- Email: [email protected]
Developmental abnormalities in autism
T H E LANCET
to be present, interictally, over many years. The mechanism responsible remains unknown, but the favoured hypothesis is that hypergraphia is the result of changes in emotional responsiveness secondary to organic disease.la6 It is not believed to be due to the memory impairment that commonly accompanies temporal lobe epilepsy. Automatic writing behaviour and hypergraphia are of interest as examples of human behavioural disorders associated with neurological disease. Clarifying the terminology is an important first step in the analysis of these disorders. Further work is required to establish whether these disorders are part of specific syndromes and what the nature and site of the critical lesion or lesions are. Such work will, it i s hoped, lead us to a better understanding of the dynamic organisation of higher nervous function. T C Britton Neuroscience Unit, King’s College Hospital, London SE5 SRS, UK van Vugt P, Paquier P,Kees L,Cras P.Increased writing activity in neurological conditions: a review and clinical study. J Neurol Neurosurg Psychiatry 1996; 61: 510-14. Yamadori A, Mori E, Tabuchi M, Kudo Y, Mitani Y.Hypergraphia: a right hemisphere syndrome. J Neural Neurosurg Psychzany 1986; 49: 1160-64. Imamura T, Yamadori A, Tsuburaya I<. Hypergraphia associated with a brain tumour of the right cerebral hemisphere. J Neurol Neurosurg Psychiatry 1992; 55: 25-27. Frisoni G, Scurratti A, Bianchetti A, Trabucchi M. Hypergraphia and brain damage. J Neurol Neurosurg Psychiaty 1993; 56: 576-77. Waxman SG, Geschwind N. Hypergraphia in temporal lobe epilepsy. Neurology 1974; 24: 629-36. Okamura T, Fukai M, Yamadori A, Hidari M, Asaba H, Sakai T. A clinical study of hypergraphia in epilespy. J Neurol Neurosurg Psychiany 1993; 56: 556-59. Trimble M. Hypergraphia. In: Trimble M, Bolwig T, eds. Aspects of epilepsy and psychiatry. London: John Wiley and Sons, 1986: 75-87.
Developmental abnormalities in autism See page 392 The finding reported by Bolton and Griffiths today of a strong association between tubers in the temporal lobes and autism in individuals with tuberous sclerosis suggests that early developmental abnormalities within the temporal lobes lead to autism and atypical autism. Similar mechanisms may be operative in other disorders that, like tuberous sclerosis, are sometimes associated with the behaviorally defined syndrome of autism. Fragile X syndrome is associated with increased right and left hippocampal volumes, though the specific morphological or functional abnormality that distinguishes individuals with fragile X syndrome and autism from the majority without autism is not yet known.’ In young children with infantile spasms and qualitatively normal computed
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Vol349 February 8, 1997
tomography (CT) and magnetic resonance imaging (MRI) scans of the temporal lobes, hypometabolism of both temporal lobes on positron emission tomography seems to be associated with autism.’ Temporal lobe abnormalities have been seen in necropsy and imaging studies of idiopathic autism and Asperger’s disorder, a slightly milder form of autism. Microscopic neuroanatomical abnormalities have been found in the limbic system of all nine autistic individuals studied by Bauman and Kemper, which suggests a curtailment of normal development. They found reduced neuronal cell size and increased cell-packing density bilaterally in the hippocampal complex, subiculum, entorhinal cortex, amygdala, mammillary body, medial septa1 nucleus, and anterior cingulate gyrus, and the complexity and extent of dendritic arbours were decreased in the hippocampus.’ Such abnormalities have also been found in a small number of individuals with Asperger’s syndrome, though to a more limited extent and degree.’ Temporal-lobe enlargement on MRI has been found in autistic children and adults and seems to be predominantly right-~ided.~ Neuropsychological findings in young children with autism suggest functional abnormality of the temporal lobe.5 Experiments in newborn monkeys provide further evidence that aberration in the development of the temporal lobes is important in the genesis of autism. When medial temporal lobe structures are removed from newborn monkeys, the monkeys develop socioemotional abnormalities as they mature. These abnormalities are similar in quality to those of autistic children. The extent of damage to medial temporal lobe structures is related to the severity and type of socioemotional disturbance in the monkeys. Though structural and functional temporal lobe abnormalities seem important in autism, in most cases they appear to be part of more widely distributed abnormalities of neuronal organisation, connectivity, and function in the brain. Microscopic neuropathological abnormalities in the cerebellum probably developing before 30 weeks of gestation have been consistently found in association with the limbic system abnormalities in the autistic individuals studied by Bauman and Kernper.’ Regional cerebral blood flow abnormalities in very young children with autism suggest abnormal maturation of frontal-lobe f u n ~ t i o n . Neuropsychological ~ and neurological studies of older children and adults with autism show deficits in complex information processing involving multiple regions of the brain.5 Macrocephaly, increased brain volume, and megalencephaly seem to be common in aurism, which suggests abnormalities of programmed cell death during early brain development. Complex volumetric MRI studies by riven and colleagues show that brain enlargement in autism seems to be due to regional enlargement of the temporal, parietal, and occipital lobes but not the frontal lobes, and is associated with additional indicators suggesting anomalous organisation and connectivity of neural n e t w o r k ~ . ~ Many important questions about the pathology and pathophysiology of autism remain unanswered. What are the primary abnormal neural events in brain development that lead to autism? Do development abnormalities in one area of the brain, such as the temporal or frontal lobe, lead to developmental, organisational, and functional 373
T H E LANCET
abnormalities in other parts of the brain in autism? Are the primary abnormalities more widely distributed in the brain? Do individuals with tuberous sclerosis and tubers exclusively in the temporal lobes develop autism, or are tubers in other areas of the brain also necessary? Is the developmental neuropathology of autism associated with profound mental retardation any different from that found in higher-functioning individuals with autism? Studies of young children with autism employing functional imaging techniques along with additional clinical, developmental, neurobiological, and necropsy studies will, it is hoped, soon explain the observation eloquently noted by Leo Kanner in 1943, that “these children have come into the world with innate inability to form the usual biologically provided affective contact with people”.
additional cases are reviewed. Two of their patients died while taking the drug for acne and a third required a liver transplant. In five of their cases rechallenge resulted in recurrence of the drug reaction. Although it is not known whether tetracycline or doxycycline can cause similar serious adverse events and although most of the serious side-effects are reversible, minocycline probably should not be the first-line oral drug for the treatment of acne until further safety studies are available. Tetracycline or erythromycin should be tried first. If a patient on minocycline develops any symptoms suggestive of the serious reactions described above, the drug should be stopped and laboratory tests done. Baseline liver-function tests and an antinuclear antibody test before starting minocycline therapy may be helpful.
Janet E Lainhart
Alice Gottlieb
Neuropsychiatric Institute, University of Utah, Salt Lake City, Utah 84108, USA
Division of Dermatology, UMDNJ-RobertWood Johnson Medical School, New Brunswick, NJ 08901, USA
Reiss AL, Lee J, Freund L. Neuroanatomy of fragile X syndrome:the temporal lobe. Neurology 1994; 44: 1317-24. Chugani HT, Da Silva E, Chugani DC. Infantile spasms: I11 prognostic implications of bitemporal hypometabolism on positron emission tomography. A n n Neurol 1996; 39: 643-49. Bauman ML. Brief report: neuroanatomic observations of the brain in penrasive developmental disorders. J Aurism Devel Disorder 1996; 26: 199-203. Piven J, Arndt S, Bailey J, Andreasen N. Regional brain enlargement in autism: a magnetic resonance imaging study. J A m Acad Child Ado1 Psychiatry 1996; 35: 530-36. Dawson G. Neuropsychology of autism: a report on the state of the science. J Autism Devel Disorders 1996; 26: 179-84. Bachevalier J. Medial temporal lobe structures and autism: a review of clinical and experimental findings. Neuropsychologia 1994; 32: 627-48. Zilbovicius M, Garreau B, Samson Y , et al. Delayed maturation of the frontal cortex in childhood autism. A m J Psychiarry 1995; 152: 248-52.
Safety of minocycline for acne See p 400 Minocycline is the most commonly used oral antibiotic for the treatment of acne in the UK. In this week’s issue Eisen reports on the prevalence of one complication, oral hyperpigmentation. Two recent articles’,’ record serious adverse events resulting from the treatment of acne patients with this drug, including autoimmune hepatitis, a serum-sickness type of reaction, and drug-induced lupus erythematosus. It is difficult to assess the true incidence because most of the evidence has come from specialty centres in the USA and UIC that collect patients with adverse reactions to medications. The side-effects can be life-threatening, and there is a report of fulminant hepatic failure requiring liver transplantation in a 39-year-old woman, 4 weeks after the start of oral minocycline for the treatment of acne.l IOlowles et all reported six patients with serumsickness-like disease and one with drug-induced lupus erythematosus. They also cite 11 other published cases of hypersensitivity syndrome reaction (rash, fever, and internal-organ involvement, usually liver), one case of serum-sickness-like illness, and 24 cases of drug-induced lupus erythematosus. Serum-sickness-like reactions developed on average 16 days, hypersensitivity syndrome reactions 24 days, and drug-induced lupus 2 years after the start of minocycline therapy. Gough et a12 record 11 cases of minocycline-induced systemic lupus erythematosus and 16 cases of hepatitis, and seven
374
Ibowles SR, Shapiro L, Shear NH. Serious adverse reactions induced by minocycline: report of 13 patients and review of the literature. Arch Demzatol 1996; 132: 934-39. 2 Gough A, Chapman S, Wagstaff I<, Emely P, Elias E. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 1996; 312: 169-72. 3 Min DI, Burke PA, Lewis WD, Jenkins RL. Acute hepatic failure associated with oral rninocycline: a case report. Phannacotherapy 1992; 12: 66-71. 1
The Lancef in figures in 1996 The Lancet has always thanked its referees privately. We did so in public too for 1991-95, but not this time. There are so many. Indeed, last year 1990 people in 41 countries assisted by peer reviewing 2080 submissions (mostly papers but including 285 letters). This advice has been invaluable to the journal, and we thank them one and all. The names are now on our website http://www.thelancet.com. Total submissions, excluding all letters but including commissioned review material, numbered 61 15. By the end of last month a final decision to accept or reject had been taken on all but 186. Of those decisions, 423 were in the authors’ favour, and the provisional 1996 acceptance rate is 6.9%. Those submissions came from 90 countries, the geographical spread being: western Europe (excluding UK) 35.6%, UIC 25.8%, North America 20.6%, Japan 6.4%, Asia 3.6%, Australasia 3.1%, Middle East 2.3%, Africa 1.2%, other 1.4%. We are now working to set reasonable targets-for editorial staff, referees, authors, and typesetters-the objective being to speed up every part of the process from initial in-house evaluation through to publication. These targets will be published, and this time next year we will disclose how well performance has matched up. Shortly too a fast-track procedure will be formalised so that, as happens sometimes already, selected papers with important clinical, scientific, and/or public health messages can be accelerated through the system. In 1996 we received 5543 letters for publication. By Jan 31 a yesino decision had been taken on all but 82. Of the 2384 comment-type Letters to the Editor, the ones now called Correspondence, 52.3% were accepted. The acceptance rate for the original-type letter (Research Letters) was 21.3%. David Sharp, John McConnell, Richard Horton The Lancet, London, UK
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Vol349 February 8, 1997
to be present, interictally, over many years. The mechanism responsible remains unknown, but the favoured hypothesis is that hypergraphia is the result of changes in emotional responsiveness secondary to organic disease.la6 It is not believed to be due to the memory impairment that commonly accompanies temporal lobe epilepsy. Automatic writing behaviour and hypergraphia are of interest as examples of human behavioural disorders associated with neurological disease. Clarifying the terminology is an important first step in the analysis of these disorders. Further work is required to establish whether these disorders are part of specific syndromes and what the nature and site of the critical lesion or lesions are. Such work will, it i s hoped, lead us to a better understanding of the dynamic organisation of higher nervous function. T C Britton Neuroscience Unit, King’s College Hospital, London SE5 SRS, UK van Vugt P, Paquier P,Kees L,Cras P.Increased writing activity in neurological conditions: a review and clinical study. J Neurol Neurosurg Psychiatry 1996; 61: 510-14. Yamadori A, Mori E, Tabuchi M, Kudo Y, Mitani Y.Hypergraphia: a right hemisphere syndrome. J Neural Neurosurg Psychzany 1986; 49: 1160-64. Imamura T, Yamadori A, Tsuburaya I<. Hypergraphia associated with a brain tumour of the right cerebral hemisphere. J Neurol Neurosurg Psychiatry 1992; 55: 25-27. Frisoni G, Scurratti A, Bianchetti A, Trabucchi M. Hypergraphia and brain damage. J Neurol Neurosurg Psychiaty 1993; 56: 576-77. Waxman SG, Geschwind N. Hypergraphia in temporal lobe epilepsy. Neurology 1974; 24: 629-36. Okamura T, Fukai M, Yamadori A, Hidari M, Asaba H, Sakai T. A clinical study of hypergraphia in epilespy. J Neurol Neurosurg Psychiany 1993; 56: 556-59. Trimble M. Hypergraphia. In: Trimble M, Bolwig T, eds. Aspects of epilepsy and psychiatry. London: John Wiley and Sons, 1986: 75-87.
Developmental abnormalities in autism See page 392 The finding reported by Bolton and Griffiths today of a strong association between tubers in the temporal lobes and autism in individuals with tuberous sclerosis suggests that early developmental abnormalities within the temporal lobes lead to autism and atypical autism. Similar mechanisms may be operative in other disorders that, like tuberous sclerosis, are sometimes associated with the behaviorally defined syndrome of autism. Fragile X syndrome is associated with increased right and left hippocampal volumes, though the specific morphological or functional abnormality that distinguishes individuals with fragile X syndrome and autism from the majority without autism is not yet known.’ In young children with infantile spasms and qualitatively normal computed
-
Vol349 February 8, 1997
tomography (CT) and magnetic resonance imaging (MRI) scans of the temporal lobes, hypometabolism of both temporal lobes on positron emission tomography seems to be associated with autism.’ Temporal lobe abnormalities have been seen in necropsy and imaging studies of idiopathic autism and Asperger’s disorder, a slightly milder form of autism. Microscopic neuroanatomical abnormalities have been found in the limbic system of all nine autistic individuals studied by Bauman and Kemper, which suggests a curtailment of normal development. They found reduced neuronal cell size and increased cell-packing density bilaterally in the hippocampal complex, subiculum, entorhinal cortex, amygdala, mammillary body, medial septa1 nucleus, and anterior cingulate gyrus, and the complexity and extent of dendritic arbours were decreased in the hippocampus.’ Such abnormalities have also been found in a small number of individuals with Asperger’s syndrome, though to a more limited extent and degree.’ Temporal-lobe enlargement on MRI has been found in autistic children and adults and seems to be predominantly right-~ided.~ Neuropsychological findings in young children with autism suggest functional abnormality of the temporal lobe.5 Experiments in newborn monkeys provide further evidence that aberration in the development of the temporal lobes is important in the genesis of autism. When medial temporal lobe structures are removed from newborn monkeys, the monkeys develop socioemotional abnormalities as they mature. These abnormalities are similar in quality to those of autistic children. The extent of damage to medial temporal lobe structures is related to the severity and type of socioemotional disturbance in the monkeys. Though structural and functional temporal lobe abnormalities seem important in autism, in most cases they appear to be part of more widely distributed abnormalities of neuronal organisation, connectivity, and function in the brain. Microscopic neuropathological abnormalities in the cerebellum probably developing before 30 weeks of gestation have been consistently found in association with the limbic system abnormalities in the autistic individuals studied by Bauman and Kernper.’ Regional cerebral blood flow abnormalities in very young children with autism suggest abnormal maturation of frontal-lobe f u n ~ t i o n . Neuropsychological ~ and neurological studies of older children and adults with autism show deficits in complex information processing involving multiple regions of the brain.5 Macrocephaly, increased brain volume, and megalencephaly seem to be common in aurism, which suggests abnormalities of programmed cell death during early brain development. Complex volumetric MRI studies by riven and colleagues show that brain enlargement in autism seems to be due to regional enlargement of the temporal, parietal, and occipital lobes but not the frontal lobes, and is associated with additional indicators suggesting anomalous organisation and connectivity of neural n e t w o r k ~ . ~ Many important questions about the pathology and pathophysiology of autism remain unanswered. What are the primary abnormal neural events in brain development that lead to autism? Do development abnormalities in one area of the brain, such as the temporal or frontal lobe, lead to developmental, organisational, and functional 373
T H E LANCET
abnormalities in other parts of the brain in autism? Are the primary abnormalities more widely distributed in the brain? Do individuals with tuberous sclerosis and tubers exclusively in the temporal lobes develop autism, or are tubers in other areas of the brain also necessary? Is the developmental neuropathology of autism associated with profound mental retardation any different from that found in higher-functioning individuals with autism? Studies of young children with autism employing functional imaging techniques along with additional clinical, developmental, neurobiological, and necropsy studies will, it is hoped, soon explain the observation eloquently noted by Leo Kanner in 1943, that “these children have come into the world with innate inability to form the usual biologically provided affective contact with people”.
additional cases are reviewed. Two of their patients died while taking the drug for acne and a third required a liver transplant. In five of their cases rechallenge resulted in recurrence of the drug reaction. Although it is not known whether tetracycline or doxycycline can cause similar serious adverse events and although most of the serious side-effects are reversible, minocycline probably should not be the first-line oral drug for the treatment of acne until further safety studies are available. Tetracycline or erythromycin should be tried first. If a patient on minocycline develops any symptoms suggestive of the serious reactions described above, the drug should be stopped and laboratory tests done. Baseline liver-function tests and an antinuclear antibody test before starting minocycline therapy may be helpful.
Janet E Lainhart
Alice Gottlieb
Neuropsychiatric Institute, University of Utah, Salt Lake City, Utah 84108, USA
Division of Dermatology, UMDNJ-RobertWood Johnson Medical School, New Brunswick, NJ 08901, USA
Reiss AL, Lee J, Freund L. Neuroanatomy of fragile X syndrome:the temporal lobe. Neurology 1994; 44: 1317-24. Chugani HT, Da Silva E, Chugani DC. Infantile spasms: I11 prognostic implications of bitemporal hypometabolism on positron emission tomography. A n n Neurol 1996; 39: 643-49. Bauman ML. Brief report: neuroanatomic observations of the brain in penrasive developmental disorders. J Aurism Devel Disorder 1996; 26: 199-203. Piven J, Arndt S, Bailey J, Andreasen N. Regional brain enlargement in autism: a magnetic resonance imaging study. J A m Acad Child Ado1 Psychiatry 1996; 35: 530-36. Dawson G. Neuropsychology of autism: a report on the state of the science. J Autism Devel Disorders 1996; 26: 179-84. Bachevalier J. Medial temporal lobe structures and autism: a review of clinical and experimental findings. Neuropsychologia 1994; 32: 627-48. Zilbovicius M, Garreau B, Samson Y , et al. Delayed maturation of the frontal cortex in childhood autism. A m J Psychiarry 1995; 152: 248-52.
Safety of minocycline for acne See p 400 Minocycline is the most commonly used oral antibiotic for the treatment of acne in the UK. In this week’s issue Eisen reports on the prevalence of one complication, oral hyperpigmentation. Two recent articles’,’ record serious adverse events resulting from the treatment of acne patients with this drug, including autoimmune hepatitis, a serum-sickness type of reaction, and drug-induced lupus erythematosus. It is difficult to assess the true incidence because most of the evidence has come from specialty centres in the USA and UIC that collect patients with adverse reactions to medications. The side-effects can be life-threatening, and there is a report of fulminant hepatic failure requiring liver transplantation in a 39-year-old woman, 4 weeks after the start of oral minocycline for the treatment of acne.l IOlowles et all reported six patients with serumsickness-like disease and one with drug-induced lupus erythematosus. They also cite 11 other published cases of hypersensitivity syndrome reaction (rash, fever, and internal-organ involvement, usually liver), one case of serum-sickness-like illness, and 24 cases of drug-induced lupus erythematosus. Serum-sickness-like reactions developed on average 16 days, hypersensitivity syndrome reactions 24 days, and drug-induced lupus 2 years after the start of minocycline therapy. Gough et a12 record 11 cases of minocycline-induced systemic lupus erythematosus and 16 cases of hepatitis, and seven
374
Ibowles SR, Shapiro L, Shear NH. Serious adverse reactions induced by minocycline: report of 13 patients and review of the literature. Arch Demzatol 1996; 132: 934-39. 2 Gough A, Chapman S, Wagstaff I<, Emely P, Elias E. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 1996; 312: 169-72. 3 Min DI, Burke PA, Lewis WD, Jenkins RL. Acute hepatic failure associated with oral rninocycline: a case report. Phannacotherapy 1992; 12: 66-71. 1
The Lancef in figures in 1996 The Lancet has always thanked its referees privately. We did so in public too for 1991-95, but not this time. There are so many. Indeed, last year 1990 people in 41 countries assisted by peer reviewing 2080 submissions (mostly papers but including 285 letters). This advice has been invaluable to the journal, and we thank them one and all. The names are now on our website http://www.thelancet.com. Total submissions, excluding all letters but including commissioned review material, numbered 61 15. By the end of last month a final decision to accept or reject had been taken on all but 186. Of those decisions, 423 were in the authors’ favour, and the provisional 1996 acceptance rate is 6.9%. Those submissions came from 90 countries, the geographical spread being: western Europe (excluding UK) 35.6%, UIC 25.8%, North America 20.6%, Japan 6.4%, Asia 3.6%, Australasia 3.1%, Middle East 2.3%, Africa 1.2%, other 1.4%. We are now working to set reasonable targets-for editorial staff, referees, authors, and typesetters-the objective being to speed up every part of the process from initial in-house evaluation through to publication. These targets will be published, and this time next year we will disclose how well performance has matched up. Shortly too a fast-track procedure will be formalised so that, as happens sometimes already, selected papers with important clinical, scientific, and/or public health messages can be accelerated through the system. In 1996 we received 5543 letters for publication. By Jan 31 a yesino decision had been taken on all but 82. Of the 2384 comment-type Letters to the Editor, the ones now called Correspondence, 52.3% were accepted. The acceptance rate for the original-type letter (Research Letters) was 21.3%. David Sharp, John McConnell, Richard Horton The Lancet, London, UK
-
Vol349 February 8, 1997