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Neurogenic Language Disorders in Children

Related Books Title: The Sciences of Aphasia: From Therapy to Theory Edited by: Was Papathanaslou & Ria De Bleser (eds) ISBN: 0080440738 Title: Speech-Language Pathology Author: Carl R. Schneiderman & Robert E. Potter ISBN: 0126278741 Title: Manifestations of Aphasia Symptoms in Different Languages Author: Michel Paradis (ed) ISBN: 0080436625 Title: Foundations of Stuttering Author: Marcel E. Wingate ISBN: 0127594515 Title: Clinical Phonetics & Phonology: Making Sense of Disordered Speech Author: Sara Howard & Barry Heselwood ISBN: 0123569184 Title: Concise Encyclopedia of Language Pathology Author: Franco Fabbro (ed) ISBN: 0080431518 Related Journals Journal of Fluency Disorders Editor: Richard Curlee Journal of Communication Disorders Editor: Theodore Glattke Journal of Neurolinguistics Editors: John Marshall & Michel Paradis Brain & Language Editor: Harry A. Whitaker

For further information on these titles, visit www.elsevier.com For free abstracts and sample copies of our journals, visit www.ScienceDirect.com

Neurogenic Language Disorders in Children EDITED BY

Franco Fabbro "E. Medea"Scientific Institute, University of I]dine

INTERNATIONAL ASSOCIATION OF LOGOPEDICS AND PHONIATRICS

2004

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© 2004 Elsevier Ltd. All rights reserved. This work is protected under copyright by Elsevier Ltd., and the following terms and conditions apply to its use: Photocopying Single photocopies of single chapters may be made for personal use as allowed by national copyright laws. Permission of the Publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use. Permissions may be sought directly from Elsevier's Rights Department in Oxford, UK: phone (+44) 1865 843830, fax (+44) 1865 853333, e-mail: [email protected]. Requests may also be completed on-line via the Elsevier homepage (http://www.elsevier.com/locate/permissions). In the USA, users may clear permissions and make payments through the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA; phone: (+1) (978) 7508400, fax: (+1) (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service (CLARCS), 90 Tottenham Court Road, London W1P 0LP, UK; phone: (+44) 20 7631 5555; fax: (+44) 20 7631 5500. Other countries may have a local reprographic rights agency for payments. Derivative Works Tables of contents may be reproduced for internal circulation, but permission of the Publisher is required for external resale or distribution of such material. Permission of the Publisher is required for all other derivative works, including compilations and translations. Electronic Storage or Usage Permission of the Publisher is required to store or use electronically any material contained in this work, including any chapter or part of a chapter. Except as outlined above, no part of this work may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without prior written permission of the Publisher. Address permissions requests to: Elsevier's Rights Department, at the fax and e-mail addresses noted above. Notice No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.

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@ The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper). Printed in The Netherlands.

V

ACKNOWLEDGEMENTS This book collects the papers presented at the International Symposium of the IALP Aphasia Committee on Neurogenic Language Disorders in Children, held in Cividale del Friuli (Udine, Italy), on 9-10 May 2003. The Symposium was organized by Scientific Institute "E.Medea" of Association "la Nostra Famiglia", the Faculty of Education of the University of Udine, and IALP. Financial support was granted by Fondazione CRUP. The success of the meeting, in terms of scientific innovation and public participation, was also due to the work of Dr. Alessandro Tavano, Scientific Secretary to the Symposium, in dealing with both scientific and organizational issues. The administrative board and organizational secretariat of IRCCS "E.Medea" of San Vito al Tagliamento (Pordenone. Italy) and Pasian di Prato (Udine, Italy) provided invaluable assistance and deserve the utmost gratitude. Editorial assistance to this volume was provided by Dr. Alessandro Tavano and Dr. Barbara Alberti.

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vii

Contents 1

Neurogenic Language Disorders in Children: An Introduction. Franco Fabbro

1-7

2

Pathophysiological Basis of Aphasia and Verbal Outome in LandauKleffner Syndrome. Marie-Noelle Metz-Lutz and Steve Majerus

9-23

3

Acquired Language Disorders and Epilepsy: From Landau -Kleffner Syndrome to Autistic Regression. Roberto Tuchman

25-35

4

Persistent Subtle Language and Learning Deficits in a Child with Acquired Epileptiform Opercular Syndrome. Paola Cipriani, Anna M. Chilosi, Claudia Casalini, Lucia Pfanner, Annarita Ferrari, Daniela Brizzolara and Renzo Guerrini

37-48

5

Cerebral Language Lateralization and Early Linguistic In Children With Focal Brain Lesions. Anna M. Chilosi, Chiara Pecini, Paola Cipriani, Daniela Brizzolara, Paola Brovedani, Giovanni Ferretti, Lucia Pfanner and Giovanni Cioni

49-63

6

Language Disorders Associated With Paroxysmal Abnormalities During NREM Sleep After Very Early Brain Lesions. Franco Fabbro, Alessandro Tavano, Guido Cristofori and Renato Borgatti

65-85

7

Language and Phonological Awareness Abilities of Children treated for Posterior Fossa Tumor. Bruce E. Murdoch, Kimberley M. Docking, and Elizabeth C. Ward

87-126

8

Language Development in Children with Cerebellar Malformations. Renato Borgatti, Alessandro Tavano, Guido Cristofori and Franco Fabbro

127-145

viii 9

Contents Crossed Aphasia in Children. Peter Marien, Philippe Paquier, Sebastiaan Engelborghs and Peter P. De Deyn

147-180

10

Recognizable Spontaneous Language Characteristics in a Young Adult Twelve Years After She Became Aphasic as a Child. Philippe F. Paquier, Valerie R. van Maldeghem, Hugo R. van Dongen and Wouter L. Creten

181 -197

11

Recovery From Aphasia After Polytrauma in a Czech Child: What Is Lost and What Is Left. Helena Leheckovd

199-229

12

Persistent Acquired Childhood Aphasia. Isabel Pavao Martins

231-251

Introduction

1

1

NEUROGENIC LANGUAGE DISORDERS IN CHILDREN: AN INTRODUCTION Franco Fabbro "E. Medea" Scientific Institute, Polo del Friuli Venezia Giulia, Italy University ofUdine, Italy

INTRODUCTION Language disorders in children are one of the most frequent causes of difficulties in communication, social interaction, learning and academic achievement. It has been estimated that over 5% of children present with some kind of language disorders (Fabbro, 1999). Language disorders in children are distinguished into: 1) acquired language disorders; 2) language disorders due to pre-perinatal lesions; 3) developmental language disorders; 4) language disorders in genetic syndromes with mental retardation (Fabbro, 2000a).

ACQUIRED LANGUAGE DISORDERS IN CHILDREN Acquired language disorders in children can be distinguished into three main groups: acquired childhood aphasia, language disorders following posterior cranial fossa lesions (PCF) and acquired epileptiform aphasias. Acquired childhood aphasia Acquired childhood aphasia refers to language deficits following brain lesions after the age of acquisition of the first sentences, generally after the age of 2. The most common etiological causes include vascular lesions, trauma, tumors and infections involving the language dominant hemisphere {see Marien et al., this volume, for a review of the cases of "crossed

2


aphasia in children" or acquired childhood aphasia after right hemisphere lesions in righthanded children). Before the late 1970s it was believed that aphasia in children was characterized by "negative symptoms" such as mutism, dysarthria, reduction in sentence length and telegraphic speech. More recently, neurolinguistic tests, including systematic analyses of spontaneous and descriptive speech, and comprehensive language batteries have allowed researchers to evaluate the different aspects of language (for example, auditory, semantic and syntactic comprehension; syllable, word and sentence repetition; naming and sentence production). In children with acquired aphasia, these methods highlight positive symptoms such as logorrhea, paraphasia, perseverations and neologisms (see Leheckovd, Paquier et al., this volume). Moreover, these symptoms correlate with clinical aphasic profiles and lesion localizations similar to those of adults. Indeed, at least in their acute phase and lesional phase aphasic syndromes in children have been found similar to most of the aphasic syndromes in adults (cf. Van Hout, 2000). Recovery of acquired childhood aphasia remains one of the most debated issue still today. Before the early 1970s language recovery in childhood aphasia was believed to be rapid and complete (Lenneberg, 1967). Later studies have shown that, even if language seems to return to normal, non-linguistic abilities (such as working memory) are affected too. Therefore, irrespective of age and lesion etiology, children encounter educational difficulties. These findings stress the need for rehabilitation and educational/professional support in the chronic stages of childhood aphasia (see Pavao Martins, this volume). Language disorders following PCF lesions Almost 50% of brain tumors in children involve the cerebellum (medulloblastomas, cerebellar astrocytomas, ependymomas; cf. Becker and Jay, 1990), a structure localized in the posterior cranial fossa (PCF). In 10% of the children surgical removal of the tumor can cause a syndrome characterized by complete but transient loss of speech (transient cerebellar mutism), followed by dysarthria. This syndrome is frequent in patients aged 2-16 years. There have been reports of patients who became mute within 12 to 48 hours of surgery and the period of mutism lasted from 1.5 to 12 week after onset. Transient cerebellar mutism seems to be due to a diaschisis on the nervous structures of the brain stem which are responsible for verbal expression (cf. Pollak, 1997; Esposito et al., 1999). Recently, the cerebellum was also attributed an important role in the regulation of linguistic, cognitive and affective functions (cf. Fabbro, 2000b). Resection of cerebellar tumors both in childhood and adult age may cause a "Cognitive - Affective Syndrome" (Levisohn et al, 2000; Riva and Giorgi, 2000) characterized by expressive language deficits, verbal memory deficits (mainly after right hemisphere cerebellar lesions), deficits in the visuo-spatial functions (after left hemisphere cerebellar lesions) and deficits in affect regulation (after vermis damage) (see Murdoch et al., this volume). Deficits in the development of linguistic and cognitive functions were also described in patients with malformation lesions localized to the cerebellum (see Borgatti et al., this volume).

Introduction

3

Acquired Epileptiform Aphasias The main clinical syndrome of acquired epileptiform aphasias is acquired aphasia with convulsive disorder. It manifests in children, generally at 3-8 years of age. It was first described by Landau and Kleffner (1957); hence, its definition as Landau-Kleffner syndrome (LKS) (cf. Lebrun and Fabbro, 2002). It affects children with normal psychomotor and linguistic development. Language disruption may occur before or after seizures. At onset, the most frequent symptom is breakdown in language comprehension, whereas hearing and interpretation of non-linguistic sounds remain intact (word deafness). Following the breakdown in comprehension, expressive language and vocabulary decay progressively, too. Unlike other forms of acquired aphasia, in LKS verbal expression may be fluent with many semantic and verbal paraphasias, neologisms and jargon. There may be an almost full recovery after the first episode, even after a short period of time (days or weeks). In other cases, recovery may be very slow (months or years). Relapse is frequent and often the development of aphasia is fluctuating, with several aphasic episodes. The clinical picture stabilizes before the end of adolescence. Language recovery is sometimes very good, at other times it is defective, in which case subjects present with aphasic disorders throughout their lives (see Metz-Lutz and Majerus, this volume). Epileptic manifestations are heterogeneous (partial motor seizures, atypical absence, generalized tonic-clonic seizures) and their frequency is quite variable. Children with LKS often show a rather limited number of seizures which can be treated with anti-epileptic drugs. Seizures may disappear completely before the age of 15. In a review of the first cases described, Mantovani and Landau (1981) reported that, after more than 20 years, none of their patients still had seizures. On waking EEG paroxysmal abnormalities in children with LKS may vary: bilateral temporal or temporoparietal spikes, bilateral 1-3 Hz slow wave activity over the temporal regions, generalized sharp waves or slow wave discharges, and multifocal or unilateral spikes. The background rhythm of the EEG in waking state is normal. Generally, the epileptic focus is never stable, even if statistically it tends to be over the left temporal regions. An extremely significant feature which seems to be common to all children with LKS is an EEG with bilateral (focalized) paroxysmal abnormalities during non-REM sleep which is constantly associated with regression of language functions (cf. Fabbro and Zucca, 2000). Recently, many other clinical syndromes were associated to Landau-Kleffner Syndrome, and they include Acquired Epileptiform Opercular Syndrome (AEOS) (see Cipriani et al., this volume), the Continuous Spike-Waves during Slow Sleep (CSWS), the Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS), and the Autistic Regression with an Epileptiform EEG. All of these clinical syndromes are associated with different degrees of cognitive disorders or mental retardation and language disorders (see Tuchman, this volume).

4


LANGUAGE DISORDERS DUE TO PRE-PERINATAL LESIONS The most frequent cause of prenatal lesion is cerebral palsy. The incidence of cerebral palsy of pre-perinatal origin is approximately 2 in 1000 births. Of these cerebral palsy cases approximately one-third have hemiplegia. The underlying unilateral hemispheric brain injury is supposed be due to a thrombotic, vasospasmic or embolic episode in the middle cerebral and/or the internal carotid artery. Between 30% and 40% of such hemiplegic cases develop a cerebral seizure disorder. As documented by many studies, the neuropsychological sequelae of early brain damage are relatively mild if compared with those of adults. Besides, contrary to the case of adults, not all cases of early brain damage show a clear-cut correlation of symptoms with characteristics of the lesion. The degree of preservation or recovery of language and other cognitive functions may be dependent on several factors such as time of injury, side of lesion, size of lesion; presence of epilepsy and role of anticonvulsant therapy. Numerous studies have been carried out to verify the effects of early left hemisphere damage (LHD) versus right hemisphere damage (RHD) on cognitive development, with particular attention to language development. Some studies show that, regardless of the affected hemisphere, linguistic functions tend to be preserved, while other studies reveal greater difficulties in children with left hemisphere damage in the acquisition of vocabulary and grammar (see Chilosi et al, this volume). Numerous reports demonstrate that seizures accompanying early brain injury are associated with poorer language and cognitive outcome (cf. Vargha-Khadem et al., 1992). The pathophysiological mechanism determining a deficit in cognitive and linguistic development in children with early hemisphere damage and epilepsy has not been clearly identified yet. Some authors have suggested that antiepileptic therapy may play an unfavorable role, while other authors have drawn the attention to some variables such as the presence of epileptiform abnormalities in NREM sleep, which associate these clinical pictures to Landau-Kleffner Syndrome (see Fabbro et al., this volume).

DEVELOPMENTAL LANGUAGE DISORDERS Developmental language disorders (DLDs) — also known as Specific Language Impairment (SLI) or Developmental Dysphasia — are language acquisition disorders manifesting in children with normal nonverbal intellectual development in the absence of hearing loss, frank neurological deficits, severe emotional disorders and environmental differences and deprivation. Children with specific language impairment show a very slow and laborious language development. They speak late as compared to peers and show comprehension and production disorders affecting more than one linguistic level (phonological, morphological, lexical, syntactic and semantic). Developmental language disorders are to be distinguished from acquired language disorders (acquired aphasia) affecting children with normal language development until their occurrence. The frequency of DLDs in children aged 5-6 years is surprisingly high, around 4% (Fletcher and Hall, 1993). Many classifications for

Introduction

5

developmental language disorders in children have been proposed, some of which are based on statistical criteria (e.g., the International Classification of Diseases, 10th Edition, ICD -10th, 1992), others on clinical data (Rapin, 1996). In the ICD-10th classification developmental language disorders are described in section F80 encompassing three syndromes: 1) Specific speech articulation disorders (F 80.0): children use sounds that are below the norm as compared to their mental age, whereas all other linguistic tasks are in the normal range; 2) Expressive language disorder (F80.1): the expressive spoken language ability of the children is markedly below the appropriate level for their mental age, and there may be an alteration in speech articulation; 3) Receptive language disorder (F80.2): the receptive ability of the children to understand spoken language is markedly below the appropriate level for their mental age and expressive language will also be markedly affected. Many studies have investigated the causes of DLDs (cf. Bishop, 1997; Leonard, 1999). At the pathophysiological level, some children are unable to discriminate language sounds at the normal speech speed (Merzenich et al, 1996), in others expressive language disorders are associated to developmental verbal dyspraxia (Shriberg et al., 1997) or to language acquisition deficits with a genetic origin (Gopnik, 2000). Several studies have shown that many children with DLDs present with paroxysmal abnormalities in non-REM sleep similar to those found in LandauKleffner Syndrome (Duvelleroy-Hommet et al, 1995). In particular, more than 50% of children with receptive language disorder (F80.2) have epileptiform abnormalities in NREM sleep (Picard et al, 1998; Fabbro et al, 2000). According to preliminary studies, an association of pharmacological treatment with valproic acid to speech therapy markedly improves language development in these children. Recently, Guerreiro et al. (2002) have made a relevant progress in understanding the causes of DLDs. They systematically studied the neuroimaging findings (MRI 2.0 T scanner) in a group of children with DLDs. All the children presented with pictures of polymicrogyria that were related to the degree of severity of dysphasia. Their findings suggest that developmental language disorders are associated to malformations of cortical development.

LANGUAGE DISORDERS RETARDATION

IN

GENETIC

SYNDROMES

WITH

MENTAL

An important line of research in modern clinical neurolinguistics is the study of language deficits in genetic syndromes with mental retardation. Recent studies have shown that some genetic syndromes such as Down Syndrome, Williams Syndrome, Fragile X Syndrome, Turner Syndrome, Prader-Willi Syndrome, etc., have deficits that are specific to each of them. For example, in Down Syndrome, the phonetic-phonological and the morphosyntactic levels are particularly affected, while in Williams Syndrome these levels are sufficiently spared, while the pragmatic level is impaired (cf. Rondal and Edwards, 1997). Language deficits peculiar to genetic syndromes are correlated with specific neurofunctional alterations that are typical of each of these pictures (cf. Tager-Flusberg, 1999).

6


CONCLUSION The different neurogenic language disorders described here and discussed in detail by the authors who contributed to this volume suggest that language disorders in children, both acquired and developmental, should be managed by an interdisciplinary approach. Each single disorder should also be studied keeping in mind the whole range of childhood language disorders.

REFERENCES Becker, L.E. and V. Jay (1990). Tumors of the central nervous system in children. In: Management of Childhood Brain Tumors (Deutsch M., ed.), pp. 5-51. Kluwer, Boston. Bishop, D. V. (1997). Uncommon Understanding. Development and Disorders of Language Comprehension in Children. Psychology Press, Hove. Duvelleroy-Hommet, C, C. Billard, B. Lucas, P. Gillet, M. A. Barthez, J. J. Santini, E. Degiovanni, F. Henry, B. De Toffol and A. Autret (1995). Sleep EEG and developmental dysphasia: Lack of consistent relationsip with paroxysmal EEG activity during sleep. Neuropediatrics, 26, 14-18. Esposito, A., G. Demeurisse, B. Alberti and F. Fabbro (1999). Complete mutism after midbrain periaqueductal gray lesion. NeuroReport, 10, 681-685. Fabbro, F. (1999). Concise Encyclopedia of Language Pathology. Pergamon, Oxford. Fabbro, F. (2000a). Languages Disorders in Children: An Introduction. Saggi, 26, 9-12. Fabbro, F. (2000b). Introduction to language and cerebellum. JNeuroling, 13, 83-94. Fabbro, F. and C. Zucca (2000). Acquired neuropsychological disorders in children with epilepsy. Saggi, 26, 23-29. Fabbro, F., C. Zucca, M. Molteni and R. Borgatti (2000). EEG abnormalities during slow sleep in children with developmental language disorders. Saggi, 25, 41-48. Fletcher, P. and D. Hall (1993). Specific Speech and Language Disorders in Children. Singular, San Diego. Gopnik, M. (2000). The investigation of genetic dysphasia. Saggi, 26, 31-40. Guerreiro, M. M., S. R. Hage, C. A. Guimaraes, D. V. Abramides, W. Fernandes, P. S. Pacheco, A. M. Piovesana, M. A. Montenegrol and F. Cendes (2002). Developmental language disorders associated with polymicrogyria. Neurology, 59, 245-250. International Statistical Classification of Diseases and Related Health Problems. Tenth Revision (1992). World Health Organization, Geneva. Landau, W. M. and F. R. Kleffner (1957). Syndrome of acquired aphasia with convulsive disorder in children. Neurology, 7, 523-530. Lebrun, Y. and F. Fabbro (2002). Language and Epilepsy. Whurr, London. Lenneberg, E. H. (1967). Biological Foundations of Language. John Wiley & Sons, New York.

Introduction

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Leonard, L. B. (1998). Children with Specific Language Impairment. MIT Press, Cambridge. Levishon, L., A. Cronin-Golomb and J. D. Schmahmann (2000). Neuropsychological consequences of cerebellar tumor resection in children. Brain, 123, 1041-1050. Mantovani, J. F. and W. M. Landau (1980). Acquired aphasia with convulsive disorder: Course and prognosis. Neurology, 30, 524-529. Merzenich, M. M., W. M. Jenkins, P. Johnston, et al. (1996) Temporal processing deficits of language-learning impaired children ameliorating by training. Science, 271, 77-81. Picard, A., F. Cheliout Heraut, M. Bouskraoui, M. Lemoine, P. Lacert and J. Delattre (1998). Sleep EEG and developmental dysphasia. Dev Med Child Neurol, 40, 595-599. Pollack, I. F. (1997). Posterior fossa syndrome. Int RevNeurobiol, 41, 411-432. Rapin, I. (1996). Preschool Children with Inadequate Communication. Mac Keit Press, London. Riva, D. and C. Giorgi (2000). The Cerebellum contributes to higher functions during development. Brain, 123, 1051-1061. Rondal, J. A. and S. Edwards (1997). Language in Mental Retardation. Whurr, London. Shriberg, L. D., D. M. Aram and J. Kwiatkowski (1997). Developmental apraxia of speech. J Speech Hear Res, 40, 273-285. Tager-Flusberg, H. (1999). Neurodevelopmental Disorders. The MIT Press, Cambridge. Van Hout, A. (2000). An outline of acquired aphasia in children. Saggi, 26, 13-21. Vargha-Khadem, F., E. Isaacs, S. Van der Werf, S. Robb, J. Wilson (1992). Development of intelligence and memory in children with hemiplegic cerebral palsy. Brain, 115, 315329.


Pathophysiology of Landau-Kleffner Syndrome

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PATHOPHYSIOLOGICAL BASIS OF APHASIA AND VERBAL OUTCOME IN LANDAU-KLEFFNER SYNDROME Marie-Noelle Metz-Lutz Louis Pasteur University, France Steve Majerus University of Liege and Fonds National de la Recherche Scientifique, Belgium

Abstract Acquired childhood aphasia with epilepsy described by Landau and Kleffncr (LKS) in 1957, differs, by its clinical features and prognosis, from other types of aphasia in children due to brain structural lesions. Several critical features appear to influence consistently the prognosis of language disorder: the age at onset and the duration of language disorder associated with EEG abnormalities during wakefulness and sleep and the location of the epileptic focus. In order to elucidate the pathophysiological basis of epileptic aphasia and particularly of its poor outcome, we reexamine neuropsychological, electrophysiological and neuro-imaging data from the long-term follow-up study of several cases of Landau and Kleffner Syndrome (LKS). Our neuropsychological findings show that although the outcome of language abilities is variable, the common residual verbal disorders associate an impaired phonological short-term memory with a permanent one-ear extinction on dichotic listening tests contraleral to the temporal cortex previously affected by the epileptic focus. To check the hypothesis of a permanent dysfunction in the auditory system suggested by these findings, we studied auditory event-related potentials studies in order to localize the level of the dysfunction in auditory language processing and along the auditory pathways. Using H215O labeled positron emission tomography (PET), we compared the brain activation for immediate serial recall of lists of 4 words, contratsted to single word repetition in three recovered LKS patients and 14 healthy controls. Both ERP's and PET's findings suggest that the residual verbal impairments at the late outcome of LKS might indeed be related to persistent dysfunction in the temporal regions that were involved in the epileptic focus during the active phase.

Keywords: childhood epilepsy, Landau-Kleffner Syndrome, language, phonological shortterm memory, pathophysiology, brain imaging

10


INTRODUCTION In 1957, Landau and Kleffner reported the cases of six children, instructed in a deaf institute of Saint Louis-Missouri, who developed aphasia in relation to convulsive disorder. They defined the syndrome as acquired childhood aphasia with convulsive disorder, called several years later Landau-Kleffner Syndrome (LKS). Following this seminal report, no new cases of acquired epileptic aphasia were described until 1968. From this date, an increasing number of reports were published providing deeper analysis of the aphasic symptoms, the electrophysiological features of epileptic discharges and the outcome of LKS. In 1992, William Landau's editorial in Annals of Neurology defined the label "Landau-Kleffner Syndrome" "an eponymic badge of ignorance" (Landau, 1992). Indeed, the still prevailing use of the generic label seems to imply that our knowledge about the aetiology, pathological physiology and therapy of the disease has made no significant progress during the 35-year history of this clinical phenomenon. Have we really made no advancements in the understanding of the pathophysiological basis of epileptic childhood aphasia or was Landau overly pessimistic in his appraisal of the scientific literature? In the present paper, we intend to provide a more optimistic review of the different studies aimed at understanding the relationship between the two main symptoms of this disease, i.e. epilepsy and aphasia. Firstly, we will summarize the main clinical and electrophysiological features of the syndrome and discuss their relationships with other agerelated epileptic conditions. From a set of recent metabolic and electrophysiological findings obtained both during the active phase and after recovery of LKS, we will set out a provisional pathophysiological account of epileptic aphasia and its residual verbal impairment.

CLINICAL FEATURES OF ACQUIRED EPILEPTIC APHASIA Beaumanoir (1992) reviewed about 200 cases described in 57 papers published between 1968 and 1990. In the following decade, no less than 145 papers were devoted to LKS adding 118 new clinical descriptions. This set of case reports provides a rather sound outline of the common clinical features of acquired epileptic aphasia. Epileptic disorders Despite its rarity - in a twenty-year cohort study of 440 epileptic children, Landau-Kleffner Syndrome represents less than 0.5 % (Kramer et al, 1998) - the syndrome comprises very typical features. It is characterised by a sudden onset between the age of 3 and 8 in children with otherwise usually normal neurocognitive development. In 70% of the cases, the onset is before age 6 and rarely occurs after the age of 8 (7%). Less than 13% of the cases may have had an impaired language development. Overt epileptic seizures are not present in all LKS children, only 72% of them present at least one seizure. One third experiences only one


11

seizure, usually at the beginning of the disease. When present, seizures are of various types, but generalised or partial motor seizures are the most frequent. Whatever seizures are present, the EEG is always abnormal with repeated large-amplitude spikes followed by a large slow wave. During wake, these spike-wave discharges (SWDs) occurring on an almost normal background activity have a focal organisation (Figure 1). Usually the epileptic focus is unilateral. The observation of bilateral or multiple foci is not rare and raises the issue of secondary epileptic foci. Initially focal, the SWDs progressively spread to the whole hemisphere, but remain predominant over the temporal derivations.

Figure 1 — A Landau-Kleffner Syndrome typical EEG recorded during wakefulness showing paroxysmal spike-wave discharges (SWDs). The higher amplitude of SWDs over the left temporal electrodes (C3/T3; T3/O1) is indicative of the temporal focus of SWDs.

Figure 2 — LKS EEG recorded during sleep showing an aspect of continuous spike wave discharges during slow sleep (CSWSS).

12


During sleep, SWDs increase in frequency and spread to the contralateral hemisphere, leading to an aspect of continuous spike wave discharges during slow sleep (CSWSS) (Figure 2), which covers at least 80% of the sleep time. This sleep EEG profile, in the presence of nonlesional acquired childhood aphasia, may be considered as a hallmark for the diagnosis of LKS. Typical neuropsychological impairments Aphasia is the first symptom in 54% of LKS case reports. Verbal impairment begins with comprehension disorder and auditory agnosia in 85% of cases. Expressive disorders appear progressively and are characterised by vocabulary loss and speech reduction leading progressively to muteness. The severe deficits in auditory comprehension are the most common feature of LKS. Often LKS children are thought, at first, to be deaf, although audiometric investigations show normal hearing. Auditory disorders often appear like an auditory agnosia involving both verbal and non-verbal discrimination (Koeda & Kohno, 1992; Maquet et al, 1995). However, an in-depth evaluation of auditory discrimination evidences a dissociation between the discrimination of environmental sounds and phonological auditory discrimination, suggesting that the primary deficit of the receptive aphasia is an impairment of auditory phonological discrimination rather than a generalised auditory agnosia (Korkman et al, 1998; Metz-Lutz et al, 1999b). In most cases reported in the literature, expressive language impairments follow the onset of auditory comprehension deficits. Expressive disorders typically begin either with a progressive loss of vocabulary or phonological disturbances. In one recent case report, stuttering was the first symptom (Tutuncuoglu et al, 2002). Some authors have seen the expressive disorders of LKS as secondary to the impairment of phonological decoding. Expressive language disorders gradually increase and children become mute within several weeks. However, various patterns of expressive disorders have been described with agrammatism, echolalia, anomia or phonetic distortions (Paquier et al, 1992). In contrast to childhood aphasia due to focal lesions, paraphasia and neologisms are frequent aphasic symptoms observed before the complete loss of expressive language that may last several months, even years, if antiepileptic treatment is ineffective. Behavioural impairments with hyperactivity are mentioned in 78% of reported LKS cases. Landau and Kleffner already mentioned attention disorders and hyperactivity, which they viewed as a psychological reaction to impaired auditory comprehension. Preservation of nonverbal abilities is another common feature of LKS. This allows the use of gestures or lipreading as an alternative mode of communication. Figure 3 illustrates the typical performance profile on the different subtests of the Wechsler Intelligence Scale for Children Revised (WISC-R) showing very poor performances on the verbal subtests, particularly the digit span and vocabulary tests. The only disturbed nonverbal subtest is typically the coding test that requires attention capacities.


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Figure 3 — Typical performance profile on the Wechsler Intelligence Scale for Children Revised observed in LKS. The stars indicate the subtests which are the more systematically affected.

CLINICAL EVOLUTION Along the course of LKS, the degree of expressive impairments fluctuates. Periods of transient recovery are often observed after the introduction or change of anti-epileptic medication that successfully normalises the EEG, for several weeks or months ( Mantovani & Landau, 1980; Dugas et al, 1982; Marescaux et al, 1990). Several group studies emphasised the almost parallel fluctuation of aphasic disorders and EEG abnormalities and discussed the pharmacological sensitivity of both symptoms (Marescaux et al, 1990; Paquier et al, 1992; Robinson, Baird, Robinson, & Simonoff, 2001). They showed that medication active on the GABAergic receptors like Benzodiazepine (BDZ) favourably influences epileptic and aphasic symptoms, but most often only transiently. Conversely, medication typically active in focal epilepsy, particularly in temporal lobe epilepsy, like carbamazepine, usually worsens epilepsy, aphasia and behavioural disorders (Beaumanoir, 1992). Although their mode of action remains unknown, the corticosteroids have been shown to be useful after relapse of epilepsy and aphasia following an initial treatment by BDZ (Marescaux et al, 1990). According to the specific pattern of aphasic disorders involving primarily auditory comprehension, the use of a manual language has been proposed to prevent continuing problems with communication (Baynes et al, 1998; Perez et al, 2001). In this way, rehabilitation strategies involving signed language or cued speech have been shown to be adequate to bypass language deprivation during the active period of LKS. Indeed, the active

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period of epileptic aphasia ranging from 3 to 10 years overlaps the most critical period for the development of phonological and syntactic skills as well as for verbal learning.

LATE OUTCOME OF LKS While epileptic seizures and EEG abnormalities completely disappear at the age of 12 or 13 (Dugas et al, 1982; Mantovani & Landau, 1980; Paquier et al, 1992), recovery of receptive and productive language is variable. The verbal outcome seems to be poorer in LKS than in acquired childhood aphasia related to head injury. Moreover, in LKS outcome appears to be better for late-onset aphasic disorders, in contrast to childhood aphasia consecutive to an acquired brain lesion (Bishop, 1985; Beaumanoir, 1992; Kaga, 1999). Finally, poorer outcome appears to be related to the duration of epileptic aphasia (Metz-Lutz et al, 1999b; Robinson et al, 2001). Some children recover normal or near to normal written and oral language (Mantovani & Landau, 1980; Soprano et al, 1994; Robinson et al, 2001). However, most LKS patients show difficulties, affecting phonological aspects of language processing most severely (Zardini et al, 1995; Metz-Lutz et al, 1996; Metz-Lutz et al, 1999a). Chronic auditory agnosia has been described in the presence of the most unfavourable verbal outcome (Baynes et al, 1998; Sieratzki et al, 2001). Residual verbal impairments have been reported to involve both phonological and metaphonological judgments (Zardini et al, 1995; Notoya et al, 1991; Ege & Mouridsen, 1998; Vance et al, 1999), phonological verbal fluency (Metz-Lutz et al, 1999b) and articulatory aspects of speech production (Soprano et al, 1994). Several long-term follow-up studies showed a better outcome for naming and syntactic skills ( Zardini et al, 1995; Metz-Lutz et al, 1999b). One very consistent finding is a deficit in phonological short-term memory (STM) performance, even in patients showing relatively good language recovery (Soprano et al, 1994; Grote et al, 1999; Metz-Lutz et al, 1999b; Plaza et al, 2001; Robinson et al, 2001; Majerus et al, 2004). For example, Soprano et al. (1994) observed that the performances of LKS patients on auditory-verbal STM tasks were more severely impaired than their performances on other language processing tasks, several months after the onset of recovery from LKS. Similarly, Grote et al. (1999) and Robinson et al. (2001) showed that LKS patients with complete or nearly complete language recovery still presented deficits on tasks involving STM processing, such as verbatim sentence recall and serial recall of letter and digit sequences. More precisely, in a recent case study of 3 young adult patients who recovered from LKS 7-10 years ago, Majerus et al. (2004) observed selective deficits on tasks requiring short-term storage of phonological information. However, performance for short-term retention of lexico-semantic information was preserved. For example, the patients' scores for immediate


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serial recall of nonword sequences and for a rhyme probe1 task were severely impaired in two patients, and more mildy impaired for the third patient, while performance on a category probe task2 was completely preserved in all three patients. Although two of the patients also presented with residual phonological processing deficits (as evidenced by impaired performance in speeded single nonword repetition and phonological awareness tasks), the severity of the phonological processing deficit was not related to the severity of their phonological STM impairment.

PATHOPHYSIOLOGICAL BASIS OF EPILEPTIC APHASIA A focal epileptic dysfunction in the temporal lobe As early as 1957, when the first LKS case report was published, a direct relationship between epilepsy and acquired aphasia was suggested. Indeed, on the basis of the EEG findings, Landau and Kleffner assumed "that persistent convulsive discharges in brain tissue largely concerned with linguistic communication result in the functional ablation of these areas for normal linguistic behavior". The almost parallel fluctuation of verbal impairments and epilepsy, more particularly with the EEG abnormalities observed in the follow-up studies, supported this assumption (Dugas et ah, 1982; Hirsch et ah, 1990; Paquier et ah, 1992; Lanzi et ah, 1994; Soprano et ah, 1994). As structural neuroimaging with computed tomography (CT) and magnetic resonance imaging (MRI) usually do not disclose structural brain lesions, several studies have looked at possible metabolic abnormalities common to LKS. Evidence from metabolic studies. Several studies using single photon emission computerised tomography (SPECT) have shown abnormal perfusion in the temporal lobe which correlates with the localisation of the epileptic focus (Mouridsen et ah, 1993; Harbord et ah, 1999). Similarly, positron emission tomography (PET) studies using 2-deoxy-2-[18F]fluoro-Dglucose (FDG) and carried out in approximately 29 LKS children consistently reported metabolic abnormalities in the temporal lobes; these abnormalities were either a unilateral or bilateral increase or decrease of glucose uptake (Maquet et ah, 1995; da Silva et ah, 1997). In one study, glucose consumption was investigated with 18FDG-PET at different times during the evolution of LKS in the same patients. This study showed that the metabolic changes appeared to be correlated with the epileptic activity, characterised by an hypermetabolic focus during the active phase of epileptic aphasia and a hypometabolic focus when EEG activity In a rhyme probe task, word lists of increasing length are presented auditorily. At the end of each list, a new word is presented and the participants are asked to determine whether this probe word rhymes with one of the words in the list. 2 The category probe task is very similar to the rhyme probe task but probes specifically STM retention for semantic information. Here, the patients are asked to determine whether the probe word presented at the end of the list belongs to the same semantic category as one of the words in the list.

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went back to normal (Maquet et al, 1995). Several improvements of PET data analyses, including the use of statistical parametric mapping (SPM), the comparison of each patient to a large control group and the co-registration of PET activity with a high resolution 3D-MRI scan of individual brains, have allowed a better definition of the spatial extent of the metabolic abnormalities. This has permitted to establish that, in the active period of epilepsy, the focus of hypermetabolism coincides with the topography of the predominant spike wave discharges recorded on waking and sleep EEG. Interestingly, these studies showed that the significantly higher glucose uptake only involved the associative but not the primary auditory cortex (Maquet et al., 1999). Neurophysiological evidences. Although the EEG recordings show both focal discharges and bilateral generalized spike-and-wave discharges, electrophysiological studies based on dipole mapping of spike discharge and magnetic source imaging provided arguments in favour of a focal source of epileptic discharges localised in the superior temporal gyms (Morrell, 1995). Using magneto-encephalographic recording (MEG) of SWD, Paetau et al. (1991) demonstrated that all spikes originated close to the auditory cortex, contaminating the ipsilateral auditory cortex and suppressing the contralateral auditory evoked potentials. Another study using auditory evoked magnetic field recordings (Paetau, 1994) in six children with LKS, suggested that the epileptiform activity may be produced by sound-responsive neurons in the non-primary auditory cortex within the middle and posterior perisylvian cortex. This set of findings is congruent with the suggestion that the apparently bilateral epileptic discharges of CSWSS are "driven" by a focal and unilateral source of primary epileptogenic activity in the superior temporal cortex. It also suggests that the bilateralisation of epileptic discharges and their generalisation during sleep makes the homotopic temporal cortex in the opposite hemisphere unavailable for auditory processing and more specifically for verbal processing. This might account for the main features of epileptic aphasia, i.e. the aphasic impairments that do not depend on the side of the temporal epileptic focus and the auditory agnosia observed in the active phase for about all LKS cases reported in the literature. An age-related focal epilepsy. The EEG pattern of SWDs and CSWSS is specific to agerelated idiopathic focal childhood epilepsy (IFCE). Indeed, SWDs are common to a wide range of so-called benign partial childhood epilepsies including rolandic epilepsy, the most frequent childhood epilepsy. SWDs and CSWSS are encountered in children aged 3-10 years and disappear in early adolescence, whatever the effectiveness of anti-epileptic treatment. Several studies showed that in IFCE, the epileptic foci are mainly located in the associative cortex whose maturation continues throughout childhood and adolescence. In LKS, the age of onset (70% before the age of 6) corresponds to the period of brain maturation that follows the peak of synaptogenesis in the associative temporal cortex. Considering the typical aspect of the epileptic discharges in LKS, it has been suggested that following a brief spike, the slow-wave component might be the manifestation of an


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inhibitory mechanism (Engel, 1995; 1996). Such a mechanism would not only prevent the occurrence of seizures dependent on the spike component but also inhibit the normal functioning of the cortical area involved in the generation of epileptic discharges. As the inhibitory component of the epileptic activity is predominant over the other EEG components, the epileptic aphasia would be the expression of an excess of inhibitory activity limited to a part of the temporal cortex. To account for this particular pattern of epileptic activity, Maquet et al. (1999) have hypothesised a focal alteration of the maturational processes leading to an imperfect neuronal wiring that induces an imbalance between inhibitory and excitatory drives generating epileptic discharges. According to this hypothesis, the large slow-wave component indicating a predominant inhibitory mechanism would result from a local excess of activity of the inhibitory interneurones within the epileptic focus. At the same time, the high density of synapses characteristic of this period of cortical maturation would facilitate the diffusion of SWDs leading to the aspect of CSWSS. The benefit of multiple subpial transection in LKS reinforced this hypothesis. Indeed, this particular surgical procedure consisting in the selective disruption of the intracortical horizontal fibers was used to mechanically interrupt the deleterious intracortical circuitry (Morrell et al, 1995). This method permitting the resumption of more normal synaptisation suppresses the focal epileptic activity and allows the recovery of the normal functioning of the temporal associative cortex.

PATHOPHYSIOLOGICAL BASIS OF VERBAL OUTCOME IN LKS The residual verbal impairments following LKS have been explained in different ways. Mantovani and Landau (1980) suggested that, like in the case of focal brain damage, the longterm effect of the epileptiform discharges on brain cells of a cortical area results in a functional hemispheric reorganisation with the shifting of language area in a cortical area spared by the epileptic activity. Bishop (1985) assumed that the loss of auditory verbal comprehension, during the active period of epileptic aphasia, deprives the child from the communicative verbal experience crucial for language development. Finally, Baynes et al. (1998) suggested that the nature of dysfunction and the outcome depend on the stage of language development at which LKS children experienced the disruption of auditory input. As regards the verbal outcome of epileptic aphasia, two points are at issue. Do the residual verbal disorders following LKS relate to some specific impairment in verbal processing? Indeed, a very consistent finding is a deficit in phonological short-term memory (STM) performance, even in patients showing relatively good language recovery as will be shown below ( Soprano et al, 1994; Grote et al, 1999; Metz-Lutz et al., 1999a, b; Plaza et al, 2001; Robinson et al, 2001; Majerus et al, 2003, 2004). The second point deals with the pathophysiological mechanisms underlying the residual verbal deficits. The data of PET studies performed at the recovery period of epileptic aphasia showing a focal hypometabolism in the temporal area initially involved in the epileptic focus suggest a persistent functional

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impairment of this cortical area. This persistent functional cortical impairment could also underlie the residual verbal deficits. Evidence for persistent dysfunction in the superior temporal cortex and its relationship to impaired phonological STM. One clinical finding consistently reported in all LKS follow-up studies including dichotic listening tasks is the one-ear dichotic listening extinction involving the ear contralateral to the temporal cortex affected by the epileptic discharges during the active phase of epilepsy (Metz-Lutz et al, 1997; Plaza et al, 2001). A similar one-ear dichotic extinction was described in patients who suffered structural lesion involving the temporal or parieto-temporal cortex and the geniculo-cortical pathway (Kimura, 1961; Damasio & Damasio, 1979). In LKS, this finding might be the expression of a permanent dysfunction in the temporal cortex. This assumption is supported by the findings of PET scan studies performed in the late recovery period in LKS patients, which disclosed a focal hypometabolism in the superior temporal region contralateral to the dichotic extinction (Maquet et al., 1999). In order to test this hypothesis, we used auditory evoked potentials (AEP) enabling us to check the whole auditory system along the auditory pathways to the temporal associative cortex in five children who had recovered from LKS and showed a right or left dichotic listening extinction. The five patients were compared to five control subjects matched for age and gender. This study showed normal and symmetrical early and middle latency auditory evoked potentials but significant alteration in the late Nib and N250 components with reduced amplitude over the temporal sites contralateral to the dichotic listening extinction (Wioland et al, 2001). The Nib and N250 components are known to arise from the temporal associative cortex. In a second study, we explored more specifically the integrity of temporal associative cortex and its relationship to the residual phonological STM deficits that characterise the late outcome of LKS, using PET imaging (Majerus et al, 2003). The three adult patients for which we had identified relatively specific phonological STM impairments (see above; Majerus et al, 2004) also participated in this second study. They were asked to repeat auditorily presented 4-word sequences (STM condition) or single words (control condition) while they underwent H2I5O-PET imaging. During the STM condition, we observed decreased activation in the bilateral posterior superior temporal gyms and adjacent perisylvian cortex in the two patients who presented the most severe phonological STM impairments. In the third patient whose phonological STM impairment was much milder, we observed increased activation in the right posterior superior temporal gyms during the STM condition. These data show that the posterior temporal cortex remains dysfunctional in the late outcome of LKS, relative to healthy controls, and is related to the persistent phonological STM impairment. Furthermore, we also observed a relationship between the regions that displayed abnormal glucose metabolism in the three patients during the active phase of the LKS (Maquet et al., 1995) and the recent brain activation pattern during the STM task. The first of the two


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patients with the most important phonological STM deficits had shown decreased glucose uptake in the left superior and middle temporal regions during the active phase of LKS as well as reduced glucose uptake bilaterally in superior temporal regions several months later. In the recent brain activation study, reduced activity in the right posterior superior temporal gyrus was observed. During the active phase the second patient had shown increased glucose metabolism in the right middle and superior temporal regions and decreased glucose metabolism in the left perisylvian cortex. In the recent study, diminished activity bilaterally in the posterior superior temporal cortex was observed. The third patient with milder phonological STM deficits had shown a very focal increase in glucose metabolism at the level of the right STG, which became hypometabolic several months later. In the recent study, increased activation in the right posterior as well as slightly reduced activity in the anterior part of the right midtemporal gyrus (although only at uncorrected P-levels) was observed. In sum, the results suggest that late outcome of LKS may indeed be characterised by a longlasting dysfunction of mainly posterior and superior temporal gyri and adjacent perisylvian areas which had also been dysfunctional during the active phase of epilepsy. Furthermore, this persistent dysfunction of superior temporal gyri appears to be related to the residual phonological STM impairments. DISCUSSION In this paper, we attempted to provide a provisional pathophysiological account of aphasic disorders and the late verbal outcome of LKS, a particular condition where acquired aphasia appears as the main clinical symptom of a focal epileptic activity. Most importantly, this epileptic activity has to be explained by a predominant inhibitory rather than by an excitatory mechanism. Indeed, the main symptoms of LKS as opposed to other childhood focal epilepsies are not sudden and brief episodes of behavioural changes in the form of seizures, but the rapidly progressive disappearance of initially normally developing language processing, appearing like an interictal disorder. Indeed, aphasic disorders are not transitory as would be the clinical expression of seizure. Furthermore, the propensity of SWDs to diffuse to the contralateral homologous region, probably due to the stage of maturation of the cortical tissue at which SWDs occur, prevents any possible compensation as long as the epilepsy is active. Thus, we think that the local excess of inhibitory mechanism can be viewed as a plausible pathophysiological account for both the "functional ablation" of verbal cortex and the inability to develop compensatory mechanisms during the active phase of epilepsy. This account suggests a more or less direct relationship between the (inhibitory) epileptic activity itself and the verbal impairment during the active phase. At outcome, a similar relationship is observed between residual phonological STM deficits and the persistent dysfunction of the superior temporal cortex that was involved in the epileptic focus during the active phase. However, this association between aphasia and epilepsy does not necessarily imply that aphasia and phonological STM deficits are exclusively and directly caused by the epileptic activity. Instead, we cannot exclude that the aphasic and epileptic symptoms during

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the active phase, as well as the residual verbal and STM impairments at later outcome, are both the result of a third variable. This third variable could represent the focal alteration of maturational processes of the cortex leading, in the case of LKS, to abnormal neuronal wiring in the superior temporal cortex, as suggested by Maquet et al. (1999). This abnormal wiring, in turn, will lead to epileptic activity within this area as well as to depressed language processing. The epileptic activity will then further aggravate the language impairments by further inhibiting functioning within the temporal cortex, via the inhibitory mechanisms discussed above. In addition, the absence of environmental verbal stimulation resulting from the severe receptive auditory-verbal impairments will also contribute to language decline. Although epileptic activity will disappear in adolescence, the wiring of superior temporal cortex may remain abnormal and thus language and STM processing will still be processed in a less efficient way. If the hypothesis of a focal alteration of the maturational processes is correct, it raises the issue of what determines this focal alteration and its more frequent localisation in the associative temporal cortex. This will be the challenge for future work on LKS. Whatever the pathophysiological considerations, one should keep in mind that during the active period of LKS, brain maturation is still in process. This maturation depends on both an internal genetically determined programme and external stimulation, notably perceptualmotor experience. Regarding verbal development, the experience of verbal input and interindividual verbal communication is especially determinant for further language development. This implies that the development of effective rehabilitation programmes, aiming at preventing and reducing the effect of deprivation of normal auditory feedback on phonological, syntactic, and lexical development, remains of utmost importance. ACKNOWLEDGEMENTS Steve Majerus is a Postdoctoral Researcher at the Fonds National de la Recherche Scientifique, Belgium.

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associated with Landau-Kleffner Syndrome: a long-term study of auditory disturbance. Auris Nasus Larynx, 18, 297-305. Paetau, R. (1994). Sounds triggers spikes in the Landau-Kleffner Syndrome. J Clin Neurophysiol, 11, 231 -241. Paetau, R., M. Kajola, M. Korkman, M. Hamalainen, M. L. Granstrom and H. Hari (1991). Landau-Kleffner Syndrome: epileptic activity in the auditory cortex. Neuroreport, 2, 201-204. Paquier, P. F., H. R. Van Dongen and C. B. Loonen (1992). The Landau-Kleffner Syndrome or "acquired aphasia with convulsive disorder". Long-term follow up of six children and a review of recent literature. Arch Neurol, 49, 354-359. Perez, E. R., V. Davidoff, A. C. Prelaz, B. Morel, F. Rickli, M. N. Metz-Lutz, P. Boyes Braem and T. Deonna (2001). Sign language in childhood epileptic aphasia (LandauKleffner Syndrome). Dev Med Child Neurol, 43, 739-744. Plaza, M., M. T. Rigoard, C. Chevriemuller, H. Cohen and A. Picard (2001). Short-term memory impairment and unilateral dichotic listening extinction in a child with Landau-Kleffner Syndrome: Auditory or phonological disorder? Brain Cogn, 46, 235240. Robinson, R. O., G. Baird, G. Robinson and E. Simonoff (2001). Landau-Kleffner Syndrome: course and correlates with outcome. Dev Med Child Neurol, 43, 243-247. Sieratzki, J. S., G. A. Calvert, M. Brammer, A. David and B. Woll (2001). Accessibility of spoken, written, and sign language in Landau-Kleffner Syndrome: a linguistic and functional MRI study. Epileptic Disord, 3, 79-89. Soprano, A. M., E. F. Garcia, R. Caraballo and N. Fejerman (1994). Acquired epileptic aphasia: neuropsychologic follow-up of 12 patients. Pediatr Neurol, 11, 230-235. Tutuncuoglu, S., G. Serdaroglu and B. Kadioglu (2002). Landau-Kleffner Syndrome beginning with stuttering: case report. J Child Neurol, 17, 785-788. Vance, M., S. Dry and S. Rosen (1999). Auditory processing deficits in a teenager with Landau-Kleffner Syndrome. Neurocase, 5, 545-554. Wioland, N., G. Rudolf and M. N. Metz-Lutz (2001). Electrophysiological evidence of persisting unilateral auditory cortex dysfunction in the late outcome of Landau and Kleffner Syndrome. Clin Neurophysiol, 112, 319-323. Zardini, G., B. Molterri, N. Nardocci, D. Sarti, G. Avanzini and T. Granata (1995). Linguistic development in a patient with Landau-kleffner Syndrome: A nine year follow-up. Neuropediatrics, 26, 19-25.


Acquired Epileptiform Aphasia

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ACQUIRED LANGUAGE DISORDERS AND EPILEPSY: FROM LANDAU-KLEFFNER SYNDROME TO AUTISTIC REGRESSION Roberto Tuchman Dan Marino Center and Miami Children's Hospital, Florida, USA

Abstract — The relationship of epilepsy, either clinical or subclinical, to the acquired aphasia or the loss of communicative intent that occurs in some children, most of whom are on the autistic spectrum, remains controversial and not understood. The report of loss of language in any child should raise concern and there are several clinical syndromes to consider when discussing the Acquired Epileptiform Aphasias (AEA). These include: Acquired aphasia with convulsive disorder or LandauKleffner Syndrome (LKS); Continuous Spike-Waves during Slow Sleep (CSWS) associated with Electrical Status Epilepticus during Slow-Wave Sleep (ESES); Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS), and Autistic Regression with an Epileptiform EEG (AREE). The lack of strict criteria and the overlap of disorders with language loss associated with epilepsy or an epileptiform EEG have made classifying children who undergo a regression of their language in the context of either clinical or subclinical seizures a confusing and controversial undertaking. An important first step in our quest to understand the pathophysiology of the acquired epileptiform aphasias and to develop rational interventions is to rigorously define these syndromes at a clinical level. The purpose of this discussion is to review the nosology of acquired language disorders associated with epilepsy. Key words: language disorders, regression, epilepsy, autism, acquired aphasias, LandauKleffner Syndrome (LKS); Continuous Spike-Waves during Slow Sleep (CSWS), Electrical Status Epilepticus during Slow-Wave Sleep

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INTRODUCTION The classification of acquired language disorders in children and their relationship to epilepsy is a complex clinical problem. The lack of strict criteria and the overlap of disorders with language loss associated with epilepsy or an epileptiform EEG have made classifying children who undergo a regression of their language in the context of either clinical or subclinical seizures a confusing and controversial undertaking. The term I prefer to use for the above disorders is Acquired Epileptiform Aphasias, as opposed to Acquired Epileptic Aphasias, since epilepsy, defined as more than one unprovoked seizure, is not always present in this group of encephalopathies. The report of loss of language in any child should raise concern. Language regression was considered rare until recent reports have indicated that up to one-third of all children with autism regress in language or in communicative intent (Tuchman & Rapin, 1997). Although it is most often parental awareness of regression or stagnation of expressive language in their toddler or preschooler that brings the child to professional attention, it may be that there are premonitory signs. Some of these are the inability to coordinate attention and share the enjoyment of an event with a social partner. One important hallmark of social communication in early development is joint attention. Joint attention skills refer to the capacity of individuals to coordinate attention with a social partner vis-a-vis some object or event. This capacity, which is an essential precursor to verbal communication, begins to emerge by 6 months of age and takes on several different forms, each of which may be measured reliably in infants and young children. The social-communication disturbance of autism is exemplified by a striking failure to develop adequate joint attention skills or by the loss of these skills once developed. Research indicates that joint attention impairment is characteristic of autism. There is also evidence to suggest that joint attention may predict language, cognitive and social outcomes in children on the autistic spectrum, and that it may be an index of the neurodevelopmental components of the disorder. Consequently, joint attention has become an important dimension to consider in early diagnosis and treatment research in autism and related disorders. There are several clinical syndromes to consider when discussing the Acquired Epileptiform Aphasias (AEA). These include: Acquired aphasia with convulsive disorder or Landau-Kleffner Syndrome (LKS); Continuous Spike-Waves during Slow Sleep (CSWS) associated with Electrical Status Epilepticus during Slow-Wave Sleep (ESES); Benign Childhood Epilepsy with Centrotemporal Spikes (BECTS), and Autistic Regression with an Epileptiform EEG (AREE). All of these clinical syndromes are associated with different degrees of cognitive function or mental retardation (MR) and the language disorder most likely to be present in the majority of the acquired epileptiform aphasias is that of Verbal Auditory Agnosia (VAA). The purpose of this paper is to define, discuss and contrast this group of encephalopathies.


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ACQUIRED APHASIA WITH CONVULSIVE DISORDER OR LANDAUKLEFFNER SYNDROME (LKS) Acquired epileptic aphasias have been used as an important model for expanding the concept of childhood epilepsy to include prolonged language, cognitive and behavioral disorders as primary epileptic manifestations (Deonna, 1991). The prototype of AEA is Landau-Kleffner syndrome. Landau-Kleffner syndrome is defined as an acquired aphasia in association with abnormal EEG demonstrating spikes, sharp waves or spike and wave discharges which are usually bilateral and occur predominantly over the temporal and parietal regions (Rapin, 1995a). The definition of LKS has been widely expanded and behavioral problems such as hyperkinesis, rage outbursts, aggressiveness, stereotypies and poor social communication skills in children with language regression and associated epilepsy or with an epileptiform EEG have been included under this eponym. Central to the original description of LKS in 1957 is language regression in association with an epileptiform EEG and either seizures or acquired aphasia are equally likely to be the first presenting complaint in this disorder (Landau & Kleffner, 1957). In LKS it is not the clinical epilepsy that is important in producing the language manifestations of LKS, but the "subclinical seizures" as indexed by epileptiform activity on the EEG as up to 25% of these patients may not have clinical seizures (Tuchman & Rapin, 2002). A rigorous definition of LKS should include only those children with primarily a regression in language and in whom the associated behavioral problems that occur are secondary to the language disorder and not due to a primary behavioral or cognitive regression (Tuchman, 1997). The primary language disorder in the majority of children with LKS is a severe receptive disorder amounting to verbal auditory agnosia (VAA) (Korkman et al., 1998; Klein et al. 2000). VAA is a receptive aphasia or dysphasia for acoustically, but not visually, presented language and arises from inadequate auditory or phonologic processing that engages activity in the primary or secondary auditory cortices and affecting output (expressive) language as well (Majerus et al, 2003). A central theme of any discussion of acquired epileptiform aphasia is the relationship of the abnormal electrical activity to the language disorder. The cortical areas responsible for VAA are the same regions where the centrotemporal epileptiform EEG activity characteristic of LKS and other AEA discussed below is found. Furthermore, VAA is associated with the highest rate of epilepsy, both among children with autistic spectrum disorders and those with developmental language disorders (Tuchman et al., 1991a). Age of symptoms may be important in differentiation of LKS from autistic regression with an epileptiform EGG (AREE) and possibly from other acquired epileptiform aphasias. The mean age of onset of the language regression in autistic spectrum disorders is 21 months and over 90% of children with autism who undergo a regression do so before age 3 years (Tuchman & Rapin, 1997). This is different from LKS where it is reported that mean age of onset is after age 4 years (Robinson et al, 2001). The prognosis in LKS for recovery of

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language and cognitive function is variable and in general not as good as it is for the seizures (Bishop, 1985; Mouridsen, 1995).

ELECTRICAL STATUS EPILEPTICUS DURING SLEEP

(CSWS) AND BENIGN WITH VENTROTEMPORAL SPIKES (BECTS)

SPIKE-WAVES DURING SLOW SLEEP EPILEPSY

(ESES): CONTINUOUS CHILDHOOD

Electrical status epilepticus during slow wave sleep (ESES) is considered an EEG-defined syndrome characterized by nearly continuous (>85%) spike-and-slow-wave-complexes during non-REM sleep, but not during REM sleep or the awake state. The clinical syndrome that has been mostly associated with ESES is continuous spike-waves during slow sleep (CSWS) (Veggiotti et al, 1999). The majority of children with CSWS have normal development prior to the onset of ESES, but almost all deteriorate cognitively and behaviorally (increased aggressiveness, poor social contact, decreased attention span, and hyperactivity) during ESES (Roulet-Perez, 1993; Nieto-Barrera et al, 1997; Veggiotti et al, 2001). Language deterioration out of proportion to other abilities occurs in some cases. At a behavioral level the major difference between reported cases of LKS and CSWS is that children with CSWS show more diffuse cognitive and behavioral deterioration with dementia and behaviors consistent with autism than do children with LKS (Galanopoulou et al, 2000). Seizures are common in CSWS, but as in LKS not always present. LKS and CSWS syndromes may be on a continuum and as such some investigators have suggested that Landau-Kleffner may be too narrowly defined (Hirsch et al, 2000). Nevertheless, I would suggest that strictly defining these syndromes will be more productive in determining the relationship of acquired language regression to clinical and subclinical epilepsy. The electroencephalographic findings in LKS resemble the EEG findings in benign childhood epilepsy with centrotemporal spikes (BECTS) both in morphology and distribution and in both of these disorders the spikes are activated by sleep (Saint-Martin et al, 2001). At a clinical level these disorders are very different and in general children with BECTS do not have the associated clinically significant language or cognitive dysfunction found in LKS or in CSWS. However, recent work suggests that there is a subgroup of children with BECTS where the evolution of the spikes takes on a more atypical nature and the clinical evolution of these children is more similar to that of children with LKS or CSWS (Fejerman et al, 2000). There is also data suggesting that differences in morphology, topography, organization, and abundance of interictal abnormalities during sleep can differentiate BECTS from LKS early on and prior to the loss of language occurring in LKS (Massa et al, 2000). The outcome of some children with BECTS with atypical evolution of their spikes on EEG and with regression in language and behavior may be similar to those with LKS and CSWS (Yung et al, 2000). Recent work using magnetoencephalography has suggested that the location and possibly orientation of the spike might account for differences in clinical presentation of


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disorders such as BECTS, LKS and AREE (Lewine et al, 1999; Sobel et al, 2000; Otsubo & Snead, 2001).

AUTISTIC REGRESSION WITH AN EPILEPTIFORM

EEG (AREE)

Autism is a life-long disorder with clinical symptoms that change with age and often improve with early intervention. Approximately one-third of parents report a regression of language, usually the loss of their toddler's first few words between 18 and 24 months, together with the appearance of autistic behaviors. Autistic regression, including regression in language may fluctuate for many months or even years and then improve, although rarely to complete recovery (Wilson et al, 2003). It is most often parental awareness of regression or stagnation of expressive language in their toddler or preschooler that brings the child to professional attention. Early on in development children with autism display a syndrome-specific inability to coordinate attention and share the enjoyment of an event with a social partner. Impairments in this domain may be assessed with measures of joint attention skills (Mundy et al, 1990). Since autistic regression occurs prior to age 2 years and as such may be associated with a the loss of only a few single words identifying loss of joint-attention skills may be a better early indicator of regression in children with autism. Autistic regression with or without an epileptiform EEG should be differentiated from children classified as having disintegrative disorder (DD) in whom language and behavioral regression is delayed and may occur as late as age 10 years (Rapin, 1995b). Children with disintegrative disorder, sometimes referred to as Heller's syndrome, are more likely to have epilepsy than children with autism (Burd et al, 1989). This group of children differs from children with LKS in the severity of their cognitive and behavioral manifestations and from the much more numerous children with typical autistic regression in two main ways: (1) the regression occurs later, usually between 3 and 6 years, prior to which development was entirely normal, in contrast to children with autism in whom the mean age at regression is 1824 months and earlier development already worrisome in some cases; and (2) the regression is even more profound and may leave these children frankly and permanently demented (Malhotra & Gupta, 1999; Dawson, 2000). The difference between disintegrative disorder and autism with regression is not crisp and what role epilepsy may play in the genesis of either or both is disputed. The relationship of epilepsy, either clinical or subclinical, to the acquired aphasia or the loss of communicative intent that occurs in autistic regression remains controversial and not understood. In a study of 314 children with autism and 237 children with language disorders examined by one child neurologist, parents of 32% of the autistic and 4.6% of the language disordered groups reported a regression (Tuchman et al, 1991a). Epilepsy (at least 2 unprovoked seizures) was correlated with motor and cognitive indices of the severity of the underlying brain dysfunction (Tuchman et al, 1991b). In an independent sample of 585 consecutive children with autistic spectrum disorders seen by another child neurologist,

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regression was stated to have occurred before age 2 years in 64% of cases and by age 3 years in 95% of cases (Tuchman & Rapin, 1997). Epilepsy was no more frequent (12%) in children who had regressed than in those without a history of regression (11%). An interesting but unexplained observation was that regression was significantly associated with an epileptiform EEG in the non-epileptic group, in that 14% of 155 non-epileptic children who had undergone a regression had an epileptiform EEG during sleep, as opposed to 6% of 364 children with neither regression nor epilepsy. There was no difference in the proportion of children with epilepsy or epileptiform EEGs who had regressed before or after 2 years of age. On the other hand, a recent multi-institutional study of 177 children with a history of language regression found that children with a history of regression prior to age 36 months were more likely to have autism than those who regressed after age 36 months, and that children with regression after age 36 months were more likely to have epilepsy than those with an earlier regression (Shinnar et at, 2001). Although all three studies found a mean age at regression between 21 to 22.8 months, mean age at referral to the specialist was uniformly over age 36 months. The studies just reviewed suggest that there are two groups of children who experience regression: somewhat older children who are more likely to have epilepsy but rarely experience a serious behavioral-autistic regression (the few who do are likely to suffer from the catastrophic disintegrative disorder phenotype), and a younger much larger group in whom epilepsy is less frequent but in whom language regression has a high probability of being associated with a serious behavioral/cognitive deterioration leading to autism. These studies also suggest that there may be neurophysiological markers of regression such as epileptiform discharges; however, their contribution to the autistic regression in this younger group is not known for two reasons: (1) a minority of children without clinical seizures undergo EEG recordings, let alone all night monitoring, and (2) the children are rarely seen at the time of the regression (the mean interval is measured in years, not months). The main cause for this long delay is that very early regression is regularly passed off because it is insidious and occurs so early in the course of language development. This early regression is not given the same importance as language regression in a fully verbal older child. This lack of early recognition may prevent early intensive intervention. Future studies will have to address this important concern.

MEDICAL AND SURGICAL MANAGEMENT OF CHILDREN WITH ACQUIRED EPILEPTIFORM APHASIAS Data regarding response to medication in well-defined subgroups of children with acquired epileptiform aphasias are very limited. The treatment strategies that have been reported for this group of children are those used for the management of children with LKS. Therapy in LKS has been the subject of numerous case reports or short series and the lack of wellcontrolled clinical trials has been frustrating to the clinician faced with a child with an acquired aphasia thought to be secondary to the clinical or subclinical epilepsy.


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Anticonvulsants, especially valproate, ethosuximide and the benzodiazepines have been reported to improve the language of a limited numbers of children with LKS (Marescaux et al, 1990; Lerman et al, 1991). The use of ACTH, steroids, or immunoglobulins has also been the subject of several clinical reports which suggest improvements in language and behavior in children with LKS treated with these medications (Prasad et al, 1996; Lagae et al., 1998; Mikati et al, 1998; Tsuru et al, 2000). Several clinical reports of the use of Valproate in children with autism with or without clinical seizures but with epileptiform abnormalities on the EEG suggest an improvement in language and behavior in this group of children with AREE (Nass & Petrucha, 1990; Plioplys, 1994; Childs & Blair, 1997; Hollander et al, 2001; Holmes & Riviello, 2001). In a selected group of children with LKS surgical transection of epileptogenic frontotemporal cortex has been performed and reported to produce short-term improvement in language and behavior in perhaps half of the children (Morrell et al, 1995; Sawhney et al, 1995). Two studies of children with autistic regression and clinical seizures state that aggressive treatment of the seizures with epilepsy surgery was associated with positive outcomes (Neville et al, 1997; Nass et al., 1999). One study suggested that, in children with autism and intractable seizures, surgery may improve the seizures but not the autism (Szabo et al, 1999). The children in these case reports had intractable epilepsy and the epilepsy surgery was being done for the treatment of the seizures and not for the behavior or language dysfunction. A controversial study suggested that multiple subpial transections in children with autism spectrum disorders, a history of language regression, multifocal epileptiform EEGs, and possible minor clinical seizures (i.e. staring episodes, rapid eye blinking) without overt clinical seizures improved in language and behavior after surgery (Lewine et al, 1999). It is important to state that the role of surgery in children with LKS and especially in those with AREE is only recommended for the treatment of the seizures and not for the concomitant language or behavioral deficits.

CONCLUSION From a clinical perspective all children with stagnation or regression in communication skills should be promptly referred to a specialist that can evaluate them from a neurological perspective. It is extremely critical that speech and language intervention is promptly begun in all such children and that all forms of verbal and non-verbal communication systems are taught. An EEG with adequate sleep should be part of the work-up of any child with a history of language regression. Careful monitoring of the language progression should be carried out and in those children who do not progress after communication intervention is begun an overnight EEG with good amount of sleep recording should be obtained. If the EEG demonstrates epileptiform activity consideration should be given to the use of antiepileptic medications.

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An important first step in our quest to understand the pathophysiology of the acquired epileptiform aphasias and to develop rational interventions is to rigorously define these syndromes at a clinical level. Progress has been made in our understanding of the clinical differences and overlaps between Landau-Kleffner Syndrome and Autistic Regression with an Epileptiform EEG. In the process we have also gained a deeper understanding of the role of epilepsy, both clinical and subclinical, in all epileptic disorders in children with associated acquired aphasia. The use of newer imaging and EEG techniques such as magnetoencephalography is enhancing our ability to determine the role not only of the quantity of EEG discharges but also of the importance of understanding how the topography of the EEG may determine specific symptoms such as language regression. Clinical studies suggest that timing of the seizures or the development of EEG discharges may also help in the differentiation of the acquired epileptiform aphasias. Acquired epileptic aphasias associated with epilepsy or epileptiform abnormalities are not specific entities. The studies reviewed here suggest that they represent part of a spectrum disorder with a common pathophysiology with varying severity of clinical manifestations dependent on the location and quantity of the epileptiform activity. The differences in clinical symptoms and in their relationship to epilepsy or EEG changes in these disorders may, in selected cases, be due only to the time period in development when the seizures occur or to the site or the amount of cortical or subcortical epileptogenic dysfunction. However, the seizures and the EEG findings do not always correlate with the clinical picture and as such the EEG and the seizures may be only epiphenomena that provides for the identification of a diverse group of language-EEG-epileptic encephalopathies with diverse etiologies.

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Persistent Language and Learning Deficits in AEOS

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4

PERSISTENT SUBTLE LANGUAGE AND LEARNING DEFICITS IN A CHILD WITH ACQUIRED EPILEPTIFORM OPERCULAR SYNDROME (AEOS) Paola Cipriani, Anna M. Chilosi,Claudia Casalini, Lucia Pfanner, Annarita Ferrari, Daniela Brizzolara and Renzo Guerrini "Stella Maris " Scientific Institute, Pisa, Italy University of Pisa, Italy

Abstract — Persistent linguistic deficits are sometimes observed after prolonged anarthric status epilepticus, even in the absence of structural abnormalities of the perisylvian cortex, leading some authors to interpret Acquired Epileptiform Opercular Syndrome (AEOS) as an expressive variant of Landau-Kleffner syndrome. The long-term outcome of children with AEOS is rarely reported, and no systematic neurolinguistic studies have been carried out with the aim of analysing the effects of abnormal articulatory experience on phonological coding in the course of language development. We report on a child who was followed at our department from age 5 years to age 8 years for a fluctuating clinical syndrome consisting of recurrent episodes of severe oral motor dysfunction, dysarthria and drooling paralleled with focal EEG abnormalities that fluctuated in phase with the clinical disorder. At follow-up, persistent subtle language and learning difficulties due to impaired phonological processing skills were observed, in spite of a good response to antiepileptic drugs, improved EEG, normal MRI and adequate nonverbal cognitive abilities. Keywords: Operculum syndrome, epilepsy, acquired speech and language dysfunction, phonological processing deficits.

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INTRODUCTION Opercular Syndrome (OS), also called Foix-Chavanny Marie Syndrome (FCMS) (Foix et al., 1926) results from a structural or functional abnormality in the opercular or perisylvian areas and is clinically manifested by anarthria/severe dysarthria and loss of voluntary muscular functions of the face and tongue as well as impaired mastication and swallowing. These symptoms result from a central disturbance of the volitional control of the facio-linguoglosso-pharingeal-masticatory muscles, with preserved automatic, involuntary and emotional innervation (automatic-voluntary dissociation). It has a variable etiology, which may be due to congenital or acquired bilateral damage of the perisylvian cortex (Christen et al, 2000; Salas-Puig et al, 2000; Gordon, 2002). Rarely does OS have an epileptic origin (Fejerman & Di Blasi, 1987; Roulet et al, 1989; Colamaria et al, 1991; Deonna et al, 1993; Shafrir & Prensky, 1995; De Saint-Martin et al, 1999; Galanopoulou et al, 2000; Shuper et al, 2000; Kramer et al, 2001; Tachikawa et al, 2001). In these cases, the underlying mechanisms are not fully understood as there is no clear link between the epileptic activity and the clinical manifestations. The term "Acquired Epileptiform Opercular Syndrome" (AEOS) was first used by Shafrir and Prensky in 1995 to describe a 5-year-old girl who developed recurrent prolonged episodes of suprabulbar palsy in association with continuous spike-and-wave activity during slow sleep. These authors interpreted the AEOS as an expressive variant of Landau-Kleffner syndrome (LKS). AEOS and LKS would represent neurological disorders, sharing similar pathophysiological mechanisms, in which long-standing electrical dysfunction of perisylvian neurons translates into bilateral neurological dysfunction. AEOS manifests with fluctuating signs of suprabulbar palsy resulting from a disruption of the connections between the cortical motor areas and the brainstem nuclei. The symptoms (identical to those attributed to bilateral structural abnormalities of the perisylvian cortex) show an intermittent course, with widely variable onset, duration and relapse. Persistent linguistic deficits are sometimes described (Deonna et al, 1993; De Saint-Martin et al, 1999; Kramer et al, 2001) after prolonged anarthric status epilepticus, but the long-term outcome of children with AEOS is rarely reported, and no systematic neurolinguistic studies have been carried out. We describe a longitudinal study of a child with functional, epilepsy-related oralmotor dysfunction who developed long-lasting oral and written language deficits.

CASE REPORT This Italian right-handed male child patient was born after an uneventful pregnancy, delivery and neonatal period and had a history of normal motor, cognitive and language development. At the age of 5 years and 3 months he had his first seizure while falling asleep with twitching of the right eyelid, corner of the mouth and right arm, lasting one minute, followed by an


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inability to speak for about 10 minutes.The following day he was admitted to our Department: He was alert and fully conscious; the main clinical features included pharyngeal, lingual and masticatory motor deficits, drooling of saliva, and severely impaired speech initiation. A video EEG showed almost continuous, high-voltage, bilateral centro-temporal synchronous and asynchronous spikes and sharp and slow waves, more prominent on the left (Figure 1). The child was severely dysarthric but responsive and able to follow commands.

Figure 1 — EEG at admission: almost continuous, high-voltage, bilateral centro-temporal synchronous and asynchronous spikes and sharp and slow waves, more prominent on the left.

Figure 2 — EEG performed 3 minutes after an intravenous administration of diazepam (5mg): marked improvement in the EEG; a slow subcontinuous activity, 2-3 Hz, persisted on the left centro-parietal areas.

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Language testing, performed during the EEG recording, revealed a severe difficulty in naming familiar objects and pictures and an inability to reproduce simple oral gestures on imitation. Morphosyntactic comprehension as tested by TCGB, a multiple-choice test of receptive grammar, (Chilosi & Cipriani, 1995), was also impaired. Intravenous diazepam abated EEG discharges; a slow subcontinuous activity (2-3 Hz) persisted on the centro-parietal areas with concomitant clinical improvement (Figure 2). The child began to name objects and pictures and made some volitional orolingual movements on request (sticking out the tongue, clicking the tongue to imitate the sound of a horse galloping). Magnetic Resonance Imaging (MRI) was normal. Treatment with sodium valproate was started and no other acute episodes of oral motor dysfunction and speech arrest occurred. The child was followed at our clinic from the post-acute phase up to the age of 8 years and 7 months. Follow-up EEGs showed normal background activity and frequent sharpwave complexes, synchronous and asynchronous on both centro-temporo-parietal regions, dramatically enhanced during sleep. In spite of these severe abnormalities, no overt clinical symptoms or changes in speech fluency were demonstrated during the EEG recording. At 5 years and 9 months and 6 years and 4 months he suffered two right-sided focal motor seizures upon falling asleep. Various combinations of drugs (sodium valproate, clonazepam, hydrocortisone, ethosuximide) only produced transient improvement on EEG paralleled by improvement of language performance. Three years after the initial symptoms, the child was seizure-free under sodium valproate, but the EEG was persistently abnormal.

LANGUAGE AND NEUROPSYCHOLOGICAL FOLLOW-UP The child's neurological status, oromotor functions, language, speech and cognitive abilities were repeatedly evaluated from 5.3 up to 8.7 years of age. The first full language and cognitive assessment was performed a few days after the acute episode. Expressive language was grammatically correct but simplified, slow and nonfluent; on a picture naming test (Brizzolara et ai, 1994), global performance was within normal limits, but it was characterised by an excessively high latency of response and by an abnormally high number of anomias, as a consequence of word retrieval deficits. The child's language comprehension was within the norms for his age (Chilosi & Cipriani, 1995). Cognitive assessment revealed a mild deficit of nonverbal (Leiter International Performance Scale, LIPS) (Leiter, 1979) and visuo-motor integration abilities (VMI, Beery, 1997) and a severe impairment of verbal short-erm memory (Digit span) (Orsini et al., 1987) and phonological working memory (recall of lists of words in the auditory-visual modality). The child's subsequent course was relatively benign, though marked by some inconsistencies in cognitive and language functioning, parallel with improvements and


41

relapses of the electroclinical conditions. The main clinical features, as summarised in Table 1 and graphically represented in Figures 3-7 are as follows: fluctuating levels of performance on nonverbal tasks (visuo-motor integration skills and performance IQ) improvements and relapses of grammatical comprehension phonological processing deficits, manifested by an impaired performance on working memory and phonemic fluency tasks slow rate of articulation and mild oral dyspraxia word-retrieval difficulties with a variable preponderance of anomias and paraphasic speech manifesting as hesitations, circumlocutions, "conduites d'approche", and/or phonemic and semantic substitutions. Table 1 — Summary of clinical, neuropsychological and EEG data from 5.3 years to 6.4 years 5.3 (acute phase)

SPEECH AND LANGUAGE

5.5

5.7

++

++

5.11 +++

6.4

EEG abnormalities

++++

Partial motor seizures

Y

N

N

N

Y

Y

+++

++

+

+

+

++

+

+

Oral motor dysfunction

COGNITIVE SKILLS

5.3 (post acute phase) ++

Dysarthria Anomias Grammatical comprehension Phonemic fluency Semantic fluency Phonological Working memory Nonverbal IQ VMI (standard score) Digit span (percentile)

ft

ft +++

+++

+++

+++

impaired

normal

ft

+++

ft ++

+

ft

ft

+++

+++

normal

normal

++

ft normal

++ impaired

n.a. n.a.

impaired impaired

impaired impaired impaired impaired impaired borderline borderline borderline

n.a.

impaired

impaired borderline borderline impaired

n.a.

67

99

67

94

92

n.a.

72

85

77

79

83

n.a.

2°

2°

22°

9°

9°

Note: U = better; 0 = worse; Y= yes; N = no; n.a. = not available ++++ = very severe; +++ = severe; ++ = moderate; += mild

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Figure 3 — Neuropsychological follow-up: non verbal abilities: Performance IQ (PIQ) and Visuomotor integration skills (VMI Standard score).

Figure 4 — Neuropsychological follow-up: Grammatical Comprehension.

Figure 5 — Neuropsychological follow-up: Phonological Working Memory (auditory-visual modality).


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Figure 6 — Neuropsychological follow-up: Verbal fluency.

Figure 1 — Neuropsychological follow-up: Lexical production (types of errors).

LONG-TERM OUTCOME When last seen, at the age of 8 years and 7 months (three years after the onset of the AEOS), the child was attending the 3rd grade of primary school. The EEG showed frequent sharp-wave complexes that were synchronous and asynchronous on both centro-temporo-parietal regions which became almost continuous during sleep, but the child was seizure-free. Upon examination, some residual signs of orofacial clumsiness and verbal dyspraxia were observed with a persistently very slow rate of speech and some prosodic alteration. Nonverbal cognitive abilities (PM47, Raven, 1956, 1984; Pruneti et al, 1996; VMI, Beery, 1997) and receptive vocabulary (Peabody Picture Vocabulary Test, PPVT, Dunn & Dunn, 1981; Stella et al, 2000) were within average range, whereas performance on morpho-syntactic comprehension, naming and phonological processing tasks was below the norms (Table 2). A

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formal assessment of literacy skills by means of standardized tests of reading and spelling (Martini, 1995; Sartori et al, 1995) revealed a severe learning disability. Reading performance was significantly impaired both for speed and accuracy. The child could read and write only disyllabic words, making use of a prevalent letter by letter strategy and manifested severe difficulties to find out the meaning of even single words. Writing to dictation was also severely impaired (Table 2).

Table 2 — Summary of residual deficits NON VERBAL ABILITIES VMI (standard score)

PM47 (percentile)

77

30°

LANGUAGE Expressive vocabulary Receptive grammar Naming test (z-score) TCGB (z-score) - ,4 102 -2.5 PHONOLOGICAL PROCESSINC Phonological Working Memory Verbal fluency (z-scores) (z-scores) Long words Phonemic Semantic Short words -2,2 -1,6 -0,9 -1,5 ACADEMIC SKILLS Writing Reading (z-scores) (single words) Speed Accuracy (z-scores) Short Letters Words Long Short words Long words -1,95 > -5 > -5 > -5 > -5 > -5 Receptive vocabulary PPVT (standard score)

DISCUSSION

This child sustained a severe functional, epilepsy-related disorder, with sudden onset of suprabulbar palsy and focal seizures. The course of epilepsy was rather favourable (despite persistent EEG abnormalities), but he was left with mild verbal dyspraxia, some expressive language difficulties and a severe disorder of reading and writing. Some other rare cases of AEOS with long-lasting high-level language deficits have occasionally been described in the literature. Deonna et al.'s case 2 (1993) was reported to have difficulty with written language (mainly severe dysorthography) and dysfluent speech. Patient 1 in the Kramer et al. 's series (2001) showed word-retrieving difficulties on a formal language test, whereas patient 3 (in the


45

same series) had poor reading skills. In the authors' opinion, the above symptoms should not be influenced by a sensorimotor deficit and represent a "higher function deficit" whose significance is unclear. In a recent review of the opercular epilepsies with oromotor dysfunction, Salas-Puig et al. (2000) pointed out that some children with perisylvian developmental disorders (bilateral opercular malformations) may present with a quite homogeneous language dysfunction that cannot be accounted for by a speech paretic disorder and by oral dyspraxia (as in the classic form of FCMS), but should imply involvement of language areas, though to a variable degree. At present, the pathophysiology of central processing disorders in AEOS rests on speculative grounds (Fejerman et al, 2000). We may hypothesise that the spreading of abnormal electrical brain activity to adjacent regions of the frontal cortex subserving phonologically-based linguistic processes would interfere with higher neurofunctional language mechanisms that sustain coding and rehearsal of phonological and lexical information. This hypothesis would also explain reading and writing difficulties, by assuming the presence of a central impairment in the acquisition of rapid and automatized rules for recoding oral language knowledge into its written form. From a neurolinguistic point of view, the relationship between AEOS and oral/verbal dyspraxia, has not been systematically addressed in the literature. This may be due, at least in part, to the following facts. First, in some papers on functional or structural Opercular Syndrome (OS), the terms dyspraxia and dysarthria have been used interchangeably, although the paretic origin of typical suprabulbar palsy is well recognised since Worster - Drought's (1974) influential work. In our patient, both paretic and praxic defects of the facio-lingualglosso-pharingeal muscles were variably present during different stages of the illness. Second, as described above, rare cases of AEOS with persisting subtle oral and written language deficits have been reported, but few explanatory hypotheses have been proposed. Third, the pathophysiology of acquired apraxia of speech in adults and of developmental apraxia of speech (DAS) in children is very controversial. The debate concerns both the nature of the disorder - in terms of a movement or a language disturbance (Robin, 1992) - and the specific brain site responsible for it. Some suggestions for speculating on the localization of DAS arise from different and sparse sources drawn from adult patients with acquired lesions and from children with both congenital and acquired speech disorders (Habib & Demonet, 1996; Vargha-Khadem et al, 1998; Van Mourik et al, 1997). However, an involvement of perirolandic cortex in the adjacency of the inferior motor strip (dedicated to the innervation of lips, tongue and glosso- pharyngeal muscles) and of the 'pars opercularis' of Broca's area has been advocated as the most likely candidate region by several authors (Alexander et al, 1990; Foundas et al, 1998). In addition, based on data from stroke patients with apraxia of speech, Dronkers (1996) identified the precentral gyrus of the insula as the brain region co-ordinating speech articulation. A functional impairment of these regions may result from epileptic activity involving them either primarily, or as a result of a spreading effect from contiguous areas. However, confirmation of this hypothesis would need sophisticated electrophysiological and neurofunctional studies, through two-dimensional topographical EEG mapping and coherence/spectrum analysis, and fMRI exploration of brain

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regions of interest. In conclusion, the long-lasting, praxic and language deficits in AEOS might be related as suggested for some permanent sequelae in Landau-Kleffner Syndrome (LKS) - to a disruption of normal synaptic connectivity in the perisylvian cortex during a sensitive stage of its development. Similarly to LKS, the effects of epileptogenic discharges on neuronal networks subserving language would 'activate and perpetuate synaptic arrangements that are functionally inappropriate' (Morrell et al, 1995).

REFERENCES Alexander, M. P., M. A. Naeser and C. Palumbo (1990), Broca's area aphasias: Aphasia after lesions including the frontal operculum. Neurology, 40, 353-362. Beery K.E. (1997) VMI. Developmental test of visual-motor integration, 4th Edition, Revised. Toronto: Modern Curriculum Press. Brizzolara, D., P. Cipriani, A. M. Chilosi and L. De Pasquale (1994). L'apprendimento del linguaggio scritto nei bambini con difficolta di acquisizione del linguaggio orale: continuita o discontinuity? In: Apprendimento e patologia neuropsichica nei primi anni di scuola. Modelli interpretativi della clinica (G. Masi and A. Martini, editors), pp. 124-135. Borla, Roma. Chilosi, A. and P. Cipriani (1995). Test di comprensione grammaticale per bambini (TCGB). Del Cerro, Tirrenia. Christen, H. J., F. Hanefeld, E. Kruse, S. Imhauser, J. P. Ernst and M. Finkenstaedt (2000). Foix-Chavany-Marie (anterior operculum) syndrome in childhood: a reappraisal of Worster-Drought syndrome. Dev Med Child Neurol, 42, 122-32. Colamaria, V., V. Sgro, R. Caraballo, M. Simeone, E. Zullini, E. Fontana, R. Zanetti, R. Grimau-Merino and B. Dalla Bernardina (1991). Status epilepticus in benign rolandic epilepsy manifesting as anterior operculum syndrome. Epilepsia, 32, 329-334. De Saint-Martin, A., C. Petiau, R. Massa, R. Maquet, C. Marescaux, E. Hirsch and M. N. Metz-Lutz (1999). Idiopathic rolandic epilepsy with "interictal" facial myoclonia and oromotor deficit: A longitudinal EEG and PET study. Epilepsia, 40, 614-620. Deonna, T. W., E. Roulet, D. Fontan and J. P. Marcoz (1993). Speech and oromotor deficits of epileptic origin in benign partial epilepsy of childhood with rolandic spikes (BPERS). Neuropediatrics, 24, 83-87. Dronkers, N. G. (1996). A new brain region for coordinating speech articulation. Nature, 384, 159-61. Dunn, L. and L. M. Dunn (1981). Peabody Picture Vocabulary Test - Revised. American Guidance Service, Circle Pines, MN. Fejerman, N. and M. Di Blasi (1987). Status epilepticus of benign partial epilepsies in children: report of two cases. Epilepsia, 28, 351-355.


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Fejerman, N., R. Caraballo, S. N. Tenembaum (2000). Atypical evolutions of benign localization-related epilepsies in children: Are they predictable? Epilepsia, 41, 380390. Foix, C, J. A. Chavany and J. Marie (1926). Diplegie facio-linguo-masticatrice d'origine cortico-sous-corticale sans paralysies des membres. Rev Neurol, 33, 214-219. Foundas, A. L., K. F. Eure, L. F. Luevano and D. R. Weinberger (1998). MRI asymmetries of Broca's area: The pars triangularis and pars opercularis. Brain Lang, 64, 282-296. Galanopoulou, A. S., A. Bojko, F. Lado and S. L. Moshe (2000). The spectrum of neuropsychiatric abnormalities associated with electrical status epilepticus in sleep. Brain Dev, 22, 279-295. Gordon, N. (2002) Worster-Drought and congenital bilateral perisylvian syndromes. Dev Med Child Neurol 44, 201-204. Habib, M., J.-F. Demonet (1996). Cognitive neuroanatomy of language: the contribution of functional neuroimaging, Aphasiology, 10, 217-234 Kramer, U., B. Ben-Zeev, S. Harel and S. Kivity (2001).Transient oromotor deficits in children with benign childhood epilepsy with central temporal spikes. Epilepsia, 42, 616-620. Leiter, R.G. (1979). Letter International Performance Scale. Stoelting Co, Chicago. Martini, A. (1995). Le difficolta di apprendimento della lingua scritta. Criteri di diagnosi e indirizzi di trattamento. Del Cerro, Tirrenia. Morrell, F., W. W. Whisler, M. C. Smith, J. H. Thomas, L. de Toledo-Morrell, S. J. C. PierreLouis, et al. (1995). Landau-Kleffner syndrome: Treatment with subpial intracortical transection. Brain, 118, 1529-1546. Orsini, A., D. Grossi, E. Capitani, M. Laiacona, C. Papagno and G. Vallar (1987). Verbal and spatial immediate memory span: normative data from 1355 adults and 1112 children. Ital J Neurol Sci, 8, 539-548. Pruned, C, A. Fenu, G. Freschi, S. Rota, D. Cocci, M. Marchionni, S. Rossi and G. Baracchini Muratorio (1996). Aggiornamento della standardizzazione italiana del test della Matrici Progressive Colorate di Raven (CPM). Bollettino di Psicologia Applicata, 217,51-57. Raven, J. C. (1956) Guide to using the Coloured Progressive Matrices, sets A, AB and B. London: H.K. Lewis. Italian version (1984): Progressivi matrici colore. Serie A, AB, B. Firenze: Organizzazioni Speciali. Robin, D. A. (1992). Developmental apraxia of speech. Am J Speech Lang Pathol, 1, 9-22. Roulet, E., T. Deonna and P. A. Despland (1989). Prolongued intermittent drooling and oromotor apraxia in benign chilhood epilepsy with centrotemporal spikes. Epilepsia, 30(5), 564-568. Salas-Puig, J., A. Perez-Jimenez, P. Thomas, I. E. Scheffer, B. Dalla Bemardina and R. Guerrini (2000). Opercular epilepsies with oromotor dysfunction. In: Epilepsy and Movement Disorders (R. Guerrini, J. Aicardi, F. Andermann and M. Hallet, editors), pp. 251-268. Cambridge University Press, Cambridge.

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Sartori, G., R. Job and P.E. Tressoldi (1995). Batteria per la valutazione della dislessia e delta disortografia evolutiva. Organizzazioni Speciali, Firenze. Shafrir, Y. and A. L. Prensky (1995). Acquired epileptiform opercular syndrome: a second case report, review of the literature, and comparison to the Landau-Kleffner syndrome. Epilepsia,36, 1050-1057. Shuper, A., B. Stahl and M. Mimouni (2000). Transient opercular syndrome: a manifestation of uncontrolled epileptic activity. Ada Neurol Scand, 101, 335-338. Stella, G., C. Pizzoli, P. E. Tressoldi (2000). Peabody. Test di Vocabolario Recettivo. Omega Edizioni, Torino. Tachikawa, E., H. Oguni, S. Shirakawa, M. Funatsuka, K. Hayashi and M. Osawa (2001). Acquired epileptiform opercular syndrome: a case report and results of single photon emission computed tomography and computer-assisted electroencephalographic analysis. Brain Dev, 23, 246-250. van Mourik, M., C. E. Catsman-Berrevoets, H. R. van Dongen and B.G.R. Neville (1997). Complex orofacial movements and the disappearance of cerebellar mutism: Report of five cases. Dev Med Child Neurol, 39, 686-690. Vargha-Kadem, F., K. Watkins, C. J. Price, J. Ashburner, K. J. Alcock, A. Connelly, et al. (1998) Neural basis of an inherited speech and language disorder. Proc Nat Acad Sci, 95, 12695-12700. Worster-Drought, C. (1974). Soprabulbar Paresis. Congenital suprabulbar paresis and its differential diagnosis, with special reference to acquired suprabulbar paresis. Dev Med Child Neurol, 16, 1-33.

Brain Language Lateralization and Focal Lesions

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5

CEREBRAL LANGUAGE LATERALIZATION AND EARLY LINGUISTIC DEVELOPMENT IN CHILDREN WITH FOCAL BRAIN LESIONS Anna M. Chilosi, Chiara Pecini, Paola Cipriani, Daniela Brizzolara, Paola Brovedani, Giovanni Ferretti, Lucia Pfanner and Giovanni Cioni "Stella Maris " Scientific Institute, Pisa, Italy

Abstract — We conducted a longitudinal study of 20 children with unilateral focal brain lesions and hemiplegia, 11 with left (LHD) and 9 with right hemisphere damage (RHD) to investigate the relationship between lesion characteristics, early linguistic development and hemisphere lateralization for language. Cerebral lateralization for language was measured by means of the Fused Dichotic Words Test. Two comprehensive assessments of language comprehension and production were performed at about 2 and 4 years of age. An early left side-specificity for language was revealed by the presence of lexical and grammatical delay in the majority of LHD children. In 90% of LHD children, plasticity and the potential for re-organization were documented by a shift in lateralization for language to the right hemisphere on the dichotic listening test. There was an association, irrespective of side, between the largest lesions, the most atypical hemispheric asymmetries (as expressed by laterality coefficients) and delay in grammatical development. Lesion type seemed to significantly affect hemispheric lateralisation and short-term language outcome, cortico-subcortical lesions being significantly associated with a greater degree of lateralization and language delay in comparison to periventricular white matter lesions. The presence of EEG abnormalities and/or seizures negatively affected language outcome. Keywords: language development, focal lesions, hemispheric lateralization, Fused Dichotic Words Test.

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INTRODUCTION Several studies report that early brain lesions have relatively mild consequences on language development in comparison to lesions acquired later in adulthood, and do not necessarily show a clear-cut association to side, site or size of lesion (Vargha-Khadem el al, 1985; Vargha-Khadem et al, 1992; Muter et al., 1997; Reilly et al., 1998). These data have been interpreted in relation to the concepts of 'plasticity' and 'equipotentiality' of the immature brain: while plasticity refers to the compensatory mechanisms underlying lesion-induced neurofunctional and behavioural reorganisation, equipotentiality refers to the analogous capacity of the two hemispheres to sub-serve language functions after unilateral brain damage (Lenneberg, 1967). This theory has been challenged by several studies which support the existence of an early specialisation of the left hemisphere for language acquisition, although the differential effect of left and right lesions seems to depend on the specific stage of language development. In fact, Bates et al. (1997) found that in the period from 10 to 17 months of age, children with a right lesion were at a greater risk for delays in word comprehension and gesture production than children with left hemisphere damage (LHD), and in the period from 10 to 44 months children with a lesion involving the left temporal lobe showed significantly greater delay in expressive vocabulary and grammar (see also Thai et al., 1991; Vicari et al, 2000; Chilosi et al, 2001). However, the effect of a left temporal damage on grammar development was no longer detected past 5-6 years of age (Reilly et al, 1998). These data on the linguistic development of LHD children suggest that 'equipotentiality' and early 'left hemisphere specialisation' may represent the two poles of a continuum: the left hemisphere may be innately predisposed to language learning and processing, but this predisposition is sufficiently plastic for the non-dominant hemisphere to successfully acquire and mediate language in conditions such as early focal brain damage (Vicari et al, 2000; Chilosi etal, 2001; Satzefa/., 1990). More recently, the plasticity of the immature brain and the concept of equipotentiality of the two hemispheres was supported by new neuroimaging evidence which found a right hemisphere specialization for language after early damage to the left language areas (Miiller et al, 1999; Lazar et al, 2000). According to these studies, the reorganization for language in the right hemisphere involves regions which are mostly homotopic to the language areas in the left hemisphere of healthy right-handers, thus suggesting a 'near-equipotentiality' of the two hemispheres also at a topological level (Staudt et al, 2002). However, it is still too early to draw general conclusions from functional neuroimaging studies, as there are in fact two main methodological limitations: a) normative data from healthy children are still scarce, and b) most of the data are collected on patients with early-onset and severe epilepsy who are candidates for neurosurgery. The issue of how language reorganises after early focal damage has been traditionally addressed by behavioural techniques, such as the dichotic listening paradigm. The use of a behavioural paradigm allows for the study of larger samples of patients and is especially


51

appropriate for investigating language lateralisation in very young children in comparison to neuroimaging methods. In the dichotic listening paradigm two competing verbal stimuli are presented simultaneously to the two ears. According to Kimura's structural model (Kimura, 1961, 1967), in this condition, controlateral auditory pathways occlude the ipsilateral pathways. This leads to a better processing of the stimuli presented to the right ear (REA, right ear advantage) as they have more direct and faster access to the language-dominant left hemisphere than the stimuli presented to the left ear, which are in fact assumed to access first the right hemisphere and then the left through the corpus callosum (for a review, see Bryden, 1981). Dichotic techniques were employed to investigate whether language reorganization after an early lesion occurs inter- or intrahemispherically in relation to the characteristics of the lesion (Brizzolara et al., 2002). The presence of epileptic activity is another factor that may in itself alter the pattern of lateralization. Piccirilli et al. (1988), using a verbal-manual dual task, found that in children with benign focal epilepsy with no documented lesion, a left unilateral epileptogenic focus was associated with a bilateral representation of language processing. Riva et al. (1993) compared the performance of epileptic children with unilateral foci and the presence or absence of CT documented lesions on a verbal-spatial tachistoscopic task and found that cerebral lateralisation was altered similarly in both groups. On the basis of these findings they suggested that epilepsy alone can change the pattern of lateralisation for verbal information processing. More recently, Isaacs et al. (1996) addressed the issue of the effect of seizure disorder on language lateralisation in hemiplegic children. On a dichotic listening task using digits, left lesioned children with a history of clinical seizures displayed a stronger LEA than left lesioned children without seizures, probably because of a more limited potential for language processing in the hemisphere where the epileptic focus was active. In a previous study conducted in our laboratory (Brizzolara et al., 2002), we investigated cerebral lateralization for language by means of the Fused Dichotic Words Test (Wexler & Halwes, 1985) in 26 hemiplegic children with congenital focal brain damage with the specific aim to investigate the relation between lesion characteristics (side, size and localisation) on MRI and the pattern of language lateralisation on the dichotic test. We found significant side and site effects at group level: while children with right lesions showed the expected right ear advantage (REA), in children with left hemisphere lesions there was a left ear advantage (LEA). An analysis of individual data, however, revealed that type of lesion (e.g., corticosubcortical versus periventricular) occurring at term or pre-term respectively, may be the primary factor responsible for inter- vs. intrahemispheric organisation of language after congenital brain lesions. Only when the left lesions involved cortico-subcortical regions encroaching the temporal lobe and occurred at term, language was reorganised in the right hemisphere; when lesions (whether left or right) involved only the periventricular white matter and occurred at pre-term, language was lateralised in the left hemisphere. However, the relationship between lesion localisation, re-organisation of language and functional effect on language development is still an open issue.

52


On the basis of these considerations, the aim of the present study was twofold: a) to analyse the course of linguistic development in relation to different lesions characteristics; b) to investigate whether there is a relation between the degree of functional specialisation for language, expressed by LEA and REA values on the dichotic test, and the timing and trajectory of linguistic development. We addressed these issues by examining language development and reorganisation from the third to the fourth year of age in a sample of children with pre- or perinatal focal brain damage.

SUBJECTS Subjects were selected from a larger population of patients with congenital focal brain lesions referred to the Division of Child Neurology and Psychiatry of the University of Pisa on the basis of the following criteria: unilateral focal brain lesions, occurring pre- or peri-natally, documented on the basis of clinical records and MRI absence of diffuse or progressive lesions or brain malformations comprehensive longitudinal linguistic assessment with at least 2 evaluations between the age of about 2 and 4 years, with an interval between the two consecutive observations of at least 8 months absence of mental retardation (Developmental Quotient > 80) at the time of the first evaluation absence of treatment- resistant epilepsy at the two evaluation time points absence of auditory deficits and personality disorders. MRI assessment Brain MRI studies were performed under sedation using a 1.5 T system (GE, Signa Advantage); images were obtained in the axial, coronal and sagittal planes with sections of 5 mm. When multiple scans were available, the most recent one was considered. MRI findings were classified retrospectively by one of the authors (GC), blind to the results of linguistic and cognitive assessment, according to the most recent indications in the literature about neuroimaging findings in congenital hemiplegia (Tailairach & Tournoux, 1988; Barkovitch, 1995; Cioni et al, 1999). Results are reported in Table 2. Lesions were classified according to three different criteria: Side and site of lesion. Patients were assigned either to the "right" or "left" unilateral lesion group. Moreover, cerebral lobes involved in the lesion and the encroachment of language areas (frontal and temporal lobes) were recorded.

Brain Language Later•alization and Focal Lesions

53

Size of lesion. Lesion size was classified by a grading system adapted (with modifications) from Vargha-Khadem et al. (1985). It consists of a six-point scale, ranging from 0 to 5, providing an index of lateral ventricular dilatation and of the extension of encephaloclastic cysts; score 5 indicates the most severe abnormality. This scale is presented in papers previously published by the authors (Vicari et al, 2000; Chilosi et al, 2001). Type of lesion. Both the pathophysiological mechanisms of the lesion and its probable timing were taken into account. Two types of lesions were observed: 1) Periventricular white matter lesions (PV), likely due to parenchymal haemorrhages (results of venous infarction or of haemorrhagic periventricular leukomalacia) or to periventricular leukomalacia. These lesions usually occur either intra or extra utero (in case of preterm birth) in the last trimester of gestation. Unilateral encephaloclastic cysts, merged into a dilated ventricle, are often observed on MRI at older ages. In the other cases, lesions consist of symmetrical or asymmetrical periventricular gliosis. 2) Cortico-subcortical (C-SC-PV) lesions, due to an infarction of a main cerebral artery (generally main branch or cortical branch of middle artery), involving the cortex, the white matter below the cortex and often the periventricular white matter. Sometimes, the lesion concerns the deepest branches (exclusively or in association with other lesions) involving diencephalic structures. These lesions usually occur at around term age. Electrophysiological assessment EEGs were obtained for all patients, the majority of whom receiving repeated recordings. EEG tracings closest to the time of linguistic and psychological observations were analysed and results were classified according to the nature of the abnormality (diffuse, focal, paroxysmal), its frequency and the condition during which it occurred (wakefulness, sleep, other types of activation). Findings were scored as normal, mildly abnormal or severely abnormal. The occurrence of clinical seizures with onset beyond the neonatal period and excluding febrile convulsions were documented. Linguistic assessment Language evaluation was performed through a combination of indirect procedures (parental interview to collect information on productive vocabulary size) and direct observations to evaluate the level of expressive and receptive grammar. The latter were based on free-speech samples and on a test of Early Verbal Comprehension (Chilosi et al, 2003). Expressive vocabulary was tested by means of the Infant's and Toddler's MacArthur Communication Developmental Inventories (Italian version: // Primo Vocabolario del Bambino - PVB) (1995), for which normative data are available in the 8-30 months age range. Because many of the children in our focal lesion sample were delayed in language development, assignment of the Infant's or Toddler's form was based on language level rather

54


than on chronological age. The analyses presented here will focus on productive vocabulary from both forms and will be expressed by total number words and by a lexical quotient (LQ) corresponding to the ratio between lexical age (i.e., the age at which a particular score corresponds to the median in the normative sample) and chronological age. Expressive grammar was evaluated on the basis of language samples collected in our laboratory during a standardised play situation involving the child and his/her parents. Speech was transcribed independently by one of the authors (L.P.) and by a trained research assistant (inter-observer agreement reached 90%). The utterances were then coded according to the Child Language Exchange System (CHILDES) (Mac Whinney & Snow, 1985). For each child the level of grammatical development was scored on a six-level rating system (see Table 1) developed by Cipriani et al. (1993), ranging from Level 0 (pre-linguistic stage) to Level 5 (complex grammar). Verbal comprehension was investigated by an acting-out task that has been standardised on a sample of Italian children. It includes 20 simple verbal commands of increasing complexity that the child is required to act out with a set of toys or familiar objects. For each child, a z-score was obtained on the basis of normative data from 6 groups of normal children aged 16-36 months (Chilosi et al, 2003). Table 1 Levels of grammatical development Level

Expressive language

Level 0

Level 4

Babble, sounds, gestures and sporadic single word utterances (SW) Single-word utterances (SWU) start to be consistently produced Emergence of combinatorial speech, but SWU prevail Ungrammatical or telegraphic multiword utterances (MWU) Fully grammatical simple sentences

Level 5

Fully grammatical complex sentences

Level 1 Level 2 Level 3

Dichotic Listening paradigm The Fused Dichotic Words Listening Test (Wexler and Halwes, 1985) (consisting of pairs of rhyming words) was used since it has been shown to be a more valid measure of cerebral lateralisation than non-fused versions (Zatorre, 1989). Fifty-five high frequency two-syllable words were used (Marconi et al., 1994), 28 CVCV and 27 CVCCV. The stimuli were recorded in Digital Audio Tape mode in a noise-protected room and sampled by a digital SoundBlaster Hard-Disk-Recording for PC. Sampling cared that words forming the dichotic pair were synchronised for the beginning of the first consonant, for length and for some


55

internal features (especially where the accent fell). Stimuli were presented by a specific program running on a PC. The experiment consisted in the dichotic presentation of 30 pairs of fused words: twenty-five pairs differed for the first consonant (e.g., cane-pane) and 5 pairs differed for the first vowel (e.g., luna-lana). Word pairs were presented twice to all subjects; in the second session the assignment of stimuli to ears was reversed. The order of presentation of the word pairs was fixed across subjects and varied across sessions. Overall, each subject heard 60 stimuli in each ear through headphones (Sony Professional MDR-V50). Children were instructed to repeat all the words they heard, after each presentation. The raw data were then converted to a laterality coefficient (Lambda) according to the procedure proposed by Bryden and Sprott (1981). It consists of the natural logarithm of the number of correct responses for the words heard by the right ear plus 1, divided by the number of correct responses for the words heard by the left ear plus 1 (Ln[(Right+l)/(Left +1)]). A positive value is indicative of REA, reflecting a left hemisphere superiority for language processing. Conversely, a negative value indicates a LEA, reflecting a right hemisphere superiority. Mean laterality coefficient values, obtained on a large sample of normal children aged 4-10 years, ranged from 0.32 to 0.54 and were stable across ages (Brizzolara et ah, 2000). In the present study the dichotic test was administered as soon as children were able to cooperate reliably, with mean chronological age of 5 years and 4 months. RESULTS Clinical and MRI characteristics According to the selection criteria, a total of 20 children (13 males and 7 females) participated in the study, 11 with LHD and 9 with RHD. Mean chronological age at the first evaluation time point (77) was 23.5 months (SD 3.0, range 16-29) for LHD children and 21.8 months (SD 5.1, range 17-32) for RHD children. At 77, mean age for LHD children was 38.3 months (SD 1.6, range 36-42) and 39.2 months (SD 3.6, range 35-44) for RHD children. The mean interval between 77 and T2 was 14.8 months for LHD children (range: 9-23) and 17.4 months for RHD children (range: 8-26). Neither age at the two time-points nor the T1-T2 interval significantly differed between the two groups (t-test). Table 2 shows the sample characteristics, time of brain injury (hypothesized on the basis of medical history and neuroradiological data), MRI findings, presence or absence of epilepsy, EEG findings and age at the two evaluation time points. Nineteen children had a documented hemiplegia of differing degree of severity. Four had epilepsy that was well controlled by mono- or polytherapy at the time of the study. Fourteen children had C-SC-PV lesions, 5 had PV lesions and only one child had a SC-PV lesion. The mean size of the lesions (grade) was 3.8, with a range between 1 and 5. Sixteen children had EEG abnormalities that were mildly abnormal in 10 and severely abnormal in 6. Four of the latter had clinical seizures at the time of the study, whereas two cases (cases 6 and 14) presented with epilepsy within two years from T2.

56


Table 2 - Clinical and neuroradiological characteristics of the sample Case/

GA

Time of

Gender

(Wk)

lesion

MRI findings Site

1/M

42

term

Side L

Extention C,SC,

Age

Age

atTl

atT2

(mo)

(mo)

EEG

Epilepsy

findings

Lobes FTP

Size 4

23

37

N

MA

sc,

FTP

4

23

38

Y

SA

sc,

PTF

4

24

37

N

MA

sc,

PO

4

25

38

Y

SA

sc,

FTPO

5

24

39

Y

SA

sc,

TPO

4

16

39

Y

SA

sc,

PTF

4

23

36

N

MA

FP

3

24

38

N

N

sc,

TPF

5

24

42

N

MA

sc,

FTP

5

29

38

N

MA

PV 2/F

39

term

L

c, PV

3/M

38

term

L

c, PV

4/F

39

pre-term

L

c, PV

5/M

40

term

L

c, PV

6/M

38

term

L

c,

7/M

41

term

L

c,

PV PV 8/F

40

pre-term

L

PV

9/M

39

term

L

c, PV

10/M

42

term

L

c, PV

11/M

41

pre-term

L

PV

PF

5

24

40

N

N

12/M

38

pre-term

R

SC, ]PV

FPT

3

20

35

N

SA

13/F

34

pre-term

R

C

sc,

FPT

4

24

40

Y

MA

sc,

PFT

4

19

44

Y

SA

sc,

FTPO

5

17

32

N

MA

sc,

FTP

4

26

40

N

MA

PV 14/M

39

term

R

c, PV

15/M

40

term

R

c, PV

16/F

40

term

R

c, PV

17/M

40

pre-term

R

PV

FTP

1

22

42

N

N

18/F

40

pre-term

R

PV

PT

3

32

40

N

MA

19/M

39

term

R

c,

T

4

21

39

N

MA

P

1

15

41

N

N

sc,

PV 20/F

34

pre-term

R

PV

Note: GA = gestational age; Wk = weeks; Mo = months; R = right, L = left, C = Cortical; SC = subcortical; PV = Periventricular; F = Frontal; P = Parietal; T = Temporal; O = Occipital; N = Normal; MA = Mild abnormalities; SA = Severe abnormalities.


57

A preliminary analysis was conducted to verify whether LHD and RHD groups differed for clinical and MRI characteristics: Lesion type: there was a slightly higher incidence of cortico- subcortical lesions in LHD than in RHD children but the difference was not significant (chi-square); Lesion size: LHD children showed a tendency to have larger lesions than RHD children, however this difference was not significant (chi-square); Lesion site: 18 children had a lesion encroaching temporal and/or frontal lobes, without significant differences between left and right lesions. EEG findings: EEG abnormalities were associated with lesion type, with a higher incidence of mild and severe abnormalities in C-SC-PV than in PV lesions (chi square = 11.7, p = 0.005); no significant associations were found with lesion side and size. Language development The mean number of words produced by the whole sample at Tl was 66.6 (SD = 102.7, range = 2-403). This corresponds to a mean age of 16.5 months and to a lexical quotient (LQ) of 78.7. At T2 the mean vocabulary raw score was 413 (SD = 218.9, range = 26 - 660; mean increase from Tl to T2 = 346.5 words) corresponding to a mean age of 29.8 months and an LQ of 77.9. The mean z-score for language comprehension at Tl was in the low average range (z = -0.9), but 70% of LHD and 37.5% of RHD children scored more than one standard deviation below the norm, showing a varying degree of delay. Table 3 shows the performance of LHD and RHD children on linguistic tests. Table 3 — Language performances of left (LHD) and right (RHD) damage children at Tl and T2 (means and standard deviations) Language assessment Vocabulary

LHD RHD

Tl T2 Tl T2

N words Mean sd 27.9 (26.7) 360.7 (192.6) 109.8 (137) 485.2 (244)

Lexical Quotient Mean sd 63 (25.7) 70.9 (15.8) 89.1 (19.1) 86.5 (17.5)

Expressive Grammar Level * 1 4 1.7 4.5

Language Comprehension Z score Mean sd -1.4 (0.8) -0.9 (0.9) -0.2 (1.1) 0.09 (0.5)

Note: * median value LHD = Left hemisphere damage; RHD = Right hemisphere damage; N words = number of words. At T2, language comprehension improved in both groups (mean z score = -0.36) with only 2 LHD children and 1 RHD child showing a persistent delay. The anova analysis revealed a significant effect of lesion side on LQ (F(l, 18) = 7.94, p < 0.01) and on verbal

58


comprehension (F(l,12) = 18.87, p < 0.001), with a lower performance in the LHD group versus the RHD group; the absence of a significant interaction between lesion side and time of evaluation indicated that this difference was stable from Tl to T2. The level of expressive grammar of the whole sample varied widely at Tl, ranging from a pre-linguistic to an early grammatical phase of development. However, while all LHD children were delayed and did not produce any word combination (level 0 or 1), only two children in the RHD group had not yet reached the level of combinatorial speech (chi square(l) = 8.14, p < 0.005). The disadvantage of LHD children was still present at T2, as 9 out of 11 showed a persistent delay in grammatical development in comparison to the 2 RHD children who maintained their delay (chi square (1) = 4.8, p < 0.05). To further analyze the effects of different variables on lexical and grammatical development, short-term language outcome at T2 was rated according to the following criteria: age-appropriate language outcome (LQ > 80; expressive grammar level >4) and delayed language outcome (LQ < 80, expressive grammar level 50% NREM sleep

One episode at 8 years of age

Receptive and expressive morphosyntax.

Two episodes at 7 and 9 years of age Between 7 and 12 years

Expressive morphosyntax, pragmatics. Transcortical motor aphasia.

No episodes

Receptive and expressive morphosyntax. Anomias.

1, MD

Normal

2, GM

Spike waves

3, RP

Spike-waves

4, LS

Spike-waves

Diffuse paroxysmal activity Diffuse paroxysmal . . , \ activity before 14 years Subcontinuous paroxysmal activity >

5, LP

Normal

Paroxysmal activity

No episodes

Verbal dyspraxia

6, GM

Normal

Paroxysmal activity

No episodes

Receptive and expressive morphosyntax.

At 8 years and 10 months she had a critical episode with loss of consciousness and right eye lateroversion, followed by an aggravation of language deficits. As her clinical picture which was typical of Landau-Kleffner Syndrome - with aphasic regression, seizures,

72


paroxysmal EEG during NREM sleep - was associated to a documented neurological lesion, we defined it Landau-Kleffner Syndrome-Like. Ethosuximide was introduced to keep seizures under control. The sleep EEG still revealed focal paroxysmal abnormalities in the right frontal region, with mainly homolateral diffusion. Administration of the NEPSY battery showed a clear aggravation of memory skills compared to the previous evaluation (from 67% correct to 54%). On the language examination her language deficits had worsened. She performed 2 SDs below the norm on the following tasks: verbal discrimination, syntactic comprehension, grammatical comprehension, sentence repetition and semantic fluency (cf. Table 2). Case 2 (GM) GM is a right-handed girl aged 10 years and 8 months. Pregnancy was uneventful with normal delivery (low birth weight: 2.4 kg). At 10 days of life she suffered an episode of low platelet count, with bruises on her face, neck and trunk. At 1 year of life a left hemisyndrome was observed. This neurological picture was attributed to perinatal brain suffering. The child received kinesitherapy and speech therapy to improve her motor skills and pragmatic problems - poor relationships with adults and peers - as well as phonological and lexical deficits. At 4 years of age her IQ was in the normal range (WIPPSI: VIQ= 87; PIQ= 95; FIQ= 90). Her speech was little intelligible and she still had relational difficulties with adults. At 6 years and a half her intellectual development had improved (WISC-R: VIQ= 96; PIQ= 100; FIQ= 97). She showed semantic and grammatical comprehension deficits, phonological deficits, reading and writing disabilities. First episode ofLKS. At 7 years and a half she suffered two generalized tonic-clonic seizures. The EEG in wakefulness evidenced spike-wave paroxysmal activity in the fronto-temporal region bilaterally, mainly prevalent on the left. She received carbamazepine (300 mg/day). Progressively the child started to show language regression: her pragmatic problems aggravated and she had difficulties in establishing relationships with others, and avoided eye contact. Her speech was unintelligible. She uttered single words, with many anomias and perseverations. To communicate, she resorted to pointing or drawing. She read very slowly. On the WISC-R she showed increased difficulties (VIQ= 87; PIQ= 83; FIQ= 83). Her clinical picture, which was typical of Landau-Kleffner Syndrome - aphasic regression, seizures, paroxysmal EEG during NREM sleep - was associated to a documented neurological lesion. Thus, we defined it Landau-Kleffner Syndrome-Like. Slowly she showed a progressive language recovery. She was started on Lamotrigine (125 mg/day). At the age of 8.06 years she underwent another neurological examination. MRI imaging and CT scan evidenced an egg-like formation, 2.5 cm in diameter, in the left parietal region near the vertex and the midline (possible outcome of prenatal lesion) (see Figure 3).

Language Disorders and EEG Abnormalities During NREMSleep

73

Figure 3 — MRI. Egg-like lesion due to an arachnoidal cyst possibly localized in the left upper parietal region, with likely areas of cortical dysplasia (coronal section, T2).

An EEG in wakefulness evidenced a symmetric and reactive 10 Hz background rhythm. On the frontal areas, isolated spikes and waves were noted, mainly prevalent on the left. Focal paroxysmal abnormalities were found (triphasic spikes followed by slow waves) in the right centro-temporal region throughout all sleep stages. Epileptiform abnormalities were repetitive and more numerous in NREM sleep (see Figure 4).

Figure 4 — EEG: Left centro-parietal paroxysmal slow focus in wakefulness and drowsiness, with immediate diffusion and generalization of paroxysms upon falling asleep.

Second episode of LKS. At the age of 9 years and a half seizures during sleep appeared again

74


(eye opening, mouth clonic spasms, scialorrhea, clonic spasms of the lower limbs) with abrupt language regression. Her verbal comprehension was minimal and spontaneous speech was absent. Only upon request did she produce single words. An important regression in IQ was noted (WISC-R: VIQ= 70; PIQ= 91; FIQ= 77) (cf. Table 1). On the EEG in wakefulness the spike-slow wave complexes were more marked in the left anterior areas. This activity was not modified in sleep. ACTH therapy was started (Synacthen Depot 1, 1 via IM) with administration of 6 doses. Valproate sodium (600 mg/day) was introduced in the AE therapy. Progressively she showed language recovery. On the 4-12 language battery (Fabbro, 1999), she showed full recovery of sentence repetition and fluency. Verbal fluency, MLU and Type/Token Ratio of descriptive speech were age-appropriate. Omissions of free grammatical morphemes and phonemic paraphasias were still present (cf. The Bird Nest Story Picture Description Task; Paradis, 1987) (cf. Table 2). Case 3 (RP) RP is a right-handed young adult male aged 24 years. Pregnancy and labor were uneventful (birth weight: 3 kg). At 2 years he was examined by a neurologist owing to severe motor and linguistic deficits - independent walking was reached only at age 2 years when the child produced only few words. The neurological examination revealed cerebellar problems and the child was referred for outpatient rehabilitation. A CT scan evidenced a small poroencephalic area in the right cerebellar lobe, with signs of olivo-ponto-cerebellar atrophy. At 7 years he had seizures during sleep. Ictal episodes lasting about 1 minute were followed by a transient disorder of language expression. In the following years he continued to suffer from abrupt regression of language skills, receptive and expressive alike. Sometimes, these episodes were associated to seizures. As his clinical picture which was typical of Landau-Kleffner Syndrome - aphasic regression, seizures, paroxysmal EEG during NREM sleep - was associated to a documented neurological lesion, we defined it Landau-Kleffner Syndrome-Like. His IQ was in the normal range (Stanford - Binet Scale: IQ=93). The neurological examination revealed phonological and morphosyntactic deficits. His expression was characterized by many phonemic paraphasias and telegraphic style. The EEG in wakefulness showed paroxysmal activity characterized by bi- and triphasic spikes, followed by slow waves, in the left central and temporal regions. He was started on Carbamazepine (1 + l A cp/day). At 8 years the child started to attend primary school at our Rehabilitation Center. He was followed for epilepsy-related neurological problems and received speech therapy and neuropsychological therapy for 12 years. At the age of 10 years his IQ was in the low normal range (WISC-R: VIQ = 54; PIQ = 81; FIQ = 66) (cf. Table 1). Language was characterized by deficits that are typical of acquired aphasia in children, with many phonological, lexical access and morphosyntactic deficits. He showed clumsiness when performing fine distal movements, intentional tremor and asynergy bilaterally. At the age of 12 years he suffered from seizures in wakefulness, followed by transient aphasia. He also had many seizures in

Language Disorders and EEG A bnormalities During NREM Sleep

75

sleep. At the age of 14 years the AE therapy (Carbamazepine: 700 mg/day) was discontinued. He no longer had seizures. Until the age of 14 years he suffered from paroxysmal abnormalities mainly in the right centro-parietal region, which became accentuated in NREM sleep. They were also present in the contralateral hemisphere. Afterwards, the EEG normalized. Despite the fact that he no longer suffered from seizures and paroxysmal abnormalities, as shown by the EEG in sleep and wakefulness, his language was still pathological, with symptoms that are typical of transcortical motor aphasia (cf. Table 2). At the age of 24 years he received a detailed neuropsychological assessment and a language evaluation. On Raven's Standard Progressive Matrices his IQ was in the low normal range (Raven: IQ= 80). On the NEPSY his visuospatial skills were sufficiently developed, while he showed sensorimotor deficits (54% correct), attentional and executive deficits (79%) and memory deficits (88%). Language skills were assessed by the Italian version of the BAT (Paradis, 1987). The BAT comes with no normative values. However, to assess the extent of language deficits, we made reference to the values obtained from a control group, described in Fabbro et al. (2004). The morphological and syntactic language levels were most impaired (morphology = 39% of correct answers,

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