35
Volume 68 September1975
561
Section of Pathology President J W Stewart MB Meeting 11 February 1975
The Pathology of Neurological Deficit Etiology of Mental Retardation Professor J P M Tizard (John Radcliffe Hospital, Oxford) pointed out the size of the problem, e.g. 6 million mental defectives in the USA, and stressed the multiplicity of factors often involved. Low intelligence could be considered 'physiological' (i.e. analogous with low height), or 'pathological', but in practice it might be impossible to make a hard and fast distinction between the two. In order to illustrate this thesis he recounted a detailed case history. A child born at 36 weeks, with low genetic endowment, developed hypoglycemia. At 3 months he developed infantile spasms. At 2 years an elevated level of blood lead and of antibodies to cytomegalovirus were reported. At 4 years of age the child's mental age was 18 months. Professor Tizard then admitted this case to be of his own invention, but felt that it gave a graphic illustration of the complexity of the situations commonly presenting.
Locomotor Disorders in Childhood Professor A E Claireaux (Hospital for Sick Children, Great Ormond Street, London WCI) described three CNS conditions affecting the newborn: kernicterus, subependymal intraventricular hemorrhage, and a group who had fits and clonic spasms and died of cystic encephalomalacia. He then surveyed the complex field of muscle disorders and their investigation. Under denervation atrophy he included acute anterior poliomyelitis, acute polyneuritis and Werdnig-Hoffmann disease. From the large number of genetically determined myopathies he made special mention of the pseudohypertrophic (Duchenne) type as a 'possibly neural' lesion, and of Pompe's disease (glycogen storage). He illustrated the fine structural abnormalities which
are likely to be of importance in future classification of the myopathies, especially changes in mitochondria.
The Leukodystrophies Dr Magda Erdohazi (Hospital for Sick Children, Great Ormond Street, London WCJ) defined leukodystrophy as an inherited progressive degeneration of cerebral white matter and, following Blackwood (1957), classified cases on a histochemical basis into three main groups: sudanophilic; PAS-positive nonmetachromatic (globoid cell type of Krabbe); and metachromatic (disorder of sulphatide). The basis of the latter two conditions has now been established as lysosomal enzyme deficiency. Most cases are inherited as autosomal recessives. Metachromatic leukodystrophy (sulphatide lipidosis) is due to deficiency in the enzyme aryl sulphatase A. Sulphatide material accumulates in myelin sheaths, Schwann cells, nerve cells and visceral organs. No sudanophilic material is found. In globoid cell leukodystrophy - a disease mainly of young infants - the conspicuous microscopical feature is the presence of large 'globoid' cells filled with material staining strongly with periodic acid-Schiff. The enzyme deficiency, that of galactocerebroside ,B galactoside, has recently been discovered. The presumed macrophage origin of the globoid cells is supported by electron microscopical studies which have shown pseudopodia and no glial fibres. In sudanophilic leukodystrophy bright staining sudanophilic material accumulates in the demyelinated areas. It is likely that diverse pathological processes can produce this picture. One type of inherited sudanophilic (Pelizaeus-Merzbacher) leukodystrophy is characterized by the relative preservation of perivascular myelin. An
562 Proc. roy. Soc. Med. Volume 68 September 1975
36
association of adrenocortical atrophy with Biochemistry of Mental Retardation sudanophilic leukodystrophy has recently been Dr J Stern (Queen Mary's Hospital for Children, recognized. The patients (all boys to date) may Carshalton, Surrey) discussed some biochemical present with symptoms of adrenal or of neuro- aspects of the pathogenesis of the mental defect logical deficit; it has been suggested that an error often found in patients with inborn errors of of membrane sterol metabolism may be respon- amino acid metabolism. sible for both lesions. Dr Erdohazi then illustrated two rare condi- Phenylketonuria: There was good evidence that in tions linked to the leukodystrophies and associated phenylketonuria a number of metabolic processes with megalencephaly: (1) Alexander's disease, were adversely affected, but the precise pathocharacterized by a dense glial network in the genic mechanism was unknown. It was unlikely white matter with large numbers of degenerate that an identical process operated in all patients astrocytes and Rosenthal fibres. (2) Canavan's or even in the same patient at all stages of developdisease (spongiform leukodystrophy), in which ment. The variability of the pathogenetic process a loose spongy network replaced the white matter. in maternal phenylketonuria was clearly seen in The problem of pathogenesis was still un- eight microcephalic mentally retarded children resolved. One possibility is that a metabolic born to a phenylketonuric woman. In classical disorder causes progressive glial and Schwann phenylketonuria the brain was most severely cell insufficiency, resulting both in the breakdown affected during the critical period of rapid growth of myelin and in the formation of structurally and differentiation extending into the second year of life, while in maternal phenylketonuria the abnormal myelin. early stages of the development of the brain and REFERENCE other organs were at risk. Blackwood W (1957) In: Cerebral Lipidoses. Ed. J N Cumings. Blackwell, Oxford; p 1
Histidinwemia: An inborn error, as indeed almost any metabolic disorder, was liable to increase the vulnerability of those affected to neuropsychiatric disorders. Thus two out of three histidinemics Effects of Viruses and seen at Queen Mary's Hospital for Children, Viral Vaccines on the CNS Dr A D Dayan ( Wellcome Research Laboratories, although not mentally retarded, had neurological Beckenham, Kent) discussed the effects of viruses and psychiatric handicaps. At present, a case for and viral vaccines on the central nervous system. dietary treatment of histidinaemia had not been First he described the histological features established. Extrapolation from phenylketonuria typifying an acute viral infection and the patterns to histidinemia was unwarranted. In particular, of neurological deficiency which might follow untreated histidinwmics diagnosed by infant both from the direct damage to nervous tissues mass screening were doing at least as well as and from secondary effects. He illustrated hypo- early treated classical phenylketonurics, and plasia of the cerebellum in piglets resulting from there was so far no evidence that the vulnerability maternal virus infection as an example of per- of histidinEemics would be materially reduced by a sistent sequelze of a short-lived disease. Viruses diet low in histidine, particularly as at least some might have selective effects upon certain types of retarded histidinemics had evidence of antenatal cells, e.g. ependyma, with aqueductal stenosis as a brain lesions. long-term result. Secondary effects resulting from the swelling associated with inflammation could Nonketotic hyperglycinamia: The striking feature include herniation of the brain, as in herpes of the history of three sisters with nonketotic simplex affecting the temporal lobes. In subacute hyperglycinemia who had reached adulthood sclerosing panencephalitis viruses produce a was that although they were mentally retarded chronic infection despite dramatic immune they had not shown any signs of deterioration responses, and in some conditions immune since infancy. A fourth patient with this disorder complexes might well be more dangerous than had died at 72 after a fulminating illness characthe virus itself. In temperate infections the failure terized by extreme hypotonia. Glycine is an of cell-mediated immunity was coming to be inhibitor of neuronal transmission at the postrecognized as important. In cases of treated synaptic level. In mammals the blood-brain leukemia and organ transplants viral infection barrier effectively excluded glycine from the might be opportunistic, because of the impaired nervous system, but this was apparently not the case in the newborn. Small elevations of the immune responses. Acute perivenous demyelination was a very blood glycine level could therefore be neurotoxic rare complication of infection by certain viruses, in the newborn, but comparatively harmless in the older child. which seemed to be due to an allergic reaction.
Volume 68 September1975
561
Section of Pathology President J W Stewart MB Meeting 11 February 1975
The Pathology of Neurological Deficit Etiology of Mental Retardation Professor J P M Tizard (John Radcliffe Hospital, Oxford) pointed out the size of the problem, e.g. 6 million mental defectives in the USA, and stressed the multiplicity of factors often involved. Low intelligence could be considered 'physiological' (i.e. analogous with low height), or 'pathological', but in practice it might be impossible to make a hard and fast distinction between the two. In order to illustrate this thesis he recounted a detailed case history. A child born at 36 weeks, with low genetic endowment, developed hypoglycemia. At 3 months he developed infantile spasms. At 2 years an elevated level of blood lead and of antibodies to cytomegalovirus were reported. At 4 years of age the child's mental age was 18 months. Professor Tizard then admitted this case to be of his own invention, but felt that it gave a graphic illustration of the complexity of the situations commonly presenting.
Locomotor Disorders in Childhood Professor A E Claireaux (Hospital for Sick Children, Great Ormond Street, London WCI) described three CNS conditions affecting the newborn: kernicterus, subependymal intraventricular hemorrhage, and a group who had fits and clonic spasms and died of cystic encephalomalacia. He then surveyed the complex field of muscle disorders and their investigation. Under denervation atrophy he included acute anterior poliomyelitis, acute polyneuritis and Werdnig-Hoffmann disease. From the large number of genetically determined myopathies he made special mention of the pseudohypertrophic (Duchenne) type as a 'possibly neural' lesion, and of Pompe's disease (glycogen storage). He illustrated the fine structural abnormalities which
are likely to be of importance in future classification of the myopathies, especially changes in mitochondria.
The Leukodystrophies Dr Magda Erdohazi (Hospital for Sick Children, Great Ormond Street, London WCJ) defined leukodystrophy as an inherited progressive degeneration of cerebral white matter and, following Blackwood (1957), classified cases on a histochemical basis into three main groups: sudanophilic; PAS-positive nonmetachromatic (globoid cell type of Krabbe); and metachromatic (disorder of sulphatide). The basis of the latter two conditions has now been established as lysosomal enzyme deficiency. Most cases are inherited as autosomal recessives. Metachromatic leukodystrophy (sulphatide lipidosis) is due to deficiency in the enzyme aryl sulphatase A. Sulphatide material accumulates in myelin sheaths, Schwann cells, nerve cells and visceral organs. No sudanophilic material is found. In globoid cell leukodystrophy - a disease mainly of young infants - the conspicuous microscopical feature is the presence of large 'globoid' cells filled with material staining strongly with periodic acid-Schiff. The enzyme deficiency, that of galactocerebroside ,B galactoside, has recently been discovered. The presumed macrophage origin of the globoid cells is supported by electron microscopical studies which have shown pseudopodia and no glial fibres. In sudanophilic leukodystrophy bright staining sudanophilic material accumulates in the demyelinated areas. It is likely that diverse pathological processes can produce this picture. One type of inherited sudanophilic (Pelizaeus-Merzbacher) leukodystrophy is characterized by the relative preservation of perivascular myelin. An
562 Proc. roy. Soc. Med. Volume 68 September 1975
36
association of adrenocortical atrophy with Biochemistry of Mental Retardation sudanophilic leukodystrophy has recently been Dr J Stern (Queen Mary's Hospital for Children, recognized. The patients (all boys to date) may Carshalton, Surrey) discussed some biochemical present with symptoms of adrenal or of neuro- aspects of the pathogenesis of the mental defect logical deficit; it has been suggested that an error often found in patients with inborn errors of of membrane sterol metabolism may be respon- amino acid metabolism. sible for both lesions. Dr Erdohazi then illustrated two rare condi- Phenylketonuria: There was good evidence that in tions linked to the leukodystrophies and associated phenylketonuria a number of metabolic processes with megalencephaly: (1) Alexander's disease, were adversely affected, but the precise pathocharacterized by a dense glial network in the genic mechanism was unknown. It was unlikely white matter with large numbers of degenerate that an identical process operated in all patients astrocytes and Rosenthal fibres. (2) Canavan's or even in the same patient at all stages of developdisease (spongiform leukodystrophy), in which ment. The variability of the pathogenetic process a loose spongy network replaced the white matter. in maternal phenylketonuria was clearly seen in The problem of pathogenesis was still un- eight microcephalic mentally retarded children resolved. One possibility is that a metabolic born to a phenylketonuric woman. In classical disorder causes progressive glial and Schwann phenylketonuria the brain was most severely cell insufficiency, resulting both in the breakdown affected during the critical period of rapid growth of myelin and in the formation of structurally and differentiation extending into the second year of life, while in maternal phenylketonuria the abnormal myelin. early stages of the development of the brain and REFERENCE other organs were at risk. Blackwood W (1957) In: Cerebral Lipidoses. Ed. J N Cumings. Blackwell, Oxford; p 1
Histidinwemia: An inborn error, as indeed almost any metabolic disorder, was liable to increase the vulnerability of those affected to neuropsychiatric disorders. Thus two out of three histidinemics Effects of Viruses and seen at Queen Mary's Hospital for Children, Viral Vaccines on the CNS Dr A D Dayan ( Wellcome Research Laboratories, although not mentally retarded, had neurological Beckenham, Kent) discussed the effects of viruses and psychiatric handicaps. At present, a case for and viral vaccines on the central nervous system. dietary treatment of histidinaemia had not been First he described the histological features established. Extrapolation from phenylketonuria typifying an acute viral infection and the patterns to histidinemia was unwarranted. In particular, of neurological deficiency which might follow untreated histidinwmics diagnosed by infant both from the direct damage to nervous tissues mass screening were doing at least as well as and from secondary effects. He illustrated hypo- early treated classical phenylketonurics, and plasia of the cerebellum in piglets resulting from there was so far no evidence that the vulnerability maternal virus infection as an example of per- of histidinEemics would be materially reduced by a sistent sequelze of a short-lived disease. Viruses diet low in histidine, particularly as at least some might have selective effects upon certain types of retarded histidinemics had evidence of antenatal cells, e.g. ependyma, with aqueductal stenosis as a brain lesions. long-term result. Secondary effects resulting from the swelling associated with inflammation could Nonketotic hyperglycinamia: The striking feature include herniation of the brain, as in herpes of the history of three sisters with nonketotic simplex affecting the temporal lobes. In subacute hyperglycinemia who had reached adulthood sclerosing panencephalitis viruses produce a was that although they were mentally retarded chronic infection despite dramatic immune they had not shown any signs of deterioration responses, and in some conditions immune since infancy. A fourth patient with this disorder complexes might well be more dangerous than had died at 72 after a fulminating illness characthe virus itself. In temperate infections the failure terized by extreme hypotonia. Glycine is an of cell-mediated immunity was coming to be inhibitor of neuronal transmission at the postrecognized as important. In cases of treated synaptic level. In mammals the blood-brain leukemia and organ transplants viral infection barrier effectively excluded glycine from the might be opportunistic, because of the impaired nervous system, but this was apparently not the case in the newborn. Small elevations of the immune responses. Acute perivenous demyelination was a very blood glycine level could therefore be neurotoxic rare complication of infection by certain viruses, in the newborn, but comparatively harmless in the older child. which seemed to be due to an allergic reaction.
