Landau-Kleffner Syndrome

Etiology

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.[2][3] 

There were suggestions regarding possible implications of autoimmune factors in the genesis of some forms of epilepsy.[4] Other studies have shown that in children with LKS, an increased rate of autoantibodies directed against brain-derived neurotrophic factor (BDNF) is present.[5] Potential involvement of the immune system and/or an inflammatory dysregulation could justify the response to corticosteroids in most cases of LKS.[6]

Epidemiology

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.[7] 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.[8] 

Pathophysiology

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.[9] 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.[10] 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.

History and Physical

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. 

Aphasia

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 

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). 

Behavioral Disorders

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.[11][12]

Evaluation

The diagnosis of Landau-Kleffner syndrome has its basis on the anamnesis, evaluation of clinical signs, and EEG findings.

Clinical Evaluation

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.

Other Evaluations

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.

Treatment / Management

While no international consensus exists on the most appropriate type of therapy, it is commonly accepted that therapy should commence as soon as possible.[10]

Epileptic Manifestations

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.

Other Treatments

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.[13] Their use, also in combination with benzodiazepines (BDZs), is recommended when the epileptic activity and language impairments persist despite therapy.[14] 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.[15] A ketogenic diet, calcium-channel blocking drugs, and amantadine are options that researchers also have examined.[16]

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.[17] More recently, Downes et al. have not found significant advantages with MST compared to medical therapy.[18] However, this latter study focused on a wider group of patients, including those with ESES.[19] The use of this invasive technique should be limited to severe and pharmaco-resistant cases and in the case of steroid dependency or toxicity.(B3)

Differential Diagnosis

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:

• Continuous spike-waves during slow sleep syndrome (CSWS)
• Atypical benign partial epilepsy (ABPE)
• Early-onset benign partial epilepsy with occipital paroxysm (or Panayiotopoulos syndrome)
• Lennox-Gastaut syndrome
• Pseudo-Lennox syndrome
• Benign childhood epilepsy with centrotemporal spikes (BECTS) or rolandic epilepsy (RE)

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.[2] 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.[20] 

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.

Prognosis

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.[12] 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.