset of EAE, but only when administered at the time of EAE induction. C...
Although arachnoid granulations (AGs) were already described by Antonio Pacchioni more than 300 y... more Although arachnoid granulations (AGs) were already described by Antonio Pacchioni more than 300 years ago, two issues draw particular attention: first, the radiological features and differential diagnosis of the so-called giant AGs (GAGs) and second, their possible association with various disease processes. In order to evaluate the frequency, size and normal distribution of GAGs, an anatomical study of the dural sinuses was carried out. It involved all the autopsies performed during the period August 2002-February 2005 and included 651 cases: 306 females and 345 males, aged 13-99 years (mean 69 years). Grossly visible GAGs were identified in 24 cases: 7 females and 17 males, aged 45-92 years (mean 69 years). This is the largest population-based anatomical study on GAGs. It shows that GAGs, in general a rare finding (3.68%), are rather common in the adult population, especially in the elderly (aged >65 years) and that they can reach remarkable size (up to 2.5 cm and more in diameter). Giant AGs should be considered in the radiological differential diagnosis of intradural lesions, particularly those occurring in the transverse sinus of the elderly.
We report a patient who was referred to our department because of generalized status epilepticus.... more We report a patient who was referred to our department because of generalized status epilepticus. His condition deteriorated rapidly and he died 1 month after admission. Autopsy confirmed the clinical diagnosis of Creutzfeldt-Jakob disease (CJD). CJD should be added to the list of rare but possible causes of generalized status epilepticus.
We report a new neurocutaneous syndrome of apparent autosomal recessive inheritance consisting of... more We report a new neurocutaneous syndrome of apparent autosomal recessive inheritance consisting of early-childhood-onset palmoplantar keratoderma followed in adulthood by progressive tetrapyramidal syndrome and cognitive impairment. Of the four affected siblings, two were available for evaluation. Investigation disclosed cerebral white-matter involvement on MRI and arylsulfatase A pseudodeficiency carrier state, which was also identified in clinically unaffected family members. Since skin biopsies showed dermal connective tissue abnormalities, we studied collagens I, III, and VI biosynthesis. Northern blotting of RNA extracted from cultured skin fibroblasts revealed an increased steady-state messenger RNA (mRNA) level of alpha 1(VI) collagen, whereas no differences were detected for pro alpha 1(I), pro alpha 1(III), and tropoelastin mRNAs. The skin content of collagen and total protein was higher in the patients than in controls. We suggest that an extracellular matrix abnormality may be involved in the pathogenesis of this disorder.
Dementia with ubiquitinated neuronal inclusions has been described only with frontotemporal demen... more Dementia with ubiquitinated neuronal inclusions has been described only with frontotemporal dementia (FTD). The authors report a patient with progressive FTD accompanied by prominent impairments in visuospatial cognitive functions. Pathology was characterized by ubiquitin-positive intranuclear and cytoplasmic neuronal inclusions. Cortical pathology was widespread and posteriorly accentuated but spared the hippocampal dentate gyrus.
Inefficient vascular supply and the resultant reduction in tissue oxygen tension often lead to ne... more Inefficient vascular supply and the resultant reduction in tissue oxygen tension often lead to neovascularization in order to satisfy the needs of the tissue. Examples include the compensatory development of collateral blood vessels in ischaemic tissues that are otherwise quiescent for angiogenesis and angiogenesis associated with the healing of hypoxic wounds. But the presumptive hypoxia-induced angiogenic factors that mediate this feedback response have not been identified. Here we show that vascular endothelial growth factor (VEGF; also known as vascular permeability factor) probably functions as a hypoxia-inducible angiogenic factor. VEGF messenger RNA levels are dramatically increased within a few hours of exposing different cell cultures to hypoxia and return to background when normal oxygen supply is resumed. In situ analysis of tumour specimens undergoing neovascularization show that the production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions) and the clustering of capillaries alongside VEGF-producing cells.
A new method that can dramatically improve the sensitivity and especially the specificity of skin... more A new method that can dramatically improve the sensitivity and especially the specificity of skin naevi screening for melanoma by physicians is introduced. The method is based on measuring the similarity to previously classified naevi images. As more naevi are being classified, the power of the method is enhanced. Thus physicians can benefit from experience accumulated by others and the screening can be performed effectively by physicians with less experience.
We have compared the clinical signs, brain pathology and visually evoked responses (VEP) of guine... more We have compared the clinical signs, brain pathology and visually evoked responses (VEP) of guinea pigs with experimental allergic encephalomyelitis (EAE). Animals immunized with myelin basic protein had a milder disease, both from the clinical and histological points of views, compared to those immunized with crude white matter extract. However, VEP findings were quite similar in both groups. The VEP of the majority of animals from both groups showed changes before or at the same time that neurological signs appeared. Electrophysiological responses were usually characterized by abnormal wave shapes and prolonged latencies. Recovery of the VEP usually preceded the recovery from clinical signs. In contrast, the severity and incidence of brain tissue pathology was not correlated to either clinical signs or VEP changes. Possible explanations of the electrophysiological, clinical and histopathological changes and their time-course are discussed.
Mast cells (MC) have been implicated in the pathogenesis of experimental allergic encephalomyelit... more Mast cells (MC) have been implicated in the pathogenesis of experimental allergic encephalomyelitis (EAE). In order to further evaluate their role, several morphological and functional studies were performed. Semiquantitative counts of histological sections showed a significant reduction in MC numbers in EAE brains. In addition, a higher proportion of EAE MC (about 50-70%) appeared degranulated compared with about 20% degranulation in controls. Central nervous system (CNS) MC exhibited staining properties of connective tissue MC and about 98% of them, both in diseased and control rats, were located in the thalamus. They were not present in the spinal cord and did not relate to EAE lesions. In vitro incubation of peritoneal MC (of connective tissue phenotype) with either MBP, or with neuropeptides such as substance P or bradykinin resulted in release of beta-hexosaminidase and histamine. The latter responses were similar in both EAE and control rats. It is suggested that the decrease in number and in granular content of CNS MC in EAE may reflect prior in vivo activation. The fact that MC were activated by MBP and by neuropeptides in vitro suggests a possible mechanism of MC activation in EAE.
The combination of progressive dystonia and optic atrophy is extremely rare and its morphological... more The combination of progressive dystonia and optic atrophy is extremely rare and its morphological, metabolic and genetic basis is unknown. In a family of 9 children (8 males) born to consanguineous Israeli-Jewish-Iraqi parents, we identified four brothers who developed the syndrome at the end of the first decade. Patients had hemi or bilateral dystonia associated with striatal, mainly putaminal, atrophy on CT and MRI, various degrees of optic atrophy, minimal corticospinal tract involvement, normal intelligence and no peripheral nervous system or systemic abnormalities. No causative metabolic defect was identified. None of the several known mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy (LHON) or with LHON with dystonia were detected. Likewise, linkage to the idiopathic torsion dystonia region on chromosome 9q34 was excluded. It is suggested that this in our patients might be due to a yet unidentified genomic, autosomal recessive mutation.
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Papers by Dov Soffer