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Landau–Kleffner syndrome: a rare childhood epileptic aphasia
Journal of Neurolinguistics 12 (1999) 167±179 www.elsevier.com/locate/jneuroling
Landau±Klener syndrome: a rare childhood epileptic aphasia Marie-NoeÈlle Metz-Lutz a,*, Caroline Seegmuller a, Catherine Kleitz a, Anne de Saint Martin a, b, Edouard Hirsch a, Christian Marescaux a a
INSERM U 398, HoÃpitaux Universitaires de Strasbourg, Clinique Neurologique, Strasbourg, 6709 Strasbourg Cedex, France b Service de PeÂdiatrie, HoÃpitaux Universitaires de Strasbourg, Strasbourg, France
Abstract Landau±Klener Syndrome (LKS), a rare epileptic aphasia which occurs at a crucial period for the development of verbal skills, arouses interest and controversy among both clinicians and neuroscientists interested in the development of language. On the one hand, the relationship between epilepsy and aphasia and the poor outcome of epileptic aphasia compared to lesional childhood aphasia is a matter of debate among the clinicians. On the other hand, the severe verbal agnosia experienced during the active period of epilepsy allows one to examine the eect of deprivation of verbal auditory input on further language development. The chronic language impairments observed in most cases following the complete recovery from epilepsy could be either a consequence of a permanent neurophysiological dysfunction (the epileptic focus) during a crucial period of functional dierentiation in the brain tissue assigned to language processing (the left superior temporal cortex), or a consequence of a lack of auditory-verbal experience. This paper reviews the clinical and experimental studies of Landau±Klener Syndrome with the aim of precisely de®ning the two main clinical features of the syndrome, the aphasic disorders and the epilepsy and examining their relationship. The recent ®ndings of a cognitive study of the components of the verbal memory system in six LKS patients who recovered from epilepsy and aphasia are presented. These data suggest the possibility of a de®cit within the phonological short-term memory system that would account for both the poor vocabulary development and the persisting impairment of verbal comprehension in the late outcome of LKS. # 1999 Elsevier Science Ltd. All rights reserved.
* Corresponding author. E-mail address: [email protected] (M.-N. Metz-Lutz). 0911-6044/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S 0 9 1 1 - 6 0 4 4 ( 9 9 ) 0 0 0 1 3 - 5
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1. Introduction The acquired aphasia with convulsive disorder initially described by Landau and Klener in 1957 [20] is a rare epileptic condition occurring between the ages of 3 and 8 in children who had experienced almost normal neuro-cognitive development until that point. Landau±Klener Syndrome (LKS) begins before the age of 6 in about 70% of cases and rarely after the age of 8. Epileptic disorders are variable. Clinical seizures do not occur in all patients. They are mentioned in only 80% of cases. When present, seizures are of various types, but generalized or partial motor seizures are the most frequent. The EEG is always abnormal with paroxysmal unilateral or bilateral spike-and-wave activities, which reach their maximal extent over the temporal regions during wakefulness. These abnormalities always increase and become almost continuous during slow wave sleep. The clinical picture may vary at onset as well as during the disease. Several group studies have emphasized the almost parallel ¯uctuation of aphasic disorders and EEG abnormalities [20,32,36]. Long-term follow-up studies have emphasized the better outcome for the epilepsy than for the language impairments: epileptic seizures and EEG abnormalities completely disappear at the age of 12 or 13 [11,32]. There is no evidence of anatomical brain lesions that could account for the major symptoms of the disorder [4,16]. However, PET-scan studies of cerebral glucose utilization during sleep show metabolic disturbances over the temporal lobes associated with symmetrical low metabolic indices of thalamic nuclei relative to cortical structures in children with LKS [16]. SPECT studies have also evidenced similar metabolic disturbances [29]. A recent study of the metabolic changes in LKS and the acquired cognitive de®cits associated with epilepsy demonstrated that the metabolic disturbances most seriously aected the associative cortex in maturation [23]. 2. Typical aphasic features of LKS Severe de®cits in auditory comprehension represent the most common feature in LKS. In many cases, they are the ®rst symptom, preceding the epileptic manifestations and expressive language impairments. Often children with LKS are thought, at ®rst, to be deaf, but audiometric investigations show normal hearing. These receptive de®cits have been interpreted in various ways. Some authors consider them to be a speci®c de®cit in phonological decoding [19,33]. However, in many cases of LKS, the inability to identify auditory information, which extends to nonverbal stimuli, has been identi®ed as an auditory agnosia involving language and environmental sounds [23,26]. In most cases reported in the literature, expressive language impairments follow the onset of auditory comprehension de®cits, with either a progressive loss of vocabulary or phonological disturbances. Some authors have seen the expressive disorders in LKS as secondary to the impairment of phonological decoding [17].
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Expressive language disorders gradually increase and children become mute within several weeks. However, various patterns of expressive disorders have been described including agrammatism, echolalia, anomia and phonetic distortions [32]. Unlike childhood aphasia due to a focal lesion, in LKS, jargon aphasia with paraphasia and neologisms are often observed before the complete loss of expressive language that may last several months or even years. Over the course of LKS, the degree of expressive impairments ¯uctuates. Periods of transient recovery are often observed after the introduction or change of an anti-epileptic drug and the EEG may be successfully normalized for several weeks or months [11,22,24]. Based on the speci®c pattern of aphasic disorders, which primarily involve auditory comprehension, the use of a manual language has been proposed to prevent continuing problems with communication [3,38]. In this way, rehabilitation strategies involving sign language or cued speech have been shown to successfully bypass language deprivation during the active period of LKS. Indeed, the active period of epileptic aphasia, ranging from 3 to 10 yr, overlaps the most critical period for the development of phonological and syntactic skills as well as for learning.
Fig. 1. GG's waking EEG showing paroxysmal spike-wave discharges (SWD) occurring against normal background activity.
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3. Epileptic disorders As mentioned by Landau and Klener [20], overt epileptic seizures are not present in all LKS children. In her review, Beaumanoir [4] noted that epileptic seizures occurred in only 72% of the children and that one-third of children who experience clinical seizures have only one seizure. However, all children showed disturbed EEGs with repeated spikes of great amplitude followed by a large slow wave (Fig. 1). During wakefulness, these spike-wave discharges (SWD), occurring against an almost normal background activity, are organized in focus. Initially focal, the SWDs progressively spread to the whole hemisphere, but remain predominant over the temporal derivations. During sleep, these discharges increase in frequency and spread to the contralateral hemisphere, leading to continuous spike-wave discharges during slow sleep (CSWSS) (Fig. 2). This EEG pattern may be considered a hallmark for the diagnosis of LKS in the presence of nonlesional acquired aphasia and the absence of clinical epileptic seizures. 4. An epileptic aphasia Language disorders ¯uctuate with epilepsy and particularly with the EEG abnormalities. They consistently improve with the normalization of the EEG and
Fig. 2. GG's sleep EEG showing continuous spike-wave discharges during slow sleep (CSWSS).
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the disappearance of spike-wave discharges on waking and sleeping EEGs. Group studies of children with CSWSS associated with cognitive de®cits have shown that language de®cits are correlated with the location of the epileptogenic focus within the temporal cortex [16,23]. Aphasic disorders are observed in LKS, whichever side the unilateral temporal epileptic focus is located on. In cases with a right temporal epileptic focus at the onset of epilepsy, the bilateralization of spike-wave discharges seems to be responsible for aphasia and auditory agnosia [23,26]. Because of the bilateralization of discharges and their generalization in CSWSS, covering almost 80% to 90% of slow wave sleep time, the homotopic temporal cortex in the opposite hemisphere is not available as a functional area for auditory and verbal processing either [27,28]. The focal epileptic activity, represented on the EEG by focal spike-wave complexes, attests to an imbalance between inhibitory and excitatory intracortical neurons of the underlying cortical area, namely the temporal cortex. It has been hypothesized that an abnormal potentiation of the inhibitory neural mechanisms represented by the slow-wave component of the SWD impedes the normal function usually subserved by the aected cortex [10,23]. The earliest and most prominent aphasic symptom in LKS, namely auditory agnosia, mainly for verbal stimuli, appears to be directly related to the involvement of the temporal cortex. One study demonstrated that the epileptic discharges originating close to the auditory cortex contaminate the event-related potentials and aect auditory processing [31]. Another recent electrophysiological study, investigating the interference of interictal paroxysmal SWDs on auditory perception in a group of six LKS children, con®rmed the direct eect of epileptiform discharges on auditory perception. The occurrence of one spike-wave discharge transiently increased the latency and reduced the amplitude of the N1 component of the Auditory Evoked Potentials [34]. Finally, with auditory evoked magnetic ®eld recordings, Paetau [30] demonstrated in six children with LKS that the epileptiform activity may be produced by sound-responsive neurons in the nonprimary auditory cortex within the middle and posterior perisylvian cortex. These ®ndings suggest that the aphasic de®cit in LKS is a direct consequence of abnormal neural activity in the cortical area involved in verbal auditory processing. One may postulate that cortical functioning is transiently disrupted by the slow wave component of the spike-wave discharges, creating a ``functional ablation'' of the cortical area concerned with language processing, as suggested by Landau and Klener in their ®rst report [20]. 5. Other language and/or speech disorders associated with childhood epilepsy The coexistence of language impairments and epileptic features in childhood is not restricted to LKS. Indeed, disturbed EEGs with comparable paroxysmal spike-wave discharges have been described in children with developmental dysphasia, even in the absence of epileptic seizures [21,25]. Also, a consistent
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pattern of language dysfunction has been documented in benign rolandic epilepsy, an idiopathic partial epilepsy of childhood, which shares most of the clinical and electrophysiological features of LKS [37]. Several cases of epileptic children with recurrent prolonged oral apraxia, expressive language disorders and drooling have been reported [6,8,12,35]. All of these acquired expressive disorders are associated with a focus of SWD localized over the centro-temporal area with bilateral spread, leading to CSWSS on the sleeping EEG. They are considered as an ``expressive variant of LKS''. Indeed, the overall electro-clinical picture is similar to that for LKS, except for the aphasic symptoms and the location of the epileptogenic focus within the cortical area involved in speech production. 6. Verbal outcome While epileptic seizures and EEG abnormalities completely disappear at the age of 12 or 13 [11,32], the verbal outcome is usually poor. In most cases, the child rapidly recovers the vocabulary and the syntactic skills acquired before the onset of LKS, but further language development seems to be hampered. Unlike childhood acquired aphasia due to a structural lesion of the left hemisphere, in LKS, the younger the age at onset, the worse the prognosis for language development [5,32], with a very poor outcome for aphasia starting before the age of 5. Besides the age at onset, the duration of the language disorder, associated with EEG abnormalities during wakefulness and sleep, is another critical feature that seems to in¯uence the prognosis [26,32]. The persistent language impairment observed in almost all long-term follow-up studies has been explained in dierent ways. Mantovani and Landau [22] suggested that, as in the case of focal brain damage, the long-term eect of the epileptiform discharges on brain cells of a cortical area results in a functional hemispheric reorganization. Bishop [5] assumes that the loss of auditory verbal comprehension, during the active period of epileptic aphasia, deprives the child of the communicative verbal experience crucial for language development, while Baynes et al. [3] suggest that the nature of the dysfunction and its outcome depend on the stage of language development at which LKS children experience the disruption of auditory input. 7. Persistent phonological short-term memory de®cits in the late outcome of LKS We had the opportunity to do a long-term follow-up study of the progressive recovery of verbal abilities in six patients who had sustained an acquired epileptic aphasia between the ages of 3 and 13 yr. 7.1. Clinical history Table 1 summarizes the main clinical data concerning the active period of epilepsy with severe aphasia. In all six children, the auditory comprehension de®cit
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Table 1 Summary of the main clinical data concerning the active period of epilepsy with severe aphasia Patients Gender Handedness Age at Epileptic onset focus of LKS
Duration Main aphasic features of aphasia during active epilepsy with epilepsy (month)
TG
M
RH (60)
5 yr 3m right temporal 22
JPH
M
RH (80)
3 yr
left temporal
DC
M
LH (ÿ80)
6 yr
right temporal 30
GG
M
RH (100)
4 yr 3m right temporal 64
JL
M
RH (50)
6 yr 6m right temporal 28
GB
M
RH (100)
5 yr 5m left temporal
46
34
severe auditory agnosia impaired oral expression auditory agnosia and severe expressive disorders de®cit in auditory comprehension, syntax and naming auditory agnosia and severe expressive disorders auditory agnosia and severe expressive disorders auditory agnosia and severe expressive disorders
was not restricted to verbal sounds. Their ability to discriminate nonverbal environmental sounds was also signi®cantly impaired. A right or left temporal epileptogenic focus was recorded in the early waking EEGs of the six patients. The focus progressively extended to the contralateral temporal area. In four children (DC, GG, JPH and JL), the focus extended anteriorly to the frontal area. An attention de®cit developed within several months of the ®rst aphasic symptoms. Three patients (JPH, DC and GG) who were also hyperactive received speci®c medication (Methylphenidate) for several months. Table 2 displays subjects' performances on psychometric evaluation tests performed during the active period of epileptic aphasia. The WISC-R showed better nonverbal cognitive abilities in the six patients. But the three children who showed, in addition to aphasia, severe attention de®cit disorder with hyperactivity, demonstrated some impairments in several subtests of the performance scale, namely the coding test. During the active period of epilepsy and aphasia, the six subjects were involved in a special education program. They were introduced to alternative means of communication including manual communication, lip-reading and cued speech. TG attended a school for deaf children for one year and was taught French sign language. JL was involved for two years in a class for children with speci®c language impairment where he learned to communicate by means of drawings and written symbols. Table 3 shows the performances obtained on standard verbal testing several months or years after the complete recovery from epilepsy. The late verbal assessment, performed while the children had completely normal EEGs and had stopped receiving anti-epileptic treatment for at least six months, showed persistent impairments in the subtests involving either phonological processing or
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Table 2 LKS subjects' performances on psychometric evaluation tests during the active period of epileptic aphasiaa Patient CSWS WISC-R IQ in duration the active (month) epileptic period
TG JPH DC GG GB JL
18 45 28 24 34 18
Verbal subtests
Performances subtests
VIQ PIQ FIQ
Inf Cp Pb Dg Sm Vc Pic Arr Geo Cub Cod
87 46 55 62 78 86
6 3 3 6 4 6
125 77 69 70 112 121
106 56 57 62 93 103
9 0 2 5 9 11
5 1 4 1 4 11
5 0 2 0 5 5
13 4 3 4 8 7
7 5 1 3 7 3
17 8 8 9 14 13
18 8 8 7 11 12
14 11 5 3 12 11
14 12 6 5 15 16
8 3 1 ± 8 14
a FIQ=full scale IQ; VIQ=verbal IQ; PIQ=performance IQ (on WISC-R or on WPPSI) Subtests, Inf=information, Cp=comprehension; Pb=problem; Dg=digits; Sm=similarity; Vc=vocabulary; Pic=picture completion; Arr=picture arrangement; Geo=geometric ®gure; Cub=Kohs cube; Cod=coding test. Scores < meanÿ1 S.D. are indicated in bold.
auditory short-term memory in almost all cases. Except for one patient (GG), the patients showed reduced forward digit span, contrasting with their normal performances on the Corsi block test, suggesting a speci®c impairment in auditory±verbal short-term memory (AVSTM). Impaired AVSTM may also explain the diculties observed in the repetition of syntactically complex sentences. The discrepancy between performance on word and non-word repetition points to a de®cit at the level of phonological processing which may be bypassed for word repetition through the lexical route. The semantic errors produced by the six subjects in the ®ve trials of the Rey auditory±verbal learning test also attested to their recourse to lexical processing in verbal memory tasks. Along with the repetition de®cit, the six children demonstrated diculties in sentence comprehension. Indeed, on the Token Test, their performances were signi®cantly low on part IV, while they performed almost normally on the four other parts of the test [9]. Moreover, on the WISC-R, despite the signi®cant improvement in their verbal abilities, the patients showed a signi®cant discrepancy between VlQ and PIQ, explained by very low scores on three subtests: information, digit and vocabulary. At school, the main complaints concern the children's lack of vocabulary, diculties in learning written language and, for the older patients, serious diculties in foreign language acquisition. The overall ®ndings provided by standard verbal testing point to a residual de®cit common to the ®ve of the patients, which could be the consequence of a speci®c impairment in phonological working memory. According to Baddeley's model of working memory [1], the modality-free controlling executive system is aided by subsidiary slave systems, ensuring temporary maintenance of information. One of these is the phonological loop system, which specializes in storing verbal material (Fig. 3). It is composed of two
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Table 3 Subjects' performances on standard verbal testing several months after recovery from epilepsy Patient TG
JPH
DC
GG
JL
GB
6 yr
4 yr
3 yr 8 m
1 yr 2 month
8 month
22 month
Auditory recognition test n 25)
3a 5 23
3a 5 21
4b 4b 22
2a 3a 16
3b 6 24
2a 5 24
Language assessment Confrontation naming n 30) Verbal ¯uency test (words/min.) Real word repetition n 15) Non word repetition n 15) Sentence repetition n 10)
30 8a 15 10a 7b
28 10a 15 9a 6a
30 12b 15 12b 8b
24 5a 13 5a 6a
28 9a 15 6a 6a
30 10a 15 6a 6a
WISC-R Verbal IQ Performance IQ
106 131
80 110
83 101
64 69
± ±
76 103
Delay after recovery of LKS Short-term memory span auditory±verbal Corsi block-tapping
a b
> 2 S.D. below mean score related to age. 2 S.D. below mean score related to age.
subsystems: the phonological store and the articulatory rehearsal process. The phonological store receives directly and mandatorily all auditory verbal information and stores it as sound-based code. Neuropsychological studies of brain-damaged patients provide evidence for the existence of this component. They also show that the phonological store contributes to auditory comprehension of syntactically complex sentences. Moreover, this subsystem is important for the development of reading abilities and the acquisition of new words [2,14,39].
Fig. 3. Baddeley's [1] model of working memory.
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7.2. Assessment of the phonological working memory To verify the hypothesis of an impairment in our patients' phonological working memory, we examined the functioning of their phonological loop system. Experimental studies demonstrated that the word-length eect evidences the use of the articulatory loop while the phonological-similarity eect re¯ects the operation of the phonological store. The word-length eect was tested using a word repetition task. The subjects had to repeat sequences of two to eight words, either monosyllabic, disyllabic or trisyllabic. The items were spoken by the examiner at a rate of one per second and sequences of increasing length were presented one after the other. Patients were asked to repeat the words of each sequence in order. They were presented with two sequences of each length. A third sequence was proposed when the patient failed to repeat one of the ®rst two. Patients' performances were compared to those of 10 controls. Performances on word repetition were similar to those obtained with sequences of digits. No dierence was observed in the repetition of mono- and disyllabic words. However, like the controls, the six patients performed less well at repeating trisyllabic words (Table 4). The phonological-similarity eect was assessed in a letter repetition task. Phonologically similar sequences of two to eight letters were constructed with the following rhyming French consonants, b, c, d, g, p, t, v and the phonologically dissimilar sequences were composed of the nonrhyming French consonants r, f, h, k, m, j, l. The procedure was similar to that used for the word repetition test. The patient had to repeat in order the sequences of consonants spoken by the examiner at a rate of one per second. Unlike the controls, our patients' performance did not decrease for sequences composed of rhyming consonants. Four patients (TG, DC, GB, JL) had similar repetition performances for similar and dissimilar consonants. The two others (JPH and GG) showed slightly better performances in repeating sequences of phonologically similar letters. However, in both conditions, their performances were at least 1 SD below the average score for controls. This pattern of repetition performance points to an impairment in the Table 4 Memory span scores of subjects and controls for mono-, di- and trisyllabic words and phonologically similar/dissimilar letters Sequence type
Monosyllabic words Disyllabic words Trisyllabic words Phonologically similar Phonologically dissimilar
Control
5.8 6.1 4.7 4.3 5.2
(0.8) (0.6) (0.3) (0.5) (0.6)
Patient TG
JPH
DC
GG
JL
GB
4 4 3 4 4
3 3 2 4 2
4 4 2 4 4
3 2 1 3 2
4 4 2 3 3
3 3 1 3 3
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phonological store rather than the articulatory rehearsal system. Indeed, the existence of a word-length eect attests to the recourse to the articulatory rehearsal system, whereas the absence of any similarity eect re¯ects the modi®ed operation of the phonological store. However, since verbal auditory information is stored in a sound-based format, a de®cit speci®cally localized in the phonological store could also result from impaired phonological processing.
8. Discussion The speci®c disturbances in the phonological short-term memory and/or phonological processing system observed in the outcome of LKS could be the consequence of a dysfunction in the cortical network involved in this processing. During the active epileptic period, the temporal cortex is aected by abnormal neural activity with an excess of inhibition impeding its normal functioning, particularly for auditory information processing. Such a condition occurring during the crucial period for the functional dierentiation of the associative cortices may result in a permanent dysfunction. And indeed, the six patients showed, in addition to the residual verbal de®cits described here, a one-ear dichotic extinction involving the auditory channel contralateral to the temporal cortex aected by the epileptic focus during the active phase of LKS [26]. A similar one-ear dichotic extinction was described in patients who sustained structural lesions involving the temporal or parieto-temporal cortex and the geniculo-cortical pathway [7,18]. The one-ear dichotic listening extinction, persisting long after the complete disappearance of epileptic discharges, indicates a permanent dysfunction in the temporal cortex. This assumption is in agreement with the ®ndings of PET scan studies obtained in the late recovery period in three patients (TG, JPH and DC), which disclosed a focal hypometabolism in the superior temporal region where a focal hypermetabolism correlated to the epileptic focus was present in the period of active epilepsy and aphasia [23]. Now, recent functional imaging studies have shown that the right and left superior temporal cortices are symmetrically involved in auditory-verbal short-term memory [13,15]. The implication that a malfunction of one of the superior temporal cortices is involved in the impairment of phonological short-term memory should be examined by means of functional imaging. The study of a large series of patients with careful documentation of their phonological, lexical and syntactic development may also help to understand the dierential impact of LKS on the setting up of the functional anatomy of verbal working memory, according to the state of phonological development at the onset of the disease.
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[25] Metz-Lutz MN, de Saint Martin A, Hirsch E, Marescaux C. Developmental dysphasia for oral and sign language in a deaf child with idiopathic partial childhood epilepsy. Brain and Cognition 1996;32:193±6. [26] Metz-Lutz MN, Hirsch E, Maquet P, de Saint Martin A, Rudolf G, Wioland N, Marescaux C. Dichotic listening performances in the follow-up of Landau and Klener syndrome. Child Neuropsychology 1997;3:47±60. [27] Morrell F. Electrophysiology of CSWS in Landau±Klener syndrome. In: Beaumanoir A, Bureau M, Deonna T, Mira L, Tassinari CA, editors. Continuous spikes and waves during slow sleep. London: John Libbey and Company Ltd, 1995. [28] Morrell F, Whistler WW, Smith MC, Hoeppner TJ, de Toledo-Morrell L, Pierre-Louis SJC, Kanner AM, Buelow JM, Ristanovic R, Bergen D, Chez M, Hasegawa H. Landau±Klener syndrome. Treatment with subpial intracortical transection. Brain 1995;118:1529±46. [29] Mouridsen SE, Videbaek C, Sogaard H, Andersen AR. Regional cerebral blood-¯ow measured by HMPAO and SPECT in a 5-year-old boy with Landau±Klener syndrome. Neuropediatrics 1993;24:47±50. [30] Paetau R. Sound triggers spikes in Landau±Klener syndrome. Journal of Clinical Neurophysiology 1994;11:231±41. [31] Paetau R, Kajola M, Korkman M, HaÈmaÈlaÈinen M, GranstroÈm M, Hari R. Landau±Klener syndrome: epileptic activity in the auditory cortex. NeuroReport 1991;2:201±4. [32] Paquier PF, Van Dongen HR, Loonen CB. The Landau±Klener syndrome or ``acquired aphasia with convulsive disorder''. Long-term follow up of six children and a review of recent literature. Archives of Neurology 1992;49:354±9. [33] Rapin I, Mattis S, Rowan AJ, Golden GG. Verbal auditory agnosia in children. Developmental Medicine and Child Neurology 1977;19:192±207. [34] Seri S, Cerquiglini A, Pisani F. Spike-induced interference in auditory sensory processing in Landau±Klener syndrome. Evoked Potential 1998;108:506±10. [35] Shafrir Y, Prensky AL. Acquired epileptiform opercular syndrome: A second case report, review of the literature and comparison to the Landau±Klener syndrome. Epilepsia 1995;36:1050±7. [36] Shoumaker MR, Bennett DR, Bray PF, Curless RG. Clinical and EEG manifestations of an unusual aphasic syndrome in children. Neurology 1974;24:10±6. [37] Staden U, Isaacs E, Boyd SG, Brandl U, Neville BGR. Language dysfunction in children with rolandic epilepsy. Neuropediatrics 1998;29:242±8. [38] Steriade M, Contreras D. Spike-wave complexes and fast components of cortically generated seizures. I. Role of neocortex and thalamus. Journal of Neurophysiology 1998;80:1439±55. [39] Vallar G, Baddeley AD. Fractionation of working memory; Neuropsychological evidence of a phonological short-term store. Journal of Verbal Learning and Verbal Behavior 1984;23:151±61.
Landau±Klener syndrome: a rare childhood epileptic aphasia Marie-NoeÈlle Metz-Lutz a,*, Caroline Seegmuller a, Catherine Kleitz a, Anne de Saint Martin a, b, Edouard Hirsch a, Christian Marescaux a a
INSERM U 398, HoÃpitaux Universitaires de Strasbourg, Clinique Neurologique, Strasbourg, 6709 Strasbourg Cedex, France b Service de PeÂdiatrie, HoÃpitaux Universitaires de Strasbourg, Strasbourg, France
Abstract Landau±Klener Syndrome (LKS), a rare epileptic aphasia which occurs at a crucial period for the development of verbal skills, arouses interest and controversy among both clinicians and neuroscientists interested in the development of language. On the one hand, the relationship between epilepsy and aphasia and the poor outcome of epileptic aphasia compared to lesional childhood aphasia is a matter of debate among the clinicians. On the other hand, the severe verbal agnosia experienced during the active period of epilepsy allows one to examine the eect of deprivation of verbal auditory input on further language development. The chronic language impairments observed in most cases following the complete recovery from epilepsy could be either a consequence of a permanent neurophysiological dysfunction (the epileptic focus) during a crucial period of functional dierentiation in the brain tissue assigned to language processing (the left superior temporal cortex), or a consequence of a lack of auditory-verbal experience. This paper reviews the clinical and experimental studies of Landau±Klener Syndrome with the aim of precisely de®ning the two main clinical features of the syndrome, the aphasic disorders and the epilepsy and examining their relationship. The recent ®ndings of a cognitive study of the components of the verbal memory system in six LKS patients who recovered from epilepsy and aphasia are presented. These data suggest the possibility of a de®cit within the phonological short-term memory system that would account for both the poor vocabulary development and the persisting impairment of verbal comprehension in the late outcome of LKS. # 1999 Elsevier Science Ltd. All rights reserved.
* Corresponding author. E-mail address: [email protected] (M.-N. Metz-Lutz). 0911-6044/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved. PII: S 0 9 1 1 - 6 0 4 4 ( 9 9 ) 0 0 0 1 3 - 5
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1. Introduction The acquired aphasia with convulsive disorder initially described by Landau and Klener in 1957 [20] is a rare epileptic condition occurring between the ages of 3 and 8 in children who had experienced almost normal neuro-cognitive development until that point. Landau±Klener Syndrome (LKS) begins before the age of 6 in about 70% of cases and rarely after the age of 8. Epileptic disorders are variable. Clinical seizures do not occur in all patients. They are mentioned in only 80% of cases. When present, seizures are of various types, but generalized or partial motor seizures are the most frequent. The EEG is always abnormal with paroxysmal unilateral or bilateral spike-and-wave activities, which reach their maximal extent over the temporal regions during wakefulness. These abnormalities always increase and become almost continuous during slow wave sleep. The clinical picture may vary at onset as well as during the disease. Several group studies have emphasized the almost parallel ¯uctuation of aphasic disorders and EEG abnormalities [20,32,36]. Long-term follow-up studies have emphasized the better outcome for the epilepsy than for the language impairments: epileptic seizures and EEG abnormalities completely disappear at the age of 12 or 13 [11,32]. There is no evidence of anatomical brain lesions that could account for the major symptoms of the disorder [4,16]. However, PET-scan studies of cerebral glucose utilization during sleep show metabolic disturbances over the temporal lobes associated with symmetrical low metabolic indices of thalamic nuclei relative to cortical structures in children with LKS [16]. SPECT studies have also evidenced similar metabolic disturbances [29]. A recent study of the metabolic changes in LKS and the acquired cognitive de®cits associated with epilepsy demonstrated that the metabolic disturbances most seriously aected the associative cortex in maturation [23]. 2. Typical aphasic features of LKS Severe de®cits in auditory comprehension represent the most common feature in LKS. In many cases, they are the ®rst symptom, preceding the epileptic manifestations and expressive language impairments. Often children with LKS are thought, at ®rst, to be deaf, but audiometric investigations show normal hearing. These receptive de®cits have been interpreted in various ways. Some authors consider them to be a speci®c de®cit in phonological decoding [19,33]. However, in many cases of LKS, the inability to identify auditory information, which extends to nonverbal stimuli, has been identi®ed as an auditory agnosia involving language and environmental sounds [23,26]. In most cases reported in the literature, expressive language impairments follow the onset of auditory comprehension de®cits, with either a progressive loss of vocabulary or phonological disturbances. Some authors have seen the expressive disorders in LKS as secondary to the impairment of phonological decoding [17].
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Expressive language disorders gradually increase and children become mute within several weeks. However, various patterns of expressive disorders have been described including agrammatism, echolalia, anomia and phonetic distortions [32]. Unlike childhood aphasia due to a focal lesion, in LKS, jargon aphasia with paraphasia and neologisms are often observed before the complete loss of expressive language that may last several months or even years. Over the course of LKS, the degree of expressive impairments ¯uctuates. Periods of transient recovery are often observed after the introduction or change of an anti-epileptic drug and the EEG may be successfully normalized for several weeks or months [11,22,24]. Based on the speci®c pattern of aphasic disorders, which primarily involve auditory comprehension, the use of a manual language has been proposed to prevent continuing problems with communication [3,38]. In this way, rehabilitation strategies involving sign language or cued speech have been shown to successfully bypass language deprivation during the active period of LKS. Indeed, the active period of epileptic aphasia, ranging from 3 to 10 yr, overlaps the most critical period for the development of phonological and syntactic skills as well as for learning.
Fig. 1. GG's waking EEG showing paroxysmal spike-wave discharges (SWD) occurring against normal background activity.
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3. Epileptic disorders As mentioned by Landau and Klener [20], overt epileptic seizures are not present in all LKS children. In her review, Beaumanoir [4] noted that epileptic seizures occurred in only 72% of the children and that one-third of children who experience clinical seizures have only one seizure. However, all children showed disturbed EEGs with repeated spikes of great amplitude followed by a large slow wave (Fig. 1). During wakefulness, these spike-wave discharges (SWD), occurring against an almost normal background activity, are organized in focus. Initially focal, the SWDs progressively spread to the whole hemisphere, but remain predominant over the temporal derivations. During sleep, these discharges increase in frequency and spread to the contralateral hemisphere, leading to continuous spike-wave discharges during slow sleep (CSWSS) (Fig. 2). This EEG pattern may be considered a hallmark for the diagnosis of LKS in the presence of nonlesional acquired aphasia and the absence of clinical epileptic seizures. 4. An epileptic aphasia Language disorders ¯uctuate with epilepsy and particularly with the EEG abnormalities. They consistently improve with the normalization of the EEG and
Fig. 2. GG's sleep EEG showing continuous spike-wave discharges during slow sleep (CSWSS).
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the disappearance of spike-wave discharges on waking and sleeping EEGs. Group studies of children with CSWSS associated with cognitive de®cits have shown that language de®cits are correlated with the location of the epileptogenic focus within the temporal cortex [16,23]. Aphasic disorders are observed in LKS, whichever side the unilateral temporal epileptic focus is located on. In cases with a right temporal epileptic focus at the onset of epilepsy, the bilateralization of spike-wave discharges seems to be responsible for aphasia and auditory agnosia [23,26]. Because of the bilateralization of discharges and their generalization in CSWSS, covering almost 80% to 90% of slow wave sleep time, the homotopic temporal cortex in the opposite hemisphere is not available as a functional area for auditory and verbal processing either [27,28]. The focal epileptic activity, represented on the EEG by focal spike-wave complexes, attests to an imbalance between inhibitory and excitatory intracortical neurons of the underlying cortical area, namely the temporal cortex. It has been hypothesized that an abnormal potentiation of the inhibitory neural mechanisms represented by the slow-wave component of the SWD impedes the normal function usually subserved by the aected cortex [10,23]. The earliest and most prominent aphasic symptom in LKS, namely auditory agnosia, mainly for verbal stimuli, appears to be directly related to the involvement of the temporal cortex. One study demonstrated that the epileptic discharges originating close to the auditory cortex contaminate the event-related potentials and aect auditory processing [31]. Another recent electrophysiological study, investigating the interference of interictal paroxysmal SWDs on auditory perception in a group of six LKS children, con®rmed the direct eect of epileptiform discharges on auditory perception. The occurrence of one spike-wave discharge transiently increased the latency and reduced the amplitude of the N1 component of the Auditory Evoked Potentials [34]. Finally, with auditory evoked magnetic ®eld recordings, Paetau [30] demonstrated in six children with LKS that the epileptiform activity may be produced by sound-responsive neurons in the nonprimary auditory cortex within the middle and posterior perisylvian cortex. These ®ndings suggest that the aphasic de®cit in LKS is a direct consequence of abnormal neural activity in the cortical area involved in verbal auditory processing. One may postulate that cortical functioning is transiently disrupted by the slow wave component of the spike-wave discharges, creating a ``functional ablation'' of the cortical area concerned with language processing, as suggested by Landau and Klener in their ®rst report [20]. 5. Other language and/or speech disorders associated with childhood epilepsy The coexistence of language impairments and epileptic features in childhood is not restricted to LKS. Indeed, disturbed EEGs with comparable paroxysmal spike-wave discharges have been described in children with developmental dysphasia, even in the absence of epileptic seizures [21,25]. Also, a consistent
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pattern of language dysfunction has been documented in benign rolandic epilepsy, an idiopathic partial epilepsy of childhood, which shares most of the clinical and electrophysiological features of LKS [37]. Several cases of epileptic children with recurrent prolonged oral apraxia, expressive language disorders and drooling have been reported [6,8,12,35]. All of these acquired expressive disorders are associated with a focus of SWD localized over the centro-temporal area with bilateral spread, leading to CSWSS on the sleeping EEG. They are considered as an ``expressive variant of LKS''. Indeed, the overall electro-clinical picture is similar to that for LKS, except for the aphasic symptoms and the location of the epileptogenic focus within the cortical area involved in speech production. 6. Verbal outcome While epileptic seizures and EEG abnormalities completely disappear at the age of 12 or 13 [11,32], the verbal outcome is usually poor. In most cases, the child rapidly recovers the vocabulary and the syntactic skills acquired before the onset of LKS, but further language development seems to be hampered. Unlike childhood acquired aphasia due to a structural lesion of the left hemisphere, in LKS, the younger the age at onset, the worse the prognosis for language development [5,32], with a very poor outcome for aphasia starting before the age of 5. Besides the age at onset, the duration of the language disorder, associated with EEG abnormalities during wakefulness and sleep, is another critical feature that seems to in¯uence the prognosis [26,32]. The persistent language impairment observed in almost all long-term follow-up studies has been explained in dierent ways. Mantovani and Landau [22] suggested that, as in the case of focal brain damage, the long-term eect of the epileptiform discharges on brain cells of a cortical area results in a functional hemispheric reorganization. Bishop [5] assumes that the loss of auditory verbal comprehension, during the active period of epileptic aphasia, deprives the child of the communicative verbal experience crucial for language development, while Baynes et al. [3] suggest that the nature of the dysfunction and its outcome depend on the stage of language development at which LKS children experience the disruption of auditory input. 7. Persistent phonological short-term memory de®cits in the late outcome of LKS We had the opportunity to do a long-term follow-up study of the progressive recovery of verbal abilities in six patients who had sustained an acquired epileptic aphasia between the ages of 3 and 13 yr. 7.1. Clinical history Table 1 summarizes the main clinical data concerning the active period of epilepsy with severe aphasia. In all six children, the auditory comprehension de®cit
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Table 1 Summary of the main clinical data concerning the active period of epilepsy with severe aphasia Patients Gender Handedness Age at Epileptic onset focus of LKS
Duration Main aphasic features of aphasia during active epilepsy with epilepsy (month)
TG
M
RH (60)
5 yr 3m right temporal 22
JPH
M
RH (80)
3 yr
left temporal
DC
M
LH (ÿ80)
6 yr
right temporal 30
GG
M
RH (100)
4 yr 3m right temporal 64
JL
M
RH (50)
6 yr 6m right temporal 28
GB
M
RH (100)
5 yr 5m left temporal
46
34
severe auditory agnosia impaired oral expression auditory agnosia and severe expressive disorders de®cit in auditory comprehension, syntax and naming auditory agnosia and severe expressive disorders auditory agnosia and severe expressive disorders auditory agnosia and severe expressive disorders
was not restricted to verbal sounds. Their ability to discriminate nonverbal environmental sounds was also signi®cantly impaired. A right or left temporal epileptogenic focus was recorded in the early waking EEGs of the six patients. The focus progressively extended to the contralateral temporal area. In four children (DC, GG, JPH and JL), the focus extended anteriorly to the frontal area. An attention de®cit developed within several months of the ®rst aphasic symptoms. Three patients (JPH, DC and GG) who were also hyperactive received speci®c medication (Methylphenidate) for several months. Table 2 displays subjects' performances on psychometric evaluation tests performed during the active period of epileptic aphasia. The WISC-R showed better nonverbal cognitive abilities in the six patients. But the three children who showed, in addition to aphasia, severe attention de®cit disorder with hyperactivity, demonstrated some impairments in several subtests of the performance scale, namely the coding test. During the active period of epilepsy and aphasia, the six subjects were involved in a special education program. They were introduced to alternative means of communication including manual communication, lip-reading and cued speech. TG attended a school for deaf children for one year and was taught French sign language. JL was involved for two years in a class for children with speci®c language impairment where he learned to communicate by means of drawings and written symbols. Table 3 shows the performances obtained on standard verbal testing several months or years after the complete recovery from epilepsy. The late verbal assessment, performed while the children had completely normal EEGs and had stopped receiving anti-epileptic treatment for at least six months, showed persistent impairments in the subtests involving either phonological processing or
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Table 2 LKS subjects' performances on psychometric evaluation tests during the active period of epileptic aphasiaa Patient CSWS WISC-R IQ in duration the active (month) epileptic period
TG JPH DC GG GB JL
18 45 28 24 34 18
Verbal subtests
Performances subtests
VIQ PIQ FIQ
Inf Cp Pb Dg Sm Vc Pic Arr Geo Cub Cod
87 46 55 62 78 86
6 3 3 6 4 6
125 77 69 70 112 121
106 56 57 62 93 103
9 0 2 5 9 11
5 1 4 1 4 11
5 0 2 0 5 5
13 4 3 4 8 7
7 5 1 3 7 3
17 8 8 9 14 13
18 8 8 7 11 12
14 11 5 3 12 11
14 12 6 5 15 16
8 3 1 ± 8 14
a FIQ=full scale IQ; VIQ=verbal IQ; PIQ=performance IQ (on WISC-R or on WPPSI) Subtests, Inf=information, Cp=comprehension; Pb=problem; Dg=digits; Sm=similarity; Vc=vocabulary; Pic=picture completion; Arr=picture arrangement; Geo=geometric ®gure; Cub=Kohs cube; Cod=coding test. Scores < meanÿ1 S.D. are indicated in bold.
auditory short-term memory in almost all cases. Except for one patient (GG), the patients showed reduced forward digit span, contrasting with their normal performances on the Corsi block test, suggesting a speci®c impairment in auditory±verbal short-term memory (AVSTM). Impaired AVSTM may also explain the diculties observed in the repetition of syntactically complex sentences. The discrepancy between performance on word and non-word repetition points to a de®cit at the level of phonological processing which may be bypassed for word repetition through the lexical route. The semantic errors produced by the six subjects in the ®ve trials of the Rey auditory±verbal learning test also attested to their recourse to lexical processing in verbal memory tasks. Along with the repetition de®cit, the six children demonstrated diculties in sentence comprehension. Indeed, on the Token Test, their performances were signi®cantly low on part IV, while they performed almost normally on the four other parts of the test [9]. Moreover, on the WISC-R, despite the signi®cant improvement in their verbal abilities, the patients showed a signi®cant discrepancy between VlQ and PIQ, explained by very low scores on three subtests: information, digit and vocabulary. At school, the main complaints concern the children's lack of vocabulary, diculties in learning written language and, for the older patients, serious diculties in foreign language acquisition. The overall ®ndings provided by standard verbal testing point to a residual de®cit common to the ®ve of the patients, which could be the consequence of a speci®c impairment in phonological working memory. According to Baddeley's model of working memory [1], the modality-free controlling executive system is aided by subsidiary slave systems, ensuring temporary maintenance of information. One of these is the phonological loop system, which specializes in storing verbal material (Fig. 3). It is composed of two
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Table 3 Subjects' performances on standard verbal testing several months after recovery from epilepsy Patient TG
JPH
DC
GG
JL
GB
6 yr
4 yr
3 yr 8 m
1 yr 2 month
8 month
22 month
Auditory recognition test n 25)
3a 5 23
3a 5 21
4b 4b 22
2a 3a 16
3b 6 24
2a 5 24
Language assessment Confrontation naming n 30) Verbal ¯uency test (words/min.) Real word repetition n 15) Non word repetition n 15) Sentence repetition n 10)
30 8a 15 10a 7b
28 10a 15 9a 6a
30 12b 15 12b 8b
24 5a 13 5a 6a
28 9a 15 6a 6a
30 10a 15 6a 6a
WISC-R Verbal IQ Performance IQ
106 131
80 110
83 101
64 69
± ±
76 103
Delay after recovery of LKS Short-term memory span auditory±verbal Corsi block-tapping
a b
> 2 S.D. below mean score related to age. 2 S.D. below mean score related to age.
subsystems: the phonological store and the articulatory rehearsal process. The phonological store receives directly and mandatorily all auditory verbal information and stores it as sound-based code. Neuropsychological studies of brain-damaged patients provide evidence for the existence of this component. They also show that the phonological store contributes to auditory comprehension of syntactically complex sentences. Moreover, this subsystem is important for the development of reading abilities and the acquisition of new words [2,14,39].
Fig. 3. Baddeley's [1] model of working memory.
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7.2. Assessment of the phonological working memory To verify the hypothesis of an impairment in our patients' phonological working memory, we examined the functioning of their phonological loop system. Experimental studies demonstrated that the word-length eect evidences the use of the articulatory loop while the phonological-similarity eect re¯ects the operation of the phonological store. The word-length eect was tested using a word repetition task. The subjects had to repeat sequences of two to eight words, either monosyllabic, disyllabic or trisyllabic. The items were spoken by the examiner at a rate of one per second and sequences of increasing length were presented one after the other. Patients were asked to repeat the words of each sequence in order. They were presented with two sequences of each length. A third sequence was proposed when the patient failed to repeat one of the ®rst two. Patients' performances were compared to those of 10 controls. Performances on word repetition were similar to those obtained with sequences of digits. No dierence was observed in the repetition of mono- and disyllabic words. However, like the controls, the six patients performed less well at repeating trisyllabic words (Table 4). The phonological-similarity eect was assessed in a letter repetition task. Phonologically similar sequences of two to eight letters were constructed with the following rhyming French consonants, b, c, d, g, p, t, v and the phonologically dissimilar sequences were composed of the nonrhyming French consonants r, f, h, k, m, j, l. The procedure was similar to that used for the word repetition test. The patient had to repeat in order the sequences of consonants spoken by the examiner at a rate of one per second. Unlike the controls, our patients' performance did not decrease for sequences composed of rhyming consonants. Four patients (TG, DC, GB, JL) had similar repetition performances for similar and dissimilar consonants. The two others (JPH and GG) showed slightly better performances in repeating sequences of phonologically similar letters. However, in both conditions, their performances were at least 1 SD below the average score for controls. This pattern of repetition performance points to an impairment in the Table 4 Memory span scores of subjects and controls for mono-, di- and trisyllabic words and phonologically similar/dissimilar letters Sequence type
Monosyllabic words Disyllabic words Trisyllabic words Phonologically similar Phonologically dissimilar
Control
5.8 6.1 4.7 4.3 5.2
(0.8) (0.6) (0.3) (0.5) (0.6)
Patient TG
JPH
DC
GG
JL
GB
4 4 3 4 4
3 3 2 4 2
4 4 2 4 4
3 2 1 3 2
4 4 2 3 3
3 3 1 3 3
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phonological store rather than the articulatory rehearsal system. Indeed, the existence of a word-length eect attests to the recourse to the articulatory rehearsal system, whereas the absence of any similarity eect re¯ects the modi®ed operation of the phonological store. However, since verbal auditory information is stored in a sound-based format, a de®cit speci®cally localized in the phonological store could also result from impaired phonological processing.
8. Discussion The speci®c disturbances in the phonological short-term memory and/or phonological processing system observed in the outcome of LKS could be the consequence of a dysfunction in the cortical network involved in this processing. During the active epileptic period, the temporal cortex is aected by abnormal neural activity with an excess of inhibition impeding its normal functioning, particularly for auditory information processing. Such a condition occurring during the crucial period for the functional dierentiation of the associative cortices may result in a permanent dysfunction. And indeed, the six patients showed, in addition to the residual verbal de®cits described here, a one-ear dichotic extinction involving the auditory channel contralateral to the temporal cortex aected by the epileptic focus during the active phase of LKS [26]. A similar one-ear dichotic extinction was described in patients who sustained structural lesions involving the temporal or parieto-temporal cortex and the geniculo-cortical pathway [7,18]. The one-ear dichotic listening extinction, persisting long after the complete disappearance of epileptic discharges, indicates a permanent dysfunction in the temporal cortex. This assumption is in agreement with the ®ndings of PET scan studies obtained in the late recovery period in three patients (TG, JPH and DC), which disclosed a focal hypometabolism in the superior temporal region where a focal hypermetabolism correlated to the epileptic focus was present in the period of active epilepsy and aphasia [23]. Now, recent functional imaging studies have shown that the right and left superior temporal cortices are symmetrically involved in auditory-verbal short-term memory [13,15]. The implication that a malfunction of one of the superior temporal cortices is involved in the impairment of phonological short-term memory should be examined by means of functional imaging. The study of a large series of patients with careful documentation of their phonological, lexical and syntactic development may also help to understand the dierential impact of LKS on the setting up of the functional anatomy of verbal working memory, according to the state of phonological development at the onset of the disease.
References [1] Baddeley AD. Working Memory. Oxford: Oxford University Press, 1986.
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