Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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Landau-Kleffner syndrome, or acquired epileptic aphasia, was first reported in 1957 and is now recognized as an epileptic encephalopathy. Many authors state that there is a spectrum, including this syndrome and the syndrome of continuous spikes-and-waves during slow sleep, and data supporting this concept are presented. An interesting pathogenetic interpretation regarding seizures and language dysfunction in Landau-Kleffner syndrome is discussed in this update. Following this line, it was interpreted that activation of spike-wave discharges during NREM sleep might alter the blood-brain barrier and provoke an autoimmune reaction. Data for 39 children with benign focal epilepsies evolving into syndromes associated with continuous spikes-and-waves during slow sleep, 5 of them with typical features of Landau-Kleffner syndrome, are presented. A long-term follow-up of 29 patients with Landau-Kleffner syndrome showed that before the onset of aphasia, developmental language and behavioral disturbances were present in 19 and 14 patients, respectively.
• Verbal auditory agnosia is present in all patients with Landau-Kleffner syndrome.
• The spike-wave index in sleep EEG may be lower than 85%.
• The prevalence of Landau-Kleffner syndrome was estimated to range from 44.2 to 59.6 among a population of 18 million children (67).
In 1957 Landau and Kleffner described 6 children with a "syndrome of acquired aphasia with convulsive disorder” (72). The language disorder was later recognized as being different from typical childhood aphasia, which is usually expressive. Instead, the aphasia of the Landau-Kleffner syndrome is an auditory verbal agnosia (111). The language disorder was initially considered to be a seizure manifestation because epileptiform activity from 1 or both temporal lobes is generally present on EEG recordings. Seizures are not a constant feature, and when present, they may precede or follow the onset of the language disorder.
Mantovani and Landau followed the 6 original cases plus 4 others and found that the outcome was variable; 5 of the children had recovered good language function as adults (83). Their hypothesis that outcome correlated with seizure frequency was not substantiated by subsequent reports (25; 62).
The 1989 International League Against Epilepsy placed this syndrome under the classification of "epilepsies and syndromes undetermined as to whether they are focal or generalized" (01). In the same category, the syndrome of continuous spikes and waves during slow sleep was included as a definite entity. However, many common features between these 2 syndromes have been recognized, and there are questions as to whether they are 2 distinct entities or subclasses of a single syndrome (28; 59; 22; 126; 117; 134; 135; 127). Furthermore, the mechanism of bilateral secondary synchronies after an initial functional spike focus seems to be the basis of language impairment and represents both for Landau-Kleffner syndrome and continuous spikes and waves during slow sleep syndrome--an explanation for the inclusion of these syndromes among the epileptic encephalopathies as proposed by ILAE´s Task Force on Classification (47; 39). In a retrospective review of 102 patients with electrical status epilepticus during sleep (ESES), 18 of the patients could be diagnosed with Landau-Kleffner syndrome. The authors concluded that Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow sleep could be classified in a dichotomous manner rather than be seen as 2 points along a continuum (146). In a survey on concepts and terminology on electrical status epilepticus during sleep and continuous spikes and waves during slow sleep syndrome (CSWSS) among 137 members of the American Child Neurology Society and the American Epilepsy Society, it was concluded that the professionals use the terms, concepts, and defining features heterogeneously (Sánchez Fenández et al 2012). We know that this EEG pattern is frequent in children with Landau Kleffner syndrome.
In November 2007, an international symposium celebrating the 50th anniversary of the seminal study by Landau and Kleffner was held in Belgium. The symposium focused on the developments during the last 15 years in the fields of neurophysiology, neuropsychology, functional neuroimaging, pathophysiology, and treatment of Landau-Kleffner syndrome (144).
Existing and future diagnostic issues and dilemmas were discussed, emphasizing the potential relevance of Landau-Kleffner syndrome to understanding other disorders (131).
The term epilepsy-aphasia spectrum has been coined encompassing Landau-Kleffner syndrome, atypical benign partial epilepsy, and intermediate epilepsy-aphasia disorders (137).
In 2016, a thorough internationally based review on idiopathic focal epilepsies and their associations with Landau-Kleffner syndrome and continuous spike wave slow-wave sleep (CSWS) or electrical status epilepticus in sleep (ESES) syndromes was published (100).
Acquired aphasia is the more prominent feature because seizures are present in only 70% to 80% of patients (05; 06; 102). Age of onset ranges from 3 to 8 years, and boys are more frequently affected than girls (05; 101). The onset of aphasia is often insidious and progressive with spontaneous improvements and aggravations in its course. The most common feature is verbal auditory agnosia, which is the reason why in many cases the first diagnosis is hearing loss (111). Agnosia may extend to familiar noises. In some cases onset may be abrupt, and different types of aphasia may occur (130). Variable time may elapse between the loss of the ability to understand language and the expressive aphasia. A reported case that was thoroughly studied with EEGs and PET presented several episodes of receptive aphasia. The authors emphasized that short episodes of predominantly receptive aphasia with near-total recovery between episodes can be 1 of the clinical presentations of Landau-Kleffner syndrome (80). In general, it is stated that patients previously had been normal in both psychomotor and language development. However, detailed history of language characteristics shows that 9 of 12 patients had previous features of developmental dysphasia (130). Rarely, stuttering may be the presenting feature (142), although it is difficult to differentiate pure stuttering from the repetitive nature of the impaired speech in early stages of acquired aphasia.
Neuropsychological and behavioral disturbances have been reported, and there are cases in which the overlapping between Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow sleep is more prominent on clinical grounds. Alternating courses with behavioral disturbances and acquired aphasia has been described in children within the mentioned spectrum (47). A prospective study on neurocognitive and behavioral profiles in 14 children with Landau-Kleffner syndrome showed that besides the receptive and expressive problems, the majority of the patients had poor reading fluency and comprehension; 86% of the cases demonstrated continued expressive problems, 50% exhibited difficulty with mathematics, and 57% evidenced attentional or other behavioral problems (114). Nevertheless, the most frequent findings are hyperkinesia and excitability. In fact, it is striking that children with such a severe handicap in understanding language only present psychotic or autistic features when aphasia appears in early ages (26; 49; 23; 69). In the context of a more global autistic regression, some young children show language regression with epileptiform EEGs, but it is controversial to state that these children are part of an extended Landau-Kleffner spectrum (88). An investigation using sleep EEGs in 64 children with autism without history of epilepsy disclosed that there was no significant difference in epileptic discharges comparing those patients that showed regression with those who did not. No child presented electrical status epilepticus in slow sleep. These results are against the suggestion that subclinical epilepsy may be causative of regression in autism (03).
Seizures are present in 70% to 80% of patients and may appear before or after onset of aphasia (25). The most common types of seizures are: eyelid myoclonia, eye blinking, atypical absences, head drops and atonic fits in upper limbs, automatisms, and occasionally, partial motor seizures with secondary generalization.
The outcome of Landau-Kleffner syndrome varies. The seizures are usually controlled with antiepileptic drugs, and EEG abnormalities disappear after a few years.
The language disorder, however, may never resolve in almost half of the patients (83; 102). Both improvement and aggravation of aphasia have been reported (23). In many cases, correlation was found between increase in EEG discharges and aphasia or even between abnormalities in the P300 wave during evoked potential studies and aphasia (49). The presence or absence of seizures as well as their frequency has no correlation with the outcome of language deficiency (54). A residual impairment in verbal short-term memory is frequent. Brain activation during immediate serial recall of lists of 4 words compared to single-word repetition using positron emission tomography was measured in 3 Landau-Kleffner syndrome patients after recovery and in 14 healthy controls. The patients had shown abnormally increased or decreased glucose metabolism in left or right superior temporal gyrus at different stages during the active phase of the disease. At the time of the study, the patients were 6 years to 10 years from the active phase of the disease. Results showed that 2 patients had impaired performance in verbal short-term memory. The data suggest that impaired verbal short-term memory at late outcome of Landau-Kleffner syndrome might be related to a persistent decrease of activity in the areas involved in the epileptic focus during the active phase (82).
Out of 10 children with electrical status epilepticus during sleep and global or specific deterioration with long-term follow-up, 3 had Landau-Kleffner syndrome and showed that electrical status epilepticus during sleep persisted for 1 to 5 years and language impairment was not modified by treatment with valproic acid or benzodiazepines (122).
Outcome at adulthood has been reported in 7 young adults, 5 who had continuous spike and wave during slow sleep syndrome and 2 with Landau-Kleffner syndrome in childhood. The intellectual functions of the 2 patients with Landau-Kleffner syndrome were normal, but their everyday lives were disrupted by severe, disabling, language disturbances. The authors emphasized the role of location of interictal EEG focus and age of onset as prognostic factors (108). Another long-term follow-up was reported in 5 children with continuous spike and waves during slow sleep, of which 4 met criteria for diagnosis of Landau-Kleffner syndrome. Again, age of onset and location of interictal EEG focus were considered as the main prognostic factors (147). Long-term prognosis was evaluated in a retrospective medical records study of 19 patients with Landau-Kleffner syndrome, and evolution of language after more than 10 years of follow-up showed that one third of them had normal language, one third had moderate language problems, and one third remained with no functional verbal language. The main concern among the parents of these patients was the long time elapsed until correct diagnosis (14). A long-term follow-up of 29 patients showed that 8 out of 29 patients recovered language completely, but the remaining patients continued to have language deficits of different degrees (11). Dementia, or more precisely, long-term deterioration of intellectual functions, is uncommon in Landau-Kleffner syndrome (36). However, in early onset cases, neuropsychological impairment is more severe (26; 07). A 30-year follow-up of a patient with typical Landau-Kleffner syndrome whose seizures reemerged in adulthood as medication-refractory complex partial seizures showed an abnormal T2 signal hyperintensity in the left mesial temporal area on brain MRI. Temporal lobectomy revealed focal cortical dysplasia in the lateral temporal neocortex and gliosis + neuronal loss in the hippocampus. The authors suggested that focal cortical microdysgenesis may be a cause of Landau-Kleffner syndrome (08). A long-term follow-up of 6 children with Landau-Kleffner syndrome who previously had rolandic epilepsy has been published (45). Present ages of the 6 children range between 13 and 38 years, and all of them had normal EEGs before the age of 12 years.
Isolated cases of Landau-Kleffner syndrome were apparently associated with overt cerebral pathology (eg, acute inflammatory disease, arteritis, cysticercosis, tumors, and arachnoid cyst) (15; 96; 104; 95; 105; 33). Pathologic study in a surgical series of 14 patients with Landau-Kleffner syndrome yielded a variety of abnormalities (128). Perisylvian polymicrogyria has been reported in 1 case (63). Incidentally, perisylvian polymicrogyria was related to mutations in sushi-repeat protein SRPX2 (116). A new etiology has been reported in a 5-year-old girl with typical Landau-Kleffner syndrome associated with mitochondrial respiratory chain-complex I deficiency (68). Nevertheless, the language symptomatology is interpreted as a dysfunctional disorder associated with the bilateral EEG discharges and deafferentation of temporal cortex (72; 54; 55; 06). The reported cases of benign childhood epilepsy with centrotemporal spikes evolving into Landau-Kleffner syndrome and the prompt response to antiepileptic drugs in some of the patients also points to a secondary bilateral synchrony type of phenomenon (47; 18). In a prospective study of 16 children with idiopathic partial epilepsies with evolution into electrical status epilepticus during sleep spectrum disorders, 1 of the cases developed a typical Landau-Kleffner syndrome, and the symptomatology and electrical status epilepticus during sleep in the EEG persisted for several years (120). In a series of 196 patients with benign childhood epilepsy with centrotemporal spikes followed for several years, 4 of them developed Landau-Kleffner syndrome (136). An interesting case of Landau-Kleffner syndrome with a behavioral disorder fulfilling the diagnostic criteria of autism, associated with right temporal ganglioglioma, was reported. Interestingly, the electrical status epilepticus was contralateral to the side of the tumor (89).
Landau-Kleffner syndrome, continuous spikes-and-waves during slow sleep syndrome (CSWS), and benign childhood epilepsy with centrotemporal spikes (BCECTS) have been considered as part of a single continuous spectrum of disorders, and genetic predisposition with simple to complex modes of inheritance have long been suspected. Reports on the involvement of SRPX2 and ELP4 genes and of the molecular networks implicated in speech-related disorders as well as the studied role of neurodevelopmental disorders of language associated with epilepsy open promising fields of research (119; 116; 99). The participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. In a study of copy number variations in 61 CSWSS and Landau Kleffner syndrome patients, several potentially pathogenic alterations were detected. In this series, 12 patients showed autistic manifestations of variable degree (77). The first molecular links sustaining the close relationship and clinical overlaps existing between autistic spectrum disorders, CSWSS, and Landau Kleffner syndrome seem to be appearing.
In a clinical genetic study of the epilepsy-aphasia spectrum, 31 probands with epileptic encephalopathy with continuous spike-and-wave during sleep, Landau Kleffner syndrome, atypical benign partial epilepsy, and intermediate epilepsy-aphasia disorders were recruited. Pedigrees were constructed for all families and the proportion of affected relatives was analyzed. The data were compared with those of patients with benign rolandic epilepsy. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures, suggesting a shared genetic predisposition between epilepsy-aphasia spectrum and focal epilepsies (137). It was reported that about 20% cases of Landau-Kleffner syndrome, CSWSS, and electroclinically atypical rolandic epilepsy can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (76). Another group of investigators identified 4 probands with GRIN2A variants accounting for 9% of the epilepsy-aphasia cases, whereas they did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies. These authors stated that GRIN2A mutations are restricted to the mentioned group of patients (12). Interestingly, Lemke and colleagues showed that mutations in GRIN2A occurred significantly more frequently in the more severe phenotypes of idiopathic focal epilepsy with rolandic spikes (73). An intent to establish the genetic basis of Landau-Kleffner syndrome in a cohort of 2 discordant monozygotic twin pairs and 11 isolated cases was published. A new mutation was found in a single patient in the GRIN2A gene. No single candidate gene was identified to cause Landau-Kleffner syndrome in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in the RELN, BSN, EPHB2, and NID2 (16). Exciting advances regarding the genetics of Landau-Kleffner syndrome–related disorders encompassed within the epilepsy-aphasia spectrum have been reported in the last few years. A striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20% patients with epilepsy-aphasia spectrum suggests that excitatory glutamate receptors play a key role in these disorders (141).
GRIN2A-related speech disorders and epilepsy are characterized by speech disorders in all affected individuals, and a range of epilepsy syndromes present in about 90% of the cases. The diagnosis of GRIN2A-related speech disorders and epilepsy is established in a proband by the identification of a GRIN2A heterozygous pathogenic variant on molecular genetic testing. The authors state that evaluation of relatives at risk is appropriate to clarify the genetic status of apparently asymptomatic relatives (94).
A de novo missense mutation in the GRIN2A gene in a patient with childhood focal epilepsy and acquired epileptic aphasia was reported (52).
Considering that atypical evolutions of rolandic epilepsies may include Landau-Kleffner syndrome, mutations of the GABRG2 gene may increase the risk of rolandic epilepsy and its atypical variants (112).
Waking EEG usually shows brief bursts of temporal or temporo-occipital spike and wave discharges, either symmetrical or asymmetrical. In fact, the most typical EEG findings appear during slow sleep as continuous 1.5 to 5 Hz spike and wave discharges, which may be seen in approximately 85% of the record (06; 28; 22; 126). Three interesting cases of Landau Kleffner syndrome were presented (143): auditory agnosia occurred between the age of 2 years and 3 years 6 months. Initial sleep EEGs, recorded weeks to months after the onset of language regression were normal. Repeat EEG obtained between 2 months and 2 years later showed epileptiform discharges strongly activated by sleep in all 3 children, with a pattern of continuous spike and wave during slow sleep in 2 of them. The authors state that EEG should be repeated frequently in children with a firm clinical diagnosis of acquired auditory agnosia. It has been stated that most of the cases have a unilateral primary epileptogenic region (92). Therefore, the presence of bilateral continuous spike-wave discharges is interpreted as a mechanism of secondary bilateral synchronies (47; 134). The reliability of EEG latency analysis for hemispheric lateralization in 7 patients with Landau-Kleffner syndrome in presurgical assessment was demonstrated (86).
Several authors have pointed to a relationship between the epileptic abnormalities of Landau-Kleffner syndrome and the benign epilepsies of childhood (37; 15; 28). Moreover, some patients were reported with a history of typical benign childhood epilepsy with centrotemporal spikes previous to the onset of Landau-Kleffner syndrome (49; 15; 29; 47; 127). Atypical evolutions of a few patients with initially typical early-onset benign childhood occipital epilepsy (Panayiotopoulos type) syndrome including language impairment secondary to the continuous spike and wave discharges during slow sleep registered in these children were also reported (10; 50). In an update of benign focal epilepsies in children, a series of 39 patients with atypical evolutions of benign childhood epilepsy with centrotemporal spikes was presented. Sixteen showed atypical benign partial epilepsy of childhood, 10 presented status of benign childhood epilepsy with centrotemporal spikes, 9 evolved into the syndrome of continuous spike waves during slow sleep, and 5 presented a typical Landau-Kleffner syndrome (44).
The differences between the frequent atypical features found in patients with benign childhood epilepsy with centrotemporal spikes (BCECTS) and the rare cases of this condition that present the previously mentioned atypical evolutions into epileptic encephalopathies, such as the continuous spikes-and-waves during sleep syndrome (CSWS) and Landau-Kleffner syndrome, have been emphasized (42). A retrospective study of 29 patients with Landau-Kleffner syndrome with a long follow up showed that the acquired verbal auditory agnosia is associated in the most of the patients with continuous or almost continuous spike-and-wave discharges during slow wave sleep (11).
The correlation between the frequency and severity of EEG abnormalities and the degree of language disturbances has been questioned, although in active periods of aphasia, epileptiform activities in the EEG are more prominent. Again, at present, all patients with Landau-Kleffner syndrome show, at some time during its course, the sleep-EEG pattern of continuous spike and wave discharges (135). In a long-term follow-up of a series of patients with Landau-Kleffner syndrome, a strict correlation between length of continuous spike and wave discharges and persistence of language impairment was found (115; 147).
Relevance of sleep processes to Landau-Kleffner syndrome was predicted using event-related EEG-fMRI, which showed that the activity of a restricted cortical area is associated with spike-wave discharges during nonrapid eye movement sleep (87). A longitudinal case study in a patient with BECTS evolving to Landau-Kleffner syndrome and back by subsequent recovery, detailed the use of fMRI, source EEG, and neuropsychological testing to evaluate a longitudinal language reorganization and the relation of outcome to adequate treatment (20).
Leveque and colleagues provided the first objective investigation of music perception skills in 4 adult patients with a diagnosis of Landau-Kleffner syndrome during childhood, covering the spectrum of severity of the syndrome from mild to severe (78). Pitch discrimination, short-term memory for melodic, rhythmic, and verbal information, as well as emotion recognition in music and speech prosody were assessed with listening tests and subjective attitude to music with a questionnaire. They observed amusia in 3 out of 4 patients, with elevated pitch discrimination thresholds and poor short-term memory for melody and rhythm. The 2 patients with the most severe Landau-Kleffner syndrome had impairments in music and prosody emotion recognition but normal perception of emotional intensity of music. Overall, performance in music processing tasks was proportional to the severity of the syndrome. Nonetheless, the 4 patients reported that they enjoyed music, felt musical emotions, and used music in their daily life. This data supports the hypothesis that beyond verbal impairments, cerebral networks involved in sound processing and encoding are deeply altered by the epileptic activity in Landau-Kleffner syndrome well after electrophysiological normalization (78).
It has been suggested that the EEG discharges and seizures are manifestations of underlying abnormalities of the cortex in the speech areas rather than the cause of the aphasia (62). A specific hypothesis has been proposed for pathophysiology of Landau-Kleffner syndrome: a persistent paroxysmal activity during the age-dependent period of synaptogenesis might strengthen synaptic contacts that should have degenerated to allow neuronal aggregates mediate normal behavior. This reinforcement of inappropriate contacts in the developing temporoparietal cortex produces a permanent language dysfunction when paroxysmal activities are bilateral (92; 126). Therefore, early treatment would be the only way to prevent persistent aphasia. This mechanism also explains why eventual normalization of the EEG is not necessarily paralleled with improvement of aphasia. Finally, epileptiform activities in EEG were also seen in a percentage of patients with developmental dysphasia, adding difficulties to the interpretation of physiopathogenic mechanisms in Landau-Kleffner syndrome (81; 38; 106).
Magnetoencephalography was used to localize the source of epileptiform activity in children with Landau-Kleffner syndrome. A thorough study of 4 right-handed Landau-Kleffner syndrome patients including video-EEG and magnetoencephalography was performed as presurgical evaluation 3 to 6 years after the first language deterioration. Conclusion was that the intrasylvian cortex is a likely pacemaker of epileptic discharges in Landau-Kleffner syndrome and that magnetoencephalography provides useful presurgical information of the cortical spike dynamics (98; 97). Magnetoencephalography was also performed in 19 patients with suspected diagnosis of Landau-Kleffner syndrome. Thirteen of the 19 children had perisylvian magnetoencephalography spikes, which were bilateral in 10 and unilateral in 3 of the children. These results suggest that magnetoencephalography might help to obviate the need for invasive video-EEG recordings when surgery is being considered for patients with this condition (129).
Abnormal auditory evoked potentials have been reported in several patients with Landau-Kleffner syndrome. Some authors found normal brainstem auditory evoked potentials and clearly abnormal long-latency evoked potentials, specifically the P300 (49). Others reported abnormal brainstem auditory evoked potentials and middle-latency evoked potentials (66). Five children who have recovered from Landau-Kleffner syndrome were compared to controls using early, middle-latency, and late auditory evoked potentials. Unilateral voltage reduction of late auditory evoked potentials over the temporal areas previously involved by epileptic discharges was found, suggesting a permanent dysfunction in the associative auditory cortex (149). All studies support the hypothesis of a deficit in the activation of the auditory cortical areas.
A new pathogenetic interpretation was provided studying 4 children with Landau-Kleffner syndrome compared to 4 controls. MRI volumetric analysis was performed focusing on various neocortical regions and emphasizing the auditory association cortex. Age of onset of the Landau-Kleffner syndrome in the patients ranged between 3 and 4.5 years, whereas the MRI volumetry was done at ages 5 to 6.5 years. Greater than 25% volume reduction in both superior temporal areas was demonstrated only after comparison with controls, and it was worse in the side with more epileptiform activity in 2 of the children. The authors were not able to determine if volume changes existed before language regression and, thus, could not distinguish tissue loss from decreased growth or dysgenesis. Besides, 2 patients received steroid treatment before the MRI study (132). The main question arising is whether the reduction of temporal cortical volume is a cause or effect of the Landau-Kleffner syndrome. Incidentally, 1 of the 2 authors who originally described the syndrome commented the aforementioned findings and envisioned the following sequence of events:
(1) Early-on temporal lobe epileptiform activity produces the positive symptom of clinical seizures and the negative symptom of language dysfunction.
(2) Excitotoxicity of unrelieved epileptic activity causes focal cortical atrophy.
(3) Cortical atrophy prevents language recovery despite disappearance of epileptiform activity (09).
If the findings of volume reduction are ratified, longitudinal volumetric analysis might become a useful tool to evaluate evolution and treatment effects in patients with Landau-Kleffner syndrome. An 8-year-old girl with typical Landau-Kleffner syndrome was studied with PET, SPECT, and magnetoencephalography, and the authors suggested that the tip of the left temporal lobe played an important role in the pathogenesis of this syndrome in their patient (124).
In a report of 2 children with Landau-Kleffner syndrome, 1 of whom having undergone multiple subpial transections, the authors concluded that the resolution of the linguistic deficit in Landau-Kleffner syndrome may be modulated by the language-specific cortex freed from interfering epileptiform activity or by reorganization of the receptive language cortex triggered by the epileptic activity (13).
The incidence of Landau-Kleffner syndrome is unknown. At least 198 cases were reported by 1992 (06). A study to determine the incidence and prevalence of Landau-Kleffner syndrome (LKS) in Japanese children was published. Chiefs of 1562 pediatric departments answered a questionnaire, and the conclusion was that incidence of children with Landau-Kleffner syndrome aged 5 to 14 years was about 1 in a million in Japan. Prevalence of children with Landau-Kleffner syndrome aged 5 to 19 under medical care was 1 in about 300,000 to 410,000 (67). Even when Landau-Kleffner syndrome shares many clinical and EEG features with the syndrome of continuous spikes and waves during slow sleep, acquired aphasia is a more frequent finding than the psychiatric disturbances described in association with continuous spike-wave activity in slow sleep.
There are no definite guidelines for prevention of idiopathic epilepsies. However, we can do something to prevent the encephalopathic course that is seen in a small percentage of children with benign focal epilepsies in childhood (47). As is emphasized in the Management section, the adequate selection of initial antiepileptic drugs may be the best way to avoid the development of Landau-Kleffner syndrome.
Progressive degenerative neurologic disorders usually affect language as part of the neuropsychological deterioration. Structural lesions in the dominant hemisphere of children less than 5 years of age do not impair language development because that function is served by the nondominant hemisphere. Therefore, receptive or expressive aphasia is unusual in young children unless they have a bitemporal lobe dysfunction. Therefore, acute or subacute aphasia in children aged 2 to 8 years, without unilateral acquired paresis or encephalitic symptoms, is most probably due to Landau-Kleffner syndrome.
The boundaries between Landau-Kleffner syndrome and the syndrome of epilepsy with continuous spikes and waves during slow-wave sleep have been widely discussed (60; 59; 133; 126; 135). This type of EEG has also been found in several children with benign childhood epilepsy with centrotemporal spikes, particularly in the reported cases with clinical and EEG status lasting weeks (48; 118; 41; 47). Intermediate cases between status of benign childhood epilepsy with centrotemporal spikes and Landau-Kleffner syndrome are also occasionally seen (123; 41).
In early-onset cases of Landau-Kleffner syndrome, differential diagnosis with developmental dysphasia associated with EEG discharges could be difficult. The same applies to children with autistic features, regression, and epileptiform EEGs (140; 139). The debate persists, and longitudinal studies are needed to know if the EEG abnormalities play a causal role in the children with early language regression and autistic features (30). Elective mutism can be readily discarded on clinical grounds and with EEG. Nevertheless, many cases of Landau-Kleffner syndrome are initially diagnosed as psychosis or severe emotional disturbance on account of their recent inability to understand spoken language, their hyperkinesia, and their anxiety. In a significant number of cases, diagnosis is delayed because an extensive workup for deafness is undertaken.
The possibility of lysosomal storage disorders should also be considered. There is a case report of a 9-year-old boy who had developed normally up to 4 years of age when his symptoms initiated with behavioral disturbances such as auditory agnosia and decreased verbal communication (113). Progression of his symptoms to seizure and ataxia, brain perfusion scan, and electroencephalography features strongly suggested Landau-Kleffner syndrome. However, results of gene sequencing analysis and high urinary glycosaminoglycan excretion confirmed mucopolysaccharidosis type III as his final diagnosis. Mucopolysaccharidosis type III (MPS III; Sanfilippo syndrome) is a metabolic disorder characterized by a lysosomal enzyme deficiency in the catabolic pathway of heparan sulfate. The patients with mucopolysaccharidosis type III usually present with declined neurocognitive functions such as speech and hearing loss. Subtle somatic features of patients with mucopolysaccharidosis type III can lead to diagnostic delay and consequently, a greater neurocognitive deterioration may happen. This case strongly recommends screening for metabolic disorders such as mucopolysaccharidosis type III in the patients diagnosed as having Landau-Kleffner syndrome (113).
Neurologic examination is normal, and special care should be given to recognition of aphasia, mainly the onset, as auditory verbal agnosia. Neuropsychological evaluation is fundamental to determine the nature of the language disorder and level of intelligence (24). In many cases, children keep their ability to write and to communicate through nonverbal means (54; 130). The workup of these patients should include detailed language testing. In a study of 10 children with continuous spike waves during slow sleep, language profiles were found to be different from those observed in children with Landau-Kleffner syndrome (21).
EEG shows a pattern of bilateral symmetrical or asymmetrical multifocal spikes and spike waves most frequently located in the temporal and parieto-occipital regions. Sleep enhances the EEG paroxysms up to the level of exhibiting spike-wave discharges in more than 85% of slow-wave sleep (05).
Serial auditory-evoked potentials constitute an important test to orient audiologists to the diagnosis of Landau-Kleffner syndrome. Normal auditory brainstem responses, a replicable Na and absent Pa of the middle latency responses, and abnormal slow cortical potentials suggest dysfunction of auditory processing at the cortical level (107).
Except in occasional cases associated with cerebral structural pathologies, MRI is normal (54).
Functional imaging with PET and SPECT has repeatedly revealed unilateral or bilateral disturbances involving the temporal lobe (84; 93; 57; 19; 79). A 4-year-old boy with repeated episodes of receptive aphasia was studied with PET. Glucose metabolism PET scan during aphasia showed intense hypermetabolism in the left temporal neocortex, whereas a repeated PET scan during remission showed hypometabolism in the same region (80). As mentioned before, MRI volumetric analysis of superior temporal areas may yield clues to understand pathogenesis and evaluate evolution. Neurophysiological correlate of altered regional cerebral glucose metabolism observed in children with epileptic encephalopathy with continuous spike-waves during sleep (CSWS) by using a multimodal approach combining time-sensitive magnetic source imaging (MSI) and positron emission tomography was investigated in 3 children with Landau-Kleffner syndrome and 3 with atypical rolandic epilepsy. The propagation of epileptic discharges to other brain areas was associated with significant focal hypermetabolism in 5 of them (31).
Treatment with standard antiepileptic drugs such as phenytoin, phenobarbital, and carbamazepine may be effective against seizures, but at present, this treatment is not recommended because these drugs may worsen the EEG discharges and neuropsychological deficit (85). Instead, valproate, ethosuximide, and benzodiazepines can be effective and deserve a trial before attempting treatments with higher risks. However, even valproate and most new antiepileptic drugs have been shown to induce continuous spike-wave discharges and worsening of clinical features in patients with atypical evolutions of benign focal epilepsies including Landau-Kleffner syndrome (109; 47; 110). Sulthiame seems to be the oldest drug of choice according to several reports (56; 74; 148; 34; 47; 63). Add-on sulthiame was used with good results in a series of 53 children with epilepsy with electrical status epilepticus syndrome (Fejerman et al 2012). One case was treated with levetiracetam with control of seizures and language improvement (70).
Treatment with high-dose corticosteroids was reported to yield the best results, and prolonged chronic or intermittent therapy may be necessary (85; 75; 138). In a series of 8 patients with Landau-Kleffner syndrome and 2 with the syndrome of continuous spike and waves during slow sleep treated with Prednisone 1 mg/Kg/day for at least 6 months, all but 1 showed significant improvement in language, cognition, and behavior (125). A multicenter control study to compare the efficacy of early versus delayed corticosteroid treatment in patients with typical Landau-Kleffner syndrome was recommended (61). In 15 patients with electrical status epilepticus during slow sleep, including 1 case with Landau-Kleffner syndrome, a strategy with a sequential order of different treatments was presented: 1) high-dose valproate (VPA); 2) a combination of VPA and ethosuximide (ESM); 3) short cycles of high-dose diazepam (DZP) for 7 days; and 4) intramuscular synthetic ACTH-Z therapy for 11 to 43 days. A remission of continuous spike and waves during slow sleep in the EEG was achieved by high-dose VPA in 7 of 15 trials, by VPA + ESM in 3 of 7 trials, by short cycles of high-dose DZP in 2 of 4 trials and by ACTH-Z therapy in 2of 5 trials. A permanent remission of ESES syndrome was only achieved with high-dose VPA or combination of VPA+ESM in 10 patients (64). Two publications report on effects of steroids in patients with Landau-Kleffner syndrome: in 2 pediatric patients with episodic epileptic verbal auditory agnosia, the pulse combination high-dose corticosteroid and benzodiazepine therapy were especially effective (32). In a group of 54 children with severe epilepsies other than infantile spasms, 11 of 15 children with continuous spike-waves in slow sleep or Landau-Kleffner syndrome responded to methylprednisolone pulse therapy. The treatment consisted of 4 pulses with single doses of 20 mg/kg/d methylprednisolone, administered on 3 consecutive days. After this initial phase, the pulses were increased based on individual factors. The pulses were exclusively administrated orally in 39 of all 54 children in the study, and 7.8% of all pulses were applied intravenously (04).
In isolated cases, the use of intravenous immunoglobulins was successful (40; 71). In 1 report, 2 of 5 children with Landau-Kleffner syndrome receiving 2 g/kg of intravenous gamma-globulin over 4 days showed excellent response; in both children the severe language and EEG abnormalities completely resolved (90). These results were questioned in a small series of 3 children with Landau-Kleffner syndrome and 3 children with CSWS syndrome: EEG findings did not improve, and neuropsychological improvement occurred in only 1 child with CSWS syndrome (02). A retrospective, multicentre study of immunoglobulin treatment for severe childhood epilepsy showed usefulness in 6 of 12 patients with epilepsy with electrical status epilepticus and in 1 of 3 children with Landau-Kleffner syndrome (53). The efficacy of immunotherapy was described in 5 patients (4 males, age range 6 months-13 years) with molecularly confirmed GRIN-related epileptic encephalopathy (4 with GRIN2A-related epilepsy-aphasia spectrum/epileptic encephalopathy with CSWS accompanied by verbal, communicative, and behavioral regression and 1 patient with GRIN2D-related infantile developmental-epileptic encephalopathy) (58). All patients had global developmental delay/intellectual disability in various degrees and were resistant to anticonvulsants but none of the patients had frequent clinical seizures. All patients received monthly infusion of IVIG 2g/kg for 6 months; 2 patients were also treated with high-dose corticosteroids with normalization or near normalization of the EEG in 3 patients, from whom 2 had mild improvement in verbal abilities and communication skills. Perceptual/spatial abilities as well as executive functions and attention span remained significantly impaired (58).
In the already referred to case of Landau-Kleffner syndrome associated with mitochondrial respiratory chain-complex I deficiency, ketogenic diet allowed for complete recovery of language functions and normalization of EEG (68). In 6 children with electrical status epilepticus in slow-wave sleep (3 of them with Landau-Kleffner syndrome), acetazolamide was added with apparently good results (51). Three children demonstrated complete resolution of spike-wave discharges, and all had improvement in communication skills and school performance.
Multiple subpial transection of the cortex to abolish epileptic discharges was used in a series of 14 children with acquired epileptic aphasia who had been unable to use language to communicate for at least 2 years; sustained improvement was obtained in 11 of them. According to the authors, success depends on selection of cases with severe EEG abnormality that can be demonstrated to be unilateral in origin despite a bilateral manifestation (91; 92). In another small series, 5 children with Landau-Kleffner syndrome aged 5.5 to 10 years underwent multiple subpial transection, and behavior and seizure frequency improved dramatically. Improvement in language also occurred in all children, although none of them reached an age-appropriate level of language even when their electrical status epilepticus during sleep was eliminated by the procedure (65). The surgical treatment of Landau-Kleffner syndrome was reviewed. Of 10 children aged 5 to 10 years with Landau-Kleffner syndrome and receiving multiple subpial transections, 7 showed language improvement, but none returned to normal functions (17). The authors concluded that data in the literature are still lacking to be sure about the value of surgery. In comparing multiple subpial transection with nonsurgery groups of children with Landau-Kleffner syndrome and ESES-related regression, the conclusion was that there is insufficient evidence to suggest that multiple subpial transection provides additional benefits over and above the mixed recovery often seen in Landau-Kleffner syndrome and related regressive epilepsies (35).
In a literature search study of 112 articles with 575 patients, superiority of steroids and surgery in encephalopathy with ESES was the mean consideration (145). Again, the authors insist that according to their experience, the results with certain antiepileptic drugs are quite different in symptomatic and idiopathic ESES, and the mentioned interpretation does not apply to the atypical evolutions of idiopathic focal epilepsies in childhood (46).
Six children with Landau-Kleffner syndrome were implanted with the vagal nerve stimulation device, and 3 of them apparently showed improvement in quality of life (103).
The utility of sign language in children with Landau-Kleffner syndrome has been questioned, in part due to the ambivalence of parents to the world and culture of the deaf. A report on the outcome of a small series of patients with severe verbal auditory agnosia treated with sign language techniques concluded that sign language may facilitate language recovery by stimulating functionally connected core language networks and by helping speech therapy and auditory training (27).
Koshi A Cherian MD
Dr. Cherian of Albert Einstein College of Medicine has no relevant financial relationships to disclose.See Profile
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, received honorariums from Cerebel for advisory committee membership.See Profile
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