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

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

PRACTICE  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 Mikati & Shamseddine

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 There is probably a correlation between the intensity of the
American University of Beirut Medical Center, Beirut, Lebanon. EEG paroxysmal activity and language deterioration in LKS.
Some investigators have suggested a direct and consistent relation-
1. Definition and Clinical Spectrum ship between the course of the language disorder and the EEG
response; concurrent improvements in speech and EEG findings
LKS, first described in 1957,[1] was defined by the have been observed. However, others have not observed such a
International League Against Epilepsy (ILAE) as “a childhood relationship.[13] In patients in whom normalization of the EEG is
disorder in which an acquired aphasia, multifocal spike, and spike not accompanied by an improvement in aphasia, aphasia may, in
and wave discharges are associated”.[2] The presentation is some cases, become permanent.[14] Paquier et al.[15] indicated that
moderate-to- severe loss of speech and auditory verbal disappearance of CSWS may result in improvement of language
understanding. Behav- ioral and psychiatric disturbances are also functions; therefore, CSWS may be responsible for the functional
frequent and consist of motor hyperactivity, impulsivity, and disorganization of the cortical speech areas. Thus, in most
aggressive behavior. Some of these disturbances may be anxiety patients, improvement in EEG findings may be necessary to
reactions in a child suddenly deprived of the understanding of achieve im- provement in LKS-associated aphasia, but EEG
spoken language. The recovery of language skills is variable in improvement is not always sufficient to guarantee an optimal
children with LKS; some children may recover completely from outcome.
aphasia after months or years, whereas others (approximately Abnormal epileptiform activity often occurs without overt
half) may show partial improve- ment or have permanent seizures. Clinical seizures do not occur in all patients with LKS
aphasia.[3] In some patients, the fluctuat- ing course of LKS is although EEG abnormalities are always present: 20–30% of chil-
characterized by remissions and relapses. dren with LKS do not manifest any clear behavioral seizures. [16]
The onset of LKS occurs between 3 and 8 years of age after a The seizures in LKS vary considerably in type, but the most
normal cognitive and language developmental course. [4] There is common are complex partial, generalized tonic-clonic, and atonic
a relationship between age of onset of LKS and long-term seizures. Occasionally, the seizures are atypical absences. Tonic
outcome. Children who have a younger age of onset show a and myoclonic seizures are uncommon.[17] In most cases, the
worse prognosis for language recovery; this is especially the case epilepsy and the EEG abnormalities disappear before the age of
in children with LKS onset before the age of 5 years.[5] Males 15 years.[1,16]
are more often
affected than females in an approximate ratio of 2 : 1.[6] The clinical presentation of LKS may, in some children,
resem- The EEG findings in patients with LKS are characterized by ble that of autistic disorders.[18] Patients who fulfill the criteria
for focal or multifocal epileptic abnormalities observed most fre- LKS but who also have autistic behavioral problems have
been quently in the temporal regions. Paroxysmal activity increases labeled as having the Landau-Kleffner variant.[18] This
condition dramatically during sleep and is usually characterized by the has to be distinguished from autistic
disorder and autistic regres- presence of continuous spike waves during slow-wave sleep sion disorder. Autistic
disorder, as defined in the Diagnostic and (CSWS),[7] otherwise described as electrical status epilepticus Statistical
Manual of Mental Disorders (4th Edition) [DSM-IV], is during sleep.[8] Whether the presence of CSWS is required for the
characterized by the presence of markedly abnormal or impaired
diagnosis of LKS is still not clear. CSWS is considered to be development in social interaction and communication and a
mark- present when the spike-wave activity occupies >85% of slow- edly restricted repertoire of activity and interests.[19]
Autistic re- wave sleep duration.[9] Epilepsy with CSWS was defined by the gression disorder (Heller syndrome or
childhood disintegrative ILAE to be a condition that “results from the association of various disorder), as defined in the
DSM-IV, is a syndrome that has a seizure types, partial or generalized, occurring during sleep, and distinctive
pattern of developmental regression following at least 2 atypical absences when awake” and that “despite the usually
years of normal development.[19] Patients who have autistic regres-
benign evolutions of seizures, prognosis is guarded because of the sion disorder suffer from impairment in verbal and non-verbal
appearance of neuropsychologic disorders”.[2] The spike slow- communication as well as in socialization. Such patients usually

 2005 Adis Data Information BV. All rights reserved. Pediatr Drugs 2005; 7 (6)
 wave activity is bilateral and predominantly generalized. CSWS is have restricted and repetitive patterns of behavior and delayed
fine clinically similar to LKS but is differentiated by EEG findings,[10] and gross motor functions. The distinction between these
disorders by the global mental deficiency in patients with CSWS, by the has at times led to intensive and long-
[11]
term video-EEG studies in dramatic comprehension deficits seen in patients with LKS, and children with autism.
Some children with autism were shown to

 2005 Adis Data Information BV. All rights reserved. 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,
[21]
activity in children with LKS is the intra and perisylvian cortex, 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
[22] [21]
to 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
[23]
but not language dysfunction. 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
The optimal treatment of LKS is still controversial because spontaneous remissions that can occur, it is very difficult to
there are no controlled clinical trials investigating treatment op- evaluate the therapeutic efficacy of any intervention. There have
tions for this syndrome. Different therapeutic approaches have been no 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
[28]
by Smith and Spitz 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
 38
20 Table I. Medications reported to be effective in Landau-Kleffner syndrome (based on open-label experience; no controlled studies have been performed) a
05 0
Ad
is Study Medication Dosage (mg/kg/day) Age (y) No. of pts Type of response
Dat
a responding
Inf
or Marescaux et al.[30] Clobazam 1–1.6 5–9 2/3b Transient moderate-to-marked improvement of
ma
tio seizures and EEG, transient moderate
n
BV improvement of speech and behavior
.
All
rig 1/3b Transient marked improvement of EEG but not
hts
res of speech and behavior
erv
ed.
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
Pe Mi
then eventually monotherapy) improvement’ in measures of receptive and
dia kat
tr
Dr
expressive language abilities i
ug &
s
20
Sh
05; Continued next page am
7 se
(6)
dd
 Table I. Contd M
20
05 an
Ad Study Medication Dosage (mg/kg/day) Age (y) No. of pts Type of response ag
is responding
Dat
e
a
Pascual-Castroviejo[34] Nicardipine with conventional 0.5–2 NS 6/6f Effects were seen within days or weeks in m
Inf en
or antiepileptic drugse some pts and not for months or even years in
t
ma
tio other pts; however, they all had ‘large’ of
n
BV improvements in language and improved La
. nd
All seizure control and EEG (EEGs of three pts
au
rig
hts became normal) -
res Kl
erv
ed. Marescaux et al.[30] Valproic acid 30–50 5–9 1/5b Moderate improvement of seizures, moderate eff
but transient improvement of EEG, speech, and ne
r
behavior Sy

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,
[29] g
Riviello Jr polytherapy) 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.
Pe
dia
tr f Five of six pts received one or more conventional antiepileptic drugs (carbamazepine, valproic acid, a hydantoin, phenobarbital).
Dr
ug
s g Fifteen of 57 pts received one or more antiepileptic drugs (phenobarbital, ethosuximide, phenytoin, and topiramate) during the course of the valproic acid therapy.
20
05;
7 NS = not specified; pts = patients.
(6)
38
1
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
Ravnik[31] reported a dramatic and prompt, but transient, bene- intractable epilepsy. These patients were treated for 26, 24, and
ficial effect of intravenous diazepam (0.3 mg/kg) on both 12 months with no significant adverse effects, and they all
language and EEG findings in a 9-year-old child. De Negri et al. showed significant and lasting improvements of language
[32]
reported on the efficacy of short cycles (3–4 weeks each) of function, behav- ior, and seizures.
high-dose oral diazepam (0.5–0.75 mg/kg/day, maintaining blood Carbamazepine has been reported to worsen the condition of
concentrations of 100–400 ng/mL) in treating patients with some patients with LKS,[10,30,40] and is, thus, not recommended.
CSWS aged 3.5–12 years, only one of whom had LKS. They Marescaux et al.[30] reported that the administration of carba-
used the rectal diazepam test (1 mg/kg) to distinguish between mazepine to three patients with LKS (aged 5–9 years)[10]
patients with CSWS and those with hypsarrhythmia. Patients with increased the duration of sleep spike-wave activity, aggravated
CSWS showed 100% response (remission of the paroxysmal clinical seizures, and caused focal nocturnal and subclinical EEG
activity) whereas those with hypsarrhythmia showed no response. se- quences. This drug either did not improve or increased speech
Responders to the rectal test were then started on the oral or intellectual disturbances. The same authors have also indicated
treatment cycles. The authors performed neuropsychologic that phenobarbital and phenytoin are ineffective or even harm-
monitoring on all patients using the following tests: Brunet-Le ful.[10,30]
´zine, Stanford-Binet, WPPSI, WISC- 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, then tapered slowly over several months depending on the
was reported to have a ‘dramatic response’ in treating a 4.5- clinical response and resolution of EEG abnormalities.
year-old
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)

20 Table II. Corticosteroids and corticotropin (adrenocorticotropic hormone) reported to be effective in Landau-Kleffner syndrome (based on open-label experience; no controlled M
05
studies have been performed) an
Ad ag
is
Dat Study Dosage and duration No. of pts Response e
a
Corticotropin m
Inf
or en
Lerman et al.[14] 3mo course starting with 80 U/day then 1/1 Disappearance of epileptic activity 3 wks after starting treatment. Speech
ma t
tio gradually reduceda returned after 6mo with complete remission of aphasia within the following of
n
BV 3mob La
. nd
All Perniola et al.[41] 0.25 mg/day for 4d (retard preparation)a 1/1 Reduced paroxysmal activity after 4d.c Expressive language recovery
rig started after 20d and was further recovered during the following weeks au
hts -
res Raybarman[42] One course (injectable; dose not specified) to 1/1 ‘Significant’ improvement in verbal output, comprehension, attention span, Kl
erv
ed. supplement antiepileptic drug therapy and hyperkinesias in 10mo eff
Tutuncuoglu et al.[43] 50 U/day for 3 days/week for 4 wks then 1/1 Speech started to recover after corticotropin and intravenous ne
2 days/week for 4 wks, followed by gradual immunoglobulin therapy. Full EEG recovery at the end of the second r
dose reductiona,d month, completely normal speech at the end of 3.5mo Sy

Dexamethasone (oral)
Lerman et al.[14] 4 mg/day for 2 wks then tapered off over 3mo 1/1 ‘Full recovery’ of speech and completely normal EEG occurred within 2
wks of starting treatment

Methylprednisolone (intravenous)
Aykut-Bingol et al.[44] 500mg infusion over 3h daily for 5 days,
followed by 250mg over 2h once per month
Tsuru et al.[6] 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
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)

Prednisone (oral)
Coutinho dos Santos 2 mg/kg/day for 2 or 6mo then decreased or 3/3e Good control of seizures and EEG, less response for aphasia
et al.[45] tapered off
Guerreiro et al.[46] 40 mg/day for 2mo followed by 20 mg/day for 3/5 Improvement after 6mo of treatment; significantly improved behavior in two
4mo 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
Lerman et al.[14] 60 mg/day (duration not specified) tapered off 1/1 ‘Prompt’ recovery of normal speech and normal EEG
over 3mo
Lerman et al.[14] 60 mg/dayf for 2mo then very gradually 1/1 ‘Prompt’ improvement in EEG followed by normal speech for 11mo, then
tapered off over 3mo. 30 mg/day (duration not relapsed. EEG and speech promptly returned to normal after treatment for
specified) then slowly tapered off over 10mo relapse
for relapse
Marescaux et al.[30] 2 mg/kg/day for 1mo then progressively 2/2g ‘Progressive’ improvement in speech after 2–3mo of treatment (to almost
reduced (long-term treatment) normal in one patient)
Pe
dia 1/1g Language recovered slowly, and 1.5 years after the start of treatment EEG
tr was normal, oral comprehension was good but expression was still limited
Dr
ug
s
20
05; Continued next page
7
(6)
38
3
384 Mikati & Shamseddine

that the beneficial effects of corticosteroid therapy were coinci-

on post- treatment speech/language, and neuropsychologic evaluations. Response

a b c led to recovery of speech and normal EEG within a few weeks. Paroxysmal activity disappeared 7d after discontinuation of corticotropin Route of administration was not specified.
dental. However, each of these two reports was based on one
single case and neither reported the prednisone dose that was
given or the time period between the onset of aphasia and
prednisone 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- 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 speech recovery within a few weeks. In
one of these patients premature reduction of the prednisone
dosage to <30 mg/day on three occasions during the treatment
caused the patient to start to 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
andofbehavior

dosages, and for a sufficient period of time.

pts

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

valproic acid or valproic acid plus ethosuximide therapy with
in language cognitionNo.

1/1

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

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.
al.[48]course of 2 mg/kg/day for 2.5mo, and another course after 2y

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

and duration

They were all seizure-free, and had completely normal awake and
asleep EEGs, and improved speech and comprehension. Two
improvement

patients did not develop any corticosteroid-associated adverse

effects but one patient developed Cushing-like syndrome and
yearly Dosage

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

1 mg/kg/day for 6mo, 1y, thenSignificant

corticotropin and hydrocortisone improved pre-existing bitempo-

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
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.
air and Snyder[47] Study Table II. Contd

Language improved 2 weeks after the initial therapy; the patient

was able to use two to five words. After 2 months, her language
pts = patients.

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

Uldall et One

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

month level before treatment) and EEG abnormalities were
suppressed. No adverse effects were seen.
cotropin treatment

efg

 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,
and immunosuppression with serious infections. Alternate day or for 5 consecutive days), and corticotropin (50 U/day for 3 days/
weekend pulse administration has been used to maintain efficacy week for 4 weeks and 2 days/week for 4 weeks, then gradually
reduced). Her speech started to recover after administration of
while minimizing adverse effects.[28]
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.
aphasic within a period of 3 months. He started to say a few words and to
In 1997, our group reported the first case of LKS in which
IVIG was successful.[51] In this report, a child with LKS presented
with a 6-month history of loss of language at the age of 6 years;
she could not speak and had moderate difficulty understanding
spoken lan- guage. She was initially followed for almost 3 years
and was not responsive to consecutive trials of valproic acid,
clonazepam, carbamazepine, and prednisone. She subsequently
had a dramatic and essentially complete clinical and EEG
response after IVIG treatment; 400 mg/kg/day was administered
for 5 days on three occasions at 5- to 6-month intervals. The
improvement occurred within 4 days after the initiation of the
first IVIG course and within 1 week after the second. She had a
relapse 3–4 months after each of these two initial courses. Her
last remission after the third IVIG course has been continuous
(for >6 years).
In 1998, Lagae et al.[7] reported a child with LKS who during a
3-year 6-month follow-up period responded twice to
corticosteroid therapy and then had a third relapse (sudden and
major deteriora- tion of all language functions). IVIG,
administered at a dosage of 400 mg/kg/day for 5 consecutive
days, resulted in a dramatic response in both language functions
and clinical and EEG abnor- malities. The authors used WISC to
assess neuropsychologic development.
Mikati and Saab[24] were the first to report initial monotherapy
with IVIG to be effective in LKS. In their report, a 2.5-year-old
child had developed LKS, gradually becoming completely
 We reported on the short-term efficacy of IVIG 2
g/kg divided over 4–5 days, in five patients with LKS;
[52]
two of these patients were included in two of the
previously mentioned publica- tions.[24,51] A severity
score for patients’ symptoms was calculated based on a
deficit scale assessing a combination of aspects (i.e.
behavior, verbal output, comprehension, seizure
frequency, and EEG findings) 1 month before IVIG
administration and 1 month after IVIG. The severity
score after IVIG was significantly lower (p = 0.025)
than the 1-month baseline score. However, only two of
five patients had complete resolution of aphasia. The
other three patients had only minimal responses that
were either clinically not significant or transient
necessitating other modes of therapy.[52] We
subsequently treated six additional patients with LKS
(total of 11 patients) [table III]. Of the 11 patients, only
two (the same two that were previously reported) had a
sustained and meaningful response; all patients received
the same dose of IVIG. Hence, it appears that IVIG may
be effective in only a fraction of patients with LKS. The
fluctuating course of the disease could be used to argue
that the observed response to IVIG might have been
coinci- dental. However, the repeated close association
between improve- ment and IVIG therapy experienced
by each of the two responding patients (at the time of
initial IVIG therapy and at the time of relapses)
indicates that the remissions in those patients were
secondary to IVIG therapy and not spontaneous. Thus,
it is reason- able to use IVIG therapy in selected
patients that are refractory to other therapies.
386 Mikati & Shamseddine

a
FP1 F3 20347 20341
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 F7F3
F3Fz
FzF4 F4F8

A1T3
T3C3
C3Cz
CzC4
C4 T4 T4 A2 T5 P3
P3Pz
PzP4 P4T6 O1O2 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
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
6 2.5 M NA 18mo –
LKS. Park[25] reported that of six patients with LKS who were
7 5.6 F <9 1y –
treated with vagal nerve stimulation, three experienced at least a
8 2.5 F 6 18mo – 50% reduction in seizure frequency at 6 months of follow-up.
9 4 M 5 1mo – Also, quality-of-life improvements were reported in all areas
10 5.8 M NA 19mo – assessed 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
Clinical Evaluation of Language Fundamentals, British Picture conversa-
Vocabulary Test, Test for Reception of Grammar, and WISC). It
was shown that MST resulted in dramatic improvements in Table IV. General guidelines that can be implemented by teachers or
clinicians to enhance the learning of children with Landau-Kleffner syn-
behav- ior (attention span, hyperactivity, and defiant
drome[53]
aggressiveness) and seizure frequency in all patients. The effect
A small ‘language-based’ classroom
on behavior was shown upon recovery from anesthesia, and all
Adequate teaching environment that might include a 1 : 1 aide
patients were seizure free within 3 months of surgery. There was
Intensive speech and language therapy focusing on the residual
also improve- ment of language and cognitive skills, but this was
language skills and teaching language in a developmental pattern
less dramatic, and none of the five children achieved an age-
Sign language as an alternative communication method if auditory verbal
appropriate lan- guage level.
agnosia is present
Thus, it appears that MST is effective in some patients with Use of visual input with pictures, color coding, and drawings on note
LKS. However, experience to date needs to be confirmed in a cards inside the classroom
larger number of patients and in other centers. This procedure is Computer programs with colorful visuals and simple verbal information to
still considered experimental by many experts. [57] Additionally, help in learning decoding skills
the inclusion criteria for surgery are quite restrictive. Smith and Functional approach to communication in the early stages of the disease
Spitz[28] reported that the ideal candidate for surgery is a child Exploration of reading and mathematics programs that best suit the
with a normal developmental history of cognitive and language functional level of the child and that bypass the difficulty of needing the
skills auditory channel for processing
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
: 60-7
of Beirut, 3 Dag Hammarskjold Plaza, 8th Floor, New York, NY 10017–2303,
USA.
E-mail: mamikati@aub.edu.lb