Landau-Kleffner syndrome (LKS) is a rare age-related epileptic encephalopathy, characterized by a developmental regression in the area of language, and electroencephalogram (EEG) anomalies located mainly around the temporoparietal areas. When present, the seizures consist of absence seizures or tonic-clonic episodes and occur more frequently during sleep. Behavioral disorders may form part of the clinical picture. The syndrome, described in 1957, is also indicated as acquired aphasia with epilepsy (ICD-10, F80.3) for outlining the main signs of this disease. It is considered a form of continuous spike-waves during slow sleep syndrome (CSWS), although the two syndromes have a different clinical presentation and diagnostic significance.
The exact etiology of Landau-Kleffner syndrome is not known. Structural brain injuries are very rare in patients with LKS are not related to pathophysiology. Moreover, genetic factors may be involved. For instance, the disease can correlate with GRIN2A mutations (16p13.2). This gene encodes for a protein called GluN2A (also known as NR2A), which is a subunit of the N-methyl-D-aspartate (NMDA) glutamate-gated ion channel receptor. Of note, NR2A can be identified in high concentrations in brain areas crucial for speech and language, whereas NMDA receptors are involved in a wide range of functions related to memory and learning. Again, GRIN2A alterations have correlations with a considerable number of neurodevelopmental disorders that can include epilepsy among the clinical manifestations.
There were suggestions regarding possible implications of autoimmune factors in the genesis of some forms of epilepsy. Other studies have shown that in children with LKS, an increased rate of autoantibodies directed against brain-derived neurotrophic factor (BDNF) is present. Potential involvement of the immune system and/or an inflammatory dysregulation could justify the response to corticosteroids in most cases of LKS.
It is difficult to express an estimate of the prevalence and incidence of the syndrome. Landau-Kleffner syndrome, indeed, is described as sporadic or limited case series. From the description of the syndrome, in 1957, no more than a few hundred cases have been reported in the literature. An epidemiologic study demonstrated that the incidence of children with LKS in Japan was about 1 in a million. Furthermore, it emerges that males are more affected than females and that the reference age is between 3 and 8 years. However, documented cases also exist of younger children or adolescents with the syndrome.
The pathophysiology of the syndrome presents multiple dark sides, as well as its etiology. Probably, the pathophysiology is the result of alterations of specific processes related to neurodevelopment and genetic factors involving mutations in the GRIN2A gene. There have been suggestions that language impairment results from epileptiform anomalies located in areas involved in language processing. According to this hypothesis, when these aberrations develop during a phase of neural development associated with effective cortical synaptogenesis and functional networks, the effect of these alterations may be expressed as language difficulties. It is important to note that clinical manifestations (aphasia) are not strictly related, in terms of severity, to seizures. Some children have severe aphasia despite not having seizures. Thus, epileptic activity and not seizures probably correlate with language impairment and its degree.
Although Landau-Kleffner syndrome may affect children and adolescents, the syndrome usually manifests itself in children aged 3 to 8 years with previously normal development. Aphasia, EEG alterations, seizures, and behavioral disorders are the main features of the syndrome.
In children with previously normal development, the new onset of aphasia is the hallmark of the disease. In particular, aphasia initially manifests as auditory verbal aphasia (receptive aphasia) that precedes the expressive aphasia featuring difficulties in the processing or interpreting verbal and/or non-verbal sounds. Children may also express babbling, neologisms, verbal perseveration, or mutism. Concerning aphasia, the typical presentation of the syndrome is characterized by a child who, despite apparently normal neurodevelopment, begins to have difficulty understanding written and spoken the language. Subsequently, over days, weeks, or months, the young patient manifests expressive difficulties along with impairment of spontaneous language that, in turn, becomes limited and altered.
Seizures occur in approximately two-thirds of individuals patients. The crises described characteristically demonstrate partial motor crises (more common), generalized clonic crises, and atypical absence seizures (e.g., eye blinking, chewing gestures, as well as lip-smacking, or slight jerking movements of the lips).
Language regression is often associated with social cognitive deficits and behavioral disorders, such as attention deficit, hyperactivity, impulsiveness, and the tendency to get distracted. Emotional lability, anxiety, and depression, sleep disorders, working memory impairment (but not long-term memory), and hypersensitive to sound may complete this clinical picture, which can sometimes be particularly complex.
The diagnosis of Landau-Kleffner syndrome has its basis on the anamnesis, evaluation of clinical signs, and EEG findings.
The acquired aphasia in a child who previously had no problem is initially receptive and then involves expressive difficulties. Behavioral disorders such as hyperexcitability and hyperactivity surround the aphasia but are sometimes very marked. At this stage, the role of the pediatrician who performs the anamnesis and coordinates several specialists is very important. An audiometric examination is a requirement to rule out hearing impairment. A thorough evaluation must be carried out by the child neuropsychiatrist and by speech therapists and psychomotor experts. Moreover, the pediatrician is the figure of connection with the neurophysiologist.
Sleep EEG Findings and Clinical Correlates
EEG examination during wakefulness and sleep is fundamental for diagnosis. The EEG shows unilateral or bilateral activity most pronounced over posterior temporal regions around the Sylvian fissure. This EEG activity becomes much more widespread and intense during sleep (non-REM sleep) when it becomes characterized by an almost continuous spike-wave pattern with a frequency of 1.5 to 2.5 spikes/sec. Background EEG activity and sleep macro architecture are normal. Yet, during REM sleep, epileptic activity may partially break off, diminish, or cease.
Clinically, these findings occasionally hesitate in an electrical status epilepticus during sleep (ESES). ESES is characterized by marked enhancement of epileptiform discharges during the transition from wake to sleep, resulting in spikes and slow (almost) continuous, bilateral, or sometimes lateralized waves. These findings are observable for a significant part of non-REM sleep. Furthermore, the ESES in Landau-Kleffner syndrome can be unilateral or bilateral.
Through a volumetric analysis using magnetic resonance (MRI), it could be possible to observe a reduction in the volume of the brain areas responsible for language development. This data, however, has no diagnostic utility but is recommended to exclude structural lesions such as brain tumors. The analysis of the GRIN2A gene is not part of routine clinical procedures, although the test is available in some specialized centers. However, because in families with a GRIN2A mutation, an autosomal dominant transmission has been proposed, genetic counseling can be suggested. In some countries, such as Norway, the evaluation of serum neuronal antibodies is a recommendation before treatment.
While no international consensus exists on the most appropriate type of therapy, it is commonly accepted that therapy should commence as soon as possible.
In the presence of a crisis (usually mild and infrequent), several antiepileptic drugs are effective, and the control of convulsions is generally easy to do. Several “spike-suppressing” medications, including valproate, clobazam, levetiracetam, ethosuximide, are usually preferred. The use of carbamazepine, oxcarbazepine, phenytoin, and phenobarbital should be avoided as they can exacerbate epileptiform discharge from ESES.
Speech Therapy and Behavioral Programs
Speech therapy includes a series of patient-centered approaches aimed at the recovery of language skills. These therapies commonly use augmentative and alternative communication devices aimed at speech training. In younger children, however, this type of approach may not be effective due to poor compliance. In these cases, a therapeutic plan should provide, in its first step, the involvement of a psychomotor therapist, later supported by the speech therapist. Furthermore, psychomotricity has a fundamental value in dealing with behavioral and relational alterations.
Corticosteroids (e.g., prednisone orally 1 mg/kg/day for 6 months or prednisolone orally 2 mg/kg/day for at least three months before gradual tapering) could be helpful for improvement or at least stabilization in language, cognition, and behavior skills. Their use, also in combination with benzodiazepines (BDZs), is recommended when the epileptic activity and language impairments persist despite therapy. Other pharmacological attempts have been made with intravenous immunoglobulin, although the results have been unsuccessful, and the studies conducted on the topic had little power. A ketogenic diet, calcium-channel blocking drugs, and amantadine are options that researchers also have examined.
Multiple subpial transections (MST) in the posterior temporal lobe of the dominant hemisphere is a surgical approach that tries to interrupt epilepsy while preserving the eloquent cortex. It consists of the transection of the horizontal corticocortical fibers while sparing the vertical cortico-subcortical fibers. In 1999, Grote et al. showed that MST might induce the restoration of language abilities in children with Landau-Kleffner syndrome. More recently, Downes et al. have not found significant advantages with MST compared to medical therapy. However, this latter study focused on a wider group of patients, including those with ESES. The use of this invasive technique should be limited to severe and pharmaco-resistant cases and in the case of steroid dependency or toxicity.
Verbal agnosia is often confused by parents as hearing loss. Moreover, the behavioral disorders related to aphasia can lead to the suspicion of a form of autistic spectrum disorder (ASD), although regressive forms of ASD show cognitive impairments in multiple domains rather than just about language. Furthermore, there might be a suspected diagnosis of conditions characterized by persistent inattention, hyperactivity, and impulsivity, such as attention deficit hyperactivity disorder (ADHD). Thus, it is mandatory to rule out a hearing loss, autism, or ADHD.
On the other side, the epileptic manifestations, impose a differential diagnosis with epileptic syndromes associated with the enhancement of epileptiform activity during sleep, such as:
Of note, LKS, CSWS, and RE can be considered as a single and continuous spectrum of childhood epilepsies and epileptic encephalopathies (i.e., the epilepsy-aphasia spectrum) featuring acquired cognitive, behavioral and speech and/or language impairment. It is significant to note that apart from those affected by "epileptic encephalopathies" such as CSWS, LKS, RE (regression is mild and transient), and West syndrome (regression is profound and permanent), the majority of children with epilepsy do not have any regression.
Finally, clinicians must also consider that aphasia can be the effect of various organic causes such as space-occupying lesions, post-traumatic effects, and infections.
In light of the rarity of the syndrome, it is difficult to have a clear picture of its prognosis, although the pathology is considered a benign epileptic encephalopathy. The prognosis varies mainly about aphasia. For instance, in a retrospective analysis conducted on eleven children, only four showed no language impairment after adolescence, whereas four manifested moderate language problems, and three severe language damages after more than ten years from the diagnosis. Of note, late-onset of aphasia, short duration of the initial receptive manifestations, and marked fluctuations in speech performances have associations with a positive outcome. Despite the limitations of the studies conducted, it is possible to deduce that language improves with treatment and at puberty, although without returning to the condition before the disease in a significant percentage of subjects. On the other side, concerning seizures, the prognosis is good as epileptic manifestations of Landau-Kleffner syndrome are easily controlled and spontaneously regress before adolescence. Thus, the therapeutic aspect is of paramount importance, especially for addressing individuals with moderate long-term language difficulties, and especially for those who, after adolescence, have a severe alteration of language.
Children with a diagnosis of Landau-Kleffner syndrome require management with an interprofessional team. Therapeutic planning and interprofessional communication among the various professional figures play an essential role in improving outcomes. The professionals involved are multiple and include a pediatrician who has the task of care coordinator, a child neuropsychiatrist, and a neurophysiologist. Also, a speech therapist and a psychomotor therapist (in the case of younger children) will have to carry out specific habilitation and rehabilitation programs. The pharmacist should encourage medication compliance, check for drug interactions, and alert the prescriber to medications that may exacerbate the condition. Specialty-trained neuroscience nursing staff can assist in monitoring treatment, as well as counseling the patients and/or parents. Additionally, the social worker should ensure that the patient has adequate facilities in the home and access to support services. Strategies aimed at strengthening communication functions require continuous calibration according to the patient's needs; this requires dynamic coordination for enhancing team performance. These are but a few examples of how an interprofessional team can improve patient care in Landau-Kleffner syndrome. [Level 5]
In children with refractory epileptic encephalopathy, an investigation with cannabidiol (tetrahydrocannabinol provided as an oil-based suspension) is ongoing (Phase 1, open-label dose-escalation study). Another randomized trial is evaluating acetazolamide (orally 8-10 mg/kg for 4-8 weeks) versus diazepam (orally 0.5 mg/kg for four weeks) in patients with CSWS and LKS. An interesting pharmacological perspective is an association between corticosteroids and BDZs. In this direction, it would be appropriate to design ad hoc studies. Among non-pharmacological strategies, Pedro et al. published a case of a patient who, after 11 years of pharmacological and specialized education interventions had no significant improvement and was successfully treated through a multimodal approach focused on facilitating inter-hemispheric communication. The experimentation of new non-pharmacological multimodal approaches is certainly another option to be investigated.
|||Landau WM,Kleffner FR, Syndrome of acquired aphasia with convulsive disorder in children. 1957. Neurology. 1998 Nov; [PubMed PMID: 9867583]|
|||Lesca G,Møller RS,Rudolf G,Hirsch E,Hjalgrim H,Szepetowski P, Update on the genetics of the epilepsy-aphasia spectrum and role of GRIN2A mutations. Epileptic disorders : international epilepsy journal with videotape. 2019 Jun 1; [PubMed PMID: 31149903]|
|||Strehlow V,Heyne HO,Vlaskamp DRM,Marwick KFM,Rudolf G,de Bellescize J,Biskup S,Brilstra EH,Brouwer OF,Callenbach PMC,Hentschel J,Hirsch E,Kind PC,Mignot C,Platzer K,Rump P,Skehel PA,Wyllie DJA,Hardingham GE,van Ravenswaaij-Arts CMA,Lesca G,Lemke JR, GRIN2A-related disorders: genotype and functional consequence predict phenotype. Brain : a journal of neurology. 2019 Jan 1; [PubMed PMID: 30544257]|
|||Husari KS,Dubey D, Autoimmune Epilepsy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2019 Jul; [PubMed PMID: 31240596]|
|||Granata T,Cross H,Theodore W,Avanzini G, Immune-mediated epilepsies. Epilepsia. 2011 May; [PubMed PMID: 21542839]|
|||Bakker DP,Catsman-Berrevoets CE,Neuteboom RF, Effectiveness of a hybrid corticosteroid treatment regimen on refractory childhood seizures and a review of other corticosteroid treatments. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2015 Sep; [PubMed PMID: 25976064]|
|||Kaga M,Inagaki M,Ohta R, Epidemiological study of Landau-Kleffner syndrome (LKS) in Japan. Brain [PubMed PMID: 23706409]|
|||Caraballo RH,Cejas N,Chamorro N,Kaltenmeier MC,Fortini S,Soprano AM, Landau-Kleffner syndrome: a study of 29 patients. Seizure. 2014 Feb; [PubMed PMID: 24315829]|
|||Stefanatos G, Changing perspectives on Landau-Kleffner syndrome. The Clinical neuropsychologist. 2011 Aug; [PubMed PMID: 21955111]|
|||Hughes JR, A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep. Epilepsy [PubMed PMID: 21242107]|
|||Besag FMC,Vasey MJ, Social cognition and psychopathology in childhood and adolescence. Epilepsy & behavior : E&B. 2019 Jun 10 [PubMed PMID: 31196824]|
|||Cockerell I,Bølling G,Nakken KO, Landau-Kleffner syndrome in Norway: long-term prognosis and experiences with the health services and educational systems. Epilepsy [PubMed PMID: 21514895]|
|||Sinclair DB,Snyder TJ, Corticosteroids for the treatment of Landau-kleffner syndrome and continuous spike-wave discharge during sleep. Pediatric neurology. 2005 May; [PubMed PMID: 15866429]|
|||Escobar Fernández L,Coccolo Góngora A,Vázquez López M,Polo Arrondo AP,Miranda Herrero MC,Barredo Valderrama E,Castro de Castro P, [Continuous spike-waves during slow-wave sleep: Experience during 20 years]. Anales de pediatria (Barcelona, Spain : 2003). 2019 Feb 13; [PubMed PMID: 30772272]|
|||Arts WF,Aarsen FK,Scheltens-de Boer M,Catsman-Berrevoets CE, Landau-Kleffner syndrome and CSWS syndrome: treatment with intravenous immunoglobulins. Epilepsia. 2009 Aug; [PubMed PMID: 19682053]|
|||Wilson RB,Eliyan Y,Sankar R,Hussain SA, Amantadine: A new treatment for refractory electrical status epilepticus in sleep. Epilepsy [PubMed PMID: 29754107]|
|||Grote CL,Van Slyke P,Hoeppner JA, Language outcome following multiple subpial transection for Landau-Kleffner syndrome. Brain : a journal of neurology. 1999 Mar; [PubMed PMID: 10094262]|
|||Downes M,Greenaway R,Clark M,Helen Cross J,Jolleff N,Harkness W,Kaliakatsos M,Boyd S,White S,Neville BG, Outcome following multiple subpial transection in Landau-Kleffner syndrome and related regression. Epilepsia. 2015 Nov; [PubMed PMID: 26337264]|
|||Kheder A,Wongwiangjunt S,Kotagal P, Comment on outcome following multiple subpial transection in Landau-Kleffner syndrome and related regression. Epilepsia. 2016 Apr; [PubMed PMID: 27041135]|
|||Camfield P,Camfield C, Regression in children with epilepsy. Neuroscience and biobehavioral reviews. 2019 Jan; [PubMed PMID: 30537476]|
|||Pedro VM,Leisman G, Hemispheric integrative therapy in Landau-Kleffner syndrome: applications for rehabilitation sciences. The International journal of neuroscience. 2005 Aug; [PubMed PMID: 16040364]|