Landau-Kleffner Syndrome: A Clinical and EEG Study of Five Cases

In five children with normal initial psychomotor development, a Landau-Kleffner syndrome appeared at age 3-7 years. No neuroanatomic lesions were noted. Aphasia and hyperkinesia were isolated in three patients and associated with global regression of higher cortical functions in one patient. Massive intellectual deterioration and psychotic behavior were associated with transient aphasia in one patient. The epilepsy (focal motor and generalized tonic-clonic seizures, subclinical EEG focal seizures during sleep, and atypical absences) always regressed spontaneously or with antiepileptic drug (AED) treatment. The EEG in waking patients showed focal and generalized spike-wave discharges on a normal background rhythm. Discharge topography and pattern changed frequently. During sleep, discharges always increased. At some time during syndrome development, all patients had bilateral spike-waves for greater than 85% of the sleep period, while at other times the discharges were discontinuous or continuous but focal or unilaterally hemispheric. Discharge topography and abundance changed from night to night. The abnormal EEG and the impaired higher functions developed and regressed together, but not with strict temporal correlation. Our own experience suggests that the Landau-Kleffner syndrome and epilepsy with continuous spike-wave activity in slow-wave sleep cannot be clearly differentiated. They may be different points on the spectrum of a single syndrome.     

Nocturnal epileptiform EEG discharges, nocturnal epileptic seizures, and language impairments in children: review of the literature

This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau-Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau-Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments.     

CSWS-related autistic regression versus autistic regression without CSWS

Continuous spike-waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) are two clinical epileptic syndromes that are associated with the electroencephalography (EEG) pattern of electrical status epilepticus during slow wave sleep (ESES). Autistic regression occurs in approximately 30% of children with autism and is associated with an epileptiform EEG in approximately 20%. The behavioral phenotypes of CSWS, LKS, and autistic regression overlap. However, the differences in age of regression, degree and type of regression, and frequency of epilepsy and EEG abnormalities suggest that these are distinct phenotypes. CSWS with autistic regression is rare, as is autistic regression associated with ESES. The pathophysiology and as such the treatment implications for children with CSWS and autistic regression are distinct from those with autistic regression without CSWS.     

Electrical status epilepticus in sleep

Electrical status epilepticus in sleep (ESES) describes an electroencephalographic pattern showing significant activation of epileptiform discharges in sleep. The terms continuous spike wave in slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS) describe the clinical epileptic syndromes seen with ESES. Although there is an overlap between these 2 syndromes, children with CSWS present with a more global regression have more problematic epilepsy and have EEG foci located predominantly in frontotemporal or frontocentral regions. In contrast, children with LKS present with an acquired auditory agnosia, fewer seizures, and EEG foci in the posterotemporal regions. ESES requires a high degree of clinical suspicion because slow-wave sleep must be recorded to confirm this diagnosis. Treatment of ESES extends beyond just control of the seizures; amelioration of the continuous epileptiform discharge must occur to improve neuropsychological outcome. Although there is little evidence to guide treatment, conventional antiepileptic drugs play only a minimal role. Steroid therapy and high-dose benzodiazepines are most commonly used, but other therapies including intravenous gamma-globulin, the ketogenic diet, and surgical therapy with multiple subpial transaction have shown efficacy in small case series. Although epilepsy resolves with time in most cases, many children are left with significant cognitive or language impairment. Longer duration of ESES appears to be the major predictor of poor outcome; markedly abnormal neuronal activity during a critical period for synaptogenesis may result in aberrant synapse formation, explaining the poorer neuropsychological outcome. Early recognition and effective therapy are necessary to improve long-term prognosis in this condition.     

Sleep electroencephalograms in young children with autism with and without regression

A link has been postulated between regressive autism and the spectrum of epileptic encephalopathic conditions including Landau-Kleffner syndrome with the suggestion that subclinical epilepsy may be causative of regression in autism. This is an audit of investigation using sleep electroencephalograms (EEG) in 64 children (56 males, 8 females; mean age 35.6mo [SD 8.2mo]; range 18-48mo) with autism. No child had a history suggestive of epilepsy. Thirty-nine of the children presented with regressive autism and 20 of the participants showed some epileptiform abnormality. There was no significant difference in epileptiform activities in those who showed regression compared with those who did not. No child showed electrical status epilepticus with continuous spike-wave discharges in slow sleep. There was no evidence that these cases of autism with and without regression were associated with epileptic encephalopathy. The significance of epileptiform discharges without epilepsy in the sleep EEG in autism remains unknown.     

Acquired epileptiform aphasia in children (Landau-Kleffner syndrome)

The association of a language disorder with epilepsy is frequent in children, but there is usually no causal relationship. In acquired epileptiform aphasia (AEA), the so-called Landau-Kleffner syndrome, there is increasing evidence that the language disorder is directly caused by epileptic discharges in critical language areas and must be viewed as a special kind of epileptic aphasia. This is based on a review of the published cases of AEA over the last 30 years and on the analogies that can be made between AEA and other epileptic syndromes, mainly benign partial epilepsy with centrotemporal spikes. AEA can start early in development and present as developmental dysphasia. It is only one among other cognitive or behavioral disturbances that can be epileptic manifestations of some particular epileptic syndromes, for example, epilepsy with continuous spike waves during slow sleep, which probably has the same pathophysiology as AEA. AEA must be seen, at least in some cases, as a particular form of resistant epilepsy. AEA is an important model because it suggests that isolated cognitive and behavioral disturbances can be epileptic manifestations in children.     

Early-onset acquired epileptic aphasia (Landau–Kleffner syndrome,LKS) and regressive autistic disorders with epileptic EEG abnormalities: The continuing debate

Early-onset acquired epileptic aphasia (Landau–Kleffner syndrome) may present as a developmental language disturbance and the affected child may also exhibit autistic features. Landau–Kleffner is now seen as the rare and severe end of a spectrum of cognitive-behavioural symptoms that can be seen in idiopathic (genetic) focal epilepsies of childhood, the benign end being the more frequent typical rolandic epilepsy. Several recent studies show that many children with rolandic epilepsy have minor developmental cognitive and behavioural problems and that some undergo a deterioration (usually temporary) in these domains, the so-called “atypical” forms of the syndrome. The severity and type of deterioration correlate with the site and spread of the epileptic spikes recorded on the electroencephalogram within the perisylvian region, and continuous spike-waves during sleep (CSWS) frequently occur during this period of the epileptic disorder. Some of these children have more severe preexisting communicative and language developmental disorders. If early stagnation or regression occurs in these domains, it presumably reflects epileptic activity in networks outside the perisylvian area, i.e. those involved in social cognition and emotions. Longitudinal studies will be necessary to find out if and how much the bioelectrical abnormalities play a causal role in these subgroup of children with both various degrees of language and autistic regression and features of idiopathic focal epilepsy. One has to remember that it took nearly 40 years to fully acknowledge the epileptic origin of aphasia in Landau–Kleffner syndrome and the milder acquired cognitive problems in rolandic epilepsies.     

Autism and autistic epileptiform regression with occipital spikes

The electroencephalographs abnormalities seen in Landau-Kleffner syndrome (LKS) (language deterioration) are non-specific, and consist of a variety of epileptiform discharge patterns including continuous slow spike-wave discharges during sleep, focal sharp waves with spikes, and centrotemporal (rolandic) spikes. Similarly, the EEG abnormalities seen in autistic epileptiform regression (language and social/behavioral deterioration) are nonspecific and overlap with those seen in LKS. By contrast, distinct epilepsy syndromes in otherwise normal children occur in the EEG-deflned benign focal epilepsies of childhood. Occipital spikes or spike-wave present either in the older child with visual symptoms and headache or in the younger child with autonomic symptoms followed by brief or prolonged partial motor seizures. Seven young children (five from a consecutive series of 42) presenting clinically with autism or autistic regression and possible or definite seizures, whose EEGs revealed occipital spikes or spike-wave characteristic of the benign epilepsies, are reported. Although occipital spikes are commonly seen in young children as an age-dependent EEG-defined benign focal epilepsy, their high frequency in this population with cognitive difficulties suggests a possible causal relation. The effects of the epileptiform discharge on cognitive functioning presumably reflect extension into temporal and parietal lobes, rather than occipital disturbances per se.     

The Landau-Kleffner syndrome or 'acquired aphasia with convulsive disorder'. Long-term follow-up of six children and a review of the recent literature.

We present six patients with acquired aphasia with convulsive disorder (Landau-Kleffner syndrome) and distill the main clinical features from a review of the recent literature. Our series showed that the clinical picture can vary at onset, as well as during the course of the illness, and that the long-term outcome of the aphasia is quite unpredictable, despite the fact that epilepsy and electroencephalographic abnormalities usually regress or disappear with the years. We also call attention to the electroencephalographic phenomenon of electrical status epilepticus during slow sleep, and we suggest that the course of the aphasia may well be linked to the appearance and disappearance of electrical status epilepticus during slow sleep. Therefore, we recommend a sleep electroencephalogram in all children with Landau-Kleffner syndrome. Finally, our findings did not demonstrate the beneficial effect of treatment with anticonvulsants on the aphasia, but recent studies have shown that treatment with corticosteroids, whether combined with anticonvulsants, is effective.     

The Electroencephalogram in Children with Developmental Dysphasia

Speech and language delay is a common developmental or acquired disorder. It can be a feature of the autistic spectrum, and if regression of language coincides with epilepsy, the diagnosis of Landau-Kleffner syndrome is considered. Slow acquisition of language without regression is called developmental dysphasia. A retrospective review of clinical and electroencephalographic (including video electroencephalographic) data on 138 children with speech/language delay, seen in a year's time, is presented. The electroencephalogram (EEG) was abnormal in 61% of children with a history of language regression. The EEG was abnormal in only 15% of children with developmental language disorder, most of whom also had clinical seizures. The difference between the two groups was highly significant (P = 0.004). Therefore obtaining an EEG in children with regression of language, especially if a history of clinical seizures is elicited, is indicated.     

Landau-Kleffner and autistic regression: the importance of differential diagnosis

Some neurological disorders may present psychiatric signs and symptoms, therefore the search for an etiological diagnosis is crucial. The aim of this study is to report the case of a patient with a neurological disorder, diagnosed during a psychiatric admission. A boy with normal neuropsychomotor development until the age of 3 years, started presenting epileptic seizures, followed by behavioral disorder and language deterioration. During neurologic follow-up, the patient was referred to the Psychiatry Department with a diagnosis of autism, in this case an autistic regression (AR). During his admission, diagnosis of Landau-Kleffner syndrome (LKS) was established on clinical and EEG grounds. LKS is characterized by acquired aphasia, epilepsy, EEG abnormalities and behavioral changes, including autistic traits. Language regression is observed LKS and AR. We stress the main differences between these two entities because misdiagnosis may postpone early intervention and consequent benefits, as observed in our case.     

Acquired Aphasia, Dementia, and Behavior Disorder with Epilepsy and Continuous Spike and Waves During Sleep in a Child

Severe persistent neuropsychological disorders sometimes develop in the course of a focal epilepsy of unknown origin in previously normal children. Very frequent bilateral focal or generalized discharges are often noted on the sleep EEG records of these patients with no evidence of clinical seizures. The relation between these paroxysms and the observed deterioration remains unclear. We report a child with a partial complex epilepsy and severe disturbances of language, cognition, and behavior acquired in the early years of development who was followed for 15 years. A correlation between the evolution of the striking EEG abnormalities during sleep and the neuropsychological disorders could be established retrospectively. The observed sequence of onset and recovery of the aphasia, the dementia, and the "psychotic" behavior makes a direct causal relation between the deficits quite unlikely. Rather it suggests an association of independent symptoms with a specific language disorder becoming manifest in the course of the evolution. This child shows many of the main characteristics of the syndromes of "acquired aphasia with convulsive disorder" (Landau-Kleffner syndrome) and "epilepsy with continuous spike waves during sleep." Both syndromes describe probably different facets of a similar underlying, still unexplained cerebral dysfunction.     

Correlation between CSWS and aphasia in Landau-Kleffner syndrome: A study of three cases

We report three typical cases of Landau-Kleffner syndrome with varied courses. The very frequent discharges in sleep EEGs, often showing the patterns of CSWS (continuous spike-waves during slow-wave sleep), either typical (spike-wave complex occupying over 85% of slow-wave sleep duration) or atypical (spike-waves occupying less than 85% of slow-wave sleep), were presented in all our cases. The CSWS seems correlated with aphasia in our cases. Since the disappearance of CSWS might be indicative of a lagged improvement in aphasia, we suggest that sufficiently long-term treatment with anticonvulsants and/or corticosteroids is worthwhile, if the EEG is improved significantly by this treatment.     

Congenital hydrocephalus and continuous spike wave in slow-wave sleep--a common association?

Early-onset hydrocephalus was identified as the common denominator in 5 of 12 consecutive patients with Landau-Kleffner syndrome or continuous spike wave in slow-wave sleep who presented during the last 6 years. This association seems to be more common than expected, and the course of epileptic disease and outcome differs from that of previous reports. We present the clinical cases and discuss the possible connection between early hydrocephalus and epilepsy, especially continuous spike wave in slow-wave sleep. A retrospective analysis was undertaken of the clinical course and electroencephalographic (EEG) data before and after the development of continuous spike wave in slow-wave sleep in a group of five children with early-onset hydrocephalus identified in three epilepsy clinics in Israel. Landau-Kleffner syndrome or continuous spike wave in slow-wave sleep was identified in 12 patients during 6 years (1995-2000). Five patients had a history of early-onset hydrocephalus. Three patients had ventriculoperitoneal shunts; two of them were never shunted. Patients' seizures and continuous spike wave in slow-wave sleep epileptiform activity was resistant to appropriate anticonvulsant treatment. Pediatric neurologists and neurosurgeons should be aware of the association between continuous spike wave in slow-wave sleep and early-onset hydrocephalus. When a child with hydrocephalus presents with behavioral, cognitive, or motor deterioration, he or she should undergo sleep EEG in addition to investigation of shunt function. Our series demonstrated the presence of continuous spike wave in slow-wave sleep and localization-related epilepsy that did not originate from the shunt site. This group of patients is heterogeneous, and the exact trigger for continuous spike wave in slow-wave sleep development is still unclear.     

Landau-Kleffner Syndrome: A Pharmacologic Study of Five Cases

Five children with Landau-Kleffner syndrome (epilepsy, acquired aphasia, and continuous spike-wave discharges during sleep), were treated with antiepileptic drugs (AEDs), sleep-modifying drugs, and corticosteroids. The pharmacologic profiles differed from those observed in focal epilepsies, resembling instead those of certain generalized epilepsies, such as West or Lennox-Gastaut syndromes. Phenobarbital (PB), carbamazepine (CBZ), and phenytoin (PHT) were ineffective or worsened the EEG and neuropsychological symptoms, whereas valproate (VPA), ethosuximide (ESM), and benzodiazepines were partially or transiently efficacious. Dextroamphetamine produced a dramatic but transient improvement in waking and sleep EEG in one of two children; aphasia did not change. Corticosteroid treatment resulted in improved speech, suppression of seizures, and normalization of the EEG in three of three children. Our own experience and data from the literature suggest that corticosteroids should be given in high doses as soon as the diagnosis is firmly established and should be continued in maintenance dose for several months or years to avoid escape. Early diagnosis, before mutism or global deterioration develops, appears to be essential for effective therapy with minimal neuropsychological sequelae.     

Long-term outcome of developmental and epileptic encephalopathies

Developmental and epileptic encephalopathies are conditions where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. Usually they have multiple etiologies. Therefore, long-term outcome is related to both etiology-related factors and epilepsy-related factors–age at onset of epilepsy, type(s) of seizure(s), type of electroencephalographic abnormalities, duration of the epileptic disorder. This paper focuses on long-term outcome of six developmental and epileptic encephalopathies with onset from the neonatal period to childhood: early epileptic encephalopathy with suppression bursts, West syndrome, Dravet syndrome, Lennox-Gastaut syndrome, epilepsy with myoclonic atonic seizures and epileptic encephalopathy with continuous spike and waves during slow-wave sleep including Landau-Kleffner syndrome. For each syndrome, definition, main etiologies if multiple, and long-term outcome are discussed.     

Epileptic aphasia: a consequence of regional hypometabolic encephalopathy?

A series of 25 children, 13 females and 12 males, who had an acquired communication disorder together with epilepsy, but did not fulfil the strict criteria of the Landau-Kleffner syndrome, was studied. All children had a clinical neurological evaluation, speech and language assessment, an awake and sleep EEG, cranial MRI, SPET scan, and audiometry. Clinical seizures were most often polymorphic in type (17 of 25). Atypical absences were the commonest individual seizure type occurring in 15 cases. All patients had an unequivocal epileptiform EEG. Normal sleep phenomena were only observed in 10 cases, enhancement of epileptiform activity in sleep was seen in 16. Cranial MRI was abnormal in six and normal in 19 cases. The SPET scans were abnormal in 22 of 25 children. The language deficits were classified neurologically as receptive aphasia, 24 of 25; expressive aphasia, 20 of 25; nominal aphasia, eight of 25; articulator dyspraxia, 10 of 25; and auditory agnosia, nine of 25. It is hypothesized that the loss of communication skills is due to an encephalopathy secondary to the persistent epileptic discharge and manifests as a hypometabolic area on the SPET scan.     

Nocturnal epileptiform EEG discharges,nocturnal epileptic seizures,and language impairments in children: Review of the literature

This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau–Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau–Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments.     

Changing perspectives on Landau-Kleffner syndrome

Landau-Kleffner syndrome (LKS) is a childhood disorder characterized by an acquired aphasia that emerges in association with epileptiform electroencephalographic abnormalities. The language loss is often characterized by a severe disturbance of auditory language comprehension (verbal auditory agnosia) combined with a substantial disruption of expressive language. Comorbid behavioral disturbances commonly involve hyperactivity and attentional problems but sometimes encompass a more pervasive pattern of difficulties resembling an autism spectrum disorder. Now one the most frequently described forms of acquired aphasia in children, LKS has had a profound influence on both neurological practice and cognitive neuroscience. Here, we review current conceptualizations of LKS, consider its pleomorphic manifestations and discuss existing and future diagnostic issues and dilemmas. The potential relevance of LKS to understanding other disorders, including autistic regression, is considered.     

Landau-Kleffner syndrome with mitochondrial respiratory chain-complex I deficiency

Landau-Kleffner syndrome is characterized by epileptic aphasia associated with electrical status epilepticus of slow wave sleep. A 5-year-old female, who had manifested normal developmental progress, was referred with principal complaints of fluctuating sensory aphasia and bizarre behavior during the preceding 4 months. Landau-Kleffner syndrome was confirmed by clinical and electroencephalographic features; in addition, the patient's mitochondrial respiratory chain-complex I deficiency was confirmed by fibroblast culture with the evidence of energy metabolism disorder. This patient's seizures were intractable to many antiepileptic drugs, adrenocorticotrophic hormone, and intravenous immunoglobulin, with catastrophic cognitive and behavioral decline, but the seizures were successfully controlled by ketogenic diet with supplementary mitochondrial cocktail including coenzyme Q10, riboflavin, L-carnitine, and high-dose multivitamins. The patient finally regained fully normal cognitive functioning. Landau-Kleffner syndrome with mitochondrial respiratory chain-complex I deficiency was controlled in this case by ketogenic diet and supplementary mitochondrial cocktail therapy.