CURRENT REVIEWS

The Landau-Kleffner Syndrome

Phillip L. Pearl, M.D.,* Enrique J. Carrazana, M.D.,
and Gregory L. Holmes, M.D.
*Department of Neurology, Childrens National Medical
Center, and George Washington University School of
Medicine, Washington, D.C.; Neurosciences Scientific
Operations, Novartis Pharmaceuticals Corporation, East
Hanover, New Jersey; Department of Neurology, Childrens
Hospital, and Harvard Medical School, Boston, Massachusetts
Landau-Kleffner syndrome (LKS), or acquired epileptiform aphasia, is an epilepsy syndrome involving progressive neuropsychological impairment related to the appearance of paroxysmal electroencephalograph (EEG) activity. LKS appears to share a common
pathophysiologic mechanism with continuous spike-wave of sleep
(CSWS), acquired epileptic opercular syndrome (AEOS), and
even benign childhood epilepsy with centrotemporal spikes (BECTS),
with differentiating factors including age of onset, area of primary
epileptogenicity, and severity of clinical presentation. This article
covers the clinical, diagnostic, therapeutic, and prognostic features
of LKS. In a child with autistic spectrum disorder, the presence of
a fluctuating clinical course or regression should raise suspicion for
the presence of associated epilepsy.

Introduction

he correlation between paroxysmal EEG discharges and

language deterioration was first suggested by Landau
and Kleffner (1957), who reported five children with acquired aphasia associated with a convulsive disorder (1). They
reported language improvement concordant with EEG improvement and suggested a functional ablation of language areas by persistent convulsive discharges as the pathophysiology.
Landau-Keffner syndrome (LKS) has been in the International Classification of Epileptic Syndromes since 1985 (2).
This rare syndrome raises epistemological questions regarding the pathogenesis of language, EEG abnormalities, and re-

Address correspondence to P.L. Pearl, M.D., Childrens National

Medical Center, 111 Michigan Avenue NW, Dept. of Neurology,
Washington, D.C. 20010; E-mail: ppearl@cnmc.org
Epilepsy Currents Vol. 1, No. 2 (November) 2001 pp. 3945
Blackwell Science Inc.
American Epilepsy Society

lated epilepsy syndromes. LKS may demonstrate a direct link

between epilepsy and language deficits (3).

Clinical Manifestations
Landau-Kleffner syndrome is characterized by acquired aphasia and paroxysmal, sleep-activated EEG paroxysms predominating over the temporal or parieto-occipital regions. Secondary symptoms include psychomotor or behavioral disturbances
and epilepsy with a favorable outcome for seizure control. The
prevalence is unclear. A male predominance exists, with an approximately 2:1 ratio. This regressive syndrome affects children after having achieved early developmental milestones,
with 39 years being the usual age of presentation (4).
The first manifestation of the language disturbance is an
apparent word deafness, or auditory verbal agnosia (5). Parents report a child no longer responds to their commands,
even with raised voices. This auditory agnosia extends to familiar noises including bells, whistles, or a ringing phone. Audiograms and brainstem auditory evoked response (BAER) are
normal. Delays and abnormalities in long-latency cortical
evoked responses suggest localization to the posterior temporal
regions (6). Dichotic listening tasks have shown permanent
one-ear extinction contralateral to the affected temporal cortex, and a study of long-latency auditory evoked potentials in
five children having recovered from LKS revealed unilateral
voltage reduction involving the N1c peak, arising from associative auditory areas, versus a normal N1b peak related to primary auditory cortex (7). The findings suggest long term dysfunction of associative auditory cortex.
Word deafness can deteriorate into total unresponsiveness
and impaired expressive communication. Expression is marked
by a gradual increase in misarticulations and telegraphic speech;
a fluent jargon, or total mutism can occur (5,7). The children
may express themselves with a crude sign system or gestures (5).
The language disorder can be progressive or incremental, characterized by remissions and exacerbations. The fluctuating course
of aphasia in LKS remains among its most puzzling features.
A relationship between younger age of onset and worse
longterm outcome has been reported. Bishop (4), in an analysis of 119 reported cases up to 1985, argued that the association between age of onset and prognosis suggests LKS is a disorder of higher-level auditory processing. In a younger child
without advanced language development, the effect is devastating, as the normal auditory route leading to acquisition of
language is blocked. In the older child the result will be less se-

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vere, since language has been partially learned. An analogous

scenario is profound deafness, when Wernickes area is intact
but the sensory input is defective. Profound deafness in a
young child has a more profound effect on language development than in an older child. Even the relatively mild and fluctuating hearing loss of otitis media may impair language in a
young child in the process of developing language (8). Children with LKS may not follow precisely an auditory processing disorder model (9). Given the usual age of presentation between 4 and 7 years, the child has not acquired sufficient
reading and writing skills; the older child, however, may lose
these skills. Partial retention of writing skills suggests a better
prognosis in the reeducation phase (10).
The language disorder of LKS has commonalities with
autism spectrum disorder. Communication deficits in autism
include abnormal development of spoken language and impaired ability to initiate or sustain conversation. The autistic
childs language is often stereotyped, repetitive, and idiosyncratic, with echolalia and neologisms (11). Confusing the picture is the fact that seizures may occur in autism, and EEG abnormalities are common (12). Furthermore, at least a third of
autistic toddlers demonstrate neurodevelopmental regression,
involving language, sociability, play, and cognition (13). LKS
represents selective loss of language in association with an abnormally paroxysmal EEG, eventually characterized by electrographic status epilepticus of slow-wave sleep (ESES).
While there is considerable overlap in the semiology of
LKS and autism, some differences emerge. The great majority
of children with autism who undergo language regression do
so before three years of age (14), versus a mean age of language
regression in LKS of 57 years. Only 10% of children with
LKS regress before three years (4). As regression in autism occurs early, it usually entails the loss of single words, versus
more drastic changes in LKS children who are typically older
and have more developed vocabulary and language. LKS does
not feature the behavioral profile that encompasses the core
deficits of autism, i.e., abnormalities of reciprocal social relatedness and restricted stereotypical patterns of interests and behaviors. There is an intricate relationship between LKS, autism, ESES, and developmental dysphasias and the interaction
between epileptiform discharges and cognitive dysfunction remains enigmatic (15). The presence of fluctuation in language
and behavioral deficits, however, should raise concern regarding an accompanying diagnosis of epilepsy (13).
Focal epilepsy can interfere with language. Aphasic status
epilepticus (16) and post-ictal aphasia (17) have been reported. Children with severe focal epilepsy from static brain
lesions involving language cortex may have episodic ictal aphasia or status epilepticus and become permanently aphasic (3).
The early stages of LKS, with hyperkinesis and mild verbal auditory agnosia, may be confused with attention deficit

hyperactivity disorder (ADHD) (10). Personality disturbances, aggressiveness, and depression are noted (18). Nonverbal developmental disorders may occur, but operational and
intellectual capacities are usually preserved in LKS (9,19,20).
The differential diagnosis also includes deafness, elective mutism, and acute psychiatric disorders.

Epileptic Manifestations
Seizures occur in approximately 70% of patients, one-third as
a single seizure or episode of status, mostly at onset (21). In
others, infrequent seizures occur between ages 510 years. After age 10, only one-fifth of patients continue with sporadic
seizures; by age 15, seizures rarely persist. Seizures are often nocturnal simple partial motor, placing LKS on a spectrum that includes BECTS. Generalized tonic-clonic seizures, atypical absences, and myoclonic-astatic seizures occur less frequently (3).
Complex partial seizures with psychomotor automatisms are
rare (22). Tonic seizures are not characteristic (3,22). The frequency and type of seizures have no influence on prognosis.
Treatment with anticonvulsant monotherapy is generally effective for seizure control, but not for the aphasia (3,9).

EEG Findings
Epileptiform abnormalities in LKS are variable, but striking.
Bilateral independent temporal or temporoparietal spikes, bilateral 13 Hz slow-wave maximally temporal activity, generalized sharp- or slow-wave discharges, and multifocal or unilateral
spikes are described (23). A report on spectral and topographic
mapping of the EEG revealed variability in the mode of propagation of paroxymal discharges (24). Background activity is often normal or borderline. There is seldom activation by hyperventilation or photic stimulation. Epileptiform discharges are
activated by sleep, especially sleep onset (Fig. 1). The significant activation of the spike-and-wave during non-REM sleep
has led some to analogize to CSWS (21). Eventually in LKS,
essentially all patients have bilateral spike-and-wave over 85%
of non-REM sleep (ESES) (21). During a given night, however,
these continuous discharges can be focal, restricted to the temporoparietal region (3). While nap recordings show the same
abnormalities as those recorded during full nocturnal sleep,
long-term EEG monitoring may be necessary to detect this
phenomena (25).
An interdependent relationship between language and epileptic manifestations has been described (26,27), though not
all studies have suggested this (22). Holmes referred to the
EEG abnormalities as epiphenomena of underlying pathology
of cortex concerned with speech, rather than the cause of the
aphasia (28). This view is supported by several observations:
transient suppression of EEG discharges with intravenous benzodiazepines does not result in improvement of aphasia (21);

Clinical Science

41

FIGURE 1 EEG in 5 year old girl with LKS. Note awake/drowsy background (left), activation of epileptiform activity in Stage 1 sleep
(middle), and ESES in NREM sleep (right). Courtesy of William D. Gaillard, M.D.

EEG changes may not be accompanied by a change in aphasia

(29); aphasia does not respond to conventional anticonvulsants despite seizure control (21,28); aphasia persists into
adulthood despite normalization of EEG (9,20). Alternatively,
improvement and worsening may coincide in the same direction, particularly in the sleep EEG (3,9). Disappearance of
continuous spike-wave may herald improvement of aphasia
(25). It seems reasonable to undertake treatment to terminate
continuous EEG discharges early in LKS.
The placement of LKS on a spectrum with BECTS poses
a challenge in the management of patients presenting with
BECTS features who develop more ominous signs including
neuropsychiatric dysfunction and medication refractoriness
(3032). Patients with otherwise classical seizures of rolandic
epilepsy may develop atypical seizures, including generalized
tonic-clonic, atonic, and atypical absences, as well as ESES
and cognitive or behavioral disturbances. Attempts to distinguish EEG patterns specifically associated with LKS have
identified unilateral slow wave foci, bilateral independent spikeand-wave discharges, and major activation of spike-and-wave
discharges during sleep (33).
The interaction between LKS and autism poses another
diagnostic dilemma. In a study of extended sleep EEGs in children with autism without epilepsy, an epileptiform EEG was
identified in 14% of 155 children with regression, versus 6% of
364 without regression (34). Our study of 894 patients with
autism spectrum disorder studied with overnight EEG revealed
epileptiform potentials in 19% and no study revealed ESES

(35). Overnight EEG appears warranted in autistic children

with regression or fluctuation in their clinical course, but otherwise is not indicated in unselected patients.

Etiology
The etiology of LKS remains unknown, and may be due to diverse causes. Encephalitis has been postulated, but not verified
(36). The clinical course is quite different from that of children with chronic encephalitis of the Rasmussen type. In a detailed report of two LKS cases that underwent partial temporal
lobectomies, Cole et al. (37) from the Montreal Neurological
Institute failed to uncover encephalitis. Pathological specimens
were normal with the exception of mild subpial gliosis and occasional fibrous astrocytes throughout cortical gray matter.
There was no evidence of inflammation, demyelination, hippocampal sclerosis, or dysgenesis. A report confirming encephalitic changes on cortical biopsy was given by Lou et al. (38).
However, their case was atypical with elevated CSF protein
and focal imaging abnormalities. Other biopsied cases did not
have encephalitic changes (22,39). Angiography has occasionally suggested isolated arteritis of small and medium-sized vessels in some studies (40), but not others (22,37).
Other etiologies reported include a genetic predisposition
(1,24,41), toxoplasmosis (42), neurocysticercosis (43,44), temporal astrocytoma (45), temporal ganglioglioma (46), hemophilus
inflluenzae meningitis (19), subacute sclerosing panencephalitis
(47), inflammatory demyelinating disease (48,49), and abnormal

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zinc metabolism (50). LKS may represent a final common pathway with multiple potential etiologies, acquired or genetic.
The language disturbance, EEG abnormalities and epilepsy
are likely the result of an insult to temporoparietal areas of the
developing brain. As with other epilepsy syndromes, it would
be useful to classify LKS into cryptogenic or symptomatic subgroups. Differences in pathogenesis, treatment, and prognosis
may emerge, analogous to the infantile spasms of West syndrome.

Diagnostic Studies
Investigations have not delineated sufficient evidence to explain
the pathophysiology. CSF (29,37,39,41), computed tomography (CT) (20,21,24,41,52), and magnetic resonance imaging
(MRI) (21,41,54) findings are normal. There are uncommonly
mild elevations of CSF protein (36,40,48), white matter
changes on CT/MRI, or a structural lesion (4346). Purists
may argue that such cases represent other conditions mimicking
LKS. Slight enlargement or asymmetry of the temporal horns
have been reported (37,54), possibly secondary to the long-term
epileptic process.
Various single photon emission computed tomography
(SPECT) and positron emission tomography (PET) studies on
small numbers of patients have shown temporal lobe abnormalities in brain perfusion and glucose metabolism (52,53,55).
Chugani et al. (54) studied 17 LKS children with FDG-PET,
demonstrating hypometabolism in the middle temporal gyri.
Decreased temporoparietal perfusion has been seen with SPECT
(55). A correlation between the aphasia of LKS with temporal
lobe hypometabolism is not certain, as similar findings are observed in children with epilepsy who are not aphasic.

Treatment
The pharmacologic treatment of LKS is problematic due to
several confounding observations. The benign course of the
epilepsy versus devastating language impairment, fluctuating
course of aphasia, lag of improvement in relation to the EEG,
possibility of spontaneous remission, and rarity of the disorder
render multiple barriers to controlled clinical trials. The determination of treatment efficacy is difficult. There is relatively
scarce mention in the literature regarding antiepileptics of
choice. Marescaux et al. (51) observed that phenobarbital, carbamazepine, and phenytoin were ineffective or even aggravating. Phenobarbital, having no effect on language, intensified behavioral problems, particularily hyperkinesis. Carbamazepine
and phenytoin appeared to increase the duration of spike-wave
activity in sleep. Valproate, ethosuximide, clonazepam, and clobazam were demonstrated to be partially or transiently effective. Clobazam has been reported to significantly reduce continuous spike-wave discharges in several small studies, associated

with language improvement (27,51,56). Vigabatrin (57) and

felbamate (58) have also been reported as effective.
Corticosteroids have been an efficacious treatment for
both clinical and EEG abnormalities. This was reported by
McKinney and McGreal (39), leading to the speculation of
chronic encephalitis as the etiology of LKS. Effectiveness may
be increased by early introduction (59). A recurrence of epileptiform EEG followed by an aphasic relapse has been described after tapering steroids (51). Prolonged, chronic, or intermittent therapy may be warranted if significant improvement
of neuropsychological function is attained (3,51). Another recent addition is IVIG (49,60,61). The rationale for its use in
LKS lies in the refractory nature of the epileptiform abnormalities, and the reports of beneficial effects in other intractable
childhood epilepsies.
Surgical therapy including temporal lobectomy in lesional
(45,46) and nonlesional (37) cases has been associated with
improvement in language and seizure control. Multiple subpial transection (MST), designed to selectively disrupt intracortical horizontal fibers with minimal injury to vertically oriented cortical columns, has been suggested in treating epilepsies
arising from eloquent or unresectable cortex. Morrell (62) reported a series of 14 LKS cases in which the epileptogenic discharges arose unilaterally, and were surgically treated with MST.
Seven patients recovered age-appropriate speech; four showed
marked improvement but continued in speech therapy programs; and the remaining three had no change. Other series
have been small and demonstrated improvements that are often temporary (63), or in one series of five patients partial improvement but associated with a later extension of the procedure
in one patient following relapse of ESES and clinical deficits
(64). The most appropriate timing of this procedure and its
long term ramifications are unknown. Further experience is
needed to clarify the role of MST in the treatment of LKS.
Speech/language therapy is indispensable with periodic
language and neuropsychological evaluations. Adverse behavioral manifestations may partly reflect frustration caused by
aphasia. Introduction of an effective communication system
could assist in alleviating such negative behavior. Some children with long standing verbal auditory agnosia are successfully integrated into schools for the deaf, although others
continue to have marked deficits in social adaptation and communication. The patients who recover verbal language will drop
the use of signs, allaying concern by some educators that there is
detrimental competition between the two systems (3,65).
Impaired comprehension secondary to background noise
in adolescents and adults who had recovered from LKS (9)
suggests that improvement in the acoustic environment may
enhance speech recognition ability. Listening may be assisted by
increasing speech volume over ambient noise. This is accomplished with low-gain output personal or classroom FM systems

Clinical Science

or acoustically modifying the classroom (66). A comprehensive linguistic study of a 26-year old, left-handed male, with
onset of LKS at age five years who learned sign language at age
13, revealed that sign language was the most efficient mode of
communication. Severe restrictions in comprehension and production of spoken English or lip reading, and lesser impairment of reading, persisted. Functional MRI (fMRI) revealed
strong activation of auditory cortex (RL) to heard speech,
little response to silent lip-reading, and strong activation of
right temporo-parieto-occipital association cortex while viewing sign language (67). Further fMRI studies may provide an
understanding of the extent of cortical impairment and applicability of various therapeutic strategies.

Prognosis
Several variables may influence prognosis, including age of onset, pattern of language deficit, frequency and topography of
EEG discharges, duration of epilepsy, and efficacy, and adverse
effects of anticonvulsants (3). There are few longterm follow
up studies and no firm conclusions regarding potential for recovery (3,9,20). Outcomes range from complete recovery to
permanent severe aphasia, with most experiencing improvement and residual moderate language deficits (68). In a study
by Soprano et al. (69), no child with persistent EEG abnormalities recovered normal or near normal language; even
among the nine whose EEG normalized; only three had complete recovery. A recent long term study of 11 patients with a
mean follow-up of nine years eight months revealed complete
language recovery in only 18.2% of cases and mental retardation in 63.6% (70). Adverse prognostic factors appear to be
onset before 4 years, duration of aphasia longer than one year,
and duration and continuity of ESES (4,70).

Conclusion
LKS is an epilepsy syndrome characterized by acquired aphasia
and epileptiform EEG abnormalities eventually characterized
by ESES. The language disorder could be the result of a paroxysmal disruption of language function during the time of its
greatest development and vulnerability (71). In experimental
animal models, there is clear evidence that functional disruption may interfere with the process of neuronal connection
and cortical function (72). Seizures during a critical period for
circuit development cause the emergence and fixation of permanent aberrant connections (73,74). LKS is a condition of
unpredictable outcome and varying severity with a potentially
relapsing remitting course, requiring constant adaptation and
resourcefulness from parents, speech/language therapists, neuropsychologists, and neurologists.

43

Acknowledgments
The authors are grateful to Suzanne Reigle, B.S., and Kathleen
Kelly, R.EEG T. for their assistance. This work was supported
by a grant to GLH from the NINDS (NS27984) and a Mental
Retardation Research Center Grant from NIH (HD18755-19).

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