AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Acquired epileptic aphasia (AEA) typically develops in healthy children who acutely or progressively lose receptive and expressive language ability coincident with the appearance of paroxysmal EEG changes. In 1957, Landau and Kleffner initially described AEA and subsequently reluctantly agreed to the attachment of their names to the syndrome. In this article, AEA is used as a synonym for Landau-Kleffner syndrome (LKS).

In most cases described in detail, a clearly normal period of motor and language development occurs before AEA symptoms appear. However, in the last 20 years, several reported cases have been difficult to classify because the patients' presenting symptoms appear to have been variants of those originally described. In 1 case, expressive language deteriorated instead of receptive language, whereas in another case, a brief period of normal language development (single words) was followed by language regression with abnormal EEG findings.

AEA must be differentiated from autism with minimal language regression, especially when it is associated with isolated EEG abnormalities. Many current researchers classify AEA as part of the syndrome of electrical status epilepticus of sleep (ESES), which is also known as continuous spike and wave of slow-wave sleep.

Pathophysiology

Whether seizures and epileptiform discharges cause language dysfunction in AEA is disputed. Aphasia and EEG abnormalities might have a common cause, for example, a left temporal brain astrocytoma or head injury. Some speculate that reinforcement of synaptogenesis mediates the neurologic deficits in AEA and that epileptiform discharges during a critical period of synaptic reinforcement or pruning in turn mediate the reinforcement of synaptogenesis.

Concrete substantiation of this hypothesis is the existence of poor speech in patients who are affected early and who do not respond to anticonvulsant measures. Some patients with AEA appear to have worsened language skills during periods of increased epileptiform activity. However, many reports describe no correlation between EEG abnormality and language dysfunction.

Most cases of AEA are spontaneous, though familial clustering has been reported. Descriptions of monozygotic twins include cases in which AEA affects only 1, cases in which AEA affect both, and cases in which AEA affects 1 and developmental dysphasia affects the other. These cases cast serious doubt on the role of epilepsy in speech dysfunction.

Frequency

United States

Population-based epidemiologic data related to AEA are limited. The Children's Hospital and Medical Center (Seattle, WA) treats 1-2 new cases of AEA each year.

International

More than 200 cases have been described in global literature. In 1957-1980, 81 cases of AEA were reported. More than 100 cases are documented every 10 years. Numbers are difficult to report because patients may be repeated in various series, as switching professional care is common because of the patient's and family's frustration with aggressive treatment that does not improve the patient's speech. An urban Israeli pediatric neurology clinic reported a 0.2% rate of AEA.

Sex

A slight predominance in boys is noted, with a male-to-female ratio of 1.7:1.

Age

Aphasia usually appears at 4-7 years of age. However, symptom onset has been described in patients as young as 18 months and in those as old as 13 years. This discussion excludes the congenital cases with typical EEG patterns and little or no language development; in such cases, the precise age of onset can never be determined.

Early Language Development: In the early descriptions of the syndrome, language dysfunction was not recognized in the early-acquisition phase in the first 18 months of life. In the last 10 years, scrutiny of the language development has revealed some minor abnormalities. In 1994, Soprano et al found signs of developmental dysphasia in 9 of 12 cases. In 2001, Robinson et al reported language delay in 4 of 18 cases.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Language symptoms
• • The first manifestation of the language problem is often word deafness or auditory verbal agnosia. In many patients, auditory verbal agnosia may include lack of recognition of familiar noises; however, alert responses to sound and tonal audiograms are usually normal. In some patients, even the capability of lateralizing and/or localizing sound may be impaired. Receptive language is often severely or profoundly impaired as a result of an interference with phonologic decoding. Although the primary problem is in the receptive sphere, this syndrome appears in a critical period of language acquisition; therefore, speech production may be affected just as badly as or even worse than language comprehension. This is often the case as the disease progresses.
  • In some cases, impairment may be most severe in expressive language. In 1 study, aphasia was predominantly expressive in 6 of 77 patients who appeared to have AEA.
  • Reading and writing may be remarkably preserved in children with little speech or auditory comprehension, and these children can be taught lip reading and writing as well. Speech disturbances may include fluent aphasia, use of jargon and paraphrase, asyntaxia, and verbal stereotypies in children who are not completely mute. Some abnormalities may superficially resemble autism or psychosis, common diagnoses given to children with AEA.
  • The age of onset of aphasia is between 18 months and 13 years, but usually after 4 years and before 7 years. A few authors include in the definition of AEA patients with limited or no language development associated with paroxysmal EEG. In such cases, being certain about the true age of onset of symptoms is difficult. Some authors have included cases of developmental dysphasia associated with seizure-related fluctuations in speech performance, whereas others have not. Further studies are necessary to determine if the response to treatment really differs to justify this separation.
  • Language deterioration commonly occurs over weeks or months, but acute onset after a seizure has also been described. Intermittent/episodic aphasia may be seen as well.
  • The present author found that 40% of patients referred for workup of language deterioration actually had other problems. In 2, a history of language deterioration was not given during the first visit to the neurology clinic; however, over time, the parents' perception of the problem changed. This change may have been due to the desire to give the child the benefit of doubt in the evaluation to differentiate AEA from autism. This parental perception springs from the notion that AEA can be treated but that autism or pervasive developmental disorder (PDD) cannot. However, this belief does not reflect the reality of the difficulties in treating AEA.
  • Course of language dysfunction and its relationship with paroxysmal EEG abnormalities
    • No consensus exists concerning the relationship between discharges on the EEG and the presence and intensity of language problems.
    • In many cases, continuous spike and wave during sleep seems to precede language deterioration.
    • Improvement in the paroxysmal EEG pattern during sleep often precedes the clinical language improvement.
    • Several authors have found that aphasia is correlated with unilateral or bilateral temporal-lobe discharges or with periods of 1 or more years of continuous bilateral spike-wave of slow sleep when language appears to worsen (Rousselle, 1995).
  • Others found this correlation to be far from reliable. Soprano et al observed persistent EEG abnormalities in patients with poor language recovery, but 6 of 9 with EEG normalization remained aphasic.
  • The relationship between aphasia and paroxysmal EEG may not be an "on-off" response. Several factors limit the reliability of the EEG data, as follows:
  • • Neurologic deficits do not closely follow the maximal EEG changes in time. Patients with unilateral motor weakness related to a seizure (Todd paralysis) often remain weak for hours, and in rare cases days, after a partial seizure is gone.
    • Repeated and long seizures are most often associated with long postictal dysfunction, which, at some point, may not recover completely.
    • Attenuation of the electrical activity of brain as it goes through the skull (see the EEG and Magnetoencephalography in Other Tests). This is especially true if the localization of the epileptiform activity is deep and has a tangential orientation.
    • The assumptions that paroxysmal EEG may or may not be correlated with the aphasia fluctuation also may be flawed because, if epileptic and/or neurotoxic brain damage is present in AEA, recovery from this damage may take time or may never happen. Two findings—that some patients improve with the use of corticosteroids or adrenocorticotropin hormone (ACTH) and that patterns on angiograms resemble those seen in cerebral arteritis—suggest that inflammation and vasospasm may play a role in some cases of AEA. This phenomenon is probably not universal because not all patients show EEG or clinical response to steroids and 2 neuropathologic specimens from temporal lobectomies revealed no inflammatory changes.
• Seizures
• • The prevalence of clinical seizures in AEA is 70-85%. In one third of patients, only a single seizure (or episode of status epilepticus) is recorded. In about one half, a seizure is the initial manifestation of AEA. In some, a few years may pass between the first seizure and the onset of any speech problems, whereas the opposite is true in others. Seizures usually appear between 4 and 10 years of age, and many series show that remission of the seizures before adulthood (often before age 15 y) is the rule.
  • Clinical seizures are often easy to treat, but normalization of EEG discharges can be challenging. Among patients in whom ictal semiology is well described, 59% had partial seizures, 39% had generalized tonic-clonic seizures, and 16% had atypical absences. Myoclonic seizures involving the face and eyes have been described. About 12% of patients have a family history of epilepsy.
• Behavioral and neuropsychological disturbances
• • Behavioral disturbances are seen in as many as 78% of the patients. Some patients may appear deaf or autistic. The diagnosis of autism is often considered because of the common presence of asyntaxia, parapsias, and verbal stereotypies. Hyperactivity and a decreased attention span are observed in as many as 80% of patients. Aggressive and oppositional behavior, including rage attacks, is not unusual. The aggression and rage may be so prominent that the patients may be admitted to a psychiatric service rather than a neurologic service, either initially or during the course of the disease. Anxiety and avoidant or bizarre behavior may also be seen.
  • Although behavior patterns are thought to be secondary to the language impairment, some patients may have complex, hard-to-explain, and bizarre behaviors, such as avoidance of interpersonal contact and gestural stereotypies. In some cases, frankly psychotic behavior has been described. As already mentioned, autism and/or psychosis are often suspected in these patients.
  • Other aspects of cognition are traditionally said to be preserved, but a discrepancy between nonverbal and verbal skills is sometimes seen. Diffuse neuropsychological deficits may appear over time. Short-term memory is a debilitating feature seen in long-standing cases.
• Controversial features
• • Some cases initially thought to be benign childhood epilepsy with centrotemporal spikes later develop into a picture of AEA.
  • In addition, some patients with early-onset benign childhood occipital epilepsy (Panayiotopoulos type) syndrome have language dysfunction because of the continuous spike-and-wave discharges during slow-wave sleep.

Physical

• Mental status examination of patients with AEA demonstrates language, speech, and behavior problems, as described in the History section above.
• A history of a poor understanding of spoken language should be substantiated by performing objective testing of all aspects of the patient's speech and language, such as his or her comprehension, repetition, reading, and writing.
• Bedside and/or office testing of language skills should be supplemented by formal neuropsychological testing.
• Besides language, speech, and behavior, physical and neurologic examination of patients with AEA shows motor clumsiness or, less frequently, apraxia. In some cases, frank abnormalities of tone and motor function are noted, but these findings are the exceptions rather than the rule.
• Patients with AEA secondary to a tumor, stroke, or head injury commonly have hemiparesis (usually right sided).
• Signs of increased intracranial pressure, such as papilledema and, in more extreme cases, erratic respirations, bradycardia, and hypertension, should alert the clinician to the possibility of a mass lesion.

Causes

• Most cases of AEA do not have a well-defined cause.
• A few cases of secondary AEA have been described.
• • Low-grade brain tumors, closed-head injury, neurocysticercosis, and demyelinating disease have been associated with the clinical picture of AEA.
  • CNS vasculitis may also be associated with AEA.
  • One case of otherwise typical AEA has been described in association with mitochondrial respiratory chain complex I deficiency.
  • Bilateral perisylvian polymicrogyria may also present with new onset of speech disturbance after a 2-year period of normal language and EEG findings typical of AEA.
• Other diagnostic considerations might be warranted.
• • The differential diagnosis of AEA is extensive. Acquired aphasia in children may be secondary to head trauma, brain tumors, stroke, or neurocysticercosis. Like AEA, head injury, brain neoplasms, and cerebrovascular thromboembolism may be associated with an epileptiform EEG and seizures. Other neurologic deficits, such as hemiparesis or signs of increased intracranial pressure, may be a clue of an underlying structural lesion. Images, especially MRIs, clarify the diagnosis. Patients with brain tumors may develop an acquired aphasia secondary to seizures and epileptic discharges generated around the neoplasm.
  • Deaf children may have many of the symptoms of AEA. Conversely, patients with AEA do not always have convulsions, and, even when present, the seizures may be missed. Some children with AEA may initially be thought to be deaf and are referred for audiologic evaluation.
  • Hyperactivity and decreased attention span are common in AEA. Patients in whom attention deficit disorder is suspected should be carefully examined for aphasia. The resemblance of AEA and attention deficit disorder is superficial, and differentiation of the 2 should not be difficult. Likewise, patients with aggressive (eg, rage attacks), oppositional, or psychotic behavior should be examined for signs of language impairment because these symptoms can be present in patients with AEA.
  • Complex and bizarre behaviors, such as interpersonal contact avoidance, gestural stereotypies, and frankly autistic behavior can be seen in AEA. A careful history is necessary in patients with autism or PDD. When in doubt, a sleep EEG is required to rule out AEA.
  • Patients who never develop language or have a poor acquisition of language must be differentiated from children with hearing deficits and mental retardation. AEA and mental retardation (congenital without intellectual deterioration) should be differentiated on the basis of information from the history, neuropsychological testing, and EEG. Patients with AEA typically have normal hearing threshold on formal testing.
  • On occasion, patients with neurodegenerative diseases may present with problems in language comprehension. This is especially true for patients with adrenoleukodystrophy in whom the initial complaint can be difficulty in processing auditory information due to dysmyelination of the white matter in the temporoparietal region. At this stage, patients do not necessarily have corticospinal tract signs; however, over time, spasticity, increased deep tendon reflexes, and upgoing toes become apparent. Seizures are infrequent (about 10%) in adrenoleukodystrophy. The age of onset of the childhood form of adrenoleukodystrophy is similar to that of AEA. T2-weighted MRIs of the brain show increased signal intensity in the affected areas.

    Table 1. Epileptiform EEG Findings in Autism, Dysphasia, and Epilepsy

    Reference	Diagnosis	No. of Patients	No. of Patients with EEGs	Patients with Abnormal EEGs (%)
    Tuchman, 1991	Autism with epilepsy	42	40	75
    	Autism without epilepsy	160	139	8
    	Dysphasia with epilepsy	19	19	58
    	Dysphasia without epilepsy	218	66	9
    Tuchman and Rapin, 1997	PDD or autism	585	392*	NA
    	With epilepsy	NA	66	59
    	Without epilepsy	NA	66	59
    	Without epilepsy but with history of regression	NA	155	14
    	Without epilepsy and without history of regression	NA	364	6

    Note.—NA = not applicable.
    ^*Sleep EEGs.
  • The rest of this section discusses various syndromes related to AEA.
• Oromotor-expressive language deficit associated with a centrotemporal epileptic focus (acquired expressive epileptic aphasia)
• • A rare syndrome has been described in which patients appear to have a primarily expressive language deficit associated with a centrotemporal epileptic focus. Temporary speech and oromotor disturbances may be seen in this syndrome. Voluntary oromotor functions and speech production may be affected depending on the location and spread of the epileptic discharges (more anterior or posterior in the perisylvian region). Like those in AEA, these deficits can occur as initial symptoms of the disorder without visible seizures. The range of symptoms in these patients goes from nonlinguistic deficits, such as intermittent drooling to oromotor apraxia, disfluency, and (in severe cases) full-blown anterior opercular syndrome.
  • Oromotor apraxia and speech problems may be congenital, or they may develop or worsen with episodes of sustained spike and wave discharges during sleep. Seizures are nocturnal and either orofaciobrachial partial or secondarily generalized. The ages of onset, progression, and recovery of the deficits are variable but depend on the degree and duration of epileptic activity. The EEG in this syndrome shows rolandic (ie, centrotemporal) discharges, which are commonly bilateral.
  • During sleep, continuous spike and wave discharges may be seen on the EEG and, that pattern may be correlated with clinical deterioration. One family with this syndrome had autosomal dominant transmission with anticipation for the seizure disorder, oral and/or speech dyspraxia, and cognitive dysfunction, raising the possibility of a triplet repeat syndrome (Scheffer, 1995). Antiepileptic medication and a ketogenic diet may affect the course of the disease in some cases.
• Developmental dysphasia or developmental expressive language disorder
• • Developmental dysphasia is a syndrome in which language acquisition does not occur despite normal intelligence and the lack of brain or hearing pathology. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) refers to this syndrome as developmental expressive language disorder, a more appropriate term than developmental dysphasia because it considers the poor development or lack of acquisition of expressive language.
  • Overnight sleep recording in patients with developmental dysphasia may show epileptiform discharges; in one study, as many as 30 of 32 cases studied had these discharges even though half of the patients studied never had a seizure. The EEG abnormalities in developmental dysphasia may be more prominent during sleep, but one study found only minimal or no worsening in the transition from sleep stages 1-2 to 3-4 (slow-wave sleep).
  • Other investigators have described patients with developmental expressive language disorder and epileptiform EEGs, which suggests that these cases are "congenital variants of the Landau-Kleffner syndrome (AEA)." As can be concluded from the name of this disorder, the main problem is with expressive language, whereas in classic AEA the primary problem is in the receptive sphere. Nonetheless, differentiation between this disorder and AEA may be difficult for the following reasons:
    • In AEA the primary problem is in the receptive sphere, but speech production may be affected just as badly or even worse than language comprehension.
    • An expressive-aphasia variant of AEA is known.
    • Cases of AEA and developmental dysphasia can be seen in the same pedigree, including one report of discordant monozygotic twins, suggesting a similar genetic abnormality with different phenotypes.
    • Many patients with developmental dysphasia also have EEG abnormalities, and 3 cases seemed to respond to ACTH therapy.
  • Because of these arguments, clinicians should be open to the possibility that some patients with developmental expressive language disorder may have abnormal EEGs and that they occasionally respond to treatments used for AEA. Differentiation of developmental expressive language disorder (developmental dysphasia) and acquired expressive epileptic aphasia (oromotor-expressive language deficit associated with centrotemporal epileptic focus) with an early onset of symptoms is difficult and may be impossible in many cases.
• AEA and autism
• • Autism is a strong consideration in patients presenting with an AEA-like picture. Not all patients with AEA have seizures, and some patients with autism may have EEG abnormalities with or without seizures. As mentioned earlier, many families change their perception of the patient's history over time. In these cases, consulting the child's initial medical records to obtain the correct information is helpful. In that sense, retrospective analysis, especially if the initial consultation notes are not accessible, may overestimate the incidence of language regression in these patients.
  • The diagnosis of autism (autistic disorder) based on criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) is divided in 3 subgroups: (1) impairment of reciprocal social interaction, (2) qualitative impairment in verbal and nonverbal communication as well as imaginative activity, and (3) markedly restrictive repertoire of activities and interests. PDD is diagnosed when qualitative impairment of reciprocal social interaction and verbal and nonverbal communication skills is present without fulfillment of the criteria for autistic disorder, schizophrenia, or schizotypal or schizoid personality disorder.
  • History of language regression is not unusual in autism and obtained retrospectively in as many as 39% of children with autism and prospectively in one third of patients with either autism or PDD. Language regression occurs equally among children with autism or PDD with or without epilepsy. Children with low cognitive function are more likely to have undergone regression than those with better cognitive skills (34% vs 20%). The age at which language regression occurs (ie, before or after 2 y) makes no difference in the proportion of children with epileptiform EEGs.
  • The frequency of overt epilepsy among patients with autism or PDD is 7.6-25%. This range partly depends on the definitions of autism and PDD and on how strictly these criteria are applied. Epilepsy is common among male patients, and the seizures start in the first year of life in more than 80% of the patients. Tuchman et al found that epilepsy was present in 14% of autistic children after they excluded patients with Rett syndrome. Other authors have reported higher frequencies than this among patients with autism.
  • The relationship between autism, epileptiform EEG, epilepsy, and language regression is complex and only partially understood. In a study in which 60% of an autistic population underwent EEG, about 22% had epileptiform abnormalities. In approximately one half of the children in whom EEG demonstrated epileptiform discharges, the discharges were located over the centrotemporal region, regardless of whether the child was epileptic or had regression. Two explanations are possible: One is that patients have comorbidity of benign (rolandic) epilepsy with centrotemporal spike-EEG trait with autistic symptoms (eg, benign epilepsy with centrotemporal spikes, one of the most prevalent epileptic syndromes). The second explanation tries to attribute a cause-effect relationship between the epileptiform abnormalities and the autistic and language regression symptoms.
  • Tuchman and Rapin prospectively studied language regression in patients with PDD and found that, in nonepileptic autistic children, a history of regression was associated with a 2-fold increase in the incidence of epileptiform EEG (P = .0095, 2-tailed chi-square test) compared with those who had not undergone regression and had no seizures. The proportion of children with epilepsy or epileptiform EEGs who had regression before or after age 2 years did not differ.
  • The subgroup of patients with autism, language regression, and epileptiform EEGs has been described as having autistic epileptiform regression. Patients in this group also have regression of their social, nonverbal, and cognitive skills, but determining whether development was completely normal before the regression is often difficult. All of the studies were biased because of the lack of universal EEG performance in patients with autism or PDD or the lack of prolonged-sleep tracing in patients with PDD.
  • The types of seizures most commonly associated with autism are infantile spasms, complex partial seizures, and generalized tonic-clonic convulsions. About one third of autistic patients with epilepsy have (or had) infantile spasms or myoclonic seizures. Severe mental retardation and motor deficit appear to be associated with an increased incidence of epilepsy in autistic patients. A high incidence of epilepsy occurs in patients with deficit in oral comprehension or verbal auditory agnosia. This finding is not unexpected because it is probably due to inclusion of patients with AEA and its variants, which all can demonstrate autistic features.
• AEA and the syndrome of continuous spike-wave during slow sleep
• • One of the main differential diagnoses of AEA is the syndrome of continuous spike-wave during slow sleep, or ESES. In fact, some authors consider AEA as part of the ESES spectrum. A few features may help differentiate ESES from AEA. In ESES, nocturnal spike and wave discharges by definition occupy more than 85% of slow-wave sleep (stages 3 and 4 non–rapid eye movement [REM]), especially during the first sleep cycle, but become focal during REM sleep. In AEA, on the other hand, generalized spike-and-wave discharges may continue to be maximal or be seen only during REM. The EEG in ESES may show frontal or frontocentral location of focal discharges, but in AEA the focal discharges often show temporal or parietal distribution.
  • The use of the source localization of the focal discharges for the differentiation of these two syndromes (AEA and ESES) has limited value since well-documented ESES cases may have primary parietal generators for secondary generalized discharges. In many cases, the generalized discharges seen in ESES also represent secondary bilateral synchrony from a consistently unilateral focus, which can be located in either hemisphere. The seizures seen in patients with ESES are similar to the ones of AEA, but drop attacks and myoclonic and unilateral clonic seizures may be more common in ESES. The nature of the cognitive deterioration is more diffuse in ESES than in AEA.
  • Besides substantial language problems, patients often have reduced temporal-spatial orientation and memory function during the active phase of ESES. As measured by using the Wechsler intelligence scales for children (WISC), cognition (ie, intelligence quotient [IQs]) severely declines. Verbal scores on the WISC are affected more than performance scores. The term disintegrative epileptiform disorder has been used in reference to patients with normal development in whom deterioration of language, sociability, nonverbal communication, and cognition occurs after age 2 years in association with an epileptiform EEG, often with an ESES pattern.
• Childhood disintegrative disorder
• • Regression of language, cognition, and behavior after age 2 years has been classified as disintegrative disorder. The definition of the term is still in flux. Rapin suggests that the term should be used for patients with autistic regression with onset after age 2 years. The DSM-IV defines childhood disintegrative disorder as loss of language, social, adaptive, and play skills between the ages of 2 and 10 years after normal development in these areas before the age of 2 years. DSM-IV criteria require abnormal functioning in at least 2 of the following areas:
    • Social interaction
    • Verbal and nonverbal communication and make-believe play
    • Stereotyped behavior, interests, activities, mannerisms, and stereotypies
  • DSM-IV diagnostic criteria of childhood disintegrative disorder require the clinician to rule out any of the other PDDs, schizophrenia, and other dementing medical conditions (eg, adrenoleukodystrophy, metachromatic leukodystrophy). The DSM-IV criteria do not specifically mention differentiation on the basis of EEG. The term disintegrative epileptiform disorder has been used to describe patients with normal development who present with deterioration of language, verbal and/or nonverbal communication, sociability, and cognition after age 2 years associated with an epileptiform EEG.
  • The EEG abnormality is often ESES with frontal predominance. The latter may be differentiated by widespread deterioration of cognition, as opposed to the picture of AEA, which affects mostly language, at times with secondary behavioral changes. Differentiation between disintegrative epileptiform disorder and ESES may be impossible on clinical and EEG grounds owing to the variability of the behavioral and cognitive findings in ESES.

    Table 2. Differential Diagnosis of Syndromes of Language and/or Cognitive and Behavioral Regression

    Diagnosis	Deterioration	EEG Patterns
    Autistic epileptiform regression	Expressive language, RL, S, verbal and nonverbal communication	Centrotemporal spikes
    Autistic regression	Expressive language, RL, S, verbal and nonverbal communication	Normal
    AEA	RL, possibly behavioral	L or R temporal or parietal spikes, possibly ESES*
    Acquired expressive epileptic aphasia	Expressive language, oromotor apraxia	Centrotemporal spikes
    ESES	Expressive language, RL, possibly behavioral	ESES*
    Developmental dysphasia (developmental expressive language disease)	No, lack of expressive language acquisition	Temporal or parietal spikes
    Disintegrative epileptiform disorder	Expressive language, RL, S, verbal and nonverbal communication, possibly behavioral	ESES*

    ^*Continuous spike and wave of slow-wave sleep (>85% of slow-wave sleep).
    ^† R indicates receptive language; S, sociability.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Acquired expressive epileptic aphasia
Adrenoleukodystrophy
Childhood disintegrative disorder
Developmental dysphasia or developmental expressive language disorder
Disintegrative epileptiform disorder
ESES

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Imaging Studies

• MRI is essential in patients with suspected AEA.
• • Cerebrovascular thromboembolism, brain tumors, demyelination, neurodegenerative disease, and CNS infections can easily be ruled out on MRI.
  • Some cases with a lesion and an EEG suggestive of AEA (ESES) may represent a secondary form of AEA. This was the case in patients described to have cysticercosis or perisylvian polymicrogyria occurring in a pattern similar to that of AEA.
  • Otherwise, MRIs in patients with AEA are grossly normal.
  • Volumetric analysis of AEA has shown reduced volumes of the planum temporale and superior temporal gyri.
• Positron emission tomography
• • In AEA, fluorodeoxyglucose (FDG) positron emission tomography (PET) reveals decreased metabolism in 1 or both temporal lobes. Hypometabolism is especially prominent in the middle temporal gyrus. Hypermetabolism can also be seen in patients with AEA.
  • Increased metabolism on FDG PET has been associated with scans performed during continuous spike and waves of slow-wave sleep; the findings often are localized to both temporal lobes but may be most prominent on the left side. These apparently contradictory findings probably could represent the difference between interictal (hypometabolism) and ictal (hypermetabolism) on FDG PET. During continuous spike and wave of slow-wave sleep, FDG PET reflects the increased metabolism induced by this ictal-like pattern.
  • In patients with intermittent or episodic aphasia, PET is associated with increased metabolism over the temporal lobes.
  • H2O¹⁵ PET has shown decrease metabolic activity over the posterior part of the superior temporal gyrus in patients with AEA who have poor short-term memory skills.
• Single-photon emission CT (SPECT) of the brain demonstrates decreased perfusion of the left temporal lobe in patients with AEA.

Other Tests

• Electroencephalography
• • Although EEG abnormalities are present in this syndrome by definition, no consensus exists about what constitutes typical abnormalities. Some authors have stated that as a rule the localization of the epileptic foci can vary in time and space (multifocal discharges). Beaumanoir also mentions that, despite the "preference" of AEA for the temporal and parieto-occipital location of the discharges, most patients do not have unilateral left anterior and/or mid temporal predominance of the epileptic foci. Other authors have stated that all patients with AEA syndrome have frequent left midtemporal spikes as well as generalized ones.
  • The meaning of the lateralization of the EEG discharges in relation to language dysfunction must take into consideration the fact that language dominance in young children is not as straightforward as in adults. One study in children aged 18-36 months with unilateral lesions revealed that left hemisphere pathology was correlated with severe deficits in only expressive language and that language dysfunction was most significant with posterior lesions. The severity of receptive language deficits did not differ with respect to side, site, or size of the lesion. Because the processing of language uses relatively widespread circuitry in children than in adults, cortical dysfunction affecting areas outside the left temporal region causing receptive language problems is not inconceivable.
  • Awake EEG
  • • On awake EEG, the background is usually normal initially. Focal theta slowing over the area of the discharges or even generalized slowing (probably secondary to medications) may be seen. In the awake state, some epileptiform abnormalities may be seen. The discharges are either focal or bilateral with temporal or parietal predominance. According to Beaumanoir, in half of the cases, the discharges had a "preference" for the temporal foci, and in one third the focus was in the parieto-occipital location. No clear-cut hemispheric predominance and variable location of the spikes in the same patient over time has been observed in this syndrome. This finding is a little baffling because the intuitive expectation is that the epileptiform abnormalities would be seen primarily over the dominant hemisphere.
    • Many well-documented cases of AEA developing after well-established language have shown exclusively or predominantly right-sided discharges. Findings from 1 study suggested a correlation between the spike morphology and etiology of epilepsy, with symptomatic and cryptogenic epilepsies, including AEA, having low amplitude, as well as "fast" spikes and the benign syndromes having high amplitude, long duration, and discharges less sharp than those of other conditions; however, further studies are necessary to confirm these findings.
  • Sleep EEG
  • • Besides the discharges seen during the wake state, sleep tends to promote the appearance of generalized paroxysmal abnormalities. Drowsiness or early sleep increases the frequency and generalization of the discharges, but maximal activation of the EEG abnormalities may not occur until stages 3 or 4 or REM sleep. Generalized spike-and-wave discharges initially have frequencies around 3-4 Hz, but during the course of the disease they may be slower, in the 1.5- to 3-Hz range.
    • In some cases, the EEG may resemble the slow spike-and-wave pattern of the Lennox-Gastaut syndrome. At least in some cases, analysis of these generalized looking spike-and-wave discharges with more precise techniques such as EEG displayed on a high-speed oscilloscope, methohexital suppression test, dipole mapping, and magnetoencephalography (MEG) demonstrate a lead from the dominant temporal region.
    • Unilateral carotid artery injection of amobarbital in patients with bilateral spikes and waves is effective in suppressing discharges on both sides if injected in the dominant side (termination of secondary bilateral synchrony). Amobarbital injection to the nondominant side abolishes only the ipsilateral part of the generalized discharges. This pattern suggests secondary bilateral synchrony as the cause of the generalized-looking discharges in AEA. Sleep activation is common in AEA and very prominent in slow-wave sleep (stages 3 and 4) when the normal elements of sleep architecture disappear and spikes may become almost continuous.
    • These findings are reminiscent of the syndrome of continuous spike-and-wave during slow sleep (ie, ESES). These similarities have led to the postulation that AEA is a variant of the ESES syndrome. However, in many patients with AEA the discharges go unabated through REM sleep, a stage in which the epileptiform abnormalities usually become focal in ESES. In 1 case, the continuous spike-and-wave discharges were initially seen exclusively during REM sleep. ESES is generally defined as continuous spike and wave discharges taking up 80% or more of the slow wave sleep, but this proportion, named spike-and-wave index (SWI), is a matter of significant debate. The UCLA group has taken a more pragmatic approach to the subject and stated that an SWI greater than 50% was more likely to be associated with global developmental disturbances than an SWI less than or equal to 50% (P <.05).
    • In 1992, Beaumanoir reported that many cases of otherwise typical AEA do not have continuous spike-and-wave during sleep. Besides that the ESES may not be stable. It was present on and off during the active phase of the disease in one of the author's patients who underwent several overnight EEGs. Many discharges in ESES have frontal or frontocentral predominance or localization, and sometimes the onset of the EEG seizures is also over the frontocentral region. Both these findings suggest that the generalized discharges in ESES may be due to secondary bilateral synchrony of frontal lobe foci as opposed to the temporal (mostly dominant side) onset in AEA. More recently, the UCLA group has confirmed this impression and found that the EEG changes tend to fluctuate over time.
    • EEG activation with sleep is often not seen or mild in children with developmental dysphasia. Patients with autistic disorder may have centrotemporal spikes during sleep. Those cases may easily be dismissed as comorbidity of benign rolandic epilepsy (benign epilepsy with centrotemporal spikes); however, a history of language regression is significantly more common among autistic patients with epileptiform EEGs than in those without it and no history of seizures. This subgroup of patients with autism, language regression, and epileptiform EEGs has been described as having autistic epileptiform regression.
  • EEG sleep stages in AEA are as follows:

• Activation and generalization of discharges - Initially with stage 1-2, non-REM sleep, maximal in stage 3-4, non-REM, and REM sleep
• Continuous spike-and-wave discharges during slow-wave sleep - Probably secondary generalized (secondary bilateral synchrony), common but not universal, may persist in REM sleep

• Magnetoencephalography
• • MEG measures variations in the magnetic field produced by electric currents generated in the brain. MEG patterns are somewhat less confusing than EEG patterns, but most of MEG studies have been done in a select subset of patients with AEA, often with long-standing disease and prominent sleep-related bisynchronous spike-and-wave discharges. In 1991, Paetau et al demonstrated that, in patients with AEA, MEG shows a vertical dipole located in the superior surface of the temporal lobe that is 2-3 cm deep. Experiences of other authors (including the present author) confirmed that finding. At times, sound triggers the MEG spikes in patients with AEA.
  • MEG analysis of the bisynchronous discharges of patients with AEA shows onset of epileptiform activity over the left temporal region. Patients may have other discharges that start in the left temporal region but a time-linked component on the right temporal region. The depth, orientation, and spread of the epileptic focus in AEA seen on MEG may at least partly explain the apparently contradictory EEG data. EEG recordings may miss data from attenuation of the electrical signal as it passes through the bone, dura mater, subcutaneous tissue, and skin, especially important in relatively deep foci, which are seen in AEA.
  • Regular EEG may not detect a vertical-tangential dipole such as that seen in AEA (on the superior surface of the temporal lobe), but this is actually the best type to be recorded on MEG. Vertical-tangential generators (electrical) produce a magnetic field that goes in and out of the scalp because the magnetic field circulates around the axis of the electrical dipole. Magnetic fields with this orientation penetrate the magnetometers (gradiometers), producing a recordable signal. Most magnetometers/gradiometers currently used can record only magnetic fields circulating in and out of the skull because they are oriented radially. The main limitations of MEG are that the apparatus is not widely available because it is expensive to purchase and maintain.
  • MEG may be help in the pre-presurgical evaluation. In a few select cases, MEG may even obviate invasive (depth and subdural grids and strips) evaluation.
• Brainstem auditory evoked potentials (BAERs) and behavioral hearing tests (BHTs)
• • BAERs or BHTs should be performed on any child who appears to have language problems.
  • BHT is performed to check the reaction of a child or toddler to a sound, generally by using positive reinforcement. For example, the child hears a unilateral sound in a semidark room, and if he or she turns to it, a bunny toy lights up and plays the drums. BHT can be tuned precisely to pitch and loudness but requires good cooperation from the child or toddler. Patients who have normal cognition can cooperate with BHT by the age of 14-18 months at the earliest.
  • BAERs are EEG signals generated in the auditory nerve, medulla, and brainstem when one hears a sound. The time-locked potentials are averaged to make readable signals by eliminating the random (ie, non–time-locked) EEG activity. BAER testing requires less cooperation than BHT, but the sound can vary only in loudness because the pitch used is standard and encompasses only the high frequency of the hearing band.
  • Sounds can also produce a cortical response, which is more difficult to measure than the one generated in the brainstem. Interest has been focused on cortical potentials. P300 potentials are often abnormal in patients with AEA. Preliminary work with steady-state auditory evoked responses to pulsed frequency modulations of a continuous tone may help in identifying patients with AEA. This technique does not help in identifying patients with expressive language dysfunction. Large studies are necessary to confirm the utility of steady-state auditory evoked responses to pulsed frequency modulations.

Histologic Findings

A few cases of AEA are secondary to brain tumors, cerebral cysticercosis, demyelination, or head injury. Pascual-Castroviejo et al described 4 cases of AEA associated with a cerebral angiographic pattern compatible with arteritis, but their findings have not been reproduced. Moreover, cases of AEA without inflammatory changes on the neuropathology have been reported.

Most patients with AEA have no clear etiology for the aphasia, abnormal EEG, and seizures. One autopsy study of patients with developmental dysphasia showed patterns similar to those seen in patients with dyslexia, including symmetry of the planum temporale, dysplasia of the insular cortex, poor lamination, neuronal rarefaction, and gliosis. One patient with congenital aphasia and complex cardiac malformation (transposition of the great vessels, ventricular septal defect with an overriding pulmonary artery) had bilateral old atrophic lesions over the opercula, insulae, and central regions.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment of AEA is far from standard, and many therapeutic modalities have been tried with variable success. Among these are anticonvulsant drugs, corticosteroids, ACTH, immunoglobulins, ketogenic diet, and surgery.

• Many commonly used anticonvulsants effective against partial or generalized seizures have been used in AEA with variable success.
  • Phenobarbital, carbamazepine, and phenytoin are often ineffective in halting the EEG discharges and aphasia.
  • In a few cases, the drugs may actually worsen the picture, especially in patients with drop seizures and atypical absences.
  • Valproic acid, ethosuximide, and benzodiazepines alone or in combination have been partially or transiently effective in some cases.
  • Benzodiazepines, especially clonazepam (in Europe) and midazolam, have been most effective when given intravenously. Both the impracticality of this mode of administration and its short-lived effect have limited it use.
  • Diazepam 0.5 mg/kg given rectally at bedtime is sometimes effective. This treatment is used in 4- to 6-wk courses on and off to avoid tachyphylaxis. The Boston Children's Hospital Epilepsy Group has used continuous diazepam 0.5-0.3 mg/kg given PO in AEA for periods of up to 1 year.
• One case report describes a patient whose condition responded to levetiracetam.
• In 1 case, felbamate 45 mg/kg/d was successful in treating seizures and aphasia. The high frequency of aplastic anemia and liver dysfunction with this drug limits its use.
• Among the drugs that the US Food and Drug Administration (FDA) has not approved, sulthiame and clobazam are effective in some patients with AEA.
• In 4 cases Lerman et al described, early corticosteroid or ACTH therapy improved symptoms of AEA and normalized the EEG. Prolonged steroid therapy with ACTH 80 IU/d (range 0.2-1 U/kg/d from other sources) has been recommended.
• Regarding steroids, prednisone 60 mg/d followed by a 3-mo taper is commonly used. Another dosing schedule is 3-5 mg/kg/d of prednisone for 3 months.
• Pulse intravenous methylprednisolone therapy has been used to induce remission in AEA. A dose of 20-30 mg/kg/d for 3-5 d has been used, intervals followed by prednisone 2 mg/kg, which is then tapered after 1-2 months.
• Steroid reduction may be associated with recurrence of symptoms; 6 months to several years of treatment may be necessary. Some authors had the impression that early steroid therapy during the deterioration phase may be associated with increased efficacy and decreased need for prolonged treatment, but this opinion awaits validation in a controlled study.
• Treatment with either corticosteroids or ACTH is associated with many complications, including immunosuppression, weight gain, cushingoid appearance, diabetes, hypertension, steroid myopathy, electrolyte imbalances, mood disorders (depression, mania), aseptic osseous necrosis, pathologic fractures, cataracts, and adrenal failure (during or after taper).
• • Corticosteroids and ACTH are contraindicated in patients with preexisting immunosuppression, a history of aseptic osseous necrosis, untreated tuberculosis, or hookworm infestation (personal case). Both tuberculosis and hookworm infestation may become widespread with corticosteroid treatment. When in doubt, a purified protein derivative (PPD) test for tuberculosis should be administered before treatment is started.
  • Diabetes, glucose intolerance, hypertension, and obesity are relative contraindications that these drugs may aggravate.
• The calcium channel blocker nicardipine has been used in the treatment of AEA. In the initial report in 4 patients that suggested the use of nicardipine for AEA, nicardipine was given in association with anticonvulsant medications (carbamazepine, valproic acid) and corticosteroids (3 of 4 cases). However, cessation of nicardipine was associated with acute speech deterioration. The dose of nicardipine was 1 mg/kg/d or 60 mg/d for large patients.
• A few case reports have demonstrated that intravenous gammaglobulin may be useful in AEA, but repeated doses may be necessary.

Surgical Care

• Multiple subpial transections (MST) have been used with variable success in AEA.
• • In this surgical treatment modality, the cortex is sliced in parallel lines in the midtemporal gyrus and perisylvian area to attenuate the spread of the epileptiform activity without causing cortical dysfunction.
  • Demarcation of the epileptiform discharge-generation area requires complete investigation by using the methohexital suppression test, an intracarotid amobarbital injection to abolish secondary bilateral synchrony, and electrical and magnetic dipole mapping.
• Morrell et al described the procedure and later reviewed the experience at Rush-Presbyterian hospital with 14 patients with AEA who underwent MST.
• • Seven of 14 patients recovered age-appropriate speech and no longer needed speech therapy or special education classes.
  • Another 4 (29%) of 14 had marked improvement of speech and understanding of instructions given verbally but still required speech therapy.
  • Eleven patients had language dysfunction for 2 or more years.
• Sawhney et al reported improvement in all 3 of their patients with AEA who underwent MST.

Consultations

• Neuropsychological testing is mandatory in all patients with AEA.
• All patients with AEA should be referred for speech therapy.
• • The speech and language therapist has an essential role in the management of these patients.
  • Learning sign language before the patient's recovery can diminish anxiety and improve socialization.
  • Learning sign language does not appear to delay the recovery of speech in cases of AEA.
• Patients with AEA who do not respond to anticonvulsant medications and steroids or ACTH may be considered for MST at a qualified epilepsy center.
• Psychotherapy and psychiatric consultation may be indicated in selected patients with AEA in whom the secondary behavioral problems need pharmacologic intervention.

Diet

• Short of the ketogenic diet, no other dietary restrictions have been recommended in patients with AEA.
• Experience with ketogenic diet in patients with AEA is limited.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No drug of choice is known for AEA, but corticosteroids and ACTH have become popular despite a lack of controlled trials. The data presented below, including dosages, are based on how corticosteroids and ACTH are commonly prescribed for patients with AEA.

Drug Category: Corticosteroids, ACTH

The mechanism of action of immunosuppressant-mediated improvement in AEA is unknown.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• Long-term outcome studies of patients with AEA are limited by the lack of uniformity in diagnostic criteria.
• • About one half of patients have some fluctuation in aphasia.
  • Fluctuations usually occur over several months. On occasion, aphasia may worsen for as long as 7 years after onset of disease.
• Worsened outcome has been noted in patients with an onset of language regression before the age 5 of years.
• Morrell found that symptoms persisting for more than 1 year are predictive of poor language recovery.
• One should be mindful that fluctuations are not unusual on the course of this disease. Both the clinical course and the EEG changes may get worse, better, and even return to the baseline.
• In many studies, these fluctuations did not always occur simultaneously for reasons explained in the History section above.
• Short-term remissions pose a challenge in evaluating responses to various therapeutic modalities.
• Robinson et al found that poor language recovery was correlated with ESES for more than 36 months. Impaired short-term memory was universal on long-term follow-up of all of their patients with AEA.
• Beaumanoir analyzed cases with follow-up of more than 10 years, which included cases published in peer-reviewed journals and those from other sources, such as a doctoral thesis reported before 1992.
  • Overall, this combined experience of long-term follow-up revealed that 40-50% of patients had language function good enough to hold a job and have a normal social life.
  • Slightly lower rates of good outcomes have been reported in the recent literature, ranging from 25-50%, with a combined rate of 36% (see Table 3 below).

  Table 3. Long-Term Follow-up of AEA

  Author	No. of Patients	Mean Follow-Up, y	No. of Patients with Normal or Mild Language Problems
  Soprano et al, 1994	12	8	3
  Mantovani and Landau, 1980	9	22	6
  Paquier, 1992	6	8.1	3
  Rossi, 1999	11	9.7	2
  Robinson, 2001	18	5.6	3
  All	56		17 (30%)

Patient Education

• Patients with AEA have special educational needs. Teaching them sign language when they are aphasic may be helpful in maintaining a useful communication channel.
• Learning sign language does not prevent or delay the recovery of aphasia. These patients may be able to read and write; therefore, these skills should be used for teaching whenever doing so is possible.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The diagnosis of AEA should be considered in any patient with language regression.
• • Obtaining brain images in a child with history of loss of language milestones is important, as it allows the clinician to rule out potentially treatable causes of aphasia, such as a brain tumor, before the patient is identified as having AEA.
  • The most precise way of confirming AEA is by obtaining overnight sleep EEGs, including EEGs during sleep stages 3 and 4.
  • The clinician should refrain from ruling out AEA before an EEG is obtained, including a slow-wave sleep tracing.
• Another potential cause of litigation in AEA is the high parental expectations for a complete and quick recovery of language and speech functions.
• • These unrealistic expectations often come from information in the lay press and from TV shows that mention isolated miracle cures in cases of AEA after treatment with steroids or other measures.
  • These cases do not represent the usual course of most children with AEA but make up good cases for TV or newspaper stories.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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