Clinics in Developmental Medicine No. 187
COMORBIDITIES IN DEVELOPMENTAL DISORDERS
Clinics in Developmental Medicine No. 187
Comorbidities in Developmental Disorders
Edited by
MARTIN CO BAX
and
CHRISTOPHER GILLBERG
2010
Mac Keith Press
© 2010 Mac Keith Press
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First published in this edition 2010
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Mac Keith Press is supported by Scope
ISBN: 978-1-907655-00-5
Mac Keith Press is supported by Scope
CONTENTS
AUTHORS’ APPOINTMENTS
FOREWORD
Christopher Verity
INTRODUCTION
Martin CO Bax and Christopher Gillberg
1INTELLECTUAL DISABILITIES AND THEIR COMORBIDITIES
Jeremy Turk
2HETEROGENEITY IN CEREBRAL PALSY: VARIATIONS IN NEUROLOGY, COMORBIDITY AND ASSOCIATED CONDITIONS
J Keith Brown and Paul Eunson
3GILLES DE LA TOURETTE SYNDROME AND ITS COMMON COMORBIDITIES
Michael Orth and Mary May Robertson
4COMORBIDITY IN NEURODEVELOPMENTAL DISORDERS: THE CASE OF ATTENTION-DEFICIT–HYPERACTIVITY DISORDER
Eric Taylor
5EARLY LANGUAGE DISORDER AS A FREQUENT COMORBIDITY IN MANY DEVELOPMENTAL DISORDERS IN YOUNG CHILDREN
Isabelle Rapin
6AUTISM AND EPILEPSY: COMORBIDITY, COEXISTENCE OR COINCIDENCE?
Christopher Gillberg and Brian Neville
7GENETIC CORRELATES OF PSYCHIATRIC COMORBIDITY: FRAGILE X SYNDROME
Sufen Chiu, David Hessl, Josh Day and Randi Hagerman
8CHANNELOPATHIES
Sameer M Zuberi
9INCREASED LONGEVITY AND THE COMORBIDITIES ASSOCIATED WITH INTELLECTUAL AND DEVELOPMENTAL DISABILITY
Alan H Bittles and Emma J Glasson
10COMORBIDITY: CLASSIFICATION ARTEFACT AND CLINICAL REALITY
Rutger Jan van der Gaag
INDEX
AUTHORS’ APPOINTMENTS
Alan H Bittles
Adjunct Professor and Research Leader, Centre for Comparative Genomics, Murdoch University, and Adjunct Professor of Community Genetics, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia
Martin CO Bax
Honorary Reader in Child Health, Imperial College London and Honorary Consultant, Chelsea and Westminster Hospital. Dr Bax is also a Fellow of the Royal Society of Literature.
J Keith Brown
Retired Consultant Paediatric Neurologist, Royal Hospital for Sick Children, and Fellow of University of Edinburgh, Edinburgh, UK
Sufen Chiu
Assistant Clinical Professor, UC Davis, Sutter Center for Psychiatry, Sacramento, CA, USA
Josh Day
Postgraduate Researcher, MIND Institute, UC Davis Medical Center, Sacramento, CA, USA
Paul Eunson
Consultant Paediatric Neurologist, Royal Hospital for Sick Children, Edinburgh, UK
Christopher Gillberg
Professor of Child and Adolescent Psychiatry, University of Gothenburg, Sweden and Institute of Child Health, London and Glasgow University, Glasgow, UK
Emma Glasson
Research Assistant Professor, School of Population Health, The University of Western Australia, and School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Perth, Australia
Randi Hagerman
Professor of Pediatrics, MIND Institute UC Davis Medical Center, Sacramento, CA, USA
David Hessl
Associate Professor, Department of Psychiatry and Behavioral Sciences and the MIND Institute, UC Davis, Sacramento, CA, USA
Brian Neville
Professor of Childhood Epilepsy, UCL Institute of Child Health, Great Ormond Street Hospital, London, and National Centre for Young People with Epilepsy, Lingfield, Surrey, UK
Michael Orth
Consultant Neurologist, Department of Neurology, Universitätskrankenhaus Ulm, Ulm, Germany
Isabelle Rapin
Professor, Saul R. Korey Department of Neurology, Department of Pediatrics, and the Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, NY, USA
Mary May Robertson
Emeritus Professor of Neuropsychiatry, University College London, Visiting Professor, St George’s Hospital Medical School, and Honorary Consultant, St George’s Hospital Department of Mental Health Sciences, University College London, London, UK
Eric Taylor
Emeritus Professor of Child and Adolescent Psychiatry, Kings College London Institute of Psychiatry & South London & Maudsley NHS Foundation Trust, London, UK
Jeremy Turk
Professor of Developmental Psychiatry and Consultant Child and Adolescent Psychiatrist, Michal Rutter Centre, Maudsley Hospital, Denmark Hill, London, UK
Rutger Jan Van der Gaag
Professor of Psychiatry (Child & Adolescent), University Medical Centre St. Radboud, and Department of Psychiatry, Karakter University Centre Child & Adolescent Psychiatry, Reinier, Nijmegen, The Netherlands
Sameer M Zuberi
Consultant Paediatric Neurologist, Fraser of Allander Neurosciences Unit, Royal Hospital for Sick Children, Glasgow, UK
FOREWORD
“We think in generalities but we live in detail.”
Whitehead
Working with children who have developmental disorders provides great challenges but also yields great rewards. The complex problems faced by such children and their families make it essential to take a holistic view of their care. In this book the editors Martin Bax and Christopher Gillberg have embraced these complexities. They are well placed to do so, having spent their professional lives not only looking after children who have developmental difficulties but also researching into the causes of their problems.
The editors challenge the reader to engage with the variety of disabilities associated with many disorders. There are common themes but the authors of each chapter provide insight and inspiration via the detailed analyses of the disorders they review. There are sections that discuss terminology but whilst it is important to consider, for instance, whether a disorder is comorbid or cocausal (or something else) it is also necessary to heed the advice given in the chapter on cerebral palsy: ‘the child would prefer you to identify the disorder and decide what to do about it’.
It is by knowing what we are looking for that we can expect to find it. The advantage of making a diagnosis is that we can give parents and carers a prognosis based on our knowledge of particular diseases or syndromes. However, even when there is a specific diagnosis such as fragile X or Tourette syndrome the possible medical and social implications of that diagnosis are varied. It is much more difficult when a child has developmental problems of unknown cause and we may not recognise the more subtle difficulties experienced by children with attention-deficit–hyperactivity disorder or autism or epilepsy, complex groups of disorders in their own right. This book emphasises the importance of considering such variations in an individual child.
Although the determinants of behaviour are poorly understood it is increasingly recognised that behavioural phenotypes may be characteristic of particular syndromes. In the section on the channelopathies it is suggested that a single ion channel mutation may produce pathology in different tissues, thus causing comorbid neurological or behavioural disorders. This basic science research complements the empirical observations reported in other chapters, adding interest to a stimulating collection of essays by expert authors. Their descriptions of a variety of complex disorders will help the reader to identify associated problems and do something about them.
Christopher Verity
Cambridge
INTRODUCTION
Martin CO Bax and Christopher Gillberg
Towards a definition of comorbidity
In the last decade the term ‘comorbidity’ has gained popularity in the field of paediatric neurodisability, yet there is still no consensus about its precise definition. The definition by Feinstein, who introduced the term in his classic paper in 1970, was as follows: ‘In a patient with a particular index disease, the term co-morbidity refers to any additional co-existing ailment’ (note the use of the word ‘ailment’ rather than disease entity). This remains the definition in dictionaries and is the basis of most definitions in the published literature, particularly in the context of additional disorders that complicate the management of the index condition. However, ‘comorbidity’ is increasingly now used, often imprecisely and loosely, to refer to the co-occurrence of conditions more frequently than would be expected by chance, which can include instances where one condition causes the other, where they share a common cause (for example, genetic), or where they are both in fact manifestations of a single condition. Is it valid to use the term ‘comorbidity’ in these instances?
What is not a comorbidity?
Perhaps it would help clarify our thinking if we look at some instances which most would agree are not examples of comorbidity in the field of developmental medicine.
A SINGLE MORBIDITY WITH THREE SYMPTOMATOLOGIES
In a study of a whole population of five-year-olds in the Isle of Wight, a child with no reported problems was identified (Bax & Whitmore 1987). Records disclosed that the child had been seen by a cardiologist at birth because of a mild congenital thrombosis which was reviewed once a year. There was also a note that cataracts had been removed around the time of birth. The mother was impressed when the clinician queried the child’s hearing, about which she was rightly concerned, the child having mild hearing loss. Clearly the clinician was correct when he made the diagnosis of rubella syndrome. The mother confirmed that she had had rubella during the pregnancy but nobody had ever mentioned it in relation to her child’s problems. The morbidity here involved three different sites in the body, one cardiac, one within the orbit of the eye, and a further one relating to the functions of the 8th nerve. Both the symptomatology and the pathology varied but a single causative mechanism had been identified and a comorbidity is therefore not suggested.
A SINGLE CAUSATIVE MECHANISM WITH DIFFERENT SYMPTOMATOLOGIES?
Hypoxia produces a morbid state in the brain. The hypoxic insult affects the parts of the brain in distinct ways, white-matter damage interfering with cerebral function in a different way from damage to the grey matter. The child’s symptomatology in the perinatal period is often due to one episode. But supposing a hypoxic episode occurs again two weeks late: can two episodes of hypoxia cause two different symptomatologies? If the two episodes of hypoxia cause two different symptomatologies should we regard these as comorbid states or as different symptomatologies arising from a single causative mechanisms, i.e. a single disorder?
MORE THAN ONE MORBIDITY, OR A CONDITION WITH A COMORBIDITY?
The situation is even more complex when we consider the problems that we see in the field of neurodisability. Autism can be regarded as a distinct syndromic entity. So can epilepsy. But what, then, do we make of the finding reported by Steffenburg and her colleagues (1996) of high rates of autism in a population of children identified initially because of epilepsy, whereas in a neighbouring autism clinic unknown cases of epilepsy were discovered? Both of these clinics thought that they provided a full clinical service, yet failed to identify significant pathologies: clearly the diagnoses were partly determined by which clinic a child attended. A paediatric neurologist saw the child in the epilepsy clinic, the child psychiatrist in the autism clinic. A full diagnosis would have been the first step in deciding whether to use the term ‘comorbidity’. For example, if a genetic cause was identified for the autism, should the co-occurrence of epilepsy be regarded as a comorbidity or as an essential part of the basic clinical situation?
Morbidity clearly makes a person more vulnerable to a second morbidity. A viral infection will make someone more susceptible to a bacterial one and a pneumonia may develop after a ‘cold’, but in these circumstances it is not appropriate to use the term ‘comorbid’. A child with tuberous sclerosis is quite likely to have autism or epilepsy or both. Should this be defined as one or two morbidities or a condition with a comorbidity? If learning difficulty occurs commonly in a condition, as it does in autism, most people would not label the learning disability as a comorbidity but some might: the issue is whether it shares the same aetiology as the other features of autism or whether in some way the autism predisposes the individual to learning difficulty.
COMORBIDITY OR CO-OCCURRENCE?
A child with Down syndrome with a cardiac condition is usually said to have comorbidities, whereas a child with Down syndrome and fragile X syndrome does not. The fragile X syndrome occurs at the same rate in the population with Down syndrome as it does in the typical population. Therefore, the two conditions are co-occurring at a rate that would be expected: their presence together does not relate to their aetiology. This suggests that the term ‘comorbidity’ could usefully be applied only when it enhances our notion of what is causing a condition rather than simply as a synonym for co-occurrence. However, our authors clearly do not all concur with this, which emphasises the lack of agreement to date and the value of the discussions in this book.
Understanding ‘comorbidity’: implications for aetiology, treatment and management
The contributors to this book have each grappled with the concept of comorbidity in the context of their own disciplines. Rutger Jan Van der Gaag in his chapter (pp 142–148) usefully gives examples from psychiatry to illustrate five aspects of the usage of the term comorbidity:
Brown and Eunson in their chapter on cerebral palsy (pp 20–39) provide a thorough review of all the ‘associated conditions’ that may accompany the index condition cerebral palsy. Their definition of a comorbidity is that it is any condition which is associated with the index condition, and which can appear as an entity in its own right. As they comment, however, the difficulty in child neurology is that many of the major conditions, such as hearing difficulty, epilepsy, cerebral palsy, attention deficit disorder, hyperkinetic syndrome and autism, are not disease entities but syndromes, all arising from brain dysfunction. They go on to propose that there is a useful distinction to be made between three kinds of association: comorbid disorders, co-causal disorders, and complications of the index condition. Thus whereas some comorbid conditions are neither caused by nor complications of the cerebral palsy, other conditions have the same aetiology (brain dysfunction); this is an example of a co-causal association. They distinguish other conditions such as constipation as complications of the cerebral palsy.
Zuberi’s account of co-morbidities in the context of channelopathies (pp 116–124) is also helpful in establishing a possible explanation for some comorbidities. He points out that somewhat similar presentations in these channelopathies might make one wonder if there is a single morbid cause but in fact a range of genes is causing the symptomatologies. Conversely, Zuberi presents examples of instances where a single ion channel mutation producing pathology in different tissues could be the explanation for co-morbid neurological or behavioural disorders in an individual. These findings are clearly interesting in relation to the issue of comorbidity but they are also important in terms of the development of new treatments.
Bittles’ (pp 125–141) discussion of a new symptomatology emerging ‘with age’ poses another set of problems: do we accept a symptomatology developing later in life as part of the original diagnostic concept or is it perhaps a comorbidity? The issue arises with Down syndrome: most people would accept that the early onset of dementia is caused by the same aetiological factors as the original learning difficulty. Bittles makes us put ‘time’ into our equation. One might question whether what he describes in older children is part of the original morbidity, is a comorbidity, or is a completely different phenomenon co-occurring with the index condition.
Can the presence of comorbidities that occur more often than would be expected by chance tell us something about the aetiology of a condition? Clinicians have for years been constantly surprised that the classic symptoms of one condition can be associated with those of another condition thought to be distinct and different. These are not part of the same disorder but they co-occur. Orth and Robertson in their chapter (pp 40–59) refer to a study in which the classic signs of Tourette syndrome – the tic-like behaviours – occurred alone in only about 10% of those who had been diagnosed with this syndrome. In the other individuals there was at least one comorbidity. They note that it is not yet clear whether Tourette syndrome and its common co-occurring disorders – such as attention-deficit–hyperactivity disorder and obsessive-compulsive disorder – are true co-morbidities, or whether they have a common genetic and/or environmental cause. As these disorders are all common their combination could be a chance co-occurrence. However, their co-occurrence is so frequent that they probably share aetiologically relevant factors. What do we mean if we use ‘comorbidity’ in these circumstances? In future would we use the label ‘Tourette syndrome’ to describe a set of symptoms as we do now or should we simply describe the presenting behaviour?
When we describe a condition we hope that this will lead us to identify a cause, whether genetic, traumatic, infective, degenerative or neoplastic. We diagnose a ‘disease’ when we know the cause of the condition and its course, symptomatology and consequences. A ‘syndrome’ is a cluster of symptoms and signs which often occur together: for example, an association between individuals who have tics and those who have coprolalia seems rational because these behaviours have often been noted together and they are both impulsive and uncontrollable behaviours. It may be, however, that the ‘tic’ behaviour alone, with its various possible causes, should be regarded in isolation, and the notion of a disease entity ‘Tourette syndrome’ should be abandoned.
Conclusion
The extensive range of manifestations seen in all the conditions discussed in this book would be depressing reading for many parents, who are often not aware of the implications of the original diagnosis. When we counsel parents on the future of their child our predictions will be better in individual patients when we know of genetic factors or signs which will allow us to recognize how particular children will develop. For the moment, perhaps the identification of comorbidities and other co-occurring events increases our knowledge but perhaps also increases our perplexities in knowing what to do in a situation and how best to help parents. We hope that this book will help the clinician discuss with parents what is happening to their children and explain the rationale of any treatment which is being devised.
It became clear to us as we collated the chapters for this book that we were not going to establish a clear agreed definition of what a comorbidity is. What we present is a stimulating set of essays on topics that the authors know well and where they, within the framework they had set themselves, wrestled with how they use the term ‘comorbid’. Indeed, what has become manifest is that many people with great experience in the field of neurodisability have slightly different concepts of the term. We have no doubt that others in the field will find these discussions of great interest.
REFERENCES
Bax M, Whitmore K (1987) The medical examination of children on entry to school. The results and use of neurodevelopmental assessment. Dev Med Child Neurol, 29, 40–55.
Feinstein A (1970) The pre-therapeutic classification of co-morbidity in chronic disease. J Chron Dis, 23, 455–468.
Steffenburg S, Gillberg C, Steffenburg U. Psychiatric disorders in children and adolescents with mental retardation and active epilepsy. Arch Neurol 1996, 53, 904–912.
This book was inspired by a study group of international experts drawn together by the Castang Foundation to discuss the concept of comorbidity and how it can contribute to the understanding and management of developmental disorders. Their deliberations are augmented by those of some additional contributors chosen to broaden the breadth of the book.