Landau-Kleffner Syndrome and CSWS

Michael C. Smith

Charles E. Polkey

Introduction

Landau-Kleffner syndrome (LKS) and the syndrome of continuous spikes-and-waves during slow sleep (CSWS) were described independently and have been considered separate disorders. Both have been given distinct recognition by the Commission on Classification and Terminology of the International League Against Epilepsy¹³ and by the World Health Organization in the International Classification of Diseases.⁷⁴ More recently, however, emphasis has been placed on the possibility that there may be common features in the pathophysiology of these two syndromes¹⁵^,²⁵^,²⁷^,²⁸^,⁴¹^,⁴³^,⁶²^,⁷¹ and that LKS may actually be a subtype of CSWS.²⁵^,⁴³^,⁴⁶^,⁶² A major symposium on this subject was held in Venice in 1993 and published in 1995.⁸

LKS and CSWS appear to represent points on a spectrum of functional age-related epilepsies ranging from the “benign” idiopathic localization-related childhood syndromes, such as benign childhood epilepsy with centrotemporal spikes (BECT), to full-blown continuous spikes-and-waves in slow sleep associated with behavioral disturbances.⁶² They differ from the secondary generalized epilepsies, such as Lennox-Gastaut syndrome (LGS), in being a truly functional disturbance induced by age-related, self-limited paroxysmal activity.

Historical Perspectives

In 1957 Landau and Kleffner³⁷ reported six children with a syndrome of “acquired aphasia with a convulsive disorder.” One of the children became aphasic and hemiplegic after a head injury, but the other five children’s developmental aphasia was related to their convulsive disorder. These five children were presented in detail, with one added as an addendum. Landau and Kleffner described an aphasia that developed over days to months that then persisted from 2 weeks to several years. The associated seizures included grand mal, petit mal, and myoclonic seizures, and the paroxysmal abnormality was usually bilateral, most prominent over the temporal lobes.

They felt that although the relationship was not perfect, the severity of the paroxysmal disturbance on the electroencephalogram (EEG) did correspond to the severity of language disturbance. Landau and Kleffner noted that the seizures were easily controlled and the prognosis was generally good. They hypothesized that persistent convulsive discharge in brain tissue responsible for linguistic communication results in the functional ablation of these areas for normal language behavior. Their thesis was supported by the fact that these children did not have clouded consciousness like patients in petit mal status and had good performance on nonverbal intelligence tests.³⁷

Since that time there have been over 350 published cases of acquired aphasia associated with a paroxysmal EEG.⁴ The EEG abnormality is a predominantly bilateral posterior temporal spike or spike-and-wave discharge that is activated by slow-wave
sleep. Most observers agree that the ultimate language outcome correlates with the age of onset of this epileptic disturbance, as well as its severity, bilateral anatomic location, and duration of the active phase.¹⁵^,²⁸^,⁴¹^,⁶²

In 1971 Patry et al.⁵² described “subclinical electrical status epilepticus” induced by sleep in children. They reported on six children who displayed seizures; cognitive decline, including language dysfunction; and severe paroxysmal EEG disturbance. The patients ranged in age from 7 to 12, four boys and two girls. There was a history of birth trauma in three, consanguinity in two, and epilepsy in the family of one. All displayed continuous spikes-and-waves in 85% of the non–rapid eye movement (REM) sleep record for an extended period of time. Seizures were described as atonic, generalized tonic–clonic, convulsive, clonic, and atypical absence. Five of the six children were mentally retarded and two failed to acquire language. The authors noted that the degree of mental retardation was related to the age of onset of the seizures and hypothesized that this syndrome represented a form of encephalopathy secondary to a focal or multifocal brain lesion. The activation of the paroxysmal activity during sleep, especially slow-wave sleep, was due to a particularly active synchronizing system during slow sleep.⁵²

Tassinari et al. later retitled this syndrome electrical status epilepsy during sleep (ESES)⁶⁹ and then CSWS,⁶⁷ as a result of the criticism that clinical seizures were not seen during the spike-and-wave discharges. Tassinari et al. concluded that the persistent continuous spike-and-wave discharges over years were responsible for the complex and severe neurologic impairment.⁶⁷

Definitions

LKS is a functional disorder of childhood usually described as having the following features: Acquired aphasia, paroxysmal EEG that is usually bitemporal, seizures that are easily treatable and self-limited, no demonstrable brain pathology that is sufficient to explain the behavioral symptomatology, and some degree of improvement when the epileptic condition resolves.¹⁷^,²⁵^,³⁶^,⁴⁶^,⁴⁹^,⁵³^,⁵⁷

Although these features are commonly cited in the literature, there are exceptions. The language disturbance is described as an acquired aphasia, but both these terms have been challenged. Rapin et al. argued that it is not an aphasia, but a verbal agnosia.⁵⁶ In fact, recent evidence suggests that it is an auditory agnosia.⁴⁹ Acquired aphasia implies a demonstrable age-appropriate language prior to onset of the CSWS. Early onset of the same process could prevent language function before any language is clearly demonstrable; however, a diagnosis of LKS would be impossible in this situation unless the aphasia is reversed by stopping the epileptic activity.

The paroxysmal EEG is commonly described as predominantly bitemporal and activated by sleep, especially slow-wave sleep. It usually becomes continuous in slow-wave sleep and persists for an extended period.⁴⁶ However, the paroxysmal disturbance may be interrupted by normal sleep EEG patterns, and eventually the epileptiform EEG disturbances disappear completely.²⁹ Furthermore, as will be discussed later, there is evidence to suggest that the primary epileptogenic region is unilateral.⁴⁶^,⁴⁹ Awake EEGs may be normal, even in the active phase of spike-and-wave during sleep. Seizures are not always seen, and when present may be quite subtle and not reported.¹⁷^,²⁷^,⁴⁹

Although there is no demonstrable brain pathology sufficient to explain the language dysfunction, multiple nonspecific structural abnormalities have been associated with LKS,⁶³ which presumably accounts for the epileptiform disturbances.

There is improvement in language function in all patients with the resolution of the active phase of spike-and-wave discharges; however, permanent sequelae in language function are usually seen, especially when there has been early onset of epileptic EEG activity⁸^,²⁵^,⁵³^,⁶² and when the epileptic activity is not eliminated before the critical period for language development is over.⁴⁴^,⁴⁹^,⁵⁷^,⁵⁸ LKS therefore represents an age-dependent functional disruption of language induced by a localized paroxysmal EEG disturbance.

CSWS is a functional disorder of childhood with the following features: Severe paroxysmal EEG disturbance, occupying at least 85% of sleep (sleep index 85%); seizures that may be severe but self-limited; behavioral deterioration, with or without premorbid developmental disturbances; no demonstrable brain pathology sufficient to explain the behavioral deterioration; and stabilization or improvement of behavior once the epileptiform EEG abnormalities resolve.⁹^,⁶⁸

These features are not invariably agreed upon. Although Tassinari et al.⁶⁸ have maintained that a sleep index of 85% is a necessary component of the diagnosis, the ILAE definition did not require it (ILAE 1989). There may be fluctuations, fragmentation, and variability in the continuity of the spike-and-wave discharges over time. Seizures are usually seen, but they may be subtle and go unreported.⁹^,⁶⁸ Traditional antiepileptic drugs usually prevent the expression of the seizures but do not eliminate the paroxysmal EEG abnormality. Although behavioral deterioration is seen in all patients, it may not be as marked in those with previously abnormal development.⁶⁸

Prior abnormal neurologic development is not uncommon in CSWS. Demonstrable brain pathology is seen, but it is insufficient to explain the deterioration of function. There is spontaneous resolution of the epileptiform discharges by the midteenage years with stabilization and often improvement of the neuropsychological and behavioral deterioration. However, significant permanent sequelae are seen in the majority of patients that appear to be related to the duration of the active phase of spike-and-wave activity.⁹^,⁵³^,⁷³ CSWS, therefore, also appears to be an age-dependent disturbance of brain function, induced by a severe paroxysmal disturbance that resolves over time.

Epidemiology

The frequency of Landau-Kleffner syndrome cannot be accurately ascertained. Using the strict diagnostic criteria discussed earlier, LKS is a rare disorder. There have been over 350 published cases since 1957. There were 81 cases reported between 1957 and 1980, but 117 cases were reported between 1980 and 1990.³ Dugas et al.²¹ observed one new case per year in a Parisian psychiatric clinic. Males are affected more commonly than females, with a peak onset between 5 and 7 years of age.¹⁰

The frequency of CSWS is also unknown. Using the strict criteria of continuous spike-and-wave discharge during 85% of sleep associated with cognitive and behavioral decline, CSWS is a rare disorder. Between 1971 and 1984, Tassinari et al. reported 19 personal cases from the Centre St. Paul in Marseille and an additional 25 from the literature.⁶⁷ Since 1984, ten new cases have been seen at the Centre St. Paul, a rate of one to two per year.⁶⁸ Males are affected more commonly than females, with a peak onset between 5 and 7 years of age.¹⁰

Etiology and Basic Mechanisms

A convergence of evidence suggests that LKS and CSWS are due to a common pathophysiologic mecha- nism,¹⁴^,²⁵^,²⁷^,²⁹^,⁴¹^,⁴³^,⁴⁶^,⁶²^,⁷¹ and a specific hypothesis has been proposed for LKS.⁴⁶^,⁴⁹ Both disorders develop during a period of cortical synaptogenesis when the basic functional circuitry is being established (age 1 to 8). Synaptogenesis involves an overabundant growth of axonal processes and synaptic contacts thought to be twice the number found in mature adults.³¹^,³²^,⁵⁴^,⁵⁵ Neuronal activity or synaptic use is the major factor that determines which synapses will be strengthened and which will be pruned.³¹^,⁵⁴ The environment, more than genetic programming, plays the crucial role in the establishment of permanent synaptic contacts. If a significant paroxysmal EEG disturbance is present during this age-dependent synaptogenesis, it acts to strengthen synaptic contacts that should have degenerated in order for the neuronal aggregates to mediate normal behavior.⁴⁹ In the case of LKS, the paroxysmal activity reinforces inappropriate contacts in the developing temporoparietal cortex, thus producing a permanent language dysfunction.⁴⁹ In addition, the disturbance must have a bilateral effect to prevent transfer of function to the contralateral homotopic cortex. In CSWS, the most prominent paroxysmal activity appears to be in the frontal area, which would disrupt higher cognitive and executive function and attention before producing language dysfunction. Because the functional disruptions induced by paroxysmal EEG activity can spread to involve a larger cortical area, the symptom complexes of LKS and CSWS tend to merge as the disease goes on, producing severe cognitive, behavioral, and social dysfunction, much like the child with severe autism.

This proposed underlying mechanism predicts that, if unsuccessfully treated, those children affected earlier in this period of synaptogenesis will suffer the most serious neuropsychological sequelae after the epileptiform disturbances remit. Several authors have reported this in their series.⁸^,²³^,⁵⁷^,⁵⁸^,⁷⁰ The importance of overactive inhibition as well as overactive excitation in these syndromes has been recently highlighted. This combination results in coexistence of a lack of overt seizures at the same time as severe cognitive/language dysfunction—a hallmark of the epileptic encephalopathies.²⁷

Multiple nonspecific pathologic abnormalities can be associated with these syndromes and, although insufficient to explain the behavioral deterioration, may be responsible for the epileptic disturbances. Common etiologies in CSWS include congenital hydrocephalus, periventricular, and diffuse atrophy.⁷^,²⁰ The pathologic findings associated with LKS in the literature are similar to those seen in other partial epilepsies; they include encephalitis, vasculitis, subpial gliosis, cysticercosis, and neuronal migration disorders.¹² The biopsy material taken from the temporal pole, at a distance from the primary epileptic site, in one surgical series of 14 patients with LKS revealed a variety of pathologic abnormalities in 13.⁶³

The mechanistic hypothesis presented here raises the question of whether other epilepsies might also induce progressive behavioral dysfunction. BECT and other idiopathic localization-related epilepsies involving frontal, temporal, parietal, and occipital lobes all could have deleterious effects on cortical development and function where the abnormality
is maximal. It may be that we cannot clinically detect the permanent sequelae because of the poor sensitivity of our testing.

Clinical Presentation

Landau-Kleffner Syndrome

LKS is an acquired epileptic aphasia or auditory agnosia, occurring in a previously normal child, in language function, in association with paroxysmal EEG abnormalities with or without clinically apparent seizures, and without a structural substrate sufficient to account for the behavioral deterioration. The disorder begins most commonly between the ages of 3 and 8 in children who have already developed age-appropriate speech. The onset may be subacute or stuttering and initially consists of a loss of verbal understanding (i.e., receptive disturbances predominate). Soon, however, speech output is affected and paraphasias and phonologic errors appear. In the most severe cases, the child becomes entirely mute and will fail to respond to even nonverbal sounds—such as the ring of a telephone, a knock on the door, or a dog barking—that were previously well attended to. Behavioral disorders such as hyperactivity and attention deficit are common. Rarely, there is progression to severe disinhibition and psychosis.³^,⁴⁶^,⁴⁹

Seizures vary in type, but most commonly are associated with eye blinking or brief ocular deviation, head drop, and minor automatisms with occasional secondary generalization. They bear a variable relationship to the language deficit, and, indeed, from 20% to 30% of patients do not exhibit behavioral seizures.⁴ The seizures have a benign course, are readily responsive to antiepileptic drugs, and generally subside by the age of 15 years. The language disturbance, as a rule, has a much less satisfactory prognosis, although early on the symptoms may show marked fluctuation, and even complete recovery, within weeks or months of onset.¹⁵ However, if the aphasia persists for more than 2 to 3 years, complete recovery is most unusual; such patients may expect a lifelong linguistic defect.⁸^,³⁶^,⁴⁶^,⁴⁹^,⁵³^,⁵⁷

A critical component of LKS is the presence of continuous 1.5- to 5-Hz spike-and-wave EEG discharges in slow sleep that fragment or disappear during REM sleep²⁹^,⁴¹^,⁴²^,⁴⁶^,⁴⁹ (Fig. 1). It is this latter feature that links the two conditions under discussion and provides the impetus to seek clinical similarities. A distinctive feature of LKS, however, is that the spike-and-wave discharges predominate in the posterior temporal regions. Most patients do not show spike-and-wave activity for 85% or more of slow sleep at the time of study, and some may not show continuous spike-and-wave during sleep at all; however, it has been assumed that this condition was met at some point during the course of the disorder.⁴⁶ During the active phase, brief posterior temporal epileptiform discharges can also be seen during wakefulness on the routine EEG, which can be localized to one posterior temporal region. With the use of the methohexital suppression test,⁴⁷^,⁶⁴ intracarotid amobarbital, EEG dipole mapping, and magnetoencephalogram (MEG), it can be shown that most, if not all, children have a unilateral primary epileptogenic region.³⁹^,⁴⁶^,⁴⁹^,⁵¹^,⁶⁵ This can involve either side, since the contralateral propagation of paroxysmal discharges creates bilateral dysfunction that disrupts normal language development, regardless of the side of origin.

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