THERAPY IN PRACTICE

Pediatr Drugs 2005; 7 (6): 377-389

1174-5878/05/0006-0377/$34.95/0

 2005 Adis Data Information BV. All rights reserved.

Management of Landau-Kleffner Syndrome

Mohamad A. Mikati and Alhan N. Shamseddine
Department of Pediatrics, and Adult and Pediatric Epilepsy Program, Faculty of Medicine, American University of Beirut,
Beirut, Lebanon

Contents
Abstract ......................................................................................................................................................................................................................... 377
1. Definition and Clinical Spectrum ......................................................................................................................................................................... 378
2. Therapeutic Approaches...................................................................................................................................................................................... 379
2.1 Antiepileptic Drugs ........................................................................................................................................................................................ 379
2.2 Corticosteroids and Corticotropin (Adrenocorticotropic Hormone)..................................................................................................... 382
2.3 Intravenous Immunoglobulin ....................................................................................................................................................................... 385
2.4 Surgery ............................................................................................................................................................................................................. 386
2.5 Speech Therapy and Behavioral Intervention .......................................................................................................................................... 387
3. Conclusions and Recommendations ................................................................................................................................................................. 388

Abstract Landau-Kleffner syndrome (LKS) is an acquired epileptic aphasia disorder in which children, usually 3–8
years of age who have developed age-appropriate speech, experience language regression with verbal auditory
agnosia, abnormal epileptiform activity, behavioral disturbances, and sometimes overt seizures. There are no
controlled clinical trials investigating the therapeutic options for LKS. Only open-label data are available. Early
diagnosis and initiation of prompt medical treatment appear to be important to achieving better long-term
prognosis.
Several antiepileptic drugs have been reported to be beneficial in treating this syndrome. These include
valproic acid (valproate sodium), diazepam, ethosuximide, clobazam, and clonazepam. Reports on the efficacy
of lamotrigine, sultiame, felbamate, nicardipine, vigabatrin, levetiracetam, vagal nerve stimulation, and a
ketogenic diet are few and more experience is needed. Carbamazepine and possibly phenobarbital and phenytoin
have been reported to occasionally exacerbate the syndrome. As initial therapy, valproic acid or diazepam is
often empirically chosen. Subsequently, other antiepileptic drugs, corticosteroids, or intravenous immunoglobu-
lin (IVIG) therapy are often used. Corticosteroid therapy should probably not be delayed more than 1–2 months
after the initial diagnosis. Various corticosteroid regimens including oral prednisone and, recently, high doses of
intravenous pulse corticosteroids, as well as corticotropin (adrenocorticotropic hormone) have been reported to
be effective in LKS. Oral corticosteroids are used more often and usually need to be maintained for a long period
of time to prevent relapses. The use of IVIG has been associated with an initial dramatic response in only a few
patients. In our experience, a long-term worthwhile improvement has been noted in only 2 of 11 patients. These
two patients had an immediate response to IVIG initially and after relapses before eventually achieving a long-
term sustained remission.
Surgical treatment by multiple subpial transection, which is reserved for patients who have not responded to
multiple medical therapies, has been followed in selected cases by a marked improvement in language skills and
behavior. However, a widely accepted consensus about suitable candidates for this surgery and about its efficacy
is still lacking.
Speech therapy, including sign language, and a number of classroom and behavioral interventions are helpful
in managing LKS, and should be used in all patients.
378
This article reviews in detail the different modes of therapy that by their clinical outcomes in adulthood (when cognitive deficits
have been used to treat patients with Landau-Kleffner syndrome persist they are global in patients with CSWS and related to speech
(LKS). It also provides updated follow-up data for patients with in patients with LKS).[12]
LKS treated with intravenous immunoglobulin (IVIG) at the
American University of Beirut Medical Center, Beirut, Lebanon.
1. Definition and Clinical Spectrum
LKS, first described in 1957,[1] was defined by the International have been observed. However, others have not observed such a
League Against Epilepsy (ILAE) as “a childhood disorder in
which an acquired aphasia, multifocal spike, and spike and wave
discharges are associated”. The presentation is moderate-to-
[2]
severe loss of speech and auditory verbal understanding. Behav-
ioral and psychiatric disturbances are also frequent and consist of
motor hyperactivity, impulsivity, and aggressive behavior. Some
of these disturbances may be anxiety reactions in a child suddenly
deprived of the understanding of spoken language. The recovery
of language skills is variable in children with LKS; some children
may recover completely from aphasia after months or years,
whereas others (approximately half) may show partial improve-
ment or have permanent aphasia.[3] In some patients, the fluctuat-
ing course of LKS is characterized by remissions and relapses.
The onset of LKS occurs between 3 and 8 years of age after a
normal cognitive and language developmental course.[4] There is a
relationship between age of onset of LKS and long-term outcome.
Children who have a younger age of onset show a worse prognosis
for language recovery; this is especially the case in children with
[5]
LKS onset before the age of 5 years. Males are more often
[6]
affected than females in an approximate ratio of 2 : 1.
The EEG findings in patients with LKS are characterized by
focal or multifocal epileptic abnormalities observed most fre-
quently in the temporal regions. Paroxysmal activity increases
dramatically during sleep and is usually characterized by the
presence of continuous spike waves during slow-wave sleep
(CSWS),[7] otherwise described as electrical status epilepticus
during sleep.[8] Whether the presence of CSWS is required for the
diagnosis of LKS is still not clear. CSWS is considered to be
present when the spike-wave activity occupies >85% of slow-
[9]
wave sleep duration. Epilepsy with CSWS was defined by the
ILAE to be a condition that “results from the association of various
seizure types, partial or generalized, occurring during sleep, and
atypical absences when awake” and that “despite the usually
benign evolutions of seizures, prognosis is guarded because of the
appearance of neuropsychologic disorders”.[2] The spike slow-
wave activity is bilateral and predominantly generalized. CSWS is
clinically similar to LKS but is differentiated by EEG findings,[10]
by the global mental deficiency in patients with CSWS, by the
dramatic comprehension deficits seen in patients with LKS,[11] and
 2005 Adis Data Information BV. All rights reserved.
Mikati & Shamseddine
There is probably a correlation between the intensity of the
EEG paroxysmal activity and language deterioration in LKS.
Some investigators have suggested a direct and consistent relation-
ship between the course of the language disorder and the EEG
response; concurrent improvements in speech and EEG findings
relationship.[13] In patients in whom normalization of the EEG is
not accompanied by an improvement in aphasia, aphasia may, in
some cases, become permanent.[14] Paquier et al.[15] indicated that
disappearance of CSWS may result in improvement of language
functions; therefore, CSWS may be responsible for the functional
disorganization of the cortical speech areas. Thus, in most patients,
improvement in EEG findings may be necessary to achieve im-
provement in LKS-associated aphasia, but EEG improvement is
not always sufficient to guarantee an optimal outcome.
Abnormal epileptiform activity often occurs without overt
seizures. Clinical seizures do not occur in all patients with LKS
although EEG abnormalities are always present: 20–30% of chil-
dren with LKS do not manifest any clear behavioral seizures. [16]
The seizures in LKS vary considerably in type, but the most
common are complex partial, generalized tonic-clonic, and atonic
seizures. Occasionally, the seizures are atypical absences. Tonic
and myoclonic seizures are uncommon.[17] In most cases, the
epilepsy and the EEG abnormalities disappear before the age of 15
years.[1,16]
The clinical presentation of LKS may, in some children, resem-
ble that of autistic disorders.[18] Patients who fulfill the criteria for
LKS but who also have autistic behavioral problems have been
labeled as having the Landau-Kleffner variant.[18] This condition
has to be distinguished from autistic disorder and autistic regres-
sion disorder. Autistic disorder, as defined in the Diagnostic and
Statistical Manual of Mental Disorders (4th Edition) [DSM-IV], is
characterized by the presence of markedly abnormal or impaired
development in social interaction and communication and a mark-
edly restricted repertoire of activity and interests.[19] Autistic re-
gression disorder (Heller syndrome or childhood disintegrative
disorder), as defined in the DSM-IV, is a syndrome that has a
distinctive pattern of developmental regression following at least 2
years of normal development.[19] Patients who have autistic regres-
sion disorder suffer from impairment in verbal and non-verbal
communication as well as in socialization. Such patients usually
have restricted and repetitive patterns of behavior and delayed fine
and gross motor functions. The distinction between these disorders
has at times led to intensive and long-term video-EEG studies in
children with autism. Some children with autism were shown to
Pediatr Drugs 2005; 7 (6)
Management of Landau-Kleffner Syndrome 379

have spike discharges, usually without any clinical seizures.[20] clinical seizures. Data on the use of vagal nerve stimulation[25]
However, unlike those with LKS or CSWS, the spikes were needs further confirmation in studies with large patient numbers.
typically of a low frequency. Also, the origin of the epileptic The outcome of LKS is variable. According to some reports,
activity in children with LKS is the intra and perisylvian cortex,[21] most patients with LKS continue to have language difficulties as
whereas children with autistic regression were found to have adults,[12] albeit the severity varies from almost no verbal ability to
[22] [21]
multi-focal independent foci. Morrell et al. proposed that mild or moderate deficits in verbal communication.[5] Mantovani
since the epileptic disturbance in LKS is presumed to be the cause and Landau[3] reported that only 40–55% have permanent difficul-
of the language and behavioral deterioration, prompt elimination ties of variable severity (see section 2.1). In this study, neuropsy-
of this epileptic abnormality should allow for more normal neocor- chologic testing was performed using the Wechsler Intelligence
tical function. However, this is not the case in patients with autism Scale for Children (WISC) and the Revised Benton Visual Reten-
or autistic regression disorder since the epileptic activity is a tion Test. Paquier et al.[15] reported variable outcomes among six
byproduct of autism rather than the underlying cause. Thus, elimi- children with LKS upon follow-up for 3–19 years; outcomes
nation of the epileptic abnormality in a child with autism or varied from complete improvement to continued severe aphasia.
autistic regression may have no effect or may improve behavior Soprano et al.[26] followed up 12 patients for a mean of 8 years
but not language dysfunction.[23] using various neuropsychologic techniques including the Wech-
LKS is a disorder of unknown etiology. However, in recent sler Preschool and Primary Scale of Intelligence (WPPSI) or the
years, multiple etiologic factors have been shown to cause LKS in WISC, Bender Visual-Motor Gestalt Test, Beery Visual Motor
some patients. These factors, almost certainly, account for some Integration Test, Rey Complex Figure, Motor-free Visual Percep-
but not all cases of LKS. They include cerebral arteritis, neurocys- tion Test, and other tests of formal language. The three patients
ticercosis, Toxoplasma gondii, Haemophilus influenzae type-B who had persisting EEG abnormalities did not recover normal or
meningitis, temporal lobe tumors, and inflammatory and demye- near normal language functions. Of the other nine patients with a
linating diseases.[7,24] One could argue that such cases should be normalized EEG, only three had complete language recovery.
classified as ‘symptomatic’ LKS whereas most cases are crypto- Rossi et al.[27] reported that epileptic seizures and EEG paroxysmal
genic or idiopathic. However, this distinction has not been adopted abnormalities (subcontinuous/continuous) in patients with LKS
yet in the literature. disappear during puberty. The authors also mentioned that aphasia
disappears in 30% of patients, improves in 45%, and persists in
2. Therapeutic Approaches 25%, and that only 40–50% of patients may lead normal lives.
Considering the fluctuating course of LKS and the spontaneous
The optimal treatment of LKS is still controversial because remissions that can occur, it is very difficult to evaluate the
there are no controlled clinical trials investigating treatment op- therapeutic efficacy of any intervention. There have been no
tions for this syndrome. Different therapeutic approaches have controlled studies of the treatment of this condition.
been proposed based on open-label data from usually relatively
small series of patients and case reports. 2.1 Antiepileptic Drugs
In treating patients with LKS, clinicians aim to normalize all
aspects and symptoms of the illness; however, speech and behav- Traditional antiepileptic drugs have usually been effective in
ior are the most important ones. Seizures are usually not a major preventing seizures in patients with LKS, but have yielded varia-
problem. Achieving a normal EEG is preferable as often, but not ble results with respect to aphasia (table I). In the study by
always, there is a correlation between a normal EEG and improve- Mantovani and Landau[3] mentioned earlier in section 2, nine
ment in aphasia. patients with LKS aged 4–9 years were treated with antiepileptic
Treatment options for LKS are either pharmacologic (anticon- drugs (not specified) and were evaluated 10–28 years after the
vulsants, corticosteroids, corticotropin [adrenocorticotropic hor- onset of aphasia. Eight of them received antiepileptic drugs for
mone], or IVIG [sections 2.1–2.3]); surgical, according to some several years up to 20 years but none of them remained on
researchers, to control the epileptiform abnormalities (section 2.4), medication at the time of the last assessment. Four patients recov-
or speech and behavioral (section 2.5). Pharmacologic treatment is ered fully, one had mild language dysfunction, and four had
the first-line form of therapy. For patients in whom the abnormal moderate language disability. In a review by Smith and Spitz[28]
epileptiform activity persists and is not controlled by medications, based on the results of three studies, the authors reported that
some experts may evaluate the child for multiple subpial transec- valproic acid (valproate sodium), clobazam, and ethosuximide,
tion (MST) irrespective of the presence or absence of intractable alone or in combination, were effective in eradicating epileptiform

 2005 Adis Data Information BV. All rights reserved. Pediatr Drugs 2005; 7 (6)
 2005 Adis Data Information BV. All rights reserved.

380
Table I. Medications reported to be effective in Landau-Kleffner syndrome (based on open-label experience; no controlled studies have been performed)a

Study Medication Dosage (mg/kg/day) Age (y) No. of pts Type of response
responding
Marescaux et al.[30] Clobazam 1–1.6 5–9 2/3b Transient moderate-to-marked improvement of
seizures and EEG, transient moderate
improvement of speech and behavior

1/3b Transient marked improvement of EEG but not

of speech and behavior

Marescaux et al.[30] Clonazepam 0.1 7.5 1/1 Transient moderate improvement of seizures,
EEG, speech, and behavior

Ravnik[31] Diazepam (intravenous) 0.3 9 1/1 Immediate and dramatic (transient) beneficial
effect on both language and EEG

De Negri et al.[32] Diazepam (high-dose oral) 0.5–0.75 (six short 5 1/1 Substantially higher IQ and disappearance of
cycles, 3–4 wks) neuropsychologic disharmonies. Total remission
of EEG paroxysmal activity (30mo)

Marescaux et al.[30] Ethosuximide (with valproic acid 20 7.5 and 8.5 2/2 Improvement of seizures and day EEG but not
[valproate sodium]) speech and behavior

Rossi et al.[27] Ethosuximide (with one or more of NS 4.5–20 7/10 ‘Effective’c

the following: valproic acid,
phenobarbital, carbamazepine,
benzodiazepine, vigabatrin, and
clonazepam)

Rossi et al.[27] Lamotrigine NS NS 1/1 Favorable effect on cognitive functions and

languagec

Glauser et al.[33] Felbamate (added to primidone and 15 initially, increased 6 1/1 Complete seizure control by the third month of
ethosuximide) weekly to 45 then to 60 therapy. ‘Significant’ improvement in receptive
after 6mo and expressive function by the fifth month to
almost normal by the ninth month

Kossoff et al.[11] Levetiracetam (added to 35 then increased to 50 4.5 1/1d Upon follow-up (9 months after dosage was
carbamazepine and valproic acid, then 60 increased to 60 mg/kg/day), ‘marked

Mikati & Shamseddine

Pediatr Drugs 2005; 7 (6)

then eventually monotherapy) improvement’ in measures of receptive and

expressive language abilities

Continued next page

 2005 Adis Data Information BV. All rights reserved.

Management of Landau-Kleffner Syndrome

Table I. Contd

Study Medication Dosage (mg/kg/day) Age (y) No. of pts Type of response
responding
Pascual-Castroviejo[34] Nicardipine with conventional 0.5–2 NS 6/6f Effects were seen within days or weeks in
antiepileptic drugse some pts and not for months or even years in
other pts; however, they all had ‘large’
improvements in language and improved
seizure control and EEG (EEGs of three pts
became normal)

Marescaux et al.[30] Valproic acid 30–50 5–9 1/5b Moderate improvement of seizures, moderate
but transient improvement of EEG, speech, and
behavior

4/5b Improvement of seizures and/or EEG but not

speech and behavior

Bharani et al.[35] Valproic acid 30 8 1/1 Improvement in speech, behavior, hyperkinesis,

and frequency of convulsions

Holmes and Valproic acid (monotherapy or 10–20 then titrated until 4.5–11 22/57 Language returned to normal in two children,
Riviello Jr[29] polytherapy)g clinical toxicity or trough improvement was ‘modest’ in the other 20
serum concentrations of
80–120 g/mL were
reached

Appleton et al.[36] Vigabatrin (added to 80 4.5 1/1 ‘Dramatic response’; improvement in

carbamazepine) comprehension and speech and complete
seizure control after 5 days of treatment

a One or more conventional antiepileptic drugs were tried before corticosteroids or corticotropin (adrenocorticotropic hormone) were given.

b Pts had different degrees of response in the same study.

c Seizure control was improved. Aphasia and cognitive function outcomes were unfavorable: they were normal in two pts, moderately compromised in five, two had a mild
comprehension improvement, one had a mild expression improvement, and language remained totally compromised in one patient (polytherapy was used in ten pts, and
monotherapy [lamotrigine] was used in one).

d The patient was monitored through five behavioral tests including the Wechsler Intelligence Scale for Children (WISC) and the Token Test for sentence comprehension.

e Nicardipine monotherapy was used as initial therapy in ‘some’ pts before it was added to existing drug regimens but had no effect.
Pediatr Drugs 2005; 7 (6)

f Five of six pts received one or more conventional antiepileptic drugs (carbamazepine, valproic acid, a hydantoin, phenobarbital).

g Fifteen of 57 pts received one or more antiepileptic drugs (phenobarbital, ethosuximide, phenytoin, and topiramate) during the course of the valproic acid therapy.

NS = not specified; pts = patients.

381
382 Mikati & Shamseddine

activity and improving language skills in about 50% of patients. In skills, and EEG findings. Maximum doses of diazepam,
a retrospective study of 57 children with LKS aged 4.5–11 years, phenytoin, carbamazepine, and sultiame were used in one patient
valproic acid (started at 10–20 mg/kg/day) was found to be helpful with no effect.[37] However, sultiame was reported to be beneficial
in improving language function (in 40% of the patients) particular- in treating patients with LKS in a study in Japan.[38] There is also a
ly in those children with an earlier age of onset of aphasia (two recent report of the effectiveness of levetiracetam 60 mg/kg/day
patients had a dramatic response).[29] In this study, Holmes and monotherapy in a patient with LKS.[11] Thus, although a number of
Riviello Jr[29] found that children who responded to valproic acid antiepileptic drugs have been reported to show encouraging re-
had an earlier age of onset of aphasia (23.6  1.63 months) than sults, more experience is still needed with most of them.
non-responders (37.6  4.05 months) [p = 0.002], and that devel- Bergqvist et al.[39] reported the successful use of a 4 : 1 keto-
opmental delay before the onset of the epileptic aphasia did not genic diet in treating three patients with acquired epileptic aphasia
correlate with later response to valproic acid (p = 0.102). Also, the aged 9–14 years. The 4 : 1 ketogenic diet is the traditional high-fat
presence or absence of epilepsy or an abnormal EEG was not (four parts saturated fats, one part proteins and carbohydrates) diet
significantly different between valproic acid responders and non- that was developed to mimic the physiologic response to starva-
responders (p = 0.218 and p = 0.152, respectively). tion by maintaining a state of metabolic ketosis in patients with
[31]
Ravnik reported a dramatic and prompt, but transient, bene- intractable epilepsy. These patients were treated for 26, 24, and 12
ficial effect of intravenous diazepam (0.3 mg/kg) on both language months with no significant adverse effects, and they all showed
and EEG findings in a 9-year-old child. De Negri et al.[32] reported significant and lasting improvements of language function, behav-
on the efficacy of short cycles (3–4 weeks each) of high-dose oral ior, and seizures.
diazepam (0.5–0.75 mg/kg/day, maintaining blood concentrations Carbamazepine has been reported to worsen the condition of
of 100–400 ng/mL) in treating patients with CSWS aged 3.5–12 some patients with LKS,[10,30,40] and is, thus, not recommended.
years, only one of whom had LKS. They used the rectal diazepam Marescaux et al.[30] reported that the administration of carba-
test (1 mg/kg) to distinguish between patients with CSWS and mazepine to three patients with LKS (aged 5–9 years)[10] increased
those with hypsarrhythmia. Patients with CSWS showed 100% the duration of sleep spike-wave activity, aggravated clinical
response (remission of the paroxysmal activity) whereas those seizures, and caused focal nocturnal and subclinical EEG se-
with hypsarrhythmia showed no response. Responders to the rectal quences. This drug either did not improve or increased speech or
test were then started on the oral treatment cycles. The authors intellectual disturbances. The same authors have also indicated
performed neuropsychologic monitoring on all patients using the that phenobarbital and phenytoin are ineffective or even harm-
following tests: Brunet-Lézine, Stanford-Binet, WPPSI, WISC- ful.[10,30]
Revised, Progressive Matrices 38 and/or 47, Hilda and/or Bender-
Santucci, and Goodenough. A positive response to treatment was 2.2 Corticosteroids and Corticotropin
seen in 64% of the patients who responded to the rectal diazepam (Adrenocorticotropic Hormone)
test. Some patients needed up to six cycles (LKS patients). [32]
In the study by Rossi et al.,[27] 11 patients with LKS (mean age Corticosteroids and corticotropin have been reported to be
of 5 years and 7 months at the first observation) were followed up effective in reversing language, cognitive, and behavioral distur-
for a mean of almost 10 years. Ethosuximide added to other drugs bances in many children with LKS, but the fluctuating nature of
(valproic acid, phenobarbital, carbamazepine, benzodiazepine) the disease makes the results difficult to assess (table II). In
was effective in six patients, and vigabatrin added to ethosux- general, oral corticosteroids are used more frequently and they
imide, carbamazepine, and clonazepam was effective in one. usually need to be maintained for a long period of time to avoid
Monotherapy with lamotrigine was used in one patient and relapses. Administration of oral prednisone at initial dosages of
showed a favorable effect on cognitive functions and language. In 2–3 mg/kg for 1–2 months is a common practice; the dosage is
addition, vigabatrin (80 mg/kg/day), added to carbamazepine, was then tapered slowly over several months depending on the clinical
reported to have a ‘dramatic response’ in treating a 4.5-year-old response and resolution of EEG abnormalities.
patient with LKS.[36] Nicardipine (0.5–2 mg/kg/day), with conven- In 1974, McKinney and McGreal[40] first reported the effective-
tional antiepileptic drugs, resulted in significant improvement in ness of corticosteroids and corticotropin in patients with LKS.
all six treated patients with LKS.[34] Glauser et al.[33] reported on a Corticotropin injections (n = 1), or corticotropin injections plus 6-
year-old boy in whom felbamate-containing polytherapy, and prednisone (n = 2), were given to three of nine patients with LKS.
eventually monotherapy (60 mg/kg/day), resulted in a dramatic, These patients showed a rapid recovery while only one of the other
rapid, and prolonged improvement in seizure control, language six patients recovered. Two subsequent reports [49,50] concluded

 2005 Adis Data Information BV. All rights reserved. Pediatr Drugs 2005; 7 (6)
 2005 Adis Data Information BV. All rights reserved.
Table II. Corticosteroids and corticotropin (adrenocorticotropic hormone) reported to be effective in Landau-Kleffner syndrome (based on open-label experience; no controlled
studies have been performed)
Study
Corticotropin
Lerman et al.[14]
Perniola et al.[41]
Raybarman[42]
Tutuncuoglu et al.[43]
Dexamethasone (oral)
Lerman et al.[14]
Methylprednisolone (intravenous)
Aykut-Bingol et al.[44]
Tsuru et al.[6]
Prednisone (oral)
Coutinho dos Santos
et al.[45]
Guerreiro et al.[46]
Lerman et al.[14]
Lerman et al.[14]
Marescaux et al.[30]
Pediatr Drugs 2005; 7 (6)
Dosage and duration
3mo course starting with 80 U/day then
gradually reduceda
0.25 mg/day for 4d (retard preparation)a
One course (injectable; dose not specified) to
supplement antiepileptic drug therapy
50 U/day for 3 days/week for 4 wks then
2 days/week for 4 wks, followed by gradual
dose reductiona,d
4 mg/day for 2 wks then tapered off over 3mo
500mg infusion over 3h daily for 5 days,
followed by 250mg over 2h once per month
20 mg/kg/day for 3 consecutive days,
repeated three times at 4-day intervals,
followed by oral prednisolone 2 mg/kg/day for
1mo then gradually withdrawn
2 mg/kg/day for 2 or 6mo then decreased or
tapered off
40 mg/day for 2mo followed by 20 mg/day for
4mo
60 mg/day (duration not specified) tapered off
over 3mo
60 mg/dayf for 2mo then very gradually
tapered off over 3mo. 30 mg/day (duration not
specified) then slowly tapered off over 10mo
for relapse
2 mg/kg/day for 1mo then progressively
reduced (long-term treatment)
Management of Landau-Kleffner Syndrome
No. of pts Response
1/1 Disappearance of epileptic activity 3 wks after starting treatment. Speech
returned after 6mo with complete remission of aphasia within the following
3mob
1/1 Reduced paroxysmal activity after 4d.c Expressive language recovery
started after 20d and was further recovered during the following weeks
1/1 ‘Significant’ improvement in verbal output, comprehension, attention span,
and hyperkinesias in 10mo
1/1 Speech started to recover after corticotropin and intravenous
immunoglobulin therapy. Full EEG recovery at the end of the second
month, completely normal speech at the end of 3.5mo
1/1 ‘Full recovery’ of speech and completely normal EEG occurred within 2
wks of starting treatment
1/1 Improvement started 2 wks after initial therapy, and after 2mo language
level increased and EEG abnormalities were suppressed
2/2 Improvement started after the first or second 3-day injection (to nearly
normal understanding and expression of speech in one patient 1–2 wks
after the third course)
3/3e Good control of seizures and EEG, less response for aphasia
3/5 Improvement after 6mo of treatment; significantly improved behavior in two
pts, and control of seizures in two pts whose seizures had not been
controlled with antiepileptic drugs. Mild improvement in cerebral perfusion
in three pts
1/1 ‘Prompt’ recovery of normal speech and normal EEG
1/1 ‘Prompt’ improvement in EEG followed by normal speech for 11mo, then
relapsed. EEG and speech promptly returned to normal after treatment for
relapse
2/2g ‘Progressive’ improvement in speech after 2–3mo of treatment (to almost
normal in one patient)
1/1g Language recovered slowly, and 1.5 years after the start of treatment EEG
was normal, oral comprehension was good but expression was still limited
Continued next page
383
384 Mikati & Shamseddine

that the beneficial effects of corticosteroid therapy were coinci-

‘Dramatic’ improvement (vocabulary) within 3mo after the first course then
Improvement in language function persisted long after corticosteroids had

plateaued at 2y. Improvement (comprehension and vocabulary) to almost

dental. However, each of these two reports was based on one

Cognitive development was assessed through tests including the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) and the Wechsler Intelligence Scale for
Corticotropin was given with valproic acid (valproate sodium) [25 mg/kg/day] and intravenous immunoglobulin (400 mg/kg/day for 5 consecutive days). Clobazam (5 mg/
Significant improvement in language cognition and behavior on post-

single case and neither reported the prednisone dose that was given
or the time period between the onset of aphasia and prednisone
treatment speech/language, and neuropsychologic evaluations.

administration.
In 1991, Lerman et al.[14] reported a direct relationship between
treatment onset and the rate of speech recovery in patients with
LKS. In one patient, they administered corticotropin 2 years after
the onset of aphasia, and it was not until 6 months later that speech
returned. However, when that patient relapsed and corticotropin
was promptly given, improvement started within a few days. In the
other three patients, corticosteroids (prednisone or dexametha-
normal after the second courseh

The patient had a relapse after 2y. Prompt corticotropin treatment led to recovery of speech and normal EEG within a few weeks.

sone) were administered without delay and at relatively high initial

dosages. This promptly resulted in a normal EEG in all three
patients and in concurrent marked clinical improvement with full
been discontinued.

speech recovery within a few weeks. In one of these patients

Any attempt to reduce this dose resulted in deterioration of speech, thus the patient was kept on 60 mg/kg for 2mo.

premature reduction of the prednisone dosage to <30 mg/day on

In one patient, prednisone was started with valproic acid, which was maintained after prednisone was tapered off.

three occasions during the treatment caused the patient to start to

Response

relapse; however, increasing the dosage again resulted in prompt

remission. These observations suggested that corticosteroid ther-
apy may be most effective when given early in the course of the
illness, in adequate dosages, and for a sufficient period of time.
No. of pts

Marescaux et al.[30] treated three patients receiving long-term

valproic acid or valproic acid plus ethosuximide therapy with
1/1
7/8

prednisone 2 mg/kg/day for 1 month followed by a dosage of

Paroxysmal activity disappeared 7d after discontinuation of corticotropin therapy.

1 mg/kg/day. After 3–6 months of treatment and when the EEG

was normalized and speech was improved in each patient, the
prednisone dosage was further reduced to 1mg every other day.
One course of 2 mg/kg/day for 2.5mo, and

The patients were followed for a period of 1–1.5 years’ treatment.

1 mg/kg/day for 6mo, 1y, then yearly

They were all seizure-free, and had completely normal awake and
asleep EEGs, and improved speech and comprehension. Two
Pts had different degrees of response in the same study.

patients did not develop any corticosteroid-associated adverse

effects but one patient developed Cushing-like syndrome and
another course after 2y

day) was administered after corticotropin therapy.

osteoporosis. In a study of seven patients by Rossi et al., [27]

Dosage and duration

corticotropin and hydrocortisone improved pre-existing bitempo-

Route of administration was not specified.

ral electrical status epilepticus during sleep dramatically.

Intravenous corticosteroids have recently been used in patients
with LKS. Aykut-Bingol et al.[44] reported an 8-year-old girl with
Children-Revised (WISC-R).

LKS who received intravenous high-dose methylprednisolone

(500mg) over 3 hours daily for 5 days. This regimen was followed
by a 250mg infusion given over 2 hours once a month. Language
Sinclair and Snyder[47]

improved 2 weeks after the initial therapy; the patient was able to
use two to five words. After 2 months, her language level in-
pts = patients.
Uldall et al.[48]

creased to the level of a 4-year 8-month-old child on the Peabody

Table II. Contd

Picture Vocabulary Test (after being at the 3-year 1-month level

Study

before treatment) and EEG abnormalities were suppressed. No

adverse effects were seen.
a
b

g
h
c

 2005 Adis Data Information BV. All rights reserved. Pediatr Drugs 2005; 7 (6)
Management of Landau-Kleffner Syndrome 385

Tsuru et al.[6] reported two children with LKS who responded to respond to simple commands by day 3 of the IVIG course (500
high doses of intravenous corticosteroids. In both patients, epilep- mg/kg/day for 4 consecutive days), and at the end of the 4 days the
tic seizures, and EEG spike and wave discharges had improved on EEG was within normal limits. Two weeks later the patient’s
a combination of valproic acid and a benzodiazepine but speech speech and behavior were back to normal. Two months later, he
disturbances persisted. Both patients received an intravenous infu- had a severe relapse, clinically and by EEG, that responded
sion of methylprednisolone sodium succinate (20 mg/kg/day) for 3 promptly (within days) to another course of IVIG; his speech and
consecutive days. This was repeated three times at 4-day intervals behavior were essentially normal at 3 months, and have remained
and resulted in a dramatic and rapid improvement in speech normal (5 years later). After the initial treatment, there was essen-
ability; improvement was observed after the first or the second tially a complete absence of the previously continuous temporal
injection series. spike discharges; however, at the time of the second course of
As mentioned above, patients with LKS may need to be treated IVIG, and despite a complete clinical response, there was only a
for several months or for >1 year. However, it is important to partial EEG response as seen in figure 1. The EEG remains
emphasize that the adverse effects of prolonged corticosteroid abnormal showing very frequent spikes after 5 years of follow-up.
therapy may require discontinuation of treatment in many patients.
Tutuncuoglu et al.[43] reported on a girl with LKS who was
Such adverse effects include avascular necrosis of the hip, hyper-
treated with valproic acid (25 mg/kg/day), IVIG (400 mg/kg/day
tension, gastric ulcers, behavioral abnormalities, hyperglycemia,
for 5 consecutive days), and corticotropin (50 U/day for 3 days/
and immunosuppression with serious infections. Alternate day or
weekend pulse administration has been used to maintain efficacy week for 4 weeks and 2 days/week for 4 weeks, then gradually
[28] reduced). Her speech started to recover after administration of
while minimizing adverse effects.
corticotropin and IVIG therapy. Clobazam (5 mg/day) was added
after corticotropin therapy. She achieved complete speech recov-
2.3 Intravenous Immunoglobulin
ery by the end of 3.5 months.
In 1997, our group reported the first case of LKS in which IVIG We reported on the short-term efficacy of IVIG 2 g/kg divided
was successful.[51] In this report, a child with LKS presented with a over 4–5 days, in five patients with LKS;[52] two of these patients
6-month history of loss of language at the age of 6 years; she could were included in two of the previously mentioned publica-
not speak and had moderate difficulty understanding spoken lan- tions.[24,51] A severity score for patients’ symptoms was calculated
guage. She was initially followed for almost 3 years and was not based on a deficit scale assessing a combination of aspects (i.e.
responsive to consecutive trials of valproic acid, clonazepam, behavior, verbal output, comprehension, seizure frequency, and
carbamazepine, and prednisone. She subsequently had a dramatic EEG findings) 1 month before IVIG administration and 1 month
and essentially complete clinical and EEG response after IVIG after IVIG. The severity score after IVIG was significantly lower
treatment; 400 mg/kg/day was administered for 5 days on three (p = 0.025) than the 1-month baseline score. However, only two of
occasions at 5- to 6-month intervals. The improvement occurred five patients had complete resolution of aphasia. The other three
within 4 days after the initiation of the first IVIG course and within patients had only minimal responses that were either clinically not
1 week after the second. She had a relapse 3–4 months after each significant or transient necessitating other modes of therapy.[52]
of these two initial courses. Her last remission after the third IVIG We subsequently treated six additional patients with LKS (total of
course has been continuous (for >6 years). 11 patients) [table III]. Of the 11 patients, only two (the same two
In 1998, Lagae et al.[7] reported a child with LKS who during a that were previously reported) had a sustained and meaningful
3-year 6-month follow-up period responded twice to corticosteroid response; all patients received the same dose of IVIG. Hence, it
therapy and then had a third relapse (sudden and major deteriora- appears that IVIG may be effective in only a fraction of patients
tion of all language functions). IVIG, administered at a dosage of with LKS. The fluctuating course of the disease could be used to
400 mg/kg/day for 5 consecutive days, resulted in a dramatic argue that the observed response to IVIG might have been coinci-
response in both language functions and clinical and EEG abnor- dental. However, the repeated close association between improve-
malities. The authors used WISC to assess neuropsychologic ment and IVIG therapy experienced by each of the two responding
development. patients (at the time of initial IVIG therapy and at the time of
Mikati and Saab[24] were the first to report initial monotherapy relapses) indicates that the remissions in those patients were
with IVIG to be effective in LKS. In their report, a 2.5-year-old secondary to IVIG therapy and not spontaneous. Thus, it is reason-
child had developed LKS, gradually becoming completely aphasic able to use IVIG therapy in selected patients that are refractory to
within a period of 3 months. He started to say a few words and to other therapies.

 2005 Adis Data Information BV. All rights reserved. Pediatr Drugs 2005; 7 (6)
386 Mikati & Shamseddine

a
20347 20341
FP1 F3
F3 C3
C3 P3
P3 O1
FP2 F4
F4 C4
C4 P4
P4 O2
FP1 F7
F7 T3
T3 T5
T5 O1
FP2 F8
F8 T4
T4 T6
T6 O2
FZ CZ
CZ PZ
EOG
EMG
EKG N.C .S

b
11295 11297
FP1 FP2
F7 F3
F3 Fz
Fz F4
F4 F8
A1 T3
T3 C3
C3 Cz
Cz C4
C4 T4
T4 A2
T5 P3
P3 Pz
Pz P4
P4 T6
O1 O2
EOG
EMG
EKG

Fig. 1. EEG findings in a child with Landau-Kleffner syndrome. (a) An EEG recorded during relapse showed essentially continuous right temporal focal
spike discharges. (b) An EEG recorded after intravenous immunoglobulin treatment showed marked reduction of the spike discharges.[24] N.C.S = no
clinical signs.

2.4 Surgery
MST for the surgical treatment of LKS was developed because
of the location of the epileptiform activity in the speech cortex.
The rationale is that sectioning the horizontal inter-neurons will
lead to attenuation of the epileptiform activity synchronized by
those inter-neurons, while at the same time preserving the physio-
logic functions of the area that are mostly dependent on the
vertical columnar organization of the cortex.
This surgical intervention was reported to result in the recovery
of age-appropriate speech in 50% of patients in a study by Morrell
et al.[21]; the patients (n = 14) had LKS and underwent this
procedure after not responding to other modes of therapy.
Sawhney et al.[53] operated on three patients with LKS and report-
ed a substantial recovery of language, and Rintahaka et al.[54]
reported on a patient with LKS who underwent MST after having
only transient responses following treatment with antiepileptic
drugs and corticotropin. MST resulted in the disappearance of
continuous spike waves during sleep and in the improvement of
language function. Grote et al.[55] reported that 11 of 14 children
with LKS who underwent MST demonstrated significant postop-
erative improvements when tests of receptive and expressive
vocabulary were conducted before and after surgery (they also
assessed postoperative language and cognitive function by tests
including WISC-III [3rd edition]). Their results indicated that
improvements in language function are most likely to be seen

 2005 Adis Data Information BV. All rights reserved. Pediatr Drugs 2005; 7 (6)
Management of Landau-Kleffner Syndrome 387

Table III. Updated long-term response data to intravenous immunoglobu- prior to the onset of language deterioration, normal non-verbal
lin in patients with Landau-Kleffner syndrome treated at the American cognitive functions, a unilateral intra and perisylvian epileptogen-
University of Beirut Medical Center, Beirut, Lebanona
ic zone, and a duration of CSWS of <3 years. Thus, only a limited
Patient Age at Sex Baseline CSF Duration of Long-term proportion of patients could be considered for this management
treatment (y) IgG indexb follow-up response
option.
1 6 F 18 6y +
Although LKS-associated psychiatric disturbances improve
2 4 M 4.8 3y –
significantly after surgery, behavioral problems may occasionally
3 4.5 M 4.28 3.5y –
persist. Continuation of previously used symptomatic therapy (i.e.
4 5.5 M NA 2y – psychostimulant or antidepressant drugs) is often required. [28]
5 2.5 M 18 3y + Vagal nerve stimulation has been used in the treatment of LKS.
6 2.5 M NA 18mo – Park[25] reported that of six patients with LKS who were treated
7 5.6 F <9 1y – with vagal nerve stimulation, three experienced at least a 50%
8 2.5 F 6 18mo – reduction in seizure frequency at 6 months of follow-up. Also,
9 4 M 5 1mo – quality-of-life improvements were reported in all areas assessed
10 5.8 M NA 19mo – for at least three of the children.
11 4.5 M 10 3mo –
a Data reported in part previously[52] in 2002. This is an update on the 2.5 Speech Therapy and Behavioral Intervention
cases (2005).
b Normal CSF-IgG index <13. Speech therapy is indicated in LKS. Fluctuation of language
CSF = cerebrospinal fluid; F = female; M = male; NA = not available; – abilities occurs throughout the course of the disorder, especially
indicates transient or no response; + indicates sustained remission when seizure activity is not well controlled. Even after treatment
(remission was considered to be present when the patient had normal or (pharmacologic and/or surgical), children with LKS continue to
near normal speech and behavior not affecting school performance, display deficits in processing oral language for some time. [55]
development, or socialization).
Thus, there is a need to use different input modalities that bypass
the auditory channel for processing.[58] A number of classroom
years instead of months after surgery, and that early diagnosis and interventions were described by Vance,[59] including sign lan-
treatment optimize outcome. A study by Irwin et al.[56] reported on guage, a daily diary of sequenced pictures of the daily classroom
the treatment of a series of five children with LKS using MST. routine, and auditory training beginning at the level of environ-
They analyzed detailed pre- and postoperative data concerning mental sounds. These interventions were helpful in a 5-year-old
behavior, seizure frequency, EEG findings, and language and child with LKS with severely impaired communication skills.
cognitive performance (using a battery of tests that included the Furthermore, Vance[59] described the use of the ‘graphic conversa-
Clinical Evaluation of Language Fundamentals, British Picture
Table IV. General guidelines that can be implemented by teachers or
Vocabulary Test, Test for Reception of Grammar, and WISC). It
clinicians to enhance the learning of children with Landau-Kleffner syn-
was shown that MST resulted in dramatic improvements in behav-
drome[53]
ior (attention span, hyperactivity, and defiant aggressiveness) and
A small ‘language-based’ classroom
seizure frequency in all patients. The effect on behavior was
Adequate teaching environment that might include a 1 : 1 aide
shown upon recovery from anesthesia, and all patients were
Intensive speech and language therapy focusing on the residual
seizure free within 3 months of surgery. There was also improve-
language skills and teaching language in a developmental pattern
ment of language and cognitive skills, but this was less dramatic,
Sign language as an alternative communication method if auditory verbal
and none of the five children achieved an age-appropriate lan- agnosia is present
guage level.
Use of visual input with pictures, color coding, and drawings on note
Thus, it appears that MST is effective in some patients with cards inside the classroom
LKS. However, experience to date needs to be confirmed in a Computer programs with colorful visuals and simple verbal information to
larger number of patients and in other centers. This procedure is help in learning decoding skills
still considered experimental by many experts.[57] Additionally, Functional approach to communication in the early stages of the disease
the inclusion criteria for surgery are quite restrictive. Smith and Exploration of reading and mathematics programs that best suit the
Spitz[28] reported that the ideal candidate for surgery is a child with functional level of the child and that bypass the difficulty of needing the
a normal developmental history of cognitive and language skills auditory channel for processing

 2005 Adis Data Information BV. All rights reserved. Pediatr Drugs 2005; 7 (6)
388
tion’ technique; words of literal conversation are placed on
‘speech balloons’ to enhance the child’s literacy development.
Van Slyke[58] presented some general guidelines that could be
implemented by a teacher or a clinician, based on the severity of
the language deficit and the auditory verbal agnosia, to further the
learning of children with LKS (table IV). The changes these
children experience during the course of the disease are rapid, thus
necessitating regular and close monitoring of the interventions
they are receiving and documentation of the individual’s progress.
Behavior modification techniques are needed to help manage
the patient’s behavioral problems. On rare occasions, medications
(psychostimulants and antidepressant drugs) to control hyperactiv-
ity or behavioral outbursts may be needed.
3. Conclusions and Recommendations
There is still no worldwide consensus on the treatment of LKS;
prospective, controlled, multicenter, therapeutic clinical trials are
required. Based on the available data, it is reasonable to start with
one of the antiepileptic drugs known to help in this syndrome
(e.g. valproic acid, ethosuximide, or a benzodiazepine). If there is
not a complete response to one or two of these medications within
1–2 months, then it is reasonable to use oral corticosteroids,
corticotropin, or a trial of IVIG. Patients refractory to oral or
intramuscular corticosteroids (which probably should not be
delayed for more than 1–2 months after the initial diagnosis is
made) should be considered for IVIG, high-dose intravenous
corticosteroids, a ketogenic diet, or further treatment with other
antiepileptic drugs. If these approaches fail, then MST or vagal
nerve stimulation may be considered. MST or focal resection may
be considered earlier if the patient has a focal epileptogenic lesion
on neuroimaging and/or has refractory and recurrent partial
seizures. Behavioral methods and speech therapy are helpful and
should be used in all patients with LKS.
Acknowledgments
Dr Mikati has received within the past 10 years research grant support and
honoraria from GlaxoSmithKline, Sanofi-Synthelabo, UCB, Janssen-Cilag,
Octapharma, and Pfizer. Mrs A. Shamseddine has received grant support from
GlaxoSmithKline. The authors have no conflicts of interest that are directly
relevant to the content of this review.
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Correspondence and offprints: Dr Mohamad A. Mikati, American University
of Beirut, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017–2303,
USA.
E-mail: mamikati@aub.edu.lb
Pediatr Drugs 2005; 7 (6)