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Corticosteroid treatment of behaviour, language and motor regression in childhood disintegrative disorder
european journal of paediatric neurology 13 (2009) 367–369
Official Journal of the European Paediatric Neurology Society
Case study
Corticosteroid treatment of behaviour, language and motor regression in childhood disintegrative disorder Santosh R. Mordekara,*, Michael Prendergastb, Arup K. Chattopadhyayc, Peter S. Baxtera a
Ryegate Children’s Centre, Tapton Crescent Road, Sheffield S10 5RS, United Kingdom Birmingham Children’s Hospital, Birmingham, United Kingdom c Royal Hallamshire Hospital, Sheffield, United Kingdom b
article info
abstract
Article history:
Childhood disintegrative disorder (CDD) (ICD-10 F84.3) is defined by a period of normal
Received 5 March 2008
development before onset followed by gradual loss of previously acquired skills with the
Received in revised form
development of characteristic abnormalities of social, communicative and behavioural
22 May 2008
functioning.
Accepted 1 June 2008
We report two children with apparent CDD, who showed amelioration of behaviour, language and motor regression after corticosteroid treatment.
Keywords:
ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Childhood disintegrative disorder Corticosteroid
1.
Introduction
Childhood disintegrative disorder (CDD) was first reported by Theodor Heller in 1908. He described six children with severe regression in social and communication skills after apparently normal development in the first 3–4 years of life.1 Various names have been used to describe this condition viz. dementia infantilis, Heller’s syndrome, progressive disintegrative psychosis, disintegrative psychosis, pervasive disintegrative disorder, or more recently in ICD-10, other childhood disintegrative disorder (‘other’ differentiating it from Rett’s syndrome) and in DSM-IV childhood disintegrative disorder.2,3 The prognosis is usually very poor and most individuals are left with severe developmental delay especially in language and social skills. There continues to be uncertainty about the extent to which this condition differs from autistic regression.2,3 We report two children with a gradual change of personality, but subsequently diagnosed as CDD, who showed
amelioration of behaviour, language and motor regression after corticosteroid treatment.
2.
Case study
2.1.
Case 1
A previously well four and half-year-old Afrocarribean boy presented with a generalised tonic clonic seizure. Over the previous 6 months he had a history of similar episodes with tonic upgaze followed by bilateral generalised tonic clonic movements. His parents and his nursery teacher reported 2 week history of a change of personality, with loss of speech and the ability to follow simple commands accompanied by withdrawn behaviour. He had a normal birth history and early milestones with no family history of epilepsy. Neurological examination was normal.
* Corresponding author. Tel.: þ44 (0) 114 2260675; fax: þ44 (0) 114 2678296. E-mail address: [email protected] (S.R. Mordekar). 1090-3798/$ – see front matter ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2008.06.001
368
european journal of paediatric neurology 13 (2009) 367–369
He had three EEG recordings (two standard and one 24-h) over 3 weeks. The initial standard EEG and the 24 h recording (7 days later) were very abnormal and showed widespread high voltage slow activity. During the awake state frequent spike discharges were seen in a generalised distribution with a frontal and right sided emphasis. The spike discharges were less frequent during sleep. This would make the diagnosis of Landau Kleffner syndrome less likely as epileptiform discharges seen in the awake record are said to be activated in sleep. An EEG 2 weeks later showed improvement with marked diminution of the spike discharges. However, the EEG continued to show an excess of slow activity in a widespread distribution. After the first EEG he was given a single dose of Midazolam, which had no effect, and was then treated with Prednisolone (40 mg; 2 mg/kg/day). His parents reported that his behaviour was vague and distant behaviour but he was still saying single words. In the first week of treatment, his personality deteriorated and he became obtunded and aphasic. On day 8 of treatment, he started having unprovoked intermittent screaming and crying episodes. However, by day 11 he was almost back to his normal self and speaking again. He was discharged home to complete a 14 day course of Prednisolone which was then weaned by reducing the dose by 5 mg each day over a week. For a week after stopping the steroid therapy he remained well. He then had a cluster of generalised tonic clonic seizures at home. His parents did not report any personality change on this occasion. He had a trial of Clobazam for 5 days in conjunction with starting Sodium Valproate. However, he then relapsed with the development of facial and upper limb twitching, intermittent generalised tonic clonic seizures, and he became aphasic and obtunded in personality with screaming episodes. He was readmitted and restarted on Prednisolone. By day 6 of treatment with Prednisolone, he was starting to talk again and his seizures stopped. He had returned to his normal self by day 8 of steroid therapy and was discharged. He completed the 14 day course of 40 mg Prednisolone once daily and then weaned by 5 mg a week over 8 weeks. Since then he has remained seizure free on Sodium Valproate (30 mg/kg/day) and at 2 year follow-up his behaviour remained normal. Sodium Valproate has been successfully withdrawn. He has since shown normal academic school progress at 30 months follow-up.
2.2.
Case 2
A previously well four and half year old Afrocarribean girl with no family history of note was admitted to another hospital following a collapse at school. She was mildly encephalopathic (GCS 12/15) and not moving her right side. Initial investigations including CT brain scan were normal. Her right sided weakness and GCS recovered fully within 24 h and she was discharged. Two weeks later she was readmitted with a deteriorating gait with ataxic features, fluctuating level of awareness (GCS 11/ 15), and altered behaviour, becoming withdrawn and mute. As an in-patient she continued to be withdrawn and mute, unresponsive to verbal requests, with episodes of extreme agitation, in which she pulled out approximately one third of her hair and screamed for 4 days. She then developed catatoniclike behaviour for 2 weeks.
An initial EEG and one repeated 8 days later showed very frequent of high voltage slow activity suggestive of an encephalopathic disorder. As language regression was seen in the following 2 weeks, an ambulatory EEG recording was attempted to see if there were frequent spike discharges during sleep as can be seen in Landau Kleffner syndrome. This was not possible as she pulled off the electrodes. The following day, sleep was induced by chloral hydrate. No epileptiform EEG discharges were seen during sleep. An ambulatory EEG was recorded 3 weeks later to see if spikes were more frequent during sleep. Multifocal spike discharges were seen in the awake record and these were much less frequent during sleep. She was commenced on Prednisolone (2 mg/kg for 2 weeks, tapered over 1 week). Over the next 3 weeks she showed a slow improvement with fewer periods of agitation. Over the next month she started showing clear understanding of some verbal commands and developed a little speech. The improvement continued and at 48 months follow-up, she is reported to be back to her usual self with no periods of agitation or ataxia, and had returned to school with normal progress. In both children, the following investigations were normal: blood: full blood count and film, sickle screen, erythrocyte sedimentation rate, urea and electrolytes, liver function tests, amino acids, lactate, thyroid function test, antithyroid antibodies, autoantibody screen, mycoplasma titres, Measles IgG, chromosomes; urine: organic acids, amino acids, toxicology, porphyria screen; CSF: microscopy, protein, glucose, viral and bacterial cultures, Measles IgG, lactate; cardiac echo, audiology testing, ophthalmology assessment and magnetic resonance imaging (MRI) brain.
3.
Discussion
The clinical presentation was of CDD in both these children although the onset was acute. Both had normal development prior to the onset of language, motor and behaviour regression with periods of unexplained agitation and a marked personality change. In both children, the EEGs in the awake state showed epileptiform discharges. Sleep, particularly at onset, is said to have a marked activating effect on EEG epileptiform abnormalities. In both children epileptiform EEG activity decreased in sleep, which would be uncharacteristic for Landau Kleffner syndrome.4–6 Epilepsy cannot be fully excluded as a cause since these syndromes do not account for all epilepsies with behaviour, motor and language regression, but it seems unlikely. Both children showed a sustained improvement in their motor, behaviour and language at 30 months and 48 months follow-up, respectively. The differential diagnosis includes an acquired inflammatory brain disease with a symptomatic epilepsy, but the normal MRI scans; CSF microscopy and protein; erythrocyte sedimentation rate and autoantibody screen do not support this possibility. CDD was diagnosed in these two cases after a review by an experienced senior Child Psychiatrist (Table 1). CDD is a rare disorder with a reported prevalence of 0.11–0.64 per 10,000.7,8 Although sex ratio has not been estimated, male seems to outnumber female cases. The causes of regression after a period of normal development include progressive neurological disorders, chronic neuro-infection
european journal of paediatric neurology 13 (2009) 367–369
references
Table 1
Previous history of seizures Seizures at onset Paroxysmal EEG changes Fluctuation of symptoms Number of relapses (behaviour, speech) Onset of improvement after Prednisolone (days) Regular AED given during and following acute period Sustained clinical improvement and normal neurodevelopment (months)
369
Case 1
Case 2
Yes
No
Yes
No
Yes 2
Yes 2
11
21
Yes
No
30
48
or epileptic encephalopathy, but so far there is no known aetiology for CDD and is a diagnosis of exclusion.9,10 There is an increased prevalence of epilepsy in CDD.11 Usually the prognosis in CDD is very poor and most individuals are left with severe developmental delay.2 However, in our cases, both children showed sustained improvement in their motor development, language abilities and behaviour at 30 months and 48 months follow-up, respectively, which appears to have been associated with steroid therapy. Corticosteroid has been used in treatment of childhood epilepsy although a recent Cochrane review found no evidence for the efficacy or safety of corticosteroids in treating childhood epilepsies.12 There has been one case report for treatment of language regression with corticosteroid in pervasive developmental disorder with amelioration of language abilities and behaviour. However, that case had physiological, metabolic and neuropsychological disturbances similar to those found in LKS.13 We conclude children with motor regression, language regression and behavioural difficulties resembling CDD, with or without seizures, may benefit from corticosteroid treatment.
1. Heller T. Uber dementia infantilis. Z Erforsch Behandl Jugndl Schwachsinns 1908;2:17–28 [in Germany]. 2. World Health Organization. The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva: WHO; 1992. 3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV). 4th ed. Washington, DC: American Psychiatric Association; 1994. 4. Tassinari CA, Rubboli G, Volpi L, Billard C, Bureau M. Electrical status epilepticus during slow sleep (ESES or CSWS) including acquired epileptic aphasia (Landau–Kleffner syndrome). In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 3rd ed. U.K.: John Libbey; 2002 [chapter 18, p. 274]. 5. Massa R, De Saint-Martin A, Hirsch E, et al. Landau–Kleffner syndrome: sleep EEG characteristics at onset. Clin Neurophysiol 2000;111(Suppl. 2):S87–93. 6. Hirsch E, Valenti MP, Rudolf G, et al. Landau–Kleffner syndrome is not an eponymic badge of ignorance. Epilepsy Res 2006;70S:S239–47. 7. Burd L, Fisher W, Kerbeshian J. A prevalence study of pervasive developmental disorders in North Dakota. J Am Acad Child Adolesc Psychiatry 1987;26:700–3. 8. Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool children. J Am Med Assoc 2001;285: 3093–9. 9. Mouridsen SE. Childhood disintegrative disorder. Brain Dev 2003 Jun;25(4):225–8. 10. Mouridsen SE, Rich B, Isager T. A comparative study of genetic and neurobiological findings in disintegrative psychosis and infantile autism. Psychiatry Clin Neurosci 2000; 54:441–6. 11. Mouridsen SE, Rich B, Isager T. Epilepsy in disintegrative psychosis and infantile autism: a long term validation study. Dev Med Child Neurol 1999;41:110–4. 12. Gayatri N, Ferrie C, Cross H. Corticosteroids including ACTH for childhood epilepsy other than epileptic spasms. Cochrane Database Syst Rev 2007 Jan 24;(1):CD005222. 13. Stefanatos GA, Grover W, Geller E. Case study: corticosteroid treatment of language regression in pervasive developmental disorder. J Am Acad Child Adolesc Psychiatry 1995 Aug;34(8): 1107–11.
Official Journal of the European Paediatric Neurology Society
Case study
Corticosteroid treatment of behaviour, language and motor regression in childhood disintegrative disorder Santosh R. Mordekara,*, Michael Prendergastb, Arup K. Chattopadhyayc, Peter S. Baxtera a
Ryegate Children’s Centre, Tapton Crescent Road, Sheffield S10 5RS, United Kingdom Birmingham Children’s Hospital, Birmingham, United Kingdom c Royal Hallamshire Hospital, Sheffield, United Kingdom b
article info
abstract
Article history:
Childhood disintegrative disorder (CDD) (ICD-10 F84.3) is defined by a period of normal
Received 5 March 2008
development before onset followed by gradual loss of previously acquired skills with the
Received in revised form
development of characteristic abnormalities of social, communicative and behavioural
22 May 2008
functioning.
Accepted 1 June 2008
We report two children with apparent CDD, who showed amelioration of behaviour, language and motor regression after corticosteroid treatment.
Keywords:
ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Childhood disintegrative disorder Corticosteroid
1.
Introduction
Childhood disintegrative disorder (CDD) was first reported by Theodor Heller in 1908. He described six children with severe regression in social and communication skills after apparently normal development in the first 3–4 years of life.1 Various names have been used to describe this condition viz. dementia infantilis, Heller’s syndrome, progressive disintegrative psychosis, disintegrative psychosis, pervasive disintegrative disorder, or more recently in ICD-10, other childhood disintegrative disorder (‘other’ differentiating it from Rett’s syndrome) and in DSM-IV childhood disintegrative disorder.2,3 The prognosis is usually very poor and most individuals are left with severe developmental delay especially in language and social skills. There continues to be uncertainty about the extent to which this condition differs from autistic regression.2,3 We report two children with a gradual change of personality, but subsequently diagnosed as CDD, who showed
amelioration of behaviour, language and motor regression after corticosteroid treatment.
2.
Case study
2.1.
Case 1
A previously well four and half-year-old Afrocarribean boy presented with a generalised tonic clonic seizure. Over the previous 6 months he had a history of similar episodes with tonic upgaze followed by bilateral generalised tonic clonic movements. His parents and his nursery teacher reported 2 week history of a change of personality, with loss of speech and the ability to follow simple commands accompanied by withdrawn behaviour. He had a normal birth history and early milestones with no family history of epilepsy. Neurological examination was normal.
* Corresponding author. Tel.: þ44 (0) 114 2260675; fax: þ44 (0) 114 2678296. E-mail address: [email protected] (S.R. Mordekar). 1090-3798/$ – see front matter ª 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2008.06.001
368
european journal of paediatric neurology 13 (2009) 367–369
He had three EEG recordings (two standard and one 24-h) over 3 weeks. The initial standard EEG and the 24 h recording (7 days later) were very abnormal and showed widespread high voltage slow activity. During the awake state frequent spike discharges were seen in a generalised distribution with a frontal and right sided emphasis. The spike discharges were less frequent during sleep. This would make the diagnosis of Landau Kleffner syndrome less likely as epileptiform discharges seen in the awake record are said to be activated in sleep. An EEG 2 weeks later showed improvement with marked diminution of the spike discharges. However, the EEG continued to show an excess of slow activity in a widespread distribution. After the first EEG he was given a single dose of Midazolam, which had no effect, and was then treated with Prednisolone (40 mg; 2 mg/kg/day). His parents reported that his behaviour was vague and distant behaviour but he was still saying single words. In the first week of treatment, his personality deteriorated and he became obtunded and aphasic. On day 8 of treatment, he started having unprovoked intermittent screaming and crying episodes. However, by day 11 he was almost back to his normal self and speaking again. He was discharged home to complete a 14 day course of Prednisolone which was then weaned by reducing the dose by 5 mg each day over a week. For a week after stopping the steroid therapy he remained well. He then had a cluster of generalised tonic clonic seizures at home. His parents did not report any personality change on this occasion. He had a trial of Clobazam for 5 days in conjunction with starting Sodium Valproate. However, he then relapsed with the development of facial and upper limb twitching, intermittent generalised tonic clonic seizures, and he became aphasic and obtunded in personality with screaming episodes. He was readmitted and restarted on Prednisolone. By day 6 of treatment with Prednisolone, he was starting to talk again and his seizures stopped. He had returned to his normal self by day 8 of steroid therapy and was discharged. He completed the 14 day course of 40 mg Prednisolone once daily and then weaned by 5 mg a week over 8 weeks. Since then he has remained seizure free on Sodium Valproate (30 mg/kg/day) and at 2 year follow-up his behaviour remained normal. Sodium Valproate has been successfully withdrawn. He has since shown normal academic school progress at 30 months follow-up.
2.2.
Case 2
A previously well four and half year old Afrocarribean girl with no family history of note was admitted to another hospital following a collapse at school. She was mildly encephalopathic (GCS 12/15) and not moving her right side. Initial investigations including CT brain scan were normal. Her right sided weakness and GCS recovered fully within 24 h and she was discharged. Two weeks later she was readmitted with a deteriorating gait with ataxic features, fluctuating level of awareness (GCS 11/ 15), and altered behaviour, becoming withdrawn and mute. As an in-patient she continued to be withdrawn and mute, unresponsive to verbal requests, with episodes of extreme agitation, in which she pulled out approximately one third of her hair and screamed for 4 days. She then developed catatoniclike behaviour for 2 weeks.
An initial EEG and one repeated 8 days later showed very frequent of high voltage slow activity suggestive of an encephalopathic disorder. As language regression was seen in the following 2 weeks, an ambulatory EEG recording was attempted to see if there were frequent spike discharges during sleep as can be seen in Landau Kleffner syndrome. This was not possible as she pulled off the electrodes. The following day, sleep was induced by chloral hydrate. No epileptiform EEG discharges were seen during sleep. An ambulatory EEG was recorded 3 weeks later to see if spikes were more frequent during sleep. Multifocal spike discharges were seen in the awake record and these were much less frequent during sleep. She was commenced on Prednisolone (2 mg/kg for 2 weeks, tapered over 1 week). Over the next 3 weeks she showed a slow improvement with fewer periods of agitation. Over the next month she started showing clear understanding of some verbal commands and developed a little speech. The improvement continued and at 48 months follow-up, she is reported to be back to her usual self with no periods of agitation or ataxia, and had returned to school with normal progress. In both children, the following investigations were normal: blood: full blood count and film, sickle screen, erythrocyte sedimentation rate, urea and electrolytes, liver function tests, amino acids, lactate, thyroid function test, antithyroid antibodies, autoantibody screen, mycoplasma titres, Measles IgG, chromosomes; urine: organic acids, amino acids, toxicology, porphyria screen; CSF: microscopy, protein, glucose, viral and bacterial cultures, Measles IgG, lactate; cardiac echo, audiology testing, ophthalmology assessment and magnetic resonance imaging (MRI) brain.
3.
Discussion
The clinical presentation was of CDD in both these children although the onset was acute. Both had normal development prior to the onset of language, motor and behaviour regression with periods of unexplained agitation and a marked personality change. In both children, the EEGs in the awake state showed epileptiform discharges. Sleep, particularly at onset, is said to have a marked activating effect on EEG epileptiform abnormalities. In both children epileptiform EEG activity decreased in sleep, which would be uncharacteristic for Landau Kleffner syndrome.4–6 Epilepsy cannot be fully excluded as a cause since these syndromes do not account for all epilepsies with behaviour, motor and language regression, but it seems unlikely. Both children showed a sustained improvement in their motor, behaviour and language at 30 months and 48 months follow-up, respectively. The differential diagnosis includes an acquired inflammatory brain disease with a symptomatic epilepsy, but the normal MRI scans; CSF microscopy and protein; erythrocyte sedimentation rate and autoantibody screen do not support this possibility. CDD was diagnosed in these two cases after a review by an experienced senior Child Psychiatrist (Table 1). CDD is a rare disorder with a reported prevalence of 0.11–0.64 per 10,000.7,8 Although sex ratio has not been estimated, male seems to outnumber female cases. The causes of regression after a period of normal development include progressive neurological disorders, chronic neuro-infection
european journal of paediatric neurology 13 (2009) 367–369
references
Table 1
Previous history of seizures Seizures at onset Paroxysmal EEG changes Fluctuation of symptoms Number of relapses (behaviour, speech) Onset of improvement after Prednisolone (days) Regular AED given during and following acute period Sustained clinical improvement and normal neurodevelopment (months)
369
Case 1
Case 2
Yes
No
Yes
No
Yes 2
Yes 2
11
21
Yes
No
30
48
or epileptic encephalopathy, but so far there is no known aetiology for CDD and is a diagnosis of exclusion.9,10 There is an increased prevalence of epilepsy in CDD.11 Usually the prognosis in CDD is very poor and most individuals are left with severe developmental delay.2 However, in our cases, both children showed sustained improvement in their motor development, language abilities and behaviour at 30 months and 48 months follow-up, respectively, which appears to have been associated with steroid therapy. Corticosteroid has been used in treatment of childhood epilepsy although a recent Cochrane review found no evidence for the efficacy or safety of corticosteroids in treating childhood epilepsies.12 There has been one case report for treatment of language regression with corticosteroid in pervasive developmental disorder with amelioration of language abilities and behaviour. However, that case had physiological, metabolic and neuropsychological disturbances similar to those found in LKS.13 We conclude children with motor regression, language regression and behavioural difficulties resembling CDD, with or without seizures, may benefit from corticosteroid treatment.
1. Heller T. Uber dementia infantilis. Z Erforsch Behandl Jugndl Schwachsinns 1908;2:17–28 [in Germany]. 2. World Health Organization. The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva: WHO; 1992. 3. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-IV). 4th ed. Washington, DC: American Psychiatric Association; 1994. 4. Tassinari CA, Rubboli G, Volpi L, Billard C, Bureau M. Electrical status epilepticus during slow sleep (ESES or CSWS) including acquired epileptic aphasia (Landau–Kleffner syndrome). In: Roger J, Bureau M, Dravet C, Genton P, Tassinari CA, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 3rd ed. U.K.: John Libbey; 2002 [chapter 18, p. 274]. 5. Massa R, De Saint-Martin A, Hirsch E, et al. Landau–Kleffner syndrome: sleep EEG characteristics at onset. Clin Neurophysiol 2000;111(Suppl. 2):S87–93. 6. Hirsch E, Valenti MP, Rudolf G, et al. Landau–Kleffner syndrome is not an eponymic badge of ignorance. Epilepsy Res 2006;70S:S239–47. 7. Burd L, Fisher W, Kerbeshian J. A prevalence study of pervasive developmental disorders in North Dakota. J Am Acad Child Adolesc Psychiatry 1987;26:700–3. 8. Chakrabarti S, Fombonne E. Pervasive developmental disorders in preschool children. J Am Med Assoc 2001;285: 3093–9. 9. Mouridsen SE. Childhood disintegrative disorder. Brain Dev 2003 Jun;25(4):225–8. 10. Mouridsen SE, Rich B, Isager T. A comparative study of genetic and neurobiological findings in disintegrative psychosis and infantile autism. Psychiatry Clin Neurosci 2000; 54:441–6. 11. Mouridsen SE, Rich B, Isager T. Epilepsy in disintegrative psychosis and infantile autism: a long term validation study. Dev Med Child Neurol 1999;41:110–4. 12. Gayatri N, Ferrie C, Cross H. Corticosteroids including ACTH for childhood epilepsy other than epileptic spasms. Cochrane Database Syst Rev 2007 Jan 24;(1):CD005222. 13. Stefanatos GA, Grover W, Geller E. Case study: corticosteroid treatment of language regression in pervasive developmental disorder. J Am Acad Child Adolesc Psychiatry 1995 Aug;34(8): 1107–11.