Landau-Kleffner syndrome
 by Natalio Fejerman and Jerome Engel
Date of submission: October 3, 1993
Date of update: November 20, 1998
Date of update: March 21, 2003
Date of update: May 10, 2004
Medline SEARCH DATE: May 2004

 

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HISTORICAL NOTE AND NOMENCLATURE

1957 Landau and Kleffner described 6 children with a "syndrome of acquired aphasia with convulsive disorder” (Landau and Kleffner 1957). The language disorder was later recognized as being different from typical childhood aphasia, which is usually expressive. Instead, the aphasia of the Landau-Kleffner syndrome is an auditory verbal agnosia (Rapin et al 1977). The language disorder was initially considered to be a seizure manifestation because epileptiform activity from one or both temporal lobes is generally present on EEG recordings. Seizures are not a constant feature, and when present, they may precede or follow the onset of the language disorder.

Mantovani and Landau followed the 6 original cases plus 4 others and found that the outcome was variable: 5 of the children had recovered good language function as adults (Mantovani and Landau 1980). Their hypothesis that outcome correlated with seizure frequency was not substantiated by subsequent reports (Deonna et al 1977; Holmes et al 1981).

The 1989 International League Against Epilepsy placed this syndrome under the classification of "epilepsies and syndromes undetermined as to whether they are focal or generalized" (Anonymous 1989). In the same category, the syndrome of continuous spikes-and-waves during slow sleep was included as a definite entity. However, in recent years many common features between these two syndromes have been recognized, and there are questions as to whether they are two distinct entities or subclasses of a single syndrome (Deonna and Roulet 1995; Hirsch et al 1995; De Negri 1997; Smith 1998; Rossi et al 1999; Tassinari et al 2002; Smith and Hoeppner 2003). Furthermore, the mechanism of bilateral secondary synchronies after an initial functional spike focus seems to be the basis of language impairment and represent both for Landau-Kleffner syndrome and continuous spikes-and-waves during slow sleep syndrome--an explanation for the inclusion of these syndromes among the epileptic encephalopathies as proposed by ILAE´s Task Force on Classification (Fejerman et al 2000; Engel 2001).


CLINICAL MANIFESTATIONS

Acquired aphasia is the more prominent feature, since seizures are present in only 70% to 80% of the patients (Beaumanoir 1985; 1992; Paquier et al 1992). Age of onset ranges from 3 to 8 years, and boys are more frequently affected than girls (Beaumanoir 1985). The onset of aphasia is often insidious and progressive with spontaneous improvements and aggravations in its course. The most common feature is verbal auditory agnosia, which is the reason that in many cases the first diagnosis is hearing loss (Rapin et al 1977). Agnosia may extend to familiar noises. In some cases onset may be abrupt, and different types of aphasia may occur (Soprano et al 1994). Variable time may elapse between the loss of the ability to understand language and the expressive aphasia. In general, it is stated that patients previously had been normal in both psychomotor and language development. However, detailed history of language characteristics show that 9 of 12 patients have had previous features of developmental dysphasia (Soprano et al 1994). Very rarely, stuttering may be the presenting feature (Tutuncuoglu et al 2002), although it is difficult to differentiate pure stuttering from the repetitive nature of the impaired speech in early stages of acquired aphasia.

Neuropsychological and behavioral disturbances have been reported, but the most frequent findings are hyperkinesia and excitability. In fact, it is striking that children with such a severe handicap in understanding language only present psychotic or autistic features when aphasia appears in early ages (Deonna et al 1982; Fejerman and Medina 1986; Deonna 1991; Klein et al 2000).

Seizures are present in 70% to 80% of patients and may appear before or after onset of aphasia (Deonna et al 1977). The most common types of seizures are: eyelid myoclonia, eye blinking, atypical absences, head drops and atonic fits in upper limbs, automatisms, and occasionally, partial motor seizures with secondary generalization.


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CLINICAL VIGNETTE

No information was provided by the author.


ETIOLOGY

Isolated cases of Landau-Kleffner syndrome were apparently associated with overt cerebral pathology (eg, acute inflammatory disease, arteritis, cysticercosis, tumors, and arachnoid cyst) (Cole et al 1988; Otero et al 1989; Pascual-Castroviejo et al 1992; Nass et al 1993; Perniola et al 1993; De Volder et al 1994). Pathological study in a surgical series of 14 patients with Landau-Kleffner syndrome yielded a variety of abnormalities (Smith et al 1992). Nevertheless, the language symptomatology is interpreted as a dysfunctional disorder associated with the bilateral EEG discharges and deafferentation of temporal cortex (Landau and Kleffner 1957; Gordon 1990; 1997; Beaumanoir 1992). The reported cases of benign childhood epilepsy with centrotemporal spikes evolving into Landau-Kleffner syndrome and the prompt response to antiepileptic drugs in some of the patients also points to a secondary bilateral synchrony type of phenomenon (Fejerman et al 2000; Dalla Bernardina et al 2002).


PATHOGENESIS AND PATHOPHYSIOLOGY

Waking EEG usually shows brief bursts of temporal or temporo-occipital spike and wave discharges, either symmetrical or asymmetrical. In fact, the most typical EEG findings appear during slow sleep as continuous 1.5 Hz to 5 Hz spike and wave discharges, which may be seen in approximately 85% of the record (Beaumanoir 1992; Deonna and Roulet 1995; De Negri 1997; Smith 1998). It has been stated that most of the cases have a unilateral primary epileptogenic region (Morrell et al 1995).

Several authors have pointed to a relationship between the epileptic abnormalities of Landau-Kleffner syndrome and the benign epilepsies of childhood (Dulac et al 1983; Cole et al 1988; Deonna and Roulet 1995). Moreover, some patients were reported with a history of typical benign childhood epilepsy with centrotemporal spikes previous to the onset of Landau-Kleffner syndrome (Fejerman and Medina 1986; Cole et al 1988; Deonna et al 1993; Fejerman et al 2000; Smith and Hoeppner 2003). More recently, atypical evolutions of a few patients with initially typical early-onset benign childhood occipital epilepsy (Panayiotopoulos type) syndrome included language impairment secondary to the continuous spike-and-wave discharges during slow sleep registered in these children (Caraballo et al 2001; Ferrie et al 2002).

The correlation between the frequency and severity of EEG abnormalities and the degree of language disturbances has been questioned, although in active periods of aphasia, epileptiform activities in the EEG are more prominent. Again, at present, all patients with Landau-Kleffner syndrome show, at some time during its course, the sleep-EEG pattern of continuous spike and wave discharges (Tassinari et al 2002). In recent long-term follow-up of series of patients with Landau-Kleffner syndrome, a strict correlation between length of continuous spike and wave discharges and persistence of language impairment was found (Robinson et al 2001; Veggiotti et al 2002).

It has been suggested that the EEG discharges and seizures are manifestations of underlying abnormalities of the cortex in the speech areas, rather than the cause of the aphasia (Holmes et al 1981). A specific hypothesis has been proposed for pathophysiology of Landau-Kleffner syndrome: a persistent paroxysmal activity during the age-dependent period of synaptogenesis might strengthen synaptic contacts that should have degenerated to allow neuronal aggregates mediate normal behavior. This reinforcement of inappropriate contacts in the developing temporo-parietal cortex produces a permanent language dysfunction when paroxysmal activities are bilateral (Morrell et al 1995; Smith 1998). Therefore, early treatment would be the only way to prevent persistent aphasia. This mechanism also explains why eventual normalization of the EEG is not necessarily paralleled with improvement of aphasia. Finally, epileptiform activities in EEG were also seen in a percentage of patients with developmental dysphasia, adding difficulties to the interpretation of physiopathogenic mechanisms in Landau-Kleffner syndrome (Maccario et al 1982; Echenne et al 1992; Picard et al 1998).

Magnetoencephalography was used to localize the source of epileptiform activity in children with Landau-Kleffner syndrome. A thorough study of 4 right-handed Landau-Kleffner syndrome patients including video-EEG and magnetoencephalography was performed as presurgical evaluation 3 to 6 years after the first language deterioration. Conclusion was that the intrasylvian cortex is a likely pacemaker of epileptic discharges in Landau-Kleffner syndrome and that magnetoencephalography provides useful presurgical information of the cortical spike dynamics (Paetau et al 1999). Magnetoencephalography was also performed in 19 patients with suspected diagnosis of Landau-Kleffner syndrome. Thirteen of the 19 children had perisylvian magnetoencephalography spikes, which were bilateral in 10 and unilateral in 3 of the children. These results suggest that magnetoencephalography might help to obviate the need for invasive video-EEG recordings when surgery is being considered for patients with this condition (Sobel et al 2000).

Abnormal auditory evoked potentials have been reported in several patients with Landau-Kleffner syndrome. Some authors found normal brainstem auditory evoked potentials and clearly abnormal long latency evoked potentials, specifically the P300 (Fejerman and Medina 1986). Others reported abnormal brainstem auditory evoked potentials and middle-latency evoked potentials (Isnard et al 1995). Five children having recovered from Landau-Kleffner syndrome were compared to controls using early, middle latency, and late auditory evoked potentials. Unilateral voltage reduction of late auditory evoked potentials over the temporal areas previously involved by epileptic discharges was found, suggesting a permanent dysfunction in the associative auditory cortex (Wioland et al 2001). All studies support the hypothesis of a deficit in the activation of the auditory cortical areas.

EPIDEMIOLOGY

The incidence of Landau-Kleffner syndrome is unknown. At least 198 cases were reported by 1992 (Beaumanoir 1992). Even when Landau-Kleffner syndrome shares many clinical and EEG features with the syndrome of continuous spikes-and-waves during slow sleep, acquired aphasia is a more frequent finding than the psychiatric disturbances described in association with continuous spike-wave activity in slow sleep.

PREVENTION

There are no definite guidelines for prevention of idiopathic epilepsies. However, we can do something to prevent the encephalopathic course which is seen in a small percentage of children with benign focal epilepsies in childhood (Fejerman et al 2000). As is emphasized in the Management section, the adequate selection of initial antiepileptic drugs treatment may be the best way to avoid the development of Landau-Kleffner syndrome.


DIFFERENTIAL DIAGNOSIS

Progressive degenerative neurologic disorders usually affect language as part of the neuropsychological deterioration. Structural lesions in the dominant hemisphere of children less than 5 years of age do not impair language development because that function is served by the nondominant hemisphere. Therefore, receptive or expressive aphasia is unusual in young children unless they have a bitemporal lobe dysfunction. Therefore, acute or subacute aphasia in children aged 2 to 8 years, without unilateral acquired paresis or encephalitic symptoms, is most probably due to Landau-Kleffner syndrome.

The boundaries between Landau-Kleffner syndrome and the syndrome of epilepsy with continuous spikes-and-waves during slow wave sleep have been widely discussed (Hirsch et al 1990; 1995; Tassinari 1995; Smith 1998; Tassinari et al 2002). This type of EEG has also been found in several children with benign childhood epilepsy with centrotemporal spikes, particularly in the reported cases with clinical and EEG status lasting weeks (Fejerman and Di Blasi 1987; Roulet et al 1989; Fejerman 1996; 2000). Intermediate cases between status of benign childhood epilepsy with centrotemporal spikes and Landau-Kleffner syndrome are also occasionally seen (Shafrir and Prensky 1995; Fejerman 1996).

In early-onset cases of Landau-Kleffner syndrome, differential diagnosis with developmental dysphasia associated with EEG discharges could be difficult. The same applies to children with autistic features, regression, and epileptiform EEGs (Tuchman and Rapin 1997). Elective mutism can be readily discarded on clinical grounds and with EEG. Nevertheless, many cases of Landau-Kleffner syndrome are initially diagnosed as psychosis or severe emotional disturbance on account of their recent inability to understand spoken language, their hyperkinesia, and their anxiety. In a significant number of cases, diagnosis is delayed because an extensive workup for deafness is undertaken.


DIAGNOSTIC WORKUP

Neurologic examination is normal, and special care should be given to recognition of aphasia, mainly the onset, as auditory verbal agnosia. Neuropsychological evaluation is fundamental to determine the nature of the language disorder and level of intelligence (Deonna 1997). In many cases children keep their ability to write and to communicate through nonverbal means (Gordon 1990; Soprano et al 1994).

EEG shows a pattern of bilateral symmetrical or asymmetrical multifocal spikes and spike-waves most frequently located in the temporal and parieto-occipital regions. Sleep enhances the EEG paroxysms up to the level of exhibiting spike-wave discharges in more than 85% of slow wave sleep (Beaumanoir 1985).

Except in occasional cases associated with cerebral structural pathologies, MRI is normal (Gordon 1990).

Functional imaging with PET and SPECT have repeatedly revealed unilateral or bilateral disturbances involving the temporal lobe (Maquet et al 1990; Mouridsen et al 1993; Guerreiro et al 1996; Da Silva et al 1997).


PROGNOSIS AND COMPLICATIONS

The outcome of Landau-Kleffner syndrome varies. The seizures are usually controlled with antiepileptic drugs, and EEG abnormalities disappear after a few years.

The language disorder, however, may never resolve in almost half of the patients (Mantovani and Landau 1980; Paquier et al 1992). Both improvement and aggravation of aphasia have been reported (Deonna 1991). In many cases, correlation was found between increase in EEG discharges and aphasia, or even between abnormalities in the P300 wave during evoked potential studies and aphasia (Fejerman and Medina 1986). The presence or absence of seizures, as well as their frequency, has no correlation with the outcome of language deficiency (Gordon 1990). A residual impairment in verbal short-term memory is frequent. Brain activation during immediate serial recall of lists of 4 words, compared to single word repetition, using positron emission tomography were measured in three Landau-Kleffner syndrome patients after recovery and in 14 healthy controls. The patients had shown abnormally increased or decreased glucose metabolism in left or right superior temporal gyrus at different stages during the active phase of the disease. At the time of the study, the patients were 6 years to 10 years from the active phase of the disease. Results showed that two patients had impaired performance in verbal short-term memory. The data suggest that impaired verbal short-term memory at late outcome of Landau-Kleffner syndrome might be related to a persistent decrease of activity in the areas involved in the epileptic focus during the active phase (Majerus et al 2003).

Outcome at adulthood has been recently reported in seven young adults, five who had continuous spike-and-wave during slow-sleep syndrome and two with Landau-Kleffner syndrome in childhood. The intellectual functions of the two patients with Landau-Kleffner syndrome were normal, but their everyday lives were disrupted by severe, disabling language disturbances. The authors emphasized the role of location of interictal EEG focus and age of onset as prognostic factors (Praline et al 2003). Dementia, or more precisely, long-term deterioration of intellectual functions, is uncommon in Landau-Kleffner syndrome (Dugas et al 1995). However, in early onset cases, neuropsychological impairment is more severe (Deonna et al 1982; Bishop 1985).


MANAGEMENT

Treatment with standard antiepileptic drugs such as phenytoin, phenobarbital, and carbamazepine may be effective against seizures, but at present, this treatment is not recommended because these drugs may worsen the EEG discharges and neuropsychological deficit (Marescaux et al 1990). Instead, valproate, ethosuximide, and the benzodiazepines can be effective and deserve a trial before attempting treatments with higher risks. However, even valproate and most of the new antiepileptic drugs have been shown to induce continuous spike-wave discharges and worsening of clinical features in patients with atypical evolutions of benign focal epilepsies including Landau-Kleffner syndrome (Prats et al 1998; Fejerman et al 2000; Prats-Vinas 2002). Sulthiame seems to be the oldest drug of choice according to recent reports (Lerman and Lerman-Sagie 1995; Gross-Selbeck 1995; Wakai et al 1997; Doose et al 1998; Fejerman et al 2000). One case was treated with levetiracetam with control of seizures and language improvement (Kossoff et al 2003).

Treatment with high-dose corticosteroids was reported to yield the best results, and prolonged chronic or intermittent therapy may be necessary (Marescaux et al 1990; Lerman et al 1991; Tsuru et al 2000). In isolated cases, the use of intravenous immunoglobulins was successful (Fayad et al 1997; Lagae et al 1998). In a recent report, 2 of 5 children with Landau-Kleffner syndrome receiving 2 g/kg of intravenous gamma-globulin over 4 days showed excellent response; in both children the severe language and EEG abnormalities completely resolved (Mikati et al 2002).

Multiple subpial transection of the cortex to abolish epileptic discharges was used in a series of 14 children with acquired epileptic aphasia who had been unable to use language to communicate for at least 2 years; sustained improvement was obtained in 11 of them. According to the authors, success depends on selection of cases having severe EEG abnormality that can be demonstrated to be unilateral in origin despite a bilateral manifestation (Morrell et al 1992; 1995). In a more recent small series, 5 children with Landau-Kleffner syndrome aged 5.5 to 10 years underwent multiple subpial transection, and behavior and seizure frequency improved dramatically. Improvement in language also occurred in all children, although none of them reached an age-appropriate level of language even when their electrical status epilepticus during sleep was eliminated by the procedure (Irwin et al 2001).

More recently, six children with Landau-Kleffner syndrome were implanted with the vagal nerve stimulation device and three of them apparently showed improvement in quality of life (Park 2003).


PREGNANCY

Not applicable.


ANESTHESIA

Not applicable.


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ILAE

ILAE Copyright Notice

ABBREVIATIONS

EEG:electroencephalogram
SPECT:single photon emission computed tomography

ICD CODE

784.69

SYNONYMS

Acquired aphasia-epilepsy syndrome
Acquired aphasia with convulsive disorder
Acquired epileptic aphasia
Acquired epileptiform aphasia

ASSOCIATED DISORDERS

Autism
Benign epilepsy of childhood
Continuous spikes and waves during slow sleep
Developmental aphasia

MAJOR KEYWORD DESCRIPTORS

aphasia
epileptiform activity
language
multifocal spikes
mutism
seizures
sleep
slow sleep
speech regression
spike-wave discharges
verbal agnosia

MINOR KEYWORD DESCRIPTORS

alternative communication
developmental delay
epilepsy
hyperactivity
language impairment
personality change
temper tantrums

AGE OF PRESENTATION

02-05 years
06-12 years

AGE OF TYPICAL PRESENTATION

02-05 years
06-12 years

POPULATION GROUP(S) PREFERENTIALLY AFFECTED

none selectively affected

OCCUPATION GROUP(S) PREFERENTIALLY AFFECTED

none selectively affected

SEX

male>female, >2:1
male>female, >1:1

FAMILY HISTORY

none

HEREDITY

none

GLOSSARY

Landau-Kleffner syndrome
A sporadic epileptic syndrome characterized by childhood onset, aphasia of an auditory verbal agnosia type, EEG abnormalities with temporal spike and wave discharges during sleep, and various seizure types.

PERMUTED TOPIC, SYNONYMS, VARIANTS

Landau-Kleffner syndrome
Kleffner syndrome, Landau-
aphasia with convulsive disorder, Acquired
convulsive disorder, Acquired aphasia with
epileptic aphasia, Acquired
aphasia, Acquired epileptic
epileptiform aphasia, Acquired
aphasia, Acquired epileptiform

RELATED TOPICS

Developmental language disorder
Electrical status epilepticus during slow sleep
Epilepsy
Limbic status epilepticus (psychomotor status)
Parasomnias
Sleep disorders
Sleep disorders associated with epilepsy

DIFFERENTIAL DIAGNOSIS

epilepsy with continuous spikes-and-waves during slow wave sleep
benign childhood epilepsy with centrotemporal spikes
developmental dysphasia associated with EEG discharges
autism
regression
elective mutism
psychosis
severe emotional disturbance
deafness

 

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